Veterinary Pharmacology Course Overview

General and Systemic Veterinary Pharmacology
VPT311
URVISHMISTRY
AAU
1|U R V I S H M I S T R Y
Contents
HistoryofPharmacology...................................................................................................................................................8 Ancientmedicine......................................................................................................................................................8 PreChristianera......................................................................................................................................................8 Mediaevalmedicine..................................................................................................................................................8 Revoltsinmedicine...................................................................................................................................................8 Modernmedicine......................................................................................................................................................8 Scopeofpharmacology.................................................................................................................................................9 Branchesofpharmacology...........................................................................................................................................9 Termsanddefinitions.....................................................................................................................................................10 Pharmacologyrelatedterms.......................................................................................................................................10 Drugrelatedterms......................................................................................................................................................10 Doserelatedterms ......................................................................................................................................................11 Sourcesofdrugs..............................................................................................................................................................11 PlantsourcesofDrugs................................................................................................................................................11 Alkaloids..................................................................................................................................................................11 Glycosides...............................................................................................................................................................12 Oils..........................................................................................................................................................................12 Tannins....................................................................................................................................................................12 Saponins..................................................................................................................................................................12 Resins......................................................................................................................................................................12 Gums.......................................................................................................................................................................12 Mineralsource............................................................................................................................................................12 Animalsourceofdrugs...............................................................................................................................................12 Syntheticsourcesofdrugs..........................................................................................................................................13 Microbialsourceofdrugs...........................................................................................................................................13 Pharmacokinetics:principlesofdrugactivity................................................................................................................. 13 Routesofadministration............................................................................................................................................13 Oraladministration.................................................................................................................................................13 Intravenousroute...................................................................................................................................................14 Subcutaneousandintramuscularroutes................................................................................................................ 15 Otherparenteralroutes..........................................................................................................................................16 Localadministration ................................................................................................................................................16 Structureofbiologicalmembranes............................................................................................................................... 17 Fluidmosaicmodels....................................................................................................................................................17 Functionsofmembranes............................................................................................................................................17 1|U R V I S H M I S T R Y
2|U R V I S H M I S T R Y Passageofdrugsacrossmembranes.............................................................................................................................. 17 Passivediffusion ..........................................................................................................................................................17 Carriermediatedtransfusion......................................................................................................................................18 Facilitateddiffusion .....................................................................................................................................................18 Activetransport..........................................................................................................................................................18 Pinocytosisandphagocytosis.....................................................................................................................................19 Filtration......................................................................................................................................................................19 Absorptionofdrugs........................................................................................................................................................19 AbsorptionofdrugsfromGItract ............................................................................................................................... 20 Roleofionizationandlipidsolubilityindrugabsorption........................................................................................... 20 HendersonandHeselbelchequation...................................................................................................................... 20 Absorptionofdrugsafterparenteraladministration................................................................................................. 21 Absorptionofdrugsafterinhalationortopicaladministration .................................................................................. 21 Distributionofdrugs.......................................................................................................................................................22 Plasmaproteinbindingofdrugs.................................................................................................................................22 Plasmaproteinbinding...............................................................................................................................................23 Tissuestorageofdrugs...............................................................................................................................................23 Barrierstodrugdistribution.......................................................................................................................................23 Biotransformationofdrugs/xenobiotics:drugmetabolism........................................................................................... 24 Sequelaeofbiotransformationreactions................................................................................................................... 25 PhaseIBiotransformationoxidationreactionsandothers...................................................................................... 25 PhaseIreactions.........................................................................................................................................................25 PhaseIIreactionssyntheticreactions...................................................................................................................... 26 Enzymeinductionandinhibition................................................................................................................................26 Excretionofdrugs...........................................................................................................................................................27 Renaleliminationofthedrugs....................................................................................................................................27 Hepaticandotherroutesofadministration............................................................................................................... 29 Pharmacokineticparameters..........................................................................................................................................29 Importantpharmacokineticparameters.................................................................................................................... 30 Modelsinpharmacokinetics.......................................................................................................................................30 Drugaccumulation......................................................................................................................................................31 PrinciplesofDrugactivityPharmacodynamics............................................................................................................ 31 Modesofdrugaction..................................................................................................................................................31 Enzymemediateddrugaction....................................................................................................................................31 Receptormediateddrugaction..................................................................................................................................32 Termsrelatedtodrugreceptorbinding..................................................................................................................... 32 2|U R V I S H M I S T R Y
3|U R V I S H M I S T R Y Receptorsstructureandfunction.................................................................................................................................33 Receptortheories.......................................................................................................................................................33 Functionsofreceptors................................................................................................................................................34 Typesofreceptors......................................................................................................................................................34 Secondmessengersystems........................................................................................................................................34 Doseresponsecurve.......................................................................................................................................................35 Plotting........................................................................................................................................................................35 Featuresofdoseresponsecurve................................................................................................................................35 Quantaldoseresponsecurve.....................................................................................................................................35 Factorsmodifyingdrugaction........................................................................................................................................35 Factorsaffectingdrugaction......................................................................................................................................35 Adverseeffectsofdrugs.................................................................................................................................................36 Typesofadverseeffects.............................................................................................................................................37 Druginteractions........................................................................................................................................................37 Drugscreeninganddrugdiscovery .................................................................................................................................38 Drugdiscovery............................................................................................................................................................38 Drugscreening............................................................................................................................................................39 Preclinicalsafetyandtoxicitytesting.......................................................................................................................... 39 Clinicaltrials................................................................................................................................................................40 Bioprospecting...........................................................................................................................................................41 Assayofdrugs.............................................................................................................................................................42 Biopharmaceuticalsandgenetherapy........................................................................................................................... 42 Biopharmaceuticals.....................................................................................................................................................42 Genetherapy..............................................................................................................................................................42 Gastrointestinalpharmacology...................................................................................................................................43 Sialagogues(sialics)andantisialagogues(antisialics)................................................................................................. 43 Sialagogues..............................................................................................................................................................43 Antisialogogues.......................................................................................................................................................43 Stomachics..............................................................................................................................................................43 Appetitestimulants.....................................................................................................................................................43 Emetics........................................................................................................................................................................44 Antiematics.................................................................................................................................................................45 Prokinetics...................................................................................................................................................................46 Ulcermanagement......................................................................................................................................................46 Antacids ...................................................................................................................................................................46 HistaminereceptorsH2antagonist...................................................................................................................... 47 3|U R V I S H M I S T R Y
4|U R V I S H M I S T R Y Sucralfate................................................................................................................................................................47 Protonpumpantagonists.......................................................................................................................................47 Cytoprotectivedrugs ...............................................................................................................................................48 Digestantsandpurgatives ...............................................................................................................................................48 Cholereticsandcholagogues......................................................................................................................................48 Purgativesandlaxatives..............................................................................................................................................48 Classification...........................................................................................................................................................49 Generalmechanismofaction.................................................................................................................................49 Osmoticpurgatives.................................................................................................................................................49 Irritantpurgatives...................................................................................................................................................50 Bulkpurgatives........................................................................................................................................................51 Lubricantpurgatives...............................................................................................................................................52 Choice,indications,combinations,abuseofpurgatives ............................................................................................. 52 Antidiarrheal...................................................................................................................................................................53 Opioids........................................................................................................................................................................53 Anticholinergics...........................................................................................................................................................54 Protectantsandadsorbants........................................................................................................................................54 Antisecretorydrugs.....................................................................................................................................................55 Protectants..................................................................................................................................................................55 Rumenpharmacology.....................................................................................................................................................55 Oesophagealgrooveclosure.......................................................................................................................................55 Ruminotorics...............................................................................................................................................................56 Rumenantacids ...........................................................................................................................................................56 Antizymotics................................................................................................................................................................56 Cardiovascularpharmacology.........................................................................................................................................56 Classesofdrugsactingonheart.................................................................................................................................56 Effectsofdrugsactingonheart..................................................................................................................................57 Congestiveheartfailure..............................................................................................................................................57 Cardiacglycosides...........................................................................................................................................................57 Chemistryofcardiacglycosides..................................................................................................................................58 ................................................................................................................ 58 Mechanismofactiononcardiacglycosides Pharmacologicaleffectsofcardiacglycosides............................................................................................................ 58 Pharamacokinetics......................................................................................................................................................59 Therapeuticusesofcardiacglycosides....................................................................................................................... 59 Digitalization...............................................................................................................................................................59 Adversereactionsofcardiacglycosides..................................................................................................................... 59 4|U R V I S H M I S T R Y
5|U R V I S H M I S T R Y Treatmentofcardiacglycosidestoxicity ..................................................................................................................... 60 Precautionsanddruginteractions.............................................................................................................................. 60 Druginteractions........................................................................................................................................................60 OtherdrugsusedinCHF.............................................................................................................................................60 Antiarrhythmicdrugs......................................................................................................................................................60 Typesofarrhythmia....................................................................................................................................................60 Arrhythmia..................................................................................................................................................................61 Antiarrhythmicdrugs..................................................................................................................................................61 Classification...............................................................................................................................................................61 Actionsofsodiumchannelblockers........................................................................................................................... 62 Adrenergicblockers..............................................................................................................................................63 Actionsonpotassiumcurrents...................................................................................................................................63 ActionsofCachannelblockers.................................................................................................................................63 Clinicalusesofantiarrhythmicdrugs.......................................................................................................................... 64 AdverseeffectsofAntiarrhythmicdrugs.................................................................................................................... 64 Adverseextracardiaceffects...................................................................................................................................64 Vasodilatorsandantihypertensivedrugs....................................................................................................................... 65 DirectactingVasodilators...........................................................................................................................................65 Indirectlyactingvasodilators......................................................................................................................................66 Clinicaluses.................................................................................................................................................................66 Vasoconstrictors..........................................................................................................................................................66 Clinicalusesofvasoconstrictors.................................................................................................................................66 Classificationofantihypertensivedrugs......................................................................................................................... 66 Antihypertensivedrugs...............................................................................................................................................67 Hematinic,coagulantsandanticoagulants..................................................................................................................... 68 Haematinics.................................................................................................................................................................68 Coagulants ...................................................................................................................................................................69 Anticoagulants............................................................................................................................................................70 Invitroanticoagulants................................................................................................................................................70 Systemicanticoagulantsinvivo............................................................................................................................... 70 Clinicalusesofanticoagulants....................................................................................................................................70 Coumarinderivatives..................................................................................................................................................70 Heparinantagonist ......................................................................................................................................................71 Respiratorypharmacologyexpectorants..................................................................................................................... 71 Expectorants...............................................................................................................................................................71 Inhalantexpectorants.................................................................................................................................................71 5|U R V I S H M I S T R Y
6|U R V I S H M I S T R Y Ingestedexpectorants................................................................................................................................................71 Mucolytics...................................................................................................................................................................71 Decongestantsandantitussives ......................................................................................................................................72 Decongestants .............................................................................................................................................................72 Antitussives.................................................................................................................................................................72 Directlyactingantitussives.........................................................................................................................................72 Centrallyactingantitussives.......................................................................................................................................73 Bronchodilators...............................................................................................................................................................73 Methylxanthene.........................................................................................................................................................74 Sympathomimetic.......................................................................................................................................................74 Parasympatholyticsspasmolytics ............................................................................................................................. 75 Corticosteroids............................................................................................................................................................75 NSAIDs.........................................................................................................................................................................75 Antihistaminics............................................................................................................................................................75 Mastcellstabilizers.....................................................................................................................................................75 Respiratorystimulants................................................................................................................................................76 Diuretics..........................................................................................................................................................................76 Physiologicaldiuresis..................................................................................................................................................76 Classificationofdiuretics............................................................................................................................................76 Osmoticdiuretics........................................................................................................................................................76 Carbonicanhydraseinhibitors....................................................................................................................................77 Loopdiuretics..............................................................................................................................................................77 Thiazidederivatives....................................................................................................................................................78 Potassiumsparingdiuretic..........................................................................................................................................79 Xanthinesandmercurial.............................................................................................................................................80 Drugsactingonurogenitalsystems................................................................................................................................80 Alkalizationofurine....................................................................................................................................................80 Acidificationofurine...................................................................................................................................................80 Ecbolics ........................................................................................................................................................................81 Tocolytics....................................................................................................................................................................81 Fluidtherapy...............................................................................................................................................................81 Choiceoffluid.............................................................................................................................................................82 PharmacotheraputicsofHormones................................................................................................................................83 Administrationofhormones.......................................................................................................................................83 Corticotrophinsandrelatedpeptides......................................................................................................................... 83 Insulin..........................................................................................................................................................................84 6|U R V I S H M I S T R Y
7|U R V I S H M I S T R Y Pharmacologicalactionsofinsulin.............................................................................................................................. 84 Preparationsofinsulin................................................................................................................................................84 Oralhypoglycemicdrugs.............................................................................................................................................85 Thyroidhormone........................................................................................................................................................85 Thyroidinhibitors........................................................................................................................................................86 Generalprinciplesincorticosteroidstherapy............................................................................................................. 86 AntiinflammatoryandsodiumretainingpotenciesofGlucocorticoids ..................................................................... 87 ReproductivehormonesandVitamins........................................................................................................................... 88 Hormonesinfluencingreproductivefunctions........................................................................................................... 88 Anteriorpituitarygonadotropins................................................................................................................................88 Placentalgonadotropins.............................................................................................................................................89 Estrogens.....................................................................................................................................................................89 Progesterone...............................................................................................................................................................90 Androgens...................................................................................................................................................................90 Anabolicsteroids.........................................................................................................................................................91 Posteriorpituitaryhormones...................................................................................................................................91 Pharmacotherapeuticsoffatsolublevitamins........................................................................................................... 91 Pharmacotherapeuticsofwatersolublevitamins...................................................................................................... 92 Drugsactingonskinandmucousmembranes............................................................................................................... 93 Counterirritants ...........................................................................................................................................................93 Penetrationenhancers ................................................................................................................................................93 Adsorbants..................................................................................................................................................................94 Demulcents.................................................................................................................................................................94 Emollients ....................................................................................................................................................................94 Astringents..................................................................................................................................................................94 Otheragentsusedonskins.........................................................................................................................................94 Bioenhancers,immunostimulantsandimmunosuppressors......................................................................................... 95 Bioenhancers...............................................................................................................................................................95 Immunostimulants......................................................................................................................................................95 Immunosuppressant...................................................................................................................................................95
History of Pharmacology

Ancientmedicine PreChristianera Mediaevalmedicine Revoltsinmedicine Modernmedicine Chinesemedicineistheearliestandrecordsdatedabout2500B.C.availabletodaygiveanideaaboutthe medicalknowledgeofChinese. InChinesemedicine,theuseofEphedraorMahuangasatonichasbeenreported. AyurvedaorIndianMedicineisequallyancient.ToformthescienceoflifenamelyAyurveda,Charaka, SushrutaandVagbhatamadeacompilationofoldandnewdrugsinthecureofdiseases. Egyptianmedicineisalsoveryancient.TheEbersPapyrusdatedabout1500B.C.givesacollectionofdrugs prevalentinEgyptatthattime,theirclassificationandtheiruse.Someofthedrugsemployednowsuchas, castoroilandpomegranatebarkarementionedinthispapyrus. Greekmedicineissaidtobetheoriginofmodernmedicineandtherapeutics.Hippocratesinfifthcentury B.C.separatedmedicinefromreligionandwasknownasthefatherofmedicine. Helaiddowncertainprinciplesonwhichmodernmedicineisbuilt.AccordingtoHippocratesthefour elementsofnaturenamelywater,fire,airandearthgaverisetothefourhumorsofthebodynamelyblood, phlegm,yellowbileorurineandblackbile.Anyimbalanceinoneormoreofthesehumorsinflicted sufferings. GalenwasafamousGreekPhysicianwhopracticedinRome.Hisnameisstillusedtorefersomedrugsas galenicaldrugs.Hewasthefatherofpolypharmacy. Galenicaldrugsarepharmaceuticalscompoundedbymechanicalmeans,mostlyofthevegetablematerial. Paracelsusintroducedinorganicchemicalslikemercuryintomedicine.HecalledthisIatroChemistryor medicinalchemistry. Heinducedpractitionerstouselaudanum(anopiumpreparation),sulphur,iron,coppersulphate,potassium sulphate,mercurialsandtincturesandfluidextractofvariousplantsfortreatmentofdiseases. Bythebeginningof19thcenturytheprincipleofshotgunprescriptionflourished(Shotgunprescriptionis onethatcontainsanumberofsubstanceswithnotherapeuticefficacy.Itisaresultofignorantattemptto curethedisease,nomatterwhatmaybeitsnature). Gregoryadvocatedmethodslikevenesection,leechingemeticsanddrasticpurgatives.Largedosesof purgativesweregiven.Thepatienteithersurvivedordied.Thissortofsymptomatictreatmentwasreferred toasallopathymeaning'othersuffering'.Thistermallopathyisnowbeingusedtorefermodernmedicine. SamuelHahnemannintroducedhomeopathymeaningsimilarsufferingatthecommencementof19th century.InGreek,homosmeanssameandpatheiameanssuffering.Hewasknownasthefatherof homeopathy.Homeopathyintroducedbyhimhadtwonewerprinciplesthatlikecureslikeanddilution potentiatestheactionofdrugs. Buccheim,aprofessorofDorpatUniversitywhowasknownasthefatherofPharmacologysetupthefirst laboratorytostudypharmacology.Hediscardedmanyremediesbecauserationalscientificactionor explanationcouldnotbedemonstratedinhislaboratory. Bythemiddleofthe19thcentury,modernmedicinehadbroughttofightdiseaseonlyoneeffectiveweapon ie.immunizationagainstsmallpox. 8|U R V I S H M I S T R Y
Ancient medicine
Pre- Christian era

Mediaeval medicine
Revolts in medicine
Modern medicine
9|U R V I S H M I S T R Y Laterinquicksuccessioncametheanaestheticsandantiseptics.Inthelastquarter,thecausativeorganisms formalaria,plaque,choleraetc.wereidentified. Beginninginthe20thcentury,thefreshwindofsyntheticchemistrybegantorevolutionisethe pharmaceuticalindustryandwithitthescienceofpharmacology. Newsyntheticdrugs,suchasbarbituratesandlocalanaesthetics,begantoappearandtheeraof antimicrobialchemotherapybeganwiththediscoveryofarsenicalcompoundsforthetreatmentofsyphilis byPaulEhrlichin1909.Hewasknownasthefatherofchemotherapy. FurtherbreakthroughscamewiththediscoveryofsulphonamidesbyGerhardDomagkin1935andthe developmentofpenicillinduringworldwarII. Theadditionofdrugstothetherapeuticjungleisgrowingwithrapidpacefromthelaterhalfofthe 20thcentury.
Scope of pharmacology
Pharmacologyisthesciencewhichinvolvesallaspectsoftheactionofdrugsonlivingsystem.Itisthestudy ofthetherapeuticvalueand/orpotentialtoxicityofchemicalagentsonbiologicalsystems.Ittargetsevery aspectofthemechanismsforthechemicalactionsofbothtraditionalandnoveltherapeuticagents. Importantandinterrelatedareasare:pharmacodynamicsandpharmacokinetics. Pharmacodynamicsisthestudyofhowdrugsactonthebodywhilepharmacokineticsisthestudyofhowthe bodyactsondrugs.Pharmacodynamicandpharmacokineticaspectsoftheactionofchemicalagentsare applicabletoallrelatedareasofstudy,includingtoxicologyandtherapeutics. Toxicologyisthestudyoftheadverseortoxiceffectsofdrugsandotherchemicalagents.Itisconcerned bothwithdrugsusedinthetreatmentofdiseaseandchemicalsthatmaypresenthousehold,environmental, orindustrialhazards. Therapeuticsfocusesontheactionsandeffectsofdrugsandotherchemicalagentswithphysiological, biochemical,microbiological,immunological,orbehavioralfactorsinfluencingdisease.Eachoftheseareasis closelyinterwovenwiththesubjectmatterandexperimentaltechniquesofphysiology,biochemistry, cellularbiology,microbiology,immunology,genetics,andpathology.TheultimategoalofPharmacologyisto designchemicalagentstocure,ameliorate,orpreventdisease
Branches of pharmacology

Neuropharmacologyisthestudyofneurophysiologicalorneurobiochemicalfunctionsofthenervoussystem includingthebrain,spinalcord,andthenervesthataremodifiedbydrugaction. Cardiovascularpharmacologyconcernstheeffectsofdrugsontheheart,thevascularsystem,andthose partsofthenervousandendocrinesystemsthatparticipateinregulatingcardiovascularfunction. Molecularpharmacologydealswiththebiochemicalandbiophysicalcharacteristicsofinteractionsbetween drugmoleculesandthoseofthecell.Itismolecularbiologyappliedtopharmacologyandtoxicology. Biochemicalpharmacologyisthestudyofactionofdrugsanddrugmetabolism,howdrugsinteractwith, andinfluences,thephysiologyoftheorganism. Behavioralpharmacologystudiestheeffectsofdrugsonbehavioroforganism.Itincludestopicssuchasthe effectsofpsychoactivedrugsonthephenomenaoflearning,memory,wakefulness,sleepandthebehavioral consequencesofexperimentalinterventioninenzymeactivityandbrainneurotransmitterlevelsand metabolism. Endocrinepharmacologyisthestudyofdrugsthatareeitherhormonesorhormonederivatives,ordrugs thatmaymodifythesectionsofnormallysecretedhormones. Clinicalpharmacologyistheapplicationofpharmacodynamicsandpharmacokineticstopatientswith diseases,italsoincludespharmacogeneticcomponent.Clinicalpharmacologistsstudyhowdrugswork,how theyinteractwiththegenomeandwithotherdrugs,howtheireffectscanalterthediseaseprocess,and howdiseasecanaltertheireffects.Clinicaltrialdesign,thepreventionofmedicationerrors,andthe optimizationofrationalprescribingarecriticalcomponentsofclinicalpharmacology. Chemotherapyistheareaofpharmacologythatdealswithdrugsusedforthetreatmentofmicrobial infectionsandmalignancies.Chemotherapeuticagentsselectivelyinhibitthegrowthof,orkill,theinfectious agentorcancercellwithoutseriouslyimpairingthenormalfunctionsofthehost. 9|U R V I S H M I S T R Y
10|U R V I S H M I S T R Y Toxicologyisthescienceofadverseeffectsofchemicals/drugsonlivingsystems.Italsoincludesproblems ofdrugsafety,effectsofdrugoverdosage. Pharmacyisaseparatedisciplineinthehealthsciences.Itistheprofessionresponsibleforthepreparation, dispensingandappropriateuseofmedication,andprovidesservicestoachieveoptimaltherapeutic outcomes.
Terms and definitions

Pharmacology related terms
Pharmacologyisthesciencethatembracestheknowledgeofthehistory,source,physicalandchemical properties,compounding,biochemicalandphysiologicaleffects,mechanismofaction,absorption, distribution,biotransformationandexcretionofdrugs.Itisalsodefinedasanexperimentalsciencedealing withthepropertiesofdrugsandtheireffectsonlivingsystem. Pharmacodynamicsisthestudyofthebiochemicalandphysiologicaleffectsofdrugsandtheirmechanism ofaction.Itistheresponseoftheorganismtotheactionofadrugintheabsenceofadisease. Pharmacodynamicsis'whatthedrugdoestothebody'. Pharmacokineticsisthestudyoftheactionsofthedrugsinthebodyoveradefinedperiodoftime.Itdeals withtheabsorption,distribution,biotransformationandexcretionofthedrug.Pharmacokineticsis'whatthe bodydoestothedrug'. Pharmacometricsisthestudyofthetechniquesusedinthemeasurementofdrugeffectstothe administereddoseofdrug. Pharmacogeneticsisthestudyofgeneticallydeterminedvariationsinanimalsthatarerevealedbythe effectofdrugs. PharmacogenomicsThistermdescribestheuseofgeneticinformationtoguidethechoiceofdrugtherapy onanindividualbasis.. Pharmacoepidemiologyisthestudyofdrugeffectsatthepopulationlevel.Itisconcernedwiththe variabilityofdrugeffectsbetweenindividualsinapopulationandbetweenpopulations. Pharmacoeconomicsaimstoquantifyineconomictermsthecostandbenefitofdrugsusedtherapeutically. Pharmacyisthesciencethatdealswiththepreparation,formulation,manufacture,standardization, preservationanddispensingofdrugs.Thetermpharmacyalsoindicatestheplacewheredrugsare dispensedorsold. Pharmacognosyisthestudyofthesourceofdrugs.Italsodealswiththephysicalandchemicalpropertiesof drugs. Materiamedicaisanobsoletedidacticsubjectthatwasconcernedwithpharmacy,posology, pharmacognosyandindicationsfortherapeuticuseofthedrug. Metrologyisthestudyofweightsandmeasuresasappliedtothepreparationandadministrationofdrugs. Chronopharmacologyisthesudyofhowtheeffectsofdrugsvarywithbiologicaltimingandendogenous periodicities. Pharmacovigilanceisthescienceandactivitiesrelatingtothedetection,assessment,understandingand preventionofadverseeffectsoranyotherdrugrelatedproblem. Pharmacoepidemiologyisthestudyoftheuseofandtheeffectsofdrugsinlargenumbersofpeople.
Drug related terms
Drugisanychemicalagentexceptfoodthatisusedtopromoteorsafeguardthehealthofhumanbeingsor animals.Itisalsodefinedasanysubstanceorproductthatisusedorintended,tobeusedtomodifyor explorephysiologicalsystemsorpathologicalstatesforthebenefitoftherecipient.Theworddrugisderived fromaFrenchwordDroguemeaningadryherb.
11|U R V I S H M I S T R Y Overthecounterdrugsarethosepreparationsthatcanbesoldwithoutanyprescriptionbecausetheycan beadequatelylabeledforlaymanuse. Prescriptiondrugsaredrugsthatcanbeusedonlyontheorderofalicensed veterinarian/physician/dentist/surgeonbasedonaprescription.Theyarealsoknownaslegenddrugs. Essentialdrugsareagentsthatsatisfythehealthcareneedsofmajorityofthepopulation.Theyshould thereforebeavailableatalltimesinadequateamountsandinappropriatedosageform. Prodrugsaredrugsthatareinactiveorhavealoworderofactivityintheformadministeredandare metabolisedtotheactiveforminthebody. Harddrugsaredrugsusedfornonmedicalpurposesthatareliabletodisabletheindividualseriouslyasa functioningmemberofthesocietybyinducingseverepsychologicaland/orphysicaldependence.eg.Heroin Softdrugsaredrugsusedfornonmedicalpurposesthatarelessdependenceproducing.Theremaybe psychologicaldependencebutnotphysicaldependence,exceptwithheavydose.eg.Amphetamine. Nootropicdrugsaredrugsthataffecttheintellect.Thesedrugsareclaimedtoenhancelearning,increase brainresistancetostressincludinghypoxiaandstimulatebrainmetabolismespeciallyinsenilepatients.eg. Piracetam Orphandrugsaredrugsorbiologicalproductsusefulfordiagnosis/treatment/preventionofararedisease conditionforwhichthereisnoreasonableexpectationthatthecostofdevelopingandmarketingitwillbe recoveredfromthesalesofthatdrug.Eg.Acetylcysteine.Thesedrugsmaybelifesavingforsomepatients, butarenotcommerciallyavailable. Placeboisavehicleforcurebysuggestionandissurprisinglyoftensuccessfulthoughonlytemporarily.Itcan beusedasacontrolinscientificevaluationofdrugsandtobenefitorpleaseapatientnotby pharmacologicalactionsbutbypsychologicalmeans(Latin:PlaceboIshallbepleasingoracceptable). Placeboreactorisanindividualwhoreportchangesofphysicalandmentalstateaftertakinga pharmacologicallyinertsubstance.
Dose related terms
Doseofthedrugisanestimateamountofadrug,thatwhenadministeredbyaparticularroutetoacertain speciesismostlikelytoproduceacertainintensityofresponse.Itisthequantityofmedicationtobe administeredatonetime.Dosageisthedeterminationandregulationofdoses. Posologyisthestudyofthemedicinedosages,whichvarieswiththespeciesofanimals,theintendedeffect ofthedrugandtheindividualtoleranceorsusceptibility. Loadingdoseisoneoraseriesofdosesthatmaybegivenattheonsetoftherapywiththeaimofachieving thetargetconcentrationrapidly. Maintenancedoseisaseriesofrelativelysmalldosesthatfollowtheloadingdoseinordertomaintainan effectiveconcentrationinthebiophase.
Sources of drugs
Plant sources of Drugs

Manydrugsavailablefromplantsareeventodayusedinthetreatmentofpathologicalconditions. Withtheincreasingtendencyfortheuseofalternatemedicine,thissourcehasgainedmoreimportancein therecentpast. Thepharmacologicalactivitiesofplantsareattributedtocertainactiveprinciplesinplants.Theyare alkaloids,glycosides,fats,oils,tannins,saponinsetc. Alkaloidsarenitrogenoussubstancesobtainedfromvariouspartsoftheplant.Alkaloidscontainingoxygen aresolidsandcomparativelynonvolatile(cocaine)whilethosethatdonotcontainoxygenareliquidsand volatile(nicotine,lobelineandconiine). Alkaloidsareinsolubleinwaterwhiletheirsalts(atropinesulphate,caffeinecitrate)aresolubleinwater. Alkaloidsarebittertotaste.Theyareincompatiblewiththealkalies,tannicacidandheavymetals. Alkaloidsrepresentthewasteproductsofplantmetabolismandtheirnamesendwithine. 11|U R V I S H M I S T R Y
Alkaloids
12|U R V I S H M I S T R Y Alkaloidsshouldbeadministeredinsmallquantitiesandwhengiveninexcesstheymayproducedeath withoutmuchpostmortemchangesfordiagnosis.(Adrenalineisconsideredasanimalalkaloid).
Glycosides

Glycosidesarenonnitrogenoussubstancesobtainedfromplants. Theglycosidesonhydrolysisyieldtwomoleculesnamelyasugarmoleculeandagenineoraglycone molecule. Sugarhelpsinthedissolutionofthepreparationwhilethepharmacologicalactionrestswiththeaglycone. Whenthesugarmoleculeisglucose,theglycosideisknownasglucoside. Cardiacglycosidesdigitalis,strophanthusandsquillplayamajorroleinthetreatmentofcongestivecardiac failure. Cyanogeneticglycosideisoneinwhichhydrocyanicacidisreleasedonglycolysis. Therearetwotypesofoilsnamelyfixedoilsandvolatileoils. Volatileoilsarealsoknownasessentialoils. Castoroil,coconutoiletc.arefixedoilswhileturpentineoil,eucalyptusoiletc.arevolatileoils. Fixedoilsareobtainedbyexpressionwhilevolatileoilsareobtainedbydistillation.(Mineraloilsareobtained fromtheearthandsomeaeusedpharmacologically.Eg:Liquidparaffin.) Thesearenonnitrogenousphenolderivativesfoundespeciallyinleavesandbark. Theyareastringentinnatureandforminkysolutionswithferricsalts.Catechuatannicacidisusedinthe controlofdiarrhoea. Eg:Blackcatechu,Palecatechu Thesearenonnitrogenoussubstancesresemblingglycosides. Theyaresolubleinwaterandonshakingtheygivepersistentfoam.Whenthesaponinistoxicitisknownas sapotoxin. Onhydrolysissaponinssplitintosugarandaglycone(sapogenin). Eg:Fenugreek,Ginsengetc. Thesearesolidbrittlesubstancesformedfromterpenesbyoxidation.Theyareinsolubleinwater. Resincanbeoleoresin,gumresinorbalsams. Eg:Asafoetida,Camphor,Storax Gumsaredriedexudatesobtainedbyincisiononstemsofvariousplants. Theyformajellywithwater. Eg:Gumacacia
Oils

Tannins

Saponins
Resins

Gums

Mineral source

Metallicandnonmetallicmineralsprovidevariousinorganicmaterialsnotavailablefromplantsoranimals. Mineralsourcesareusedastheyoccurinnatureorcanbecombinedwithotheringredients. Thedrugsthatareincludedinthiscategoryincludemetalsandtheirsalts,nonmetals,metalloids,acids, alcoholsandcoaltardrugsetc. Examplesare:sodiumchloride,coppersulphate,magnesiumsulphate,potassiumpermanganate,etc. Theyareusedinthepurifiedformasdrugs.
Animal source of drugs

Thebodyfluidsorglandsofanimalsarealsonaturaldrugsources.Thedrugsobtainedfromanimalsourcesinclude: hormones,suchasinsulin 12|U R V I S H M I S T R Y
13|U R V I S H M I S T R Y oilsandfats(usuallyfixed),suchascodliveroil enzymes,whichareproducedbylivingcellsandactascatalysts,suchaspancreatinandpepsin vaccines,whichincludesuspensionsofkilled,modified,orattenuatedmicroorganisms,orantigenic materialsobtainedfromthese.
Synthetic sources of drugs

Anumberofdrugssynthesizedinthelaboratoryareusedmostcommonly. Evennaturalproductssuchashormones,antimicrobialsetc.arealsosynthesizedinthelaboratory.
Microbial source of drugs
Microbesprovideanimportantsourceofdrugsespeciallytheantibiotics.Alltheantibioticsusedagainsta varietyofpathogensandalsocancerareobtainedfromfungi,bacteriaoractinomycetes.Somesystemic drugslikeergotalkaloids(fungalsource)arealsoobtainedfrommicrobes. Eg:PenicillinfromPenicilliumnotatum Streptomycin,Tetracyclines,ChloramphenicolfromStreptomycessp.
Pharmacokinetics: principles of drug activity

Routes of administration
Routesofdrugadministrationcanbedividedintothreemainclassesasenteral,parenteralandtopical. o Enteraladministrationreferstoadministrationofdrugsviathegut. o Parenteral(parbeyond,enteralintestinal)administrationcoversintravenous,intramuscular, subcutaneous,intraperitonealetc. o Topicalapplicationreferstoapplicationofdrugsontheskinandmucousmembrane. Factorsgoverningthechoiceofrouteare: o Physicalandchemicalpropertiesofthedrug(solid/liquid/gas;solubility,stability,pH,irritancy) o Siteofdesiredactionlocalizedorgeneralized o Rateandextentofabsorptionofthedrugfromdifferentroutes o Effectofdigestivejuicesandfirstpassmetabolismofthedrug o Rapiditywithwhichtheresponseisdesired(routinetreatmentoremergency) o Accuracyofdosagerequired(intravenousandinhalationneedfinetuningofdose) o Conditionofthepatient(unconscious,vomiting)
Oral administration
Dosageformsavailablefororaluseinclude Liquids:Aqueoussolutions,suspension(dispersionofasolidinaliquid)andemulsion(dispersionofaliquid inliquid) Solids:Powders,tablet,entericcoatedtablet,capsule,granules Fortabletsandcapsulesthefactorsthataffecttheactualamountofthedrugabsorbedoravailableinclude disintegration,coating,adjuvantsused,compression,drugparticlesizemicronization,amountofthedrug, chemicalform(salt),physicalstate(amorphousorcrystalline,solvatedoranhydrous)andlocalpHofthe absorptivearea. Advantagesoforalroute Generallythesafestroute 13|U R V I S H M I S T R Y

14|U R V I S H M I S T R Y Economical Convenientandrelativelysimpleforowner Noneedforsterileequipment Systemicdistributioncanbeachieved Disadvantages Absorptionmaybevariable Gastricirritationmaycausevomiting Notusefulifanimalisvomiting Requirescooperationofpatient,whichisnotusuallyforthcominginaveterinarypatient Drugsmaybedestroyedbygastricacidity,gutflora,mucosalenzymesandliverenzymes Onsetofeffectisusuallyslow Notgenerallypreferredinruminantssincethedruggetsdilutedinthevoluminousruminalcontents Whenantimicrobialsareadministeredtoruminantsorallyforalongerdurationoftime,theymayaffectthe microbialecosystemoftherumen Presenceoffoodandotherdrugsmayaltertheabsorptionpatternleadingtounpredicatabilityinthe desiredaction. Entericcoatedpreparations Drugsthataredestroyedbythegastricjuiceorthatcausegastricirritationcanbeadministeredorallywitha coatingthatpreventsdissolutionintheacidicgastriccontents. Theydissolveoncetheyreachtheduodenumandreleasetheactivedrug.Onsetofdrugactioncan bedelayedwithentericcoatedtablets. Sublingualtablets Drugsthatarelipidsolubleandnonirritatingcanbeadministeredsublingually,sothatabsorptiondirectly fromtheoralcavityisachievedwhenarapidresponseisrequired,particularlywhenthedrugiseither unstableatgastricpHorrapidlymetabolisedbytheliver.Eg.Glyceryltrinitrate. Drugsabsorbedbymouthpassdirectlyintothesystemiccirculationwithoutenteringtheportalsystemand soescapethefirstpassmetabolism.Thistypeoftabletisusefulinthetreatmentofanginapectoriswhere thedrugentersdirectlyintothesystemiccirculationandprovidesimmediateeffect.Oncetherequired effecthasbeenachieved,theexcesstabletcanbespitoff. Timedreleasepreparations Timedreleasepreparationsaredesignedtoproduceslowuniformreleaseandabsorptionofthedrugovera periodof8hoursormore.Theyarealsoknownasspansulesortimesules. Advantages o Lessfrequentadministration o Lastsovernight o Druglevelsaremoreconstantanddonotpeakaftereachadministration(lesstoxiceffects) o Goodforshortactingdrugs Disadvantages o Marketedpreparationsaresometimesnotreliable o Dissolutionratesmaybeirregular o Notneededforlongactingdrugs o Notgoodforabrieftherapeuticeffect Rectaladministration Thisrouteofadministrationisusefulwhentheanimalisunconsciousorvomiting. Rectalabsorptionisoftenincompleteanderratic. Drugscanbeadministeredrectallyintheformofenemaorsuppository. Irritantandunpleasantdrugscanbeadministeredperrectum.However,rectalinflammationmayoccurdue tohighlyirritantdrugs.
Intravenous route
Parenteraladministration Whileconsideringparenteraladministration,thepointsofimportanceinclude o Volumetobeadministered 14|U R V I S H M I S T R Y
15|U R V I S H M I S T R Y o Concentrationofthedrug o pH o Toxicity o Viscosity o Particlesize,ifsuspensionisused o Adjuvantusedinthepreparation Ingeneral,parenteraladministrationrequiresskillofinjectionanduseofsterileequipment.Parenteral preparationsarenormallyusedassolutionsorsuspensions. Intravenousadministration Advantages o Extremelyrapidonsetofaction o Initialabsorptionstepisbypassed o Druglevelscanbecontrolledmoreaccurately o Suitableforirritantdrugs o Suitableforlargevolumesofdrugs Disadvantages o Mostdangerousrouteastoxicitycaneasilyoccur o Drugsmustbeinaqueoussolution o Mustbeperformedslowly o Onceinjected,drugcannotberetrieved Sitesforvenipunctureindifferentspecies Cattle,sheepandgoatAtanypointalongthewholelengthofthejugularveininthejugularfurrow,onthe venterolateralaspectoftheneckoneitherside HorseExternaljugularveininthejugularfurrowonlyinthecranialpartoftheneck. PigAuricularvein Dogsaphenousveinonthemedialaspectofthelegorrecurrenttarsalveinonthedorsalaspectoftheleg.
Subcutaneous and intramuscular routes

Subcutaneousadministration Thisrouteisusefulwhenslowandcontinuousabsorptionisrequired.Theformulationmustbeisotonicand atphysiologicalpH. Certaindrugsthatareirritatingcancauseseverepainandnecrosis.Therateofdistributionofthedrugis largelydependentonbloodflowandhence,therateofdistributioncanbeslowedbyincludinga vasoconstrictor. Warmthorvigorousmassagewillincreasedistribution.Additionofhyaluronidasecanenhancedrug dispersion.Thisenzymehydrolysesthehyaluronicacidpolymersthatcomprisestheintercellularcementand thusfacilitatesdiffusionthroughthetissues. Specialisedsubcutaneouspreparationsincludedermojetandpelletimplantation. Dermojetisaprocesswherenoneedleisused.Ahighvelocityjetofthedrugsolutionisprojectedfroma microfineorificeusingagunlikeimplement.Thesolutionpassesthroughthesuperficiallayerandgets depositedinthesubcutaneoustissue.Itisessentiallypainlessandsuitableformassinoculation. Pelletimplantationprovidessustainedreleaseofthedrugoverweeksormonths.Thepelletimpregnated withthedrugisimplantedinthesubcutaneoustissue.Sialistic(nonbiodegradable)andbiodegradable implantsareused. Crystallinedrugispackedintubesmadeofsuitablematerialandimplantedundertheskin.Constantblood levelscanbemaintainedasthedrugisreleaseduniformlyoveraperiodoftime.Ifnonbiodegradable implantisused,itshouldberemovedafterthespecifiedperiodoftime. Sitesforsubcutaneousinjectionindifferentspecies Cattle,sheepandgoatFoldofflankextendingfromthecaudoventralabdominalwalltothecraniomedial aspectofthethighnearstiflejointorlooseskinonthelateralaspectoftheneck. HorseLooseskinonthelateralaspectoftheneck.Normallysubcutaneousinjectionisnotpreferredin horses. DogFoldoftheflank 15|U R V I S H M I S T R Y
16|U R V I S H M I S T R Y Intramuscularadministration Drugsinaqueoussolutionarerapidlyabsorbedafterintramuscularadministration.However,veryslow constantabsorptionoccursifthedrugisadministeredinoilorsuspendedinotherrepositoryvehiclesas depotpreparations.Itcanbeusedforrelativelyirritantdrugsandsuchdrugsmustbeadministereddeep intramuscularly.Intramuscularinjectionsarealwayspainfulandlargevolumescannotbeinjected. Adisadvantageofthisrouteisthepossibilityofimproperdepositioninnerves,bloodvessels,fatorbetween musclebundlesinconnectivetissuesheaths.Wheneverdrugsareadministeredintramuscularly,itisalways advisabletoconfirmthattheneedleisnotinthebloodvessel. Sitesforintramuscularinjectionindifferentspecies: Cattle,sheepandgoat1.Hindlimba)Glutealregioncoveredbyglutealmusclesandb)posterioraspectof thighbetweenthesemimembranousandsemitendinous.(Insheepandgoat(b)ispreferred). 2.NeckIntheheavymusclesonthecaudodorsalaspectoftheneck.Needlecanpiercethroughthe followingstructuresskin,fascia,trapezius,rhomboideus,spleniusandcomplexus,dependinguponthe lengthoftheneedleandforceapplied.Thissiteispreferredonlyinwellbuiltanimals.Careshouldbetaken toavoidvertebralcolumnandthedorsalbranchoftheXIcranialnerve. Inindigenouscattlewithhump,humpisalsopreferredtoadministerintramuscularly. HorseNeckregionandbrisketregion(pectoralmuscles) DogHindlimbbetweenthesemimembranosusandsemitendinosus.
Other parenteral routes

Intraperitonealadministration Thisrouteisparticularlyusefulinlaboratoryanimalmedicineandneonatalanimalsandforthe administrationoflargevolumes. Thereisaverylargeabsorbingareaandabsorptionisrapid.Thereisadangerofinfectionandperitoneal adhesions.Thusitisnotusedroutinely.Peritonealdialysisisbecomingmorefrequentlyusedinsmall animalswithrenalfailureandrenalinsufficiency. Intradermaladministration Thisrouteisusedmainlyfordiagnosticpurposeseg.forTuberculinandJohnintestingincattleandalsofor hypersensitivitytestingbeforeadministeringsomedrugsknowntoinducehypersensitivity. Intrathecaladministration Inthisroutethedrugisadministeredthroughthemembranesenclosingthecentralnervoussysteminthe lumbarareaorintothecisternamagna. Itisoccasionallyusedforradiographicexaminationsandchemotherapyofcentralnervoussysteminfections andneoplasms. Epiduraladministration Thisrouteismainlyusedtoanaethetiseanimalsforsurgerylikeparturitionincattle. Thedrugisadministeredbetweenthefirstandsecondcoccygealvertebrae. Intraarticularadministration Thisrouteisusedtoadministerantiinflammatoryagentsintothejointcapsule. Theotherparenteralroutesofdrugadministrationrarelyusedareintraarterial,intramedullary, intratesticular,intracardiacetc.
Local administration

Localadministrationofdrugsreferstoexternalapplicationorapplicationtoalocalizedsitesuchaseye.ear. mucousmembranesetc. Someofthelocalsitesofadministrationinclude: o Skin:Applicationofdrugsontotheskinsuchaspowder,lotion,ointmentetc. o Mucousmembrane: Mouthandpharynx:mouthwash,gargle,paintetc. Eye,earandnose:Drops,spray,irrigation GItract:nonabsorbabledrugssuchaskaolin,antacids,someantibioticswhichareintended toremainwithintheGItractandnotabsorbed 16|U R V I S H M I S T R Y
17|U R V I S H M I S T R Y Bronchiandlungs:aerosol,inhalations Vagina:Pessary,bolus,tablets Rectum:Suppository,enemaetc. o Tissues:Drugscanbeadministeredtosomeofthetissuebutareintendedtoactonlyonthesiteof absorption.eg.Intraauricular,intrathecal o Arterial:Somedrugsaregivenintraarteriallytoactonthelocalizedareasuppliedbytheartery.Eg: angiography,anticancerdrugs.
Structure of biological membranes

Fluid mosaic models

Biologicalmembranesmaybeviewedasmosaicsoffunctionalunitscomposedoflipoproteincomplex. Mostmembranesarecomposedofafundamentalstructurecalledtheunitmembraneorplasma membrane,thatis80to100Athick,surroundssinglecellsandnuclei. Complexbarrierssuchastheintestinalepitheliaandtheskinarecomposedofmultiplesofthisfunctional structure. Theplasmamembraneconsistsofabilayerofthiclipidswiththeirhydrocarbonchainsorientedwithinto formacontinuoushydrophobicphaseandtheirhydrophilicheadsorientedoutward. Individuallipidmoleculesinthebilayercanmovelaterally,makingthemembranefluid,flexibile,electrically resistantandrelativelyimpermeabetohighlypolarmolecules. Thisviewofmembranestructureisknownasthefluidmosaicmodel. o Membraneproteinsembeddedinthebilayerservesasreceptorstoelicitelectricalorchemical signalingpathwaysandprovideselectivetargetsfordrugaction. o Theproteinsareabletofreelyfloatthroughthemembraneandsomeoftheintrinsicones,which extendthroughthefullthicknessofthemembrane,surroundfineaqueouspores.Paracellular spacesorchannelsalsoexistbetweencertainepithelialorendothelialcellsandotherproteinshave enzymaticorcarrierproperties. o Biologicalmembranesbehaveasiftheywerelipoidspuncturedbyaqueousporesandallowdrugs andphysiologicalmaterialscrossbypassiveorcarriermediatedprocess.Whichmechanismoperates isdeterminedbythephysicochemicalpropertiesofdrugsandtheoptionsavailableinthe membrane.
Functions of membranes
Membranesperformthefollowingfunctions: 1. Theyprovidestructuralstabilitytothecell 2. Theyactasbarriersrestrictingtheentryofsubstancesinsidethecell. 3. Theyprovidevitalcommunicationthroughtheentryofmessengersforvariouscellularprocesses.
Passage of drugs across membranes

Passive diffusion
Passivediffusionisarandommovementofdrugmoleculesfromanareaofhigherconcentrationtoanarea oflowerconcentration.Whenadrugisinjectedintothebody,itpassivelydiffusesfromtheinjectionsiteto areasoflowerconcentration,eventuallyreachingabloodcapillaryandenteringthesystemiccirculation.In thisprocessnocellularenergyisexpendedandnotransportcarrierproteinisinvolved.Hencethe termpassivediffusionisused. Manydrugspassthroughthebiologicalmembranessuchascellmembranesbypassivediffusion.Foradrug topassivelydiffusefromonesidetoanother,thedrugmustdissolveinthemembranethatiscomposedof phospholipids,anddiffusedowntheconcentrationgradient. Passivediffusioncontinuesuntilenoughmoleculeshavepassedfromanareaofhigherconcentrationtoan areaoflowerconcentrationtillequilibriumisattainedoneithersideofthemembrane.Drugmolecules continuetomove,however,suchthatanequalnumbermoveintoandoutofboththeareas. 17|U R V I S H M I S T R Y
18|U R V I S H M I S T R Y Passivediffusionisthemostimportantmechanismformajorityofdrugs.Lipidsolubledrugsdiffuseby dissolvinginthelipoidalmatrixofthemembrane.Therateoftransportbeingproportionaltolipid:water partitioncoefficientofthedrug. Passivediffusionismostlydependentupon: o Concentrationgradient(greateristhedifferenceintheconcentrationofthedrugonthetwosidesof themembrane,fasterisitsdiffusion) o Drugmolecularsize(smallermoleculesmovemorerapidlythanbiggermolecules) o Lipophilicnatureofthemolecule(higherthelipidsolubilityhigheristhediffusion) o Temperature(lowerthetemperature,slowerthediffusion) o Thicknessofthemembrane(thethickerthemembranetheslowerthediffusion)
Carrier mediated transfusion

InCarriermediatedtransport,thedrugcombineswithacarrierpresentinthemembraneandthecomplex thentranslocatesfromonesideofthemembranetotheother. Thecarriersforpolarmoleculesappeartoformahydrophobiccoatingoverthehydrophyllicgroupsandthus facilitatepassagethroughthemembranes.Substancespermittingtransitofionsacrossmembranesare calledionophores. Carriertransportisspecific,saturableandcompetitivelyinhibitedbyanaloguesthatutilisethesamecarrier. Intestinalabsorptionsometimesdependsoncarriermediatedtransport. Examplesofcarriermediatedtransportare: levodopaistakenupbyacarrierthatnormallytransportsphenylalanine; Fluorouracilistransportedbythesystemthatcarriesnaturalpyrimidines; ironisabsorbedviaaspecificcarrieronthesurfaceofthemucosalcellsinthejejunumand CalciumisabsorbedbymeansofavitaminDdependentcarriersystem. Thiscarriermediatedtransportisoftwotypes,namely o facilitateddiffusionand o activetransport
Facilitated diffusion

Facilitateddiffusionisatransportmechanismacrossbiologicalmembranesthatinvolveaspecialcarrier moleculeinthemembranewhichfacilitatesthemovementofcertainmoleculesacrossthemembrane. Asinpassivediffusion,facilitateddiffusioninvolvesnoenergytomovethedrugmoleculesandthedirection ofthedrugmovementisdeterminedbytheconcentrationgradient. Inaddition,oncetheequilibriumisattained,thenumberofdrugmoleculescrossingthemembraneineither directionremainsthesame. Thisprocessproceedsmorerapidlythansimplediffusionandeventranslocatesnondiffusiblesubstrates, butalongtheirconcentrationgradient. However,thetransportermaybecomesaturatedandothercompoundsmaycompeteorinhibitthe transport. Examplesoffacilitateddiffusionare: o VitaminB12absorbedfromthegut. o Transportofsugarsandaminoacidsacrossmembranes.
Active transport
Likefacilitateddiffusion,activetransportalsoinvolvesaspecializedcarriermolecule.However,inactive transportadrugmoleculeistakenupbyaspecializedcarriermoleculeinthemembraneandthecell expendsenergytomovethedrugmoleculesacrossortoresetthecarriermoleculeforthenexttransport movement. Unlikediffusioninwhichthedirectionofnetdrugmovementisdeterminedbytheconcentrationgradient, activetransportcanmovedrugmoleculesagainsttheconcentrationgradient(fromareasoflower concentrationtoareasofhigherconcentration). 18|U R V I S H M I S T R Y
19|U R V I S H M I S T R Y Glucoseentrywithincellisfacilitateddiffusionwhilepassageacrossgastricmucosaandexcretionby proximalrenaltubularcellsisactivetransport. Drugsrelatedtonormalmetabolitesareactivelyabsorbedfromthegutbyaromaticaminoacidtransport processes. Drugsactivelytransportedmaypotentiallyreachveryhighconcentrationswithincellsthattheyexertatoxic effecteg.aminoglycosideantibiotics. Whentheenergyproductionofthecellisdisrupted(suchastoxicities),activetransportofdrugmolecules acrossbiologicalmembranesmaybeprevented. Nonspecificactivetransportofdrugsandtheirmetabolitesoccursinrenaltubulesandhepaticsinusoids separatelyfororganicacidsandorganicbases.Certaindrugshavebeenfoundtobeactivelytransportedinto thebrainandchoroidplexusalso. Examplesforactivetransportarelevodopacrossingthebloodbrainbarrier,secretionsomedrugsintothe bileandsecretionofmanyorganicacidsandbasesbyrenaltubularcells.
Pinocytosis and phagocytosis

Pincytosis(Celldrinking)andphagocytosis(Celleating) Drugmoleculesmayenteracellbybeingphysicallyengulfedbythecell.Inbothpinocytosisand phagocytosis,aportionofthecellularmembranesurroundsthedrugmoleculeandtakesitwithinthecell. Intheseprocessestransportacrossthecellmembraneisfacilitatedbyformationofvesicles.Thisisanactive processandrequiresthecelltoexpendenergy.Iftheengulfedparticleisnotsusceptibletoenzyme degradation,itwillpersistlikeparticlesoftalcordropletsofliquidparaffin. Pincytosisandphagocytosisareespeciallyimportantformovementoflargedrugmoleculessuchascomplex proteinsorantibodiesthatwouldotherwisebeunabletoenteracellorpassintactthroughamembrane barrier.Theabsorptionofimmunoglobulinsthroughthegutmucosaofyoungcalvesdependson phagocytosis. Pinocytosisandphagocytosisareoflittleinterestinpharmacology.
Filtration
Filtrationisthepassageofdrugsthroughaqueousporesinthemembraneorthroughparacellularspaces. Thiscanbeacceleratedifhydrodynamicflowofthesolventisoccurringunderthehydrostaticorosmotic pressuregradient. Lipidinsolubledrugscrossbiologicalmembranesbyfiltrationiftheirmolecularsizeissmallerthanthe diameterofthepores.Majorityofthecellshaveverysmallporesanddrugswithhighermolecularweight willnotbeabletopenetrate.Howevercapillaries(exceptthoseinbrains)havelargeporesandmostdrugs canfilterthroughthesepores. Passageofdrugsacrosscapillariesisdependentontherateofbloodflowthroughthemratherthanonlipid solubilityofthedrugorpHofthemedium. Filtrationseemstoplayalmostaminorroleindrugtransferwithinthebodyexceptforglomerularfiltration, removalofdrugsfromCSFandpassageofdrugsacrosshepaticsinusoidalmembrane.
Absorption of drugs

Absorptionisthemovementofdrugfromthesiteofadministrationtocirculation. Oftentheentirequantityofadministereddrugdoesnotreachthesystemiccirculation.Onlythefractionof drugthatwasabsorbedisavailableforaction. Duringtheprocessofabsorption,thequantityofdrugabsorbedandalsotherateofdrugabsorbed determinethedrugaction. Inallroutesofadministration,exceptwithintravenousadministration,thedrugshavetocrossthebiological membranesforenteringthesystemiccirculationandhencearegovernedbyfactorsaffectingpassage ofdrugsacrossmembranes.
Absorption of drugs from GI tract
Beforeadrugcanbeabsorbed,itmustdissolveintheaqueouscontentsofthegut.Thus,theactualamount ofthedrugpresentinadoseisonlyoneofthefactorsthatwillaffecttheamountofdrugactuallyabsorbed oravailable. Factorsaffectingabsorptioninclude o Molecularsizeofthedruganditsconcentration o Degreeofionization(dependsonthepKaofthedrugandpHofthemedium) o Lipidsolubilityoftheneutralornonionizedformofthedrug. o Chemicalorphysicalinteractionwithcoadministeredpreparationsandfoodconstituents o Pharmaceuticalpreparationanddosageform,especiallytheirdisintegrationrateanddissolution rate o Gastricmotilityandsecretionaswellasgastricemptying o Intestinalmotilityandsecretionaswellasintestinaltransittime o Fluidvolumewithinthegastrointestinaltract o Osmolalityoftheintestinalcontents o Intestinalbloodandlymphflow o Disruptionofthefunctionalandstructuralintegrityofthegastricandintestinalepithelium o Drugbiotransformationwithintheintestinallumenbymicrofloraorwithinthemucosabyhost enzymes o Volumeandsurfaceareaoftheabsorbingsurface.Stomachhasarelativelysmallsurfacearea comparedtotheduodenum.Henceabsorptionismoreintheduodenum. o Presenceoffoodinthestomach.Normallyinfullstomachthereisadelayinabsorptionbecausethe druggetsdilutedinthestomachcontents.
Role of ionization and lipid solubility in drug absorption
Manydrugsareweakelectrolytesie.theycanionizetoagreaterorlesserextent,accordingto environmentalpH.Usuallymostmoleculesarepresentpartlyintheionizedandpartlyintheunionised state. Thedegreeofionizationinfluenceslipidsolubilityand,inturn,theirabsorption,distributionandelimination. Thedegreetowhichthesedrugsarelipidsoluble(nonionized,theforminwhichdrugsareabletocross membranes)isdeterminedbytheirpKaandthepHofthemediumcontainingthedrug. pKaofadrugisthepHatwhich50%ofthedrugisionizedand50%isnonionized. InmonogastricanimalswithalowstomachpH,weakacidssuchasaspirinwithapKaof3.5tendtobebetter absorbedfromthestomachthantheweakbasesbecauseoftheacidicconditions. Weakbasesarepoorlyabsorbedfromthestomachbecausetheyexistmostlyintheionizedstateinthe acidicenvironmentofthestomach.Weakbasesarebetterabsorbedfromthesmallintestinewherethe environmentalpHismorealkaline. HendersonHasselbalchequationisusedtocalculatethepercentofadrugthatexistsinionizedformorto determinetheconcentrationofadrugacrossthebiologicmembrane.
Henderson and Heselbelch equation
Giventhisformula,ifadrugishavingapKaof4.4,andgiventhepHofplasmaandgastricmucosaare7.4 and4.4respectively,then
Absorption of drugs after parenteral administration
Drugsinjectedintramuscularlyorsubcutaneouslymayreadilydiffusethroughtissuefluidandreacha capillarytobeabsorbed.Anythingthatinterfereswithdiffusionofthedrugfromthesiteofadministration oraltersthebloodflowtotheinjectionsitecandelayabsorptionofthedrug.Themajorfactorthat determinestheabsorptionisthebloodflowtothemuscle. Aqueoussolutionsofdrugsareusuallyabsorbedfromintramuscularinjectionsitewithin1030minutes providedthebloodflowisunimpaired.Fasterorslowerabsorptionispossible,dependingonthe concentrationandlipidsolubilityofthedrug,vascularityofthesite,volumeofinjection,theosmolalityof thesolutionandotherpharmaceuticalfactors. Absorptionofdrugsfromsubcutaneoustissuesisinfluencedbythesamefactorsthatdeterminetherateof absorptionfromintramuscularsites.Somedrugsareabsorbedasrapidlyfromsubcutaneoustissuesasfrom muscles,althoughabsorptionfrominjectionsitesinsubcutaneousfatisalwayssignificantlydelayed. Increasingthebloodsupplytotheinjectionsitebyheating,massageorexercisehastenstherate ofabsorption.Spreadingandabsorptionofalargefluidvolume,whichhasbeeninjectedsubcutaneously maybefacilitatedbyincludinghyaluronidaseinthesolution.
Absorption of drugs after inhalation or topical administration

Thevolatileandgaseousanaestheticsarethemostimportantgroupofdrugsadministeredbyinhalation. Thesesubstancesenterthecirculationbydiffusionacrossthealveolarmembranes.Sincetheyallhave relativelyhighlipidwaterpartitioncoefficientsandgenerallyarerathersmallmolecules,theyequilibrate practicallyinstantaneouslywiththebloodinthealveolarcapillaries. Particlescontainedinaerosolsmaybedeposited,dependingonthesizeofthedroplets,onthemucosal surfaceofthebronchiorbronchioles,oreveninthealveoli. Absorptionofdrugsfromtopicalsitesofapplication 21|U R V I S H M I S T R Y
22|U R V I S H M I S T R Y Drugsmaybeabsorbedthroughtheskinfollowingtopicalapplication.Theintactskinallowsthepassageof smalllipophilicsubstances,butefficientlyretardsthediffusionofwatersolublemoleculesinmostcases. Highlylipidsolublepreparationsmaybeabsorbedinconsiderableproportionsencouragingtheuseofthe topicalrouteespeciallyinveterinarypractice.Pouronpreparationsofanthelminticsisatypicalexample. Lipidinsolubledrugsgenerallypenetratetheskinslowlyincomparisonwiththeirratesofabsorption throughtheotherbodymembranes.Absorptionofdrugsthroughtheskinmaybeenhancedbyinunctionor morerarelybyiontophoresisifthecompoundisionized.Certainsolventslikedmethylsulfoxidemay facilitatethepenetrationofdrugsthroughtheskin. Damaged,inflamedorhyperemicskinallowsmanydrugstopenetratethedermalbarriermuchmore readily.Thesameprinciplesthatgoverntheabsorptionofdrugsthroughtheskinalsoapplytothe applicationoftopicalpreparationsontheepithelialsurfaces. Manydrugstraversethecorneaatratesthatarerelatedtotheirdegreeofionizationandlipidsolubility. Thusorganicbasessuchasatropine,ephedrineandpilocarpineoftenpenetratequitereadily,whereasthe highlypolaraminoglycosideantibioticsgenerallypenetratecorneapoorly.
Distribution of drugs
Drugstakenthroughoutthebodybybloodstream Onceabsorbed,itgetsdistributedtoothertissueswhichhadnodrug Thefactorsthatgovern Lipidsolubility,pH,pKaetc. Bloodflowtotheorgan Bindingandtissueaffinityofdrugs Circulatorydisorders,kidneydiseases Competitionamongdrugsforbindingsites Bloodflowratelimitingstepindistribution HighlyperfusedorganssuchasLiver,Kidney,GItract,Brain,Lungsreceiverapidlyhighlevelsofdrug. Lesserlevelsareachievedinlessperfusedorganslikemuscle,fattissue.

Plasma protein binding of drugs

Drugstendtobecomeassociatedwithseveralbloodconstituents. Manydrugsareboundtoplasmaproteins. Itisonlytheunboundorfreefractionofadrugthatcandiffuseoutofcapillariesintotissues. Factorsaffectingplasmaproteinbindinginclude o Drugconcentration o Numberofdrugbindingsitesontheprotein o Proteinconcentration o Lipidsolubilitythereisagoodcorrelationbetweenthisandthebindingofpenicillinsand tetracyclines o Weakacidslikepenicillinsareboundmoreextensivelythanweakbases o Competingmolecules o Speciesvariation o Disease Albuminandotherplasmaproteinsareessentiallycontainedwithinbloodvesselsandsothedistributionof drugsthatareboundisrestricted.Whenmorethan7080%ofthedrugisboundtoplasmaprotein,itacts asacirculatingreservoirforthedrug. Whentwoormoredrugscanbindtothesamesiteoftheplasmaproteins,administrationofaseconddrug maysignificantlyaffectthebindingofthefirstdrug. Atitstherapeuticconcentrationwarfarinis97.4%bound.Ifatherapeuticdoseofthenonsteroidalanti inflammatorydrugphenylbutazoneisadministered,boundwarfarindecreasesto92%.Thusfreewarfarin increasesfrom2.6to8%.Thisincreasestheanticoagulanteffectofwarfarinconsiderably.Italsoreducesits halflifefrom18.4to9.6hourssinceitisalsomoreavailableforbiotransformationandexcretion.
23|U R V I S H M I S T R Y Changesinbindinghavethegreatesteffectontheproportionoffreedrugwhenthepercentboundishigh. Reducingthebindingfrom98%to96%willdoubletheamountoffreedrugfrom2%to4%andthusthehalf lifeofthedrugwouldbereducedmuch. Thedrugproteinbindingreactionisreversibleandobeysthelawofmassaction. Drug+protein=>Drugproteincomplex Acidicdrugsareboundprimarilytoalbuminandbasicdrugsareboundprimarilyto1acidglycoprotein. Bindingdoesnotpreventadrugfromreachingitssiteofactionbutitslowstherateatwhichadrugreaches aconcentrationsufficienttoproduceapharmacologiceffect. Drugproteinbindinglimitsglomerularfiltrationoraneliminationprocess,becausebounddrugcannotbe filtered.However,bindingdoesnotlimittheeliminationofdrugsbyactivesecretionormetabolizedbythe liver,becausethefractionofthedrugthatisfreeistransportedandmetabolized. Whenfreedrugconcentrationislowered,thereisrapiddissociationofthedrugreceptorcomplexto maintaintheamountofdruginthefreestate.
Plasma protein binding
Somedrugsthatbind Toalbumin NSAIDs Barbiturates Phenytoin Penicillins Tetracyclines Toalpha1 acidglycoprotein Verapamil Lidocaine Bupivacaine Quinidine Prazosin
Drugswithinthesamegroupbindvariably Eg.Sulfonamides: Sulfamethazine30%,Sulfadiazine50% Sulfamethoxazole60%,Sulfisoxazole90%
Tissue storage of drugs

Somedrugsaccumulateinspecifictissues Examplesare HeartDigoxin LiverChloroquine,digoxin,cadmium Kidneydigoxin,chloroquine,cadmium Irisatropine Boneandteethtetracycline Adiposetissuethiopentone,ether,DDT storageinfatlongduetopoorbloodsupply MercuryRBC Arsenic=Nailandhair Thesespecificstoragesitesaretobeborneinmindwhenthesedrugsareadministeredorintreatingtheirtoxicities Redistribution OccursinhighlyfatsolubledrugsInitiallytakenupbybrain,heart,kidney Laterdepositedinlessvasculartissuesmuscle,fat Onredistribution,plasmaconcentrationfallsleadingtolossofdrugaction Onrepeateddoses,thesesitesfillupleadingtolongeractionofthedrug.
Barriers to drug distribution

Bloodbrainbarrier:(BBB) Aphysical/functionalbarrierwhichdoesnotpermitionizedandnonlipidsolubledrugstopassthroughinto theCentralNervousSystem
24|U R V I S H M I S T R Y ItismainlyformedbytheendothelialcellsoftheCNSbloodvessels.Itspurposeistoprotectthebrainfrom thechemicalenvironmentoftherestofthebodyduetothedelicatebalancebetweenexcitationand inhibitionmaintainedwithintheCNS. Thebraincapillariesdonotcontainfenestrations(holes).Therearemoretightjunctionsinbraincapillaries decreasingtherateofdiffusionthroughinterstitialspaces.Glialcellsensheaththebraincapillariesproviding asecondsetofcellmembraneswhichmustbetraversedaswellasasecondintracellularcompartment wherecellularmetabolicprocessescantransformenteringsubstances ChemicalorenzymaticbarrierMonoAmineOxidase,cholinesteraseThisbarrierprevents5HT, catecholamines,AChfromentryintoCNS Carriermediatedtransporttofacilitateexitofdrugs Highlylipophilicdrugsentereasilybecausetheycrossmembranes.(Fig.18)Unionizedformsofdrugsenter moreeasilythanionizedforms.Penicillin,streptomycin,gentamicindonotcrosstheBBB ChloramphenicolcancrosstheBBB Placenta Virtuallynotabarrier Anydrugtakenbymotherislikelytoaffectthefetus Hencecaremustbetakenwhileadministeringdrugstopregnantanimals.Onlyhighlyioniseddrugsand drugswithlowlipidsolubilityareexcludedfrompassingthroughtheplacenta. Itisimportantfromthepointofviewofteratogenicityofdrugs Milk Governedbyrulesofpassageacrossmembranes. Themammaryglandepithelium,liketheotherbiologicalmembranesactasalipidbarrierandmanydrugs readilydiffusefromtheplasmaintothemilk. ThepHofmilkvariessomewhat;butingoatsandcowsitisgenerally6.56.8ifmastitisisnotpresent. Weakbasestendtoaccumulateinmilkbecausethefractionofionized,nondiffusibledrugishigher.Agents deliveredbyintramammaryinfusioncandiffuseintotheplasmatoagreaterorlesserdegreebasedonpH differencesandthepKaofthedrug. IncowsMaximumResidueLevels(MRL)inmilkhasbeenrecommendedformanydrugstominimisehuman exposurerisk. Incaseofdrugadmnistration,milktobediscardeduptowithdrawaltime.
Biotransformation of drugs/xenobiotics: drug metabolism

Thechemicalalterationofdrugsinthebody Torendernonpolarlipidsolublecompoundsintopolarwatersolublecompoundstoenhancetheirexcretion fromthebody Intendedtoprotectbodyfromtheforeignsubstancesbymakingthemlesstoxicandeasilyexcreted Primarysiteliver Otherimportantsitesarekidney,intestine,lungsandplasma GeneralPatternofbiotransformationbiphasic
Sequelae of biotransformation reactions

Biotransformationreactionscanleadtoanyoneofthefollowing: Inactivationmostdrugsarerenderedpharmacologicallyinactive o Example:Manydrugsmorphine,chloramphenicol,procaineetc. Formationofactivemetabolitethemetaboliteformedpossessesbiologicalactivity o Ciprofloxacinfromenrofloxacin o OxyphenbutazonefromPhenylbutazone o Salicylicacidfromaspirin Inactivedrugtoactivedrug(Prodrug)Aninactivedruggetsconvertedintoanactivemetaboliteonceit undergoesbiotransfomationinsidethebody o Example: Hetacillintoampicillin Prontosiltosulfanilamide Lessactiveorinactivedrugisconvertedintoamoretoxicdrug(Lethalsynthesis) o Example: Parathiontoparaoxon Fluoroaceticacidtofluorocitrate
Phase-I Biotransformation - oxidation reactions and others

Althougheverytissuehassomeabilitytometabolizedrugs,theliveristheprincipalorganofdrug metabolism.Othertissuesthatdisplayconsiderableactivityincludethegastrointestinaltract,thelungs,the skinandthekidneys. Drugbiotransformationinvivocanoccurbyspontaneous,noncatalysedchemicalreactions(Hofmann degradation),whichhoweverisveryrare. Thevastmajorityofxenobioticsundergobiotransformationthereactionsofwhicharecatalysedbyspecific cellularenzymes.Atthesubcellularlevels,theseenzymesmaybelocatedintheendoplasmicreticulum, mitochondria,cytosol,lysosomesoreventhenuclearenvelopeorplasmamembrane. Manydrugmetabolisingenzymesarelocatedinthelipophilicmembranesoftheendoplasmicreticulumof theliverandothertissues.Whentheselamellarmembranesareisolated,theyreformintovesicles calledmicrosomes.Theroughmicrosomestendtobededicatedtoproteinsynthesisandthesmooth microsomesarerelativelyrichinenzymesresponsibleforoxidativedrugmetabolism.Theycontainthe importantclassofenzymesknownastheMixedFunctionOxidasesormonooxygenasesorCYP450 enzymes(CytochromeP450enzymesystem) Microsomalenzymes/mixedfunctionoxidases catalyseoxidativeandglucuronideconjugationreactions RequiresmolecularO2,CYP450(ahemeprotein),NADPH(reducednicotinamideadeninedinucleotide phosphate) NADPH+CYP450(A)+H+AH2+NADP+ AH2+O2activeoxygencomplex Drug+activeoxygencomplexoxidizeddrug+A+H2O
Phase I reactions
Reaction Oxidativereactions NandOdealkylation Aliphaticandaromatichydroxylation NOxidation Sulphoxideformation Example phenacetin,morphine Phenobarbital,phenytoin Guanethidine,acetaminophen Chlorpromazine 25|U R V I S H M I S T R Y
26|U R V I S H M I S T R Y Deaminationofamine Desulfuration Hydrolysisofestersandamides Reduction a.Azoreduction b.Nitroreductionhloramphenicol

Amphetamine Thiobarbital,parathion Procaine Prontosil Chloramphenicol
Nonmicrosomalreactions MonoAmineOxidase(forbiogenicandotheramines) Esterases(forcholineanddietaryesters) Dehydrogenases(foralcoholsandaldehydes)
Phase II reactions - synthetic reactions

Conjugationofafunctionalgrouptothedrugoritsmetabolitetomakeitwatersoluble ThepresenceofOH,COOH,NH2,SHgroupsfavourformationofconjugates(thesegroupsareaddedto (or)exposedinPhaseI) Glucuronidation Themostimportantreactionmostdrugsincl.endogenoussteroidsandbilepigmentsundergothis reaction. Glucuronideconjugationtakesplaceinmicrosomes. ThesourceofglucuronideisUDPGAthroughglucuronyltransferase. Theproductishighlysolubleandisexcretedbyurine(ifMW<300500)orviabile(if>500) Betaglucuronidaseinintestinemayliberatetheactivedrugwhichisagainreabsorbedandundergoes enterohepaticrecirculationwhichleadstolongerdurationofactionofthedrug Sulfateconjugation(nonmicrosomal) Formsetherealsulfateseg.Phenols,acetaminophen,morphineandendogenousheparin,chondroitinand somesteroids Acetylation(nonmicrosomal) Acetylatesareformedeg.SulphonamidesacetylCoAisthedonor Acetylatesarepoorlysolubleinwaterandlipidandarelikelytocausecrystalluria Methylation(nonmicrosomal) AddsmethylradicalsTheaminoacidsmethionineandcysteinearethedonors eg.Histamine,adrenaline,sexsteroids Glycineconjugation(nonmicrosomal) Notamajorpathway,eg.Salicylates Glutathioneconjugation Notamajorpathwayformsmercapturicacidsimportantforremovaloftoxicradicals(superoxides, epoxidesandtoxicintermediates) Ribonucleoside/Ribonucleotidesynthesis Thesereactionsareimportantfortheactivationofpurineandpyrimidineantimetbolitesusedincancer therapy Drugconjugateswereoncebelievedtorepresentterminalinactivationeventsandassuchhavebeenviewed astruedetoxificationreactions. However,thisconceptmustbemodified,sinceitisnowknownthatcertainconjugationreactionsmaylead totheformationofreactivespeciesresponsibleforthehepatotoxicityofthedrug.

Enzyme induction and inhibition

Enzymeinhibition SomedrugsonrepeatedadministrationhavetheabilitytoinhibitcytochromeP450enzymeactivity. Thesedrugscauseareductioninthemetabolismofotherdrugsthatareadminsteredsubsequently. 26|U R V I S H M I S T R Y
27|U R V I S H M I S T R Y Somedrugsthatactasinhibitorsarechloramphenicol,cimetidine,dicumarol,oralcontraceptives,ethanol andisoniazid.Thisisanimmediateprocessduetodirectinhibitionoftheenzymeorcompetitionamong drugsfortheenzymesite Asaresulttheconcentrationofdrugincreasesleadingtoincreaseddrugeffect Enzymeinductionorstimulation SomedrugsonrepeatedadministrationhavetheabilitytoinducecytochromeP450byenhancingitsrate ofsynthesisorbyreducingitsrateofdegradation. Inductionresultsinanaccelerationofmetabolismandusuallyinadecreaseinthepharmacologicactionof theinducerandalsoofcoadministereddrugs. Increaseinenzymeconcentrationduetoinductionofproteinsynthesis(hencecalledINDUCERS)andtakes longtimetosetinandoncetheinducingdrugisstopped,takeslongtimetoreturntooriginalvalues. Somedrugsthatactasinducersaregriseofulvin,phenobarbital,phenylbutazone,phenytoinandrifampin. Significanceofenzymeinduction/inhibition Inhibitorsprolongtheactivityofcoadministereddrugs Italsoincreasesthetoxiceffectsofunchangeddrugs,ifany Drugmetabolismvariesinsmokersandalcoholics(inhumanpatients) Incaseofcombinedadministration,alterationofdosemayberequired Factorsaffectingbiotransformation Age:Biotransformationispoorinneonatessinceenzymesystemsarenotwelldeveloped.Biotransformation ispoorinoldanimals,too Disease:Diseasesoftheliverhepatitis,cirrhosisetc..andalsodiseasescausinglowbloodflowtoliversuch asCHF,shocketc.willalterbiotransformation Speciesdifferences: o Catsaredeficientinglucuronidation(lowlevelofglucuronyltransferase) o Dogslackacetylation o Pigshavelowcapacityforsulfation o Geneticdifferencesdoexistinhumanracesinmetabolizingmanydrugs(eg..metoprololinman) o Losartananantihypertensiveeffectiveinmanbutlesssoindogssincetheactivemetaboliteis notformedindogs o Rabbitspossessatropinasethereforedonotsufferfromtoxicityduetoatropine(indeadlynight shadepoisoning) Coadministrationofotherdrugsinducerorinhibitor Habitslikealcoholismandsmokingorindustrialpollutants,pesticidesmayaltermetabolismofsomedrugs Firstpassmetabolism Referstotheprocessofmetabolismofadrugbeforeitreachessystemiccirculation. Normallyhappensindrugsadministeredbyoralroute.Besidesoralroute,itcanoccurintopical(skin)and lungs,too(howeveratlowlevels) Effectsoffirstpassmetabolism: o Increasedoraldoseofthedrug o Unpredictableabsorptionoforaldosevariationamongindividualsindrugaction o Oralbioavailabilityincreased,ifthereisliverdisease Enterohepaticrecirculation Somedrugsafterbiotransformationbyglucuronideconjugation,undergobiliaryexcretion.Inthelarge intestinetheyaredetachedfromtheconjugate,leadingtoreleaseoffreedrugwhichisabsorbedagainand entersliver.Thusthedrugrecirculatesleadingtolongerdurationofaction. Eg:Phenalpthaelinusedaspurgative.
Excretion of drugs
Renal elimination of the drugs
Routesofelimination
28|U R V I S H M I S T R Y Drugsareexcretedmainlybythekidneysintotheurineandbytheliverintothebileandsubsequentlyinto thefeces. Alveolareliminationisofmajorsignificancewheninhalantanaestheticsareused.Themainfactorsgoverning eliminationbythisrouteareconcentrationinplasmaandalveolarairandtheblood/gaspartitioncoefficient. Otherlesscommonroutesofeliminationincludemilk,saliva,tearsandsweat.Thesalivaryrouteofexcretion isimportantinruminantsbecausetheysecretesuchvoluminousamountsofalkalinesalivaandmammary excretionisimportantinlactatinganimals. Renaleliminationofdrugs Thebasicfunctionsofthekidneysaretomaintainthevolumeandcompositionofbodyfluids,controlacid basebalance,eliminateendproductsofmetabolismandeliminateforeigncompoundslikedrugs. Thekidneysconstitutelessthan1%ofthetotalbodyweight,butreceiveabout25%ofthecardiacoutput. Afferentarteriolesfromtherenalarterysupplybloodtotheglomerulusatarterialpressureandabout20% ofthisisconvertedtoglomerularultrafiltrate. Furtherabsorptionandreabsorptiontakesplaceatvariouspointsalongthenephron.Thefinalproductis onlyablut1%ofthevolumeoftheoriginalglomerularfiltrate. Inthekidneys,circulatingdrugsareclearedfromthebloodthroughfiltrationandactivesecretion. Reducedrenalbloodflowdecreasesfiltrationofdrugsintheglomerulus,resultingindecreasedelimination. Thisisthereasonforreduceddosageofthedruginolderanimalswithreducedrenalfunctionandinanimals withhypotension. Theporesizeoftheglomerularcapillariesisabout40Ao.Theglomerularultrafiltratewillthereforecontain solubledrugsandothermoleculesincludingsmallproteins.Albuminisnotfilteredandhencedrugsthatare boundtoplasmaproteinsarealsonotfiltered.Theglomerularfiltrationratehasamajoreffectonrenal clearanceofdrugs. Increasedglomerularfiltrationresultsinmorerapidremovalofdrugmoleculesfromthesystemic circulation. Intheproximalconvolutedtubules,thereisactivesecretionofionizeddrugsintothelumen.Thisensures thatdrugs,whichareproteinboundareexcreted.Thetransportsystemsarenonspecificandareoftwo types.Onetransportsystemtransportsorganicacidsandtheothertransportsorganicbases.Secretionof drugmoleculesrequiressignificantenergy.Anythingthatinterfereswithcellularenergyproductionreduces theexcretionofthesedrugsfromthebody.Tubularsecretionbeinganactiveprocess,itcanbesuppressed bycompetingsubstances.Drugsexcretedbyacarriermediatedprocessintheproximaltubuleinclude: Acids PenicillinG Ampicillin Sulfosoxazole Phenylbutazone Furosemide Probenecid paminohippurate Bases Procainamide Dopamine Neostigmine Nmethylnicotinamide Trimethoprim
Glucuronicacidconjugates Etherealsulphates
FromtheproximalconvolutedtubulethedrugmovestotheloopofHenle,wheresomedrugsare reabsorbedfromthefiltrateintocirculation.Thisoccursbypassivediffusion.Drugmoleculesthatare nonionizedarereabsorbedwhilethosethatareionizedareexcreted.Butthedegreeofionizationdepends onthepHofurineandalterationsinurinarypHcanaltertheeliminationofdrugs. 28|U R V I S H M I S T R Y
29|U R V I S H M I S T R Y Highlylipidsolubledrugswillberapidlyreabsorbedfromthekidneytubule.Forthisreasonexcretionoflipid solubledrugsoftenoccurafterconversiontomorepolarmetabolite.Eventhough,manyproteinbound drugsareactivelysecretedintotheproximaltubule,reabsorptionmaybefavouredespeciallywithdrugs thatarelargelyproteinboundinplasma. IncaninetheurinarypHrangefrom5.07.0andinherbivorestheurinarypHmayrangefrom7.08.0. ExcretioncanbeenhancedfordrugsexcretedbythekidneysbyalteringthepHoftheurine.Forpractical purposesthisprinciplecanbeappliedonlytoweakacidicorweakbasicdrugswithpH5.08.0.Quarternary drugsarepolaratallurinepH.Theyareeliminatedrapidlybecausetheycannotbereabsorbed.
Hepatic and other routes of administration

Hepaticeliminationofdrugs Hepaticallyeliminateddrugsusuallymovebypassivediffusionfromthebloodintothehepatocytefrom wheretheyaresecretedintothebileormetabolisedfirstandthensecretedintothebile. Thebilethenconveysthistotheduodenum.Inacuteliverdiseasesandinchronicdegenerativeprocesses likecirrhosis,theliversabilitytometaboliseand/oreliminatedrugsisreduced.Thereforethedoseofthe drugseliminatedbylivermustbereducedinliverdisordersinordertopreventdrugaccumulationintoxic concentrations. Cholereticsorahighfatintakepromotebileflowandtherefore,biliaryexcretionandenhancethehepatic secretionofdrugs.Broadspectrumantibacterialagentsareexpectedtodiminishthehydrolyticactionof intestinalfloraandthus,maypreventeffectiveenterohepaticcycles. Largepolarmolecules(molecularweight>300)areoftenexcretedandarenotreabsorbedintheintestine. Theabilitytoexcretepolarcompoundsinbilewithmolecularweightsbetween300and500isgoodindog, chickenandrat,moderateincatandsheepandpooringuineapig,rabbit,monkeyandman. Compoundsthatundergobiliaryexcretion Unchangeddrugsandendogenous substances Erythromycin Clindamycin Digitoxin Steroidhormones Compoundsexcretedasglucuronide conjugates Chloramphenicol Trimethoprim Sulphadimethoxine Morhine
Excretionofdrugsinmilk Thisrouteofexcretionhasboththerapeuticandpublichealthimportance. Theprinciplesofexcretionthroughthemammaryglandaresimilartothoseactinginthekidneys,namely thediffusionofunionisedlipidsolubleformsofthedrugsdiffusingthroughtheepithelialcellsofthe mammarygland. ThepHofplasmaandmilkareimportantfactors.Sincemilkisusuallymoreacidicthanplasmathebasic compoundsmaybeslightlymoreconcentratedandacidiccompoundsarelessconcentratedinmilkthan plasma. ExcretionofdrugsisalteredincasesofmastitisduetochangesinthepHofmilk.
Pharmacokinetic parameters
Pharmacokinetics Themathematicaldescriptionofdrugconcentrationinthebody Theimportanceofkineticstudy: Forarrivingatthedosageregimen(doseamountanddosinginterval) Forunderstandingtheabsorption,distribution,metabolismandexcretionofdrugs Forcomparisonofdrugroutes Forcomparisonofdifferentformulations(bioequivalence) Asanessentialpartofanydrugdevelopmentstudy 29|U R V I S H M I S T R Y
30|U R V I S H M I S T R Y Fortherapeuticdrugmonitoring
Important pharmacokinetic parameters

Mostimportantparameters t1/2,ClB,Vd,AUC Halflife(t1/2)Plasmahalflifethetimetakenfortheplasmaconcentrationtobereducedtohalfitsoriginalvalue Eliminationhalflife(t1/2)thehalflifecalculatedfromtheeliminationcurve(logdoseinyaxisvstime) t1/2b=0.693/(eliminationrateconstant)(where=slopeofthecurvex2.303) Longerthehalflifelongeristhedurationofaction Atonet1/250%ofdrugiseliminated Attwot1/275%ofdrugiseliminated(50+50%ofremaining50) Atthreet1/287.5%ofdrugiseliminated At4t1/293.75%ofdrugiseliminated AUC=AreaUndertheconcentrationtimeCurve Calculatedbythetrapezoidalrule. Importantincalculatingbioavailabilityandotherparameters VolumeofDistribution(Vd) Itisdefinedastheamountofbodyfluidcontainingthedruganapparentnotanaccuratevaluethedrug tobeequallydistributedinthewholebodyfluid. Vd=dosegiven/conc.ofthedruginplasma Foramoreaccuratedescription, o Vdarea=Dose/xAUCfori.v.(or)DosexF/xAUCfornoni.v. Vdisindicativeofextentofdrugpenetration. MoredistributiongreaterVd HighlyproteinboundandtissuebounddrugshavehigherVd DrugswithhigherVdpreferredfortreatmentinremotesitesskin,bone,muscle,etc. Clearance(Cl) Totalbodyclearance(ClB)Anindexofefficiencyofdrugelimination Definedasthevolumeofbodyfluidclearedofthedrugperunittime Foragivendrugbythegivenroute,ClandVdarecharacteristicandhelpindosedetermination Vd=Cl/
Models in pharmacokinetics
LinearvsNonlineardrugelimination Ifrateofeliminationproportionaltoplasmaconcentration linearorfirstorder(constantfractionofthedrugeliminatedperunittime) occursformostnormalkineticprocesses. Ifrateofeliminationisconstantirrespectiveofconcentration>nonlinearorzeroorderreaction(constant amountofthedrugeliminatedperunittime) Occursintoxicity,saturablemechanismsofelimination, Atveryhighdose,reactionchangesfromfirstordertozeroorder Conc.increasesdisproportionatelywithincreaseindose Compartmentalmodels Amathematicaldescriptionofprocessesbasedonthenumberofphases.Onecompartmentortwo compartmentormulticompartmentaconceptofimaginarydivisionofthebodyintonumberof compartments.Thecompartmentsdonotcorrelatetoanyphysicaloranatomicalcompartments Asinglecompartmentmodelconsistsofonlyoneeliminationphase.Atwocompartmentmodelconsistsofa rapiddistributionphaseandasloweliminationphase Usually,IcompartmentindicatesbloodandhighlyperfusedtissuesandIIcompartmentindicatesperipheral tissues.Inrarecasesathirdcompartmentcorrespondingtoadeepertissuecomponent. Eliminationisonlyfromcentralcompartment Mostdrugsfollowtwocompartmentopenmodelswithfirstorderprocessesofabsorptionandelimination 30|U R V I S H M I S T R Y
Drug accumulation

Infirstorderkinetics,onrepeateddosewithinthecompleteeliminationofthepreviousdose,drug accumulatesinthebody. Plateau(steadystate)achievedwithin45halflives.TheCssistheaverageofmin.andmax.ofthesteady stateortheplateaustate. Forlongtermtherapy,itisaimedtohavethetherapeuticconc.asCss TargetCp=Css Doserate=(targetCpxCl)(mg/kgpertime)/F Insomecasesimmediatehigherdoseistobegiven(otherwisetargetCpwillbereachedonlyafter45half lives) Insuchcases,Loadingdose=(targetCpxVd)/F
Principles of Drug activity Pharmacodynamics

Modes of drug action
Pharmacodynamicswhatthedrugdoestothebody? Principlesofdrugaction Drugsdonotimpartnewfunctionsexceptgenetherapies Basictypesofdrugactionsare: Stimulationenhancementofexistinglevelofaction o Eg.adrenalineonheart,pilocarpineonsalivarygland Depressionselectivediminutionofactivityofspecializedcells o Eg.barbituratesonCNS,Acetylcholineonheart Irritationanonselective,oftennoxiousstimuli.Mildirritationonsomecells(skin,connectivetissue) stimulatesomefunctionsforabeneficialeffect. o Eg.Bitters,topicalcounterirritantsbutsevereirritationinflammation,necrosis,damage Replacementofnaturalsubstanceseg..hormonaltherapy,deficiencies Cytotoxicityeg.Antibacterials,antivirals,anticanceragents Mechanismsofdrugaction Physicalactionphysicalpropertyofthedrugcausesthemainaction Eg.massofthedrugbulklaxatives Adsorptioncharcoal Osmosismannitol Radioactivity131Iforhyperthyroidism Radioopacityascontrastmedia(barum) Chemicalactionchemicalpropertyofthedrugresponsibleforaction AntacidsAlOH2 acidifiers,NH4Cl alkalinizers,NaHCO3 oxidizersKmnO4,H2O2 chelatingagentsCaNaEDTA,BAL,Pencillamine
Enzyme mediated drug action

EnzymesareubiquitousbiologicalcatalystsmaintargetsofdrugactionsDrugseitherincreaseordecrease enzymemediatedreactionsStimulationisdonebyendogenoussub.(cofactors)vitaminsandminerals Rateofreactionincreases Enzymeinductionmicrosomalinductionbydrugsincreasedsynthesisofproteins Enzymeinhibitionamostcommonmodeofdrugaction Nonspecificmetalsalts,acids,alkalisinhibitnonspecifically Specificparticularenzymeaffectedeithercompetitiveornoncompetitive Competitivecompetitionwithnormalsubstrate Equilibratingtype 31|U R V I S H M I S T R Y
32|U R V I S H M I S T R Y Increasingtheconcentrationofnormalsubstratereversesdrugaction Eg.sulfonamidesandPABAforfolatesynthetaseneostigmineandAchforcholinesterase Nonequilibratingtype Reactwiththesamesiteasthatofsubstratebutformstrongcovalentbondsorhaveveryhighaffinitythan thenormalsubstrateeg..organophosphatesformcovalentbondwithcholineesterasemethotrexate 50,000timesmoreaffinityfortheenzymeDHFRthanDHFAcid Noncompetitivereactswithsomeothersiteandnotonthecatalyticsitebutalterstheenzymelossof catalyticpropertyeg..aspirinCyclooxygenasedisulfiramaldehydedehydrogenasedigoxinNa+K+ATPase
Receptor mediated drug action

Mostimportanttypeofdrugaction Receptorisabindingsitewithinbiologicaltissuesforeitherendogenousorexogenous(!!!)substances Macromoleculessituatedonthesurfaceofthecellorinsidethecell Regulatecriticalfunctionslikeenzymeactivity,permeability,structuralfeatures,etc Evidence Manydrugsshowstructuralspecificityminorsubstitutionalterstheeffect. Stereospecificityofdrugsdpropranolollessactivethanlisomer,lnoradrenalinemorepotentthand noradrenaline antagonismbetweensubstancesofcloselyrelatedstructuressomechemicalidentityLangley(1878) proposedthetermreceptivesubstance ThisideadevelopedbyClark(1920)propoundedtheReceptoroccupationtheoryD+RDRE(effect) Thepostulatesofthetheoryare: o Intensityofresponsefractionofreceptorsoccupied;maximalresponsewhenallreceptorsare occupiedallornoneactionofdrugoneachreceptoreachreceptoriseitherfullyactivatedornot atalldrugandreceptorhavestructurallylockandkeyarrangement
Terms related to drug receptor binding

Agonists Agonistsareagentsthatmimictheeffectsoftheendogenousregulatorycompound. Agonistsmaybedefinedasdrugsthatpossessaffinityforaparticularkindofareceptorandhastheability tocauseachangeinthereceptorthatgivesrisetoanobservableeffect.Theirvalueinclinicalpracticeoften restsontheirgreatercapacitytoresistdegenerationandthusactsforalongerdurationthanthenatural substancestheymimic.Forthisreason,bronchodilatationproducedbysalbutamollastslongerthanthat inducedbyadrenaline. Thepropertiesexhibitedbyagonistsincludeaffinity,intrinsicactivity,maximalefficacy,potency,selectivity andspecificity. Affinityofaligand(drugorendogenoussubstance)isameasureofitscapacitytobindtothereceptor. Affinitymayvarygreatlyamongagonistsaswellasantagonists.Intrinsicactivityisameasureoftheabilityof theagonistreceptorcomplextoinitiatetheobservedbiologicalresponse.Afullagonisthasanintrinsic activityof1. Maximalefficacyreflectstheupperlimitofthedoseresponserelationshipwithouttoxiceffectsbeing evident.Agonistsdifferfromeachotherinthisregard. Potencyreferstotherangeofconcentrationsoverwhichanagonistproducesincreasingresponses.Highly potentdrugsproducetheireffectsatlowerconcentrations;thismayimpartanadvantagetotheirclinical use,providedtheincreaseinpotencyisnotaccompaniedbyanincreaseintoxicity. Agonistsintheiroccupationofreceptorsexhibitselectivityandspecificity.Fewagonistsaresospecificthat theyinteractonlywithasinglesubtypeofreceptor.However,severalagonistsdoshowevidencesof selectivityforcertainsubpopulationofreceptors. Fullagonists Fullagonistsareagoniststhatproduceamaximalresponsebyoccupyingallorafractionofreceptors. Partialagonists
33|U R V I S H M I S T R Y Partialagonistsaredrugsthatactbothasagonistsandantagonists.Thesedrugsinadditiontoblocking accessofthenaturalagonisttothereceptorarecapableofalowdegreeofactivation.Theseagentsproduce lessthanamaximalresponseevenwhentheyoccupyallofthereceptors. InverseagonistsSomesubstancesproduceeffectsthatarespecificallyoppositetothoseofagonistsandare calledasinverseagonists. Antagonists Theseareagentsthatarethemselvesdevoidofanyintrinsicactivitybutcausetheeffectsbyinhibitionofthe actionofanagonist.Drugsthathavenoactivatingeffectwhatsoeveronthereceptoraretermedaspure antagonists. Theyaresufficientlysimilartothenaturalagonisttoberecognizedbythereceptorandtooccupywithout activatingit,therebypreventingthenaturalagonistfromexertingitseffect. Downregulation Whentissuesarecontinuouslyexposedtoanagonist,thenumberofreceptorsdecreasesandthismaylead toareductioninthenumberofreceptors.Thismaybeareasonfortachyphylaxis. Upregulation Prolongedcontactwithanantagonistleadstoformationofnewreceptorsandthisphenomenonisknownas upregulation. Sparereceptors Thistermreferstotheproductionofamaximaltissueresponsewhenonlyafractionofthetotalnumberof receptorsisoccupied. EC50:TheconcentrationofanagonistthatproduceshalfmaximaleffectisknownasEC50. IC50:TheconcentrationofanantagonistthatproduceshalfmaximalinhibitionisknownasIC50.
Receptors - structure and function

Receptor theories
Occupationtheories A.J.Clarkpropoundedtheoccupationtheorywhichassumesthattheextenttowhichatissueisdependent ontheproportionofitsreceptorpopulationthathasbeenoccupiedbyadrugandmaximalresponseis reachedwhenallthereceptorsareoccupied.Hepresumedthateachoccupiedreceptordeliveredaconstant unitofresponseandthatthisindividualoccupancystimuliwassummatedinmathematicalfashiontogivea linearlyproportionalresponse.Butthistheorywasnotapplicableinallsituations.Inthecaseofpartial agonistsamaximalresponsecouldnotbeexhibitedeventhoughallthereceptorswereoccupied. E.J.Ariens,dividedthebiologicalresponseintotwoseparateparametersnamelyaffinityandintrinsic activity.Affinitydescribedthebindingofthedrugtothereceptorandwasassumedtobegovernedbymass action.Intrinsicactivitywasrelatedtotheabilityofthedrugtoinduceaneffectafterbinding.The assumptionsarethesameasthoseforClarkestheory.However,thenotionofpartialagonismcanbe accountedforbyassumingalowerintrinsicactivityforapartialagonistthanforafullagonist.Again,a discrepancybetweenEC50andKDvaluesandtheobservationsofsparereceptorscouldnotbeexplained. R.P.Stephenson,assumedthatthedrugreceptorcomplexprovidesastimulustothetissuesandthatthe stimulusisdirectlyproportionaltothefractionofreceptorsoccupied.Theresponseisthenrelatedtothe stimulusbyanunspecifiedfunction.Theproportionalityfactorbetweenthefractionaloccupancyofthe receptorpopulationwasdefinedastheefficacy.Theefficacyofadrugreferstotheactionofthedrugto producearesponseinagiventissue.Anadditionalparameter,intrinsicactivitywasdefinedtodescribethe stimulantactivityofthedrugitselfindependentofthetissue.TheproblemwithStephensonsmodelisthat theexactlinkbetweeneffectandoccupancyremainsunclear. Ratetheory RatetheorywasdevelopedbyW.D.M.Patonandpostulatesthatthebiologicalresponseisproportionalto therateatwhichthedrugcombineswiththereceptorthatis,eachassociationofthedrugwithreceptor resultsinaquantumofexcitation.Thisimpliesthatanagonistmustdissociaterapidlyfromthereceptorto enableothersuccessfulassociationsandsubsequentgenerationofquantumofexcitation.
34|U R V I S H M I S T R Y Ontheotherhand,anantagonistisassumedtodissociateslowlytopreventthegenerationofotherquanta ofexcitation.Thus,dissociationrateconstantwasconsideredtobethefactor,whichdeterminedwhethera ligandwasanagonist,antagonistorpartialagonist.Theexperimentalanalysisofdrugdissociationratesdid notsupportthismodel. Allosterictheories Twoallostericmodelsoriginallydevelopedtodescribeenzymeregulationhavebeenproposed. Theideaoftheallosterictheoryisthatreceptorscanexistinavarietyofdiscreteconformationalstates differingintheirabilityofthatstatetoproducearesponse. Ligandstheninteractwiththereceptorinsuchawaysoastocontroltheconformationalstate.These modelsdefinepreciselytherelationshipbetweenbindingandeffect. Receptorssubservetwoessentialfunctionviz.,recognitionofthespecificligandmoleculeandtransduction ofsignalwitharesponse.Accordingly,thereceptorhasaligandbindingdomain(spatiallyandenergetically suitableforbindingthespecificligand)andeffectordomain,whichundergoesafunctionalconformational change.
Functions of receptors
Thefunctionsofreceptorsare Topropagateregulatorysignalsfromoutsidetowithintheeffectorcellwhenthemolecularspeciescarrying thesignalcannotitselfpenetratethecellmembrane Toamplifythesignal Tointegratevariousextracellularandintracellularregulatorysignals Toadapttoshorttermandlongtermchangeswithregulatorymilieuandmaintainhomeostasis.
Types of receptors
TypeIChannellinkedreceptors(ligandgatedionchannelsorinotropicreceptor)Thesearealsoknownas ionotropicreceptors.Thesearemembranereceptorsthatarecoupleddirectlytoionchannelsandarethe receptorsonwhichfastneurotransmittersact.Examplesincludenicotinicacetylcholinereceptorsand glutamatereceptors. TypeIIGProteincoupledreceptors(metabotropicreceptors)Thesearealsoknownasmetabotropic receptorsor7transmembranespanningreceptors.Theyaremembranereceptorsthatarecoupledto intracellulareffectorsystemsviaaGprotein.Thisclassincludesreceptorsformanyhormonesandslow transmitters.Examplesincludemuscarinicacetylcholinereceptorsandadrenergicreceptors. TypeIIIKinaselinkedreceptorsThesearemembranereceptorsthatincorporateanintracellularprotein kinasedomainwithintheirstructure.Theyincludereceptorsforinsulin,variouscytokinesandgrowth factors.Closelyrelatedarereceptorslinkedtoguanylatecyclasesuchastheatrialnatriureticfactorreceptor. TypeIVReceptorsthatregulategenetranscription(nuclearrecptors)Thesearealsoknownasnuclear receptors,thoughsomeareactuallylocatedinthecytosolratherthanthenuclearcompartment.They includereceptorsforsteroidhormonesandthyroidhormone.
Second messenger systems
Manyhormones,neurotransmitters,autacoidsanddrugsactonspecificmembranereceptors,the immediateconsequenceofwhichisactivationofacytoplasmiccomponentofthereceptor,whichmaybean enzymesuchasadenylatecyclase,guanylcyclaseoractivationofatransportsystemoropeningofanion channel. Thesecytoplasmiccomponentswhichcarryforwardthestimulusfromthereceptorsareknownassecond messengers.Thereceptoritselfisthefirstmessenger. ExamplesofsecondmessengersarecAMP,cGMP,Ca2+,GProteins,IP3,DAGetc. cAMPservesassecondmessengerforadenosine,opioid,VIP,2andadrenoceptorsandH2receptors. cGMPservesassecondmessengerforangiotensinreceptor. IP3andDAGserveassecondmessengersfor1adrenoceptors,H1receptorsandcholecystokinin. cAMPhasvariedregulatoryeffectsoncellularfunctions,forexample,energymetabolism,celldivisionand celldifferentiation,iontransport,ionchannelfuntion,smoothmusclecontractilityetc. 34|U R V I S H M I S T R Y
35|U R V I S H M I S T R Y cGMPhasbenidentifiedincardiaccells,bronchialsmoothmusclecellsandothertissues.Formosteffects producedcAMPseemstobestimulatorywhilecGMPseemstobeinhibitoryinnature.WhenthecAMPand cGMPsystemsarebothepresentinasinglecellortissue,theyarelinkedtoreceptorsthroughwhichdrugs produceoppositeeffects. IP3andDAGaredegradationproductsofmembranephospholipidbytheenzymephospholipaseC.
Dose response curve

Plotting

Asthenameindicatesthisreferstotheplottingofthedosevsresponse,withthedoseinXaxisand responseinsomemeasurableunitsintheYaxis. Thefeaturesofthecurvesoobtainedwillprovideusefulinformationabouttheactionofthedrugorin comparisonamongdrugs.
Features of dose response curve

Plottingofdoseresponsecurve EffectYaxisandDoseXaxishyperbola EffectYaxisandLogDoseXaxissigmoidcurve Bytakinglogdosealinearrelationshipin3070%rangegivesapossibilityofpredictionofresponsein thisrange Responseisproportionaltoanexponentialfunctionofthedose Logdoseresponsecurvesareusedto o displaywiderangeofdoseeffect o compareagonistsandantagonists Potencyamountofdrugrequiredtoelicitaresponse Relativepotencymoremeaningfulthanabsolutepotency o Eg.DrugA(potency10mg)morepotentthandrugB(100mg) A10timesmorepotentthanBrightwardshiftofDRcurveiflesspotent Potencyneednotmeanclinicalsuperiority EfficacythemaximaleffectproducedbyadrugandreferstothepeakobtainedintheDRcurve. Eg.Morphineproducesveryhighanalgesiathatcannotbeobtainedwithanydoseofaspirin Morphinehighlyefficaciousthanaspirin
Quantal dose response curve

QuantalDRcurveduetobiologicalvariation(diff.amongindividualsinresponsetosametreatment)the responsetodrugdoseinapopulationoccursasafrequencydistribution. Acumulativefreq.Distribution(as%ofindividualsshowingeffectplottedagainstlogdose>yieldsthe quantalDRcurve Thedosethatproducesdesiredeffectin50%ED50 Thedosethatproducesdeathin50%LD50 Therapeuticindex=LD50/ED50
Factors modifying drug action

Factors affecting drug action
Factorsmodifyingdrugaction: Bodysize:influenzestheconc.achievedatthesiteofaction.Dosesarenormallygivenforadultsofmedium build.Inextremecasesdosetobeactuallycalculatedbasedonperkgdose. o Bodysurfaceareaisalsoanimportantparameterusedincalculationofdoseforanticancerdrugs o (BSAinsq.m.=KxBWinGrams2/3x104(K=10fordogs,10.1cats) Age:drugbehaviordiffersininfantsandchildren.lowGFR, 35|U R V I S H M I S T R Y
36|U R V I S H M I S T R Y o BloodBrainBarriermorepermeable,absorptionisalteredpoormetabolizingcapacityupto4weeks ofage o Intheold,poormetabolizingcapacity,lowPPbinding,slowerAbsorptiondosealterationneeded inbothcases Sex:Femalessmallerinsizeandmayneedlowerdose. o Pregnancyinducedchangesdelayedabsorption,plasmaalbuminfalls,acidglycoproteinincreases, renalbloodflowincreases,inductionofCYP450enzymesalltheseaffectthekineticsofdrug o Besidespossibilityofdrugaffectingfetusortheyoungonesthromilk Specieschangesinsp.inthepatternofmetabolismrabbitsresist o Atropine,dogsarepooracetylators,catsdeficientinglucuronidation RaceBlacksneedhigheratropinetodilatepupilMongolsneedlowerdose o FewerreportsofaplasticanemiaafterchloramphenicoluseinAsianscomparedtotheWest Dietandplaneofnutritiondrugactionpredictableingoodplaneofnutrition GeneticsG6PDdeficiencyhemolysiswithantimalarialagentsMalignanthyperthermiaafterhalothanein somehumanindividualsandpigs Routeofadministration:Besideskinetics,insomecasesroutemayalteractioneg.MgSO4orally purgation,skindecreaseswelling,i/vCNSandcardiacdepressionIodineantisepticandantigoitre EnvironmentInsecticides,tobaccosmoke,charcoalbroiledmeatinducemetabolism. o Hypnoticstakenatnightatbedworkwell. Psychologicalbeliefs,attitudes,expectationsmoreinhumans o Placebo(LatinIshallplease)usedintrialsandtotreatotherwisenormalpatients(hypochondriacs) o Placebosinduceendorphinsinbrainanalgesia Diseasestates DiseasesofGItractorallygivendrugsalteredabsorption LiverdiseasesBioavailabilityofdrugswithFirstpassmetabolism IncreasedRenaldiseaseaffectsexcretionofdrugs Inalltheabovechangeofdoseneeded. ImmunocompetenceNormallyinveryyoungandveryoldpatientsimmunityiscompromised.So, bacteriostatictobereplacedbybactericidals Druginteractionsphysicalorchemicalinactivationorincompatibility Fooddruginteractionsavailabilityoffooddelaysabsorption. Ingredientsoffoodmaycausespecificinteractions PharmacologicalInteractionsmaybebeneficialepinephrine+localanaestheticspreanaesthetics, antibacterialcombinations penicillin+probenecid,ampicillin+sulbactamharmfulinteractionsaminoglycosideswithNeuromuscular blockingagents Enzymeinhibitorsandinducers ToleranceandTachyphylaxisToleranceistherequirementofhigherdosetoproducegivenresponse Naturalindividuallesssensitivetodrug(rabbits) Acquiredbyrepeateduseofthedruginanindividualwhowasinitiallyrespondingmaybeduetofaster eliminationofthedrugonlonguseorchangesinreceptorsensitivity(downregulation) Crosstolerancetoleranceamongcloselyrelateddrugs(morphineandpethidine) Tachyphylaxisrapiddevelopmentoftoleranceafteronlyafewdoses Seeninephedrine,tyraminewhichdepletestoresofcatecholamines
Adverse effects of drugs

Adverseeffectsofdrugs Anyundesirableorunintendedconsequenceofdrugadministrationmaybetrivial,seriousorfatal Alldrugsarecapableofproducingsideeffects Definition:Anynoxiouschangewhichissuspectedtobeduetoadrugatnormaldoses,requirestreatment ordecreaseindoseorcautioninfutureuseofthedrug. Notuncommonseenin1025%ofthecases.Stilldrugsareusedconsideringthebenefitvsrisk 36|U R V I S H M I S T R Y
37|U R V I S H M I S T R Y Predictable(typeI)basedonthepharmacologicalpropertiesofthedrug.Sideeffects,toxiceffectsanddrug withdrawalsymptoms Unpredictable(typeII)basedonpeculiaritiesofthepatientandnotonknowndrugeffect. Severity Minornotherapyneeded Moderatemayneedchangeindrug/oritsdosageorprolonghospitalstay Severepotentiallylifethreatening,causespermanentchangeorrequiresintensivemedicaltreatment Lethalcontributestothedeath Preventionofadverseeffectsofdrugs FollowingstepstominimizeADE o Avoidinappropriateuses o Usecorrectdoseandrouteofthedrug o Considerprevioushistoryofreactions,ifany o Findoutifanyotherallergicdiseaseexisted,andtakecaution o Ruleoutharmfulinteractionsamongdrugsprescribed o Adoptcorrectdrugadministrationtechnique o Carryoutcorrectlab.procedurestoruleoutreactions
Types of adverse effects

Sideeffectexpectedeffectandunavoidableeg..drynessofmouthinatropinetreatment Secondaryeffectindirectconsequencesofaprimaryeffecteg..weakeningofhostimmunityby corticosteroidsflareupofTB Toxiceffectduetooverdosage.eg..Paracetamolinducedliverdamage,comabybarbiturates,auditory disturbanceinstreptomycin Intoleranceappearanceoftoxiceffectsattherapeuticdosesinsomeindividuals..eg..onlyfewdosesof carbamazepineataxiainsomepatients Idiosyncracygeneticallydeterminedabnormalreactivitytoachemicalandalsosomeuncharacteristic reactionstodrugsegg.Barbiturateinducedexcitementandconfusioninsomepatients. Drugallergyimmunologicallymediatedreactionnotrelatedtotheactionofthedrug (hypersensitivitybutnotsuprsensitivity)needsaprimingdoseandtheseconddoseproducesviolent reactions.drugactsasantigen(hapten)andcapableofstimulatingthebodytoproduceAntibodiesagainst it. TypeIanaphylactic(Immediatehypersensitivity)itching,urticaria,asthmaetc.. TypeIIcytolyticcausesdecreaseofbloodcellsandorgandamage TypeIIIArthusreactiononvascularendotheliumserumsickness,fever,arthralgiaetc.. TypeIV(delayedhypersensitivity)takesmorethan12htodevelopeg..contactdermatitis,rashes,fever etc.. Treatmentstoppingtheoffendingdrug,administrationofantihistamines,glucocorticoids,adranalineetc.. Examplesofdrugscausinghypersensitivity:Penicillin,sulfonamide,tetracycline,salicylates,quinolones,Anti TBdrugs,etc PhotosensitivitycutaneousreactionduetodruginducedsensitizationoftheskintoUVlightorradiation. Eg..phenothiazine(phototoxic),sulfonamide,griseofulvin(photoallergic) Dependencepsychologicalpatientfeelsthathewillbealrightonlyifhetakesthedrug Withdrawalreactionsfornonaddictivedrugs..eg..seizuresonwithdrawalofanantiepilepticdrug. Teratogenicityabilitytocausefetalabnormalitieseg..thalidomide,anticancerdrugs,tetracyclines. Mutagenicityandcarcinogenicity.eg..anticancerdrugs,estrogen,radioactivity,tobaccoetc.. Druginduceddiseases(iatrogenicphysicianinduced)eg..ulcerbyNSAIDs..
Drug interactions
Aveterinarianisoftenposedwiththenecessityoftreatingapatientwithmorethanonedrug simultaneously.Itishighlyprobablethatonedrugmightaffecttheactionoftheother,theresultofwhich maybebeneficialorharmfultothepatient.Aclinicianshouldpossessadequateknowledgeaboutsuch interactionstoavoidanyadverseeffects. 37|U R V I S H M I S T R Y
38|U R V I S H M I S T R Y Drugsexhibitsynergismorantagonism Synergism:Itisthecooperationbetweentwodrugswherethepresenceofonedrugfacilitatesorincreases theactionoftheother.Itcanbeoftwotypes: o Synergismadditive(1+1=2)theneteffectisonlythesumoftheindividualeffects.eg.Aspirin+ paracetamol(analgesic+antipyretic),ephedrine+theophylline(bronchodilator) o Supraadditiveorpotentiation(1+1=3)neteffectismorethanthesumoftheindividualeffects o Sulfonamide+trimethoprim(bacteriostaticbecomesbactericidal),Ach+physostigmine (inhibitionofbreakdown) Antagonism:Referstoadecreaseorreversalofthepharmacologicresponseofonedrugbyanotherdrug. Thedrugwhichantagonizestheactionofonedrugiscalledanantagonist.Antagonismisofthefollowing types: o Antagonism(1+1=0or<1) o Canbe physicalbasedonphysicalpropertyadsorptionofalkaloidsbycharcoal chemicalbasedonchemicalpropertyantacidslikeNaHCO,chelatingagentsBAL,EDTA forheavymetals Physiologicalorfunctional o histamineandadrenalineonbronchialmuscle o Insulinandglucagonsonbloodsugar Receptorantagonismantagonistbindswiththereceptorandinhibitsgenerationofresponsemaybe competitiveornoncompetitive CompetitiveandNoncompetitive Competitiveantagonism:Theantagonistischemicallysimilartotheagonistandcompeteforthesame bindingsite.Theantagonistblockstheeffectoftheagonistandtheantagonisticeffectcanbeovercomeby increasingtheconcentrationoftheagonist.Itisalsocalledsurmountableantagonism.Eg:acetylcholineand itsantagonistatropine. Noncompetitiveantagonist:Theantagonistisnotchemicallyrelatedtotheagonistbutmodifiesthebinding oftheagonisttothereceptorbybindingtoanothersite.Theantagonisticeffectcannotbeovercomeby increasingtheconcentrationoftheagonist.Itisalsocalledunsurmountableantagonism.Eg:Acetylchloline anddecamethonium. Pharmacokineticantagonism:whereonedrugalterstheactionoftheotherdrugbypreventingorreducing anyoneofthepharmacokineticprocessessuchasabsorption,distribution,biotransformationandexcretion. Eg:Antacidspreventtheabsorptionofotherdrugs(absorption) Aspirindisplaceswarfarinfromitsplasmaproteinbindingsite(distribution) Microsomalinducersandinhibitorsmodulatethemetabolismofotherdrugs(biotransformation) Probenecidantagonizespenicillinexcretionbycompetingforthebindingsite(excretion)
Drug screening and drug discovery

Drug discovery
Mostnewdrugsordrugproductsarediscoveredordevelopedthroughoneofthefollowingmethods: 1. Identificationorelucidationofanewdrugtarget. 2. Rationaldrugdesignbasedonanunderstandingofbiologicalmechanisms,drugreceptorstructure,enzymes sitesetc. 3. Chemicalmodificationofanexistingmolecule. 4. Screeningforbiologicactivityofnaturalproducts,previouslydiscoveredchemicalentities,andlibrariesof peptides,nucleicacids,andotherorganicmolecules. 5. Theexplosivegrowthinbiotechnologyandcloninghaspavedthewaytoidentifygenestoproducepeptides andproteins.Effortscontinuetofocusonthediscoveryofnewtargetsandapproaches,basedonstudies withgenomics,proteomics,nucleicacidsandmolecularpharmacologyfordrugtherapy. 6. Combinationsofknowndrugstoobtainadditiveorsynergisticeffectsorarepositioningofaknowndrugfor anewtherapeuticuse. 38|U R V I S H M I S T R Y
Drug screening
Drugscreeningreferstoasequenceofexperimentsandcharacterizationusingavarietyofbiologicassaysat themolecular,cellular,organsystem,andwholeanimallevelstodefinetheactivityandselectivityofthe drug.Forexample,antiinfectivedrugsmaybetestedagainstavarietyofinfectiousorganismssome ofwhichareresistanttostandardagents. Themoleculewillalsobestudiedforabroadarrayofotheractionstoestablishthemechanismofactionand selectivityofthedrug.Thiswillrevealanysuspectedandunsuspectedtoxiceffects. Occasionally,anunexpectedtherapeuticactionisdiscoveredbychance..Itbecomesveryimportantto developsuitablepreclinicalinvitroandinvivomodelstopredictdrugaction. Duringdrugscreening,studiesareperformedtodefinethepharmacologicprofileofthedrugatthe molecular,cellular,system,organ,andorganismlevels. Atthemolecularlevelthedrugwouldbetestedforreceptorbindingactivitytotargetrecptors,metabolizing enzymesetc. Atthecellularlevel,thedrugwouldbestudiedtodeterminewhetheritstimulatesorinhibitsthecellular function. Attheorganlevelthepharmacologicactivityandselectivityfortheorganstudiedwouldbestudied.Isolated organstudiesesp.smoothmusclesandotherinvitropreparationscanbeused. Wholeanimalstudiesaregenerallynecessarytodeterminetheeffectofthedrugonorgansystemsand diseasemodels.Cardiovascularandrenalfunctionstudiesofallnewdrugsaregenerallyfirstperformedin normalanimals. Whereappropriate,studiesondiseasemodelswouldbeperformed.Evidencewouldbecollectedon durationofactionandefficacyfollowingoralandparenteraladministration. Iftheagentpossessedusefulactivity,itwouldbefurtherstudiedforpossibleadverseeffectsonothermajor organsystems,includingtherespiratory,gastrointestinal,endocrine,andcentralnervoussystems. Thesestudiesmightsuggesttheneedforfurtherchemicalmodificationtoachievemoredesirable pharmacokineticorpharmacodynamicproperties.Forexample,oraladministrationstudiesmightshowthat thedrugwaspoorlyabsorbedorrapidlymetabolizedintheliver;modificationtoimprovebioavailability mightbeindicated. Ifthedrugwastobeadministeredlongterm,anassessmentoftolerancedevelopmentwouldbemade.For drugsrelatedtoorhavingmechanismsofactionsimilartothoseknowntocausephysicaldependence, abusepotentialwouldalsobestudied.Foreachmajoractionfound,apharmacologicmechanismwouldbe sought. Theoutcomeofthisscreeningprocedureiscalledaleadcompound,i.e.,aleadingcandidateforasuccessful newdrug.
Preclinical safety and toxicity testing

Alldrugsaretoxicatsomedose.Tocorrectlydefinethetoxicitiesofdrugsandthetherapeuticindex comparingbenefitsandrisksofanewdrugisanessentialpartofthedrugdevelopment. Mostdrugcandidatesfailtoreachthemarket,duetothelimitationsoftoxicity. Leaddrugsthatsurvivetheinitialscreeningandprofilingproceduresmustbecarefullyevaluatedfor potentialrisksbeforeandduringclinicaltesting. Althoughnochemicalcanbecertifiedascompletely"safe"(freeofrisk),theobjectiveistoestimatetherisk associatedwithexposuretothedrugcandidateandtoconsiderthisinthecontextoftherapeuticneedsand durationoflikelydruguse. Toxicitytestingistimeconsumingandexpensive.Twotosixyearsmayberequiredtocollectandanalyze dataontoxicityandestimatesoftherapeuticindexbeforethedrugcanbeconsideredreadyfortestingin humans. Largenumbersofanimalsmaybeneededtoobtainvalidpreclinicaldata.Owingtothesituationarisingout ofconcernsofanimalusage,animaltestinghasbecomeapublicissueandsomesegmentsofthepublic attempttohaltallanimaltestingintheunfoundedbeliefthatithasbecomeunnecessary. Extrapolationsoftherapeuticindexandtoxicitydatafromanimalstohumansarereasonablypredictivefor manybutnotforalltoxicities. 39|U R V I S H M I S T R Y
Clinical trials
Ineachofthethreeformalphasesofclinicaltrials,volunteersorpatientsmustbeinformedofthe investigationalstatusofthedrugaswellasthepossiblerisksandmustbeallowedtodeclineortoconsentto participateandreceivethedrug. Inphase1,theeffectsofthedrugasafunctionofdosageareestablishedinasmallnumber(2550)of healthyvolunteers.Ifthedrugisexpectedtohavesignificanttoxicity,asisoftenthecaseincancerandAIDS therapy,volunteerpatientswiththediseaseareusedinphase1ratherthannormalvolunteers. o Phase1trialsaredonetodeterminewhetherhumansandanimalsshowsignificantlydifferent responsestothedrugandtoestablishtheprobablelimitsofthesafeclinicaldosagerange. o Thesetrialsarenonblindor"open";thatis,boththeinvestigatorsandthesubjectsknowwhatis beinggiven.Manypredictabletoxicitiesaredetectedinthisphase. o Pharmacokineticmeasurementsofabsorption,halflife,andmetabolismareoftendoneinphase1. o Phase1studiesareusuallyperformedinresearchcentersbyspeciallytrainedclinical pharmacologists. Inphase2,thedrugisstudiedinpatientswiththetargetdiseasetodetermineitsefficacy. o Amodestnumberofpatients(100200)arestudiedindetail.Asingleblinddesignisoftenused,with aninertplacebomedicationandanestablishedactivedrug(positivecontrol)inadditiontothe investigationalagent. o Phase2trialsareusuallydoneinspecialclinicalcenters(eg,universityhospitals). o Abroaderrangeoftoxicitiesmaybedetectedinthisphase. Inphase3,thedrugisevaluatedinmuchlargernumbersofpatientswiththetargetdiseasesometimes thousandstofurtherestablishsafetyandefficacy. o Usinginformationgatheredinphases1and2,phase3trialsaredesignedtominimizeerrorscaused byplaceboeffects,variablecourseofthedisease,etc.Therefore,doubleblindandcrossover techniquesarefrequentlyused. o Phase3trialsareusuallyperformedinsettingssimilartothoseanticipatedfortheultimateuseof thedrug.Theinvestigatorsareusuallyspecialistsinthediseasebeingtreated. o Certaintoxiceffects,especiallythosecausedbyimmunologicprocesses,maybecomeapparentonly inphaseIII. Phase4beginsonceapprovaltomarketadrughasbeenobtained. o Thisconstitutesmonitoringthesafetyofthenewdrugunderactualconditionsofuseinlarge numbersofpatients. o Thecarefulandcompletereportingoftoxicitybyphysiciansaftermarketingcanrevealsomeside effectsmayafterchronicdosing. o Severalhundredthousandpatientsmayhavetobeexposedbeforethefirstcaseisobservedofa toxicitythatoccurswithanaverageincidenceof1in10,000. o Phase4hasnofixedduration
Bio prospecting

Referstothesearchforusefulapplications,processorproductwithcommercialvalueinthebiosphere. Itisthemanipulationofnaturesbountytofindnewersubstanceswitheconomicimportance. Manyofthedrugsinvoguetodayhavecomefromtraditionalknowledgeontheuseoftheplantsinvarious biodiversityregions. Afterthediscoveryofpenicillin,asystematicsearchofsoilbacteriaandmicrobeshaveledtothediscovery oflargegroupsofantibiotics,whichareverysuccessfullyemployedinthetreatmentofmanybacterial infectionsinmanandanimals. Scientistsareonaconstantsearchintothedeepestandfarthestcornersoftheearthforanewproductto beusedasadrugformanydiseases. Bioprospectinghasitsownissuesandconcerns.Oftenitleadstomanynewdrugdiscoveriesandtreatment ofdiseasesbuttheindigenouspeoplewhowereinstrumentalarelefttolanguishwithnosupportandcredit. Successfulbioprospectingrequiresthedevelopmentofasustainablemodelinwhichabenefitsharing systemisevolvedamongindustries,ecosystemandtheprojectedcommunities. Cureformanyadreadeddiseasesmustbehiddenintheremotestforests,deepoceansandhighest mountainsandbioprospectingisaninstrumenttouncoversuchnewknowledge. Whenperformedinalargescaleoperation,theeffortisreferredtoasmassbioprospecting. Experiencesfromthemassbioprospectingeffortsdemonstratethatmassbioprospectingisacomplex process,involvingexpertisefromdiverseareasofhumanendeavors,whatisimportantistherecognitionof issuesongeneticaccess,priorinformedconsent,intellectualpropertyandthesharingofbenefitsthatmay ariseasaresultoftheeffort. 41|U R V I S H M I S T R Y
42|U R V I S H M I S T R Y Futuremassbioprospectingendeavorsmusttakeheedofthelessonslearnedfrompastandpresent experiencesintheplanningforasuccessfulmassbioprospectingventure.
Assay of drugs
Assayofdrugsreferstothequantitativeestimationofadrug/itsactivecomponentinaformulation. Itiscarriedoutforthefollowingpurposes: o Totestthepurityofadrugpreparation. o Tocomparethepotencyofadrugwiththatofastandard. o Toassesstheefficiencyofpreparationwhilepurifyingthedrugfromamixture/naturalproduct. Assaysareofdifferenttypes Chemicalassay o Inthistheconcentrationofdrugisdeterminedbychemicalmethodssuahasspectrophotometry, fluorometry,HPLCormassspectroscopy.Thesemethodsuseoneofthephysiochemicalproperties ofthecompoundssuchasabsorbance,fluorescence,polarity,chargetomassratioetc.Theseare themostcommonlyusedmethods. Bioassay o Inthistheconcentrationofbiologicallyactivecomponentinaunitquantityofthetestdrugis comparedtotheresponseproducedbythestandardorreferencedrug.Bioassaysaremore cumbersomebutlessaccuratewhencomparedtochemicalassays.Eg:assayofhistamineinisolated guineapigileum,assayofacetylcholineinfrogrectusabdominismuscleandassayofantibiotics usingbacteria. Immunoassay o Thisiscommonlyusedfortheassayofhormones.Themethoddependsonthebindingbetweenthe radiolabelledhormoneandthecorrespondingantibody.Themethodishighlysensitivetodetect minutequantitiesofthehormonesinbodyfluids.

Biopharmaceuticals and gene therapy

Biopharmaceuticals

Thesearetherapeuticagentsproducedthroughbiotechnologicalmeans,butnotbyconventionallaboratory (chemical)synthesis. Biopharmaceuticalshavetheiroriginfromtheadvancementintheknowledgeofbiotechnologyand molecularcellbiology. BiopharmaceuticalspopularlycalledasDesignerProteinsarethepromisingtherapeutictollsofthefuture. Examplesarefunctionalhumanpeptidessuchas: o ADH,oxytocin,GnRH,ACTH,TSH/TRH,Calcitonin,Insulin,Somatostatin,GrowthHormone, Cyclosporinetc.,and o Enzymes/proteins(Streptokinase,Asparaginase,DNAase,glucocerebrosidase,erythropoietin, clottingfactors,interferons,MonoclonalAntibodies,Vaccinesetc)Daclizumab(Zenopox). GeneticallyengineeredhumanIgG(immunosuppressantmonoclonalantibodybindsspecificallytoachainof IL2receptor)usedtolowertherateofrejectionphenomenoninkidneytransplantrecipients. ThroughDNArecombinanttechnology,bacteriaareinducedtoproducehormoneslikeinsulinandgrowth hormoneandenzymeslikeLasparaginase.
Gene therapy

Itmeanspreventionortreatmentofdiseasesthroughmanipulationofgenefunction.Itisdonebyinsertion ofspecificgenes(therapeuticgenes)exogenouslyintotheanimalcells. Itinvolvesreplacingthedefectivegeneorsupplementationtoanonfunctionalgeneorsuppressionofan abnormalgene. RecombinationDNAtechnologyformsthebasisofsynthesisoftherapeuticgenes. Genedeliveryintohostishighlycomplicatedanddifferentfromthatofconventionaldrugdeliverysystems. Theprocessinvolvesinsertingatherapeuticgenefirstintoavector(Viralvectors:RetroorAdenovirusesor NonviralVectors:Liposomes,microspheresandplasmidDNA). 42|U R V I S H M I S T R Y
43|U R V I S H M I S T R Y Avectorwiththegeneisthenintroducedintothepatientthrougheitherinvivoorexvivomeans. Theinvivomethodinvolvesinjectingthesuspensionofthevectorhavingthetherapeuticgeneintravenously orintothetargettissue/organ. Theexvivomethodinvolvesfirstinsertingthetherapeuticgeneintostemcellsobtainedfromthepatient( bloodorbonemarrow)andinjectthesameintothepatient. Genetherapyiscurrentlyaimedattreatmentofdiseasesnotrespondingtoconventionaldrugtherapy,such asinheritedmetabolicdiseasesthrougheithercorrectionofadeficiencyorblockadeofanabnormal metabolicreaction. Itisalsoappliedtoinducesynthesisofadeficientproteininthehostscellsandtreatmentofavarietyof cancers(melanoma,renalcarcinoma,lungcancer,cysticfibrosisetc)certainimmunedeficienciesand infectiousdiseases(likeHIV).
Gastro intestinal pharmacology

Sialagogues (sialics) and antisialagogues (antisialics)
Sialagogues

Sialogoguesareagentsthatincreasethevolumeofsaliva,therebyincreasingtheappetiteandthe digestabilityoffood. Suchremediesareusedinlargeanimalpracticeastonics. Increasedsalivationisobtainedbyadministeringsubstancesthatstimulatetastebudslikethevegetable bitters. Substanceswiththistypeofactivityincludegentian,quassiaandnuxvomica. Increaseinsalivationisalsoachievedonadministrationofparasympathomimetics. Antisialagogues(antisialics)areagentsthatdecreasethevolumeofsalivarysecretions. Theantisialagogueeffectmayberequiredduringsurgeryofthemouthorafterexcisionofsalivarycysts. Parasympatholyticdrugshaveantisialagogueeffect.Atropineorglycopyrrolatearecommonlyusedto reducesecretionsasapremedicantduringsurgerytoreducesalivaryandbronchialsecretions. Stomachicsareagentsthatincreasethetoneandfunctionofstomachandincreaseappetite. Eg:Bitterstomachicssuchasginger,gentian,chirata.Theseplantbasedpreparationsstimulatethetaste budsandreflexlystimulatethestomach.
Antisialogogues
Stomachics

Appetite stimulants

Inappetanceoranorexiaiscommonindiseasestatesandtheresultantmalnutritioncandelayrecoveryand mayaggravatetheunderlyingdisease. Thevariouswaysbywhichappetitecanbeimprovedare: o Enteralalimentationwithliquidsupplementsisusefulinsmallanimals o Smallamountsofpalatablefoodshouldbeofferedatfrequentintervals.Warmingthefoodmay enhanceappetiteincarnivores o Variousdrugsareusedfortheshorttermstimulationofappetite. Benzodiazepinese.g.,Diazepam,Oxazepam Theantiserotonergiceffectdepressesthesatietycenterinthehypothalamus. Benzodiazipinesareusedmostfrequentlyincatsandlessfrequentlyinhorses,dogs andgoatsforashorttermstimulationofappetiteafterwhichtheeffectsdiminish. Diazepamcanbeadministeredorally,intravenously,intramuscularlyonceortwice daily, Oxazepamcanadministeredoncedailyorally. Theadverseeffectsincludesedationandataxia. Cyproheptadine 43|U R V I S H M I S T R Y
44|U R V I S H M I S T R Y Cyproheptadineactsasaserotoninandahistamine(H1)antagonistandsuppresses thesatietycenterinthehypothalamus. Cyproheptadinestimulatesappetiteincatsandinhumans,butnotindogs. AdverseeffectsincludesCNSexcitementandmarkedaggressivebehaviourincats. Glucocorticoidse.g.,Prednisolone,Dexamethasone Glucocorticoidsstimulateappetiteduetoglucocorticoidinducedeuphoria. Insmallanimalsprednisoloneordexamethasoneisadministeredintramuscularly oncedailyoreveryotherdaywhereasinlargeanimalsitisadministered intramuscularlyoncedaily. Adverseeffectsofglucocorticoidsincludeimmunosuppressionandgastric ulceration. Bitterslikeplantderivedcompoundssuchasnuxvomica,chiretta,ginger Theseareusedassalivarystimulantsandtheireffectonappetiteisquestionable. However,bittersareacomponentoftonicsforappetitestimulationinlargeanimals intraditionalmedicine.
Emetics
Emeticsareagentsthatinducevomitionandareclassifiedas centrallyactingand reflexactingemetics. Themainareainthebrainresponsibleforvomitingisthevomitingcenter.Thisareaislocatedinthelateral reticularformationofthemedulla. Itreceivesinputfrommanyareaslike: o Chemoreceptortriggerzone:Thisislocatedinthefloorofthefourthventricleanditpicksup circulatingchemicals/toxinsintheblood(e.g.bacterialfoodpoisoningtoxins,drugsusedfor chemotherapy)andcausevomiting. o Vestibularapparatus o Tractussolitariusvagalafferentsfromthegut,heartandtestes o Directinputfromgut(reflex) Theneurotransmittersinvolvedintheemeticresponseare o OntheCTZ:5HT3,D2 o Onthevagalafferents:5HT3 o Inthevomitingcenter:Muscarinic,H1receptors Centrallyactingemetics Thisincludes: ApomorphineisaD2agonistthatactsontheCTZtocausevomiting. o Apomorphineiscontraindicatedincatsasitmaycauseextremeexcitementincat. o Apomorphinecanbeadministeredsubcutaneouslyorasalamella(eyetablet)intheconjunctival sac. o Sinceapomorphinedepressestheemeticcentre,repeateddosingisnotrecommendedwhenthe initialdosingisieffective. Xylazineisusedasanemeticincats. SyrupofIpecacunhaisalsousedasanemetic. o Itactsbothcentrallyandlocally(reflexly)asanemetic. o Itirritatesthegastricmucosaandwithin1530minutesafteradministrationemesisisobserved. o Itproducesatoxicmetaboliteandhenceifemesisdoesnotoccurafteradministeringthesyrup,it shouldberemovedbyadministeringagastriclavage. o Highconcentrationsofipecacarecardiotoxic. o Animalswithipecacoverdosemayexhibitarrhythmias,hypotensionandmyocarditis. o Activatedcharcoal(aconstituentofuniversalantidote)shouldnotbeadministeredwithipecacas thecharcoaladsorbsthesyrupofipecacandpreventsitfromirritatingthegastricmucosaandin turnproducingemesis. Locallyactingemetics 44|U R V I S H M I S T R Y
45|U R V I S H M I S T R Y Warmwater Warmsaturatedsodiumchloridesolution Sodiumchloridecrystalsplacedatthebackofthetongue Sodiumcarbonateascrystals Coppersulphate50mlofa1%solution Zincsulphate50mlasa1%solution Freshlygroundmustardpaste Hydrogenperoxideasa3%solution Clinicalusesofemeticsinclude removalofingestedpoison(exceptwhencorrosivepoisonsofpetroleumproductshavebeeningested) emptyingthestomachcontentsinemergencysurgery Emeticsshouldnotbeadministeredinanunconsciouspatient,weakanddebilitatedpatientandpatients withclinicalcircumstanceslikepregnancy,bowelobstructionsandhernia.
Antiematics
Antiemeticsareagentsthatareusedtocontrolemesis Specieslikethehorses,rabbitsandrodentsareunabletovomit. Protractedvomitingisundesirableindogs,catsandotherspecies. Vomitingusuallyoccurssecondarytoanotherdiseaseprocess.Iftheprimarycauseistreatedthenvomiting disappears. Antiemeticsareusefulinmotionsickness,uremia,liverdisease,endotoxemia,canineparvovial gastroenteritisandincancerchemotherapy. Useofantiemeticsmaymasktheprimarydisease. Prolongedvomitingleadstoelectrolyteandacidbaseimbalancesanddehydration.Antiemeticsmayalsobe locallyactingorcentrallyacting. Centrallyactingantiemetics Phenothiazinederivatives Anumberofphenothiazinederivatives(chlorpromazine,promethazine,prochlorperazine,trifluopromazine etc.)areclassifiedasbroadspectrumantiemetics. Theyactbyblockingthechemoreceptortriggerzoneatlowdosesandtheemeticcentreinthebrainat higherdoses. PromethazineisaH1antagonist(classicalantihistaminic)whichalsohasantimuscarinicactions.Itisvery effectiveatpreventingmotionsickness(sincethevestibularafferentsinputinthevomitingcenterwhichhas H1andmuscarinicreceptors). ProchlorperazineisaD2antagonistandhasnoantipsychoticeffects.Itisusefulasanantiemeticaswellas fordizziness.Ithasminoranticholinergiceffects.SinceitblocksD2receptorselsewhere(e.g.substantia nigra),itmaycauseextrapyramidaleffects. Chlorpromazine,anotherphenothiazine,canalsobeusedasanantiemetic,althoughittendstobesedative. Italsohasantipsychoticeffects. Hyoscine(scopolamine)isamuscarinicantagonist(M2).Itisusedasapatchbehindtheearforcontrolling CTZmediatedvomiting. MetoclopromideisaD2antagonistwhichisalsoaweak5HT3antagonist.Itincreasesthemotilityofthegutin theupperregions(doesnotcausediarrhoeaonlyfacilitatesgastricemptying).Itisusefulingastricstasisin anumberofspeciesincludingthecattleandhorses.Metoclopromidewillhelptheabsorptionofdrugs becauseitstimulatesgastricemptying.Thisdrugisusefulinvomitingassociatedwithvagalafferents(gut disorders,heart,testes,gutirritantsallstimulatethe5HT3receptoronthevagalafferents). Ondansetronisa5HT3antagonistandisapotentantiemetic.Itisveryeffectiveinpatientsreceivingcancer chemotherapy.ItcanalsobeusedforCTZnausea. Locallyactingantiemetics H2antagonistslikecimetidine,ranitidineetc.Thesedrugsreducetheacidoutputandhencedecreasethe irritatingeffectsonacidstomachlining.Asaconsequence,afferentsignalstovomitingcentresare decreased.Antacidslikesodiumbicarbonatearealsouseful. 45|U R V I S H M I S T R Y

Prokinetics
Prokineticsareagentsthatpromotegastricmotilityandthushastentheprocessofemptyingofthegastric contentsintotheintestine,becauesoftheirabilitytoevacuatethegastriccontentstheyareofvalueas antiemetics. Theyarealsoindicatedingastritis,gastricrefluxanddyspepsia.Theyareknowntoactvia5HT4receptors. Eg:Cisapride,metoclopromide,tegeserodetc.
Ulcer management
Factors Factorsthatplayaroleinpepticulcerformationingastricandduodenalulcers: o Ulcerogenicfactorsinclude acidhypersecretion pepsin drugs(NSAIDs,corticosteroids,ethanol,chemotherapeuticagents,cigarettes) infection tumors stressheadtrauma,shock/sepsis,emotional alterationofprotectivefactors disruptionofmucosalintegrityand decreasedbicarbonatesecretion Symptomsofulcersareduetoacombinedeffectofhydrochloricacidandpepsin. Acidcausespainbutnottissuedamage. Pepsin,whichisactivatedinacidenvironment,digestsmucosal,muscularandvascularlayersofstomach& intestines. Gastric(stomach)ulcersarenotduetotoomuchacid. Alkalinerefluxfromintestinesmayinflamegastricmucosa. Duodenal(intestinal)ulcersareduetoincreasedacidsecretioninstomach. Whenstomachemptiesintointestinesthereistoomuchacidforpancreaticsecretionstoneutralizeandthis aciderodestissues. MostcommoncausesareH.pyloriandNSAIDsaswellasgastrinhypersecretion. Goalsofdrugtherapyforulcersinclude neutralizeexistinggastricacidantacids inhibitacidsecretionH2antagonists,protonpumpinhibitors treatinfection(H.pylori)antibiotics,bismuthsubsalicylate protectulcerfromfurtherdamagesucralfate
Antacids
Antacidsareagentswhichneutralizeexcessacid. Someofthecommonlyusedantacidsincludesodiumbicarbonate,aluminiumhydroxideanddihydroxy aluminium,calciumcarbonateandmagnesiumhydroxide. Theweakbasereactswiththegastrichydrochloricacidtoformasaltandwater. ThisreactioncausesanincreaseinthegastricpHandabovepH4,pepsinisinactive. Antacidsdifferin o neutralizingcapacitydeterminesdosage o timetoonsetsloworrapid o durationofactionlongorbrief o sideeffectconstipationvs.diarrhea o potentialtoproduceelectrolytedisturbances o convenienceliquidvs.tablet o palatability o cost Sodiumbicarbonate Ithasarapidonsetofaction. 46|U R V I S H M I S T R Y

47|U R V I S H M I S T R Y Butitisnotanidealantacidduetothereboundacidityi.e.,stimulationofacidproductiononcethepH exceeds4,duetogastrinsecretion. Assodiumbicarbonateisreadilyabsorbedintosystemiccirculation,italterssystemicpHandproduces electrolytedisturbances. Thisinturnmayleadtoedema,hypertensionorheartfailure. Aluminiumhydroxide Theinsolublealuminumchloridethatisformedduetothereactionofhydrochloricacidandaluminium hydroxideoftencausesconstipation. Italsobindswithtetracyclinetoinhibititsabsorption. Calciumcarbonate Theabsorptionof~10%ofcalciumchloridemayresultinhypercalcemia(muscleweakness,kidneystone formation)andreboundgastricacidity. Constipationmayoccurwithhighdoses. Magnesiumhydroxide Thiscausesprolongedneutralizingeffectduetoslowstomachemptying. Poorabsorptionofmagnesiumsaltsmayresultindiarrhoea. Combinationsofaluminumorcalciumcontainingantacidswithmagnesiumcontainingantacidscannullify theadverseeffectsonbowelfunction.
Histamine receptors H2 antagonist

Endogenoushistaminereleasedfromparacrineenterochromaffinlikecellsormastcellsstimulatesparietal H2receptors. HistamineactivatesacyclicAMPpathway,activatesH+_K+ATPaseandleadstoincreasedH+ingastric lumen.H2receptorantagonistscanblockthishistamineinducedsecretionandarehelpfulreducingacid secretionduringulcers. ExamplesofH2receptorantagonistsincludecimetidine,ranitidine,famotidine,nizatidineetc. Ingeneral,thesedrugsarewelltoleratedwithfewsideeffects(lessthan3%withcimetidineand<1%with otherdrugs). Cimetidineexhibitsantiandrogenicpropertiesleadingtodecreasedspermcount,gynecomastiaandalso inhibitshepaticdrugmetabolism. InhibitionofcytochromeP450activitybycimetidineleadstopotentialdruginteractions. Thisfeatureisnotseenwithranitidine,famotidineandnizatidine. Itisacomplexofsulfatedsucroseandaluminumhydroxideandisknownasgastricbandaid. SucralfatepolymerizestoaviscousgelatapHlessthan4. Itcombineswithproteinsandadherestoulcerformingabarrierresistanttoacidandpepsinandbindsto bilesaltswhichareimplicatedinulcerpathogenesis. Itprecipitatessurfaceproteinsattheulcerbaseandactsasaphysicalbarrierpreventingacid,pepsinand bilefromcomingincontactwiththeulcerbase. Itdoesnotdecreasegastricacidsecretionorneutralizeacidorstimulatehealing. Thedrugrequiresanacidicenvironmenttobemoreeffective. Itisaseffectiveascimetidineorantacidsathealingpepticulcersandisusefulintreatinggastricreflux. ItisaGastricprotective. Use:Sucralfateisusedinthetreatmentofgastricandduodenalulcersindogs,catsandfoals. Adverseeffect:Constipationmayoccurwithlongtermtherapy. Itinteractswithmanydrugsandshowntointerferewithabsorptionoftetracyclines,fluoroquinolones, cimitidine,phenytoinanddigoxin. Protonpumpinhibitorsarealsocalledasacidblockers.Examplesofthisgroupofdrugsareomeprazole, lansoprazole,pantoprazoleetc.
Sucralfate
Proton pump antagonists
48|U R V I S H M I S T R Y ThesedrugsirreversiblyinhibitK+H+ATPaseprotonpumpingastrointestinalparietalcellsi.e.inhibitsentry ofH+ionentryintolumen. ThesedrugsalsoappeartohaveantimicrobialactivityagainstH.pylori. Thesedrugsbreakdownintheacidenvironmentofthestomachandmustbegivenorallyasentericcoated preparationsandtheyhaveshortplasmahalflivesbutarelongacting. Theyinhibithepaticdrugmetabolismandareverywelltolerated. ThesedrugshealduodenalulcersmorerapidlythanH2antagonists. Theyareusedprimarilyforulcersrefractorytoothertreatmentsandarealsousedforrefluxesophagitisand managementofgastrinomas.
Cytoprotective drugs
Misoprostol,ananalogueofprostaglandin(PGE1)analogisusedasacytoprotectivedrug. Prostaglandins(membranederivedsecondmessengers)haveprotectiveactionsongastricmucosa. Theyincreasemucosaformationandincreasesreleaseofbicarbonate(HCO3). Adverseeffectsarenotcommonexceptdiarrhoeaandabdominalcramping. Asthisdrugmaycauseabortion,itisnotrecommendedforuseinpregnantanimals. Itisusedforshorttermmanagementofpepticulcersandalsotoreducegastrointestinalirritation associatedwithNSAID(aspirinlikedrugs)therapy. DrugsthateradicateHelicobacterpyloribacteria multipleantibiotics(metronidazole+amoxicillinortetracycline) bismuthsubsalicylate MosteffectivetreatmentisacombinationofmultipleantibioticswithH2antagonistorprotonpump inhibitorfor6months.

Digestants and purgatives

Choleretics and cholagogues
Cholereticsareagentsthatincreasethevolumeofsecretionofbile Bileacids(e.g:cholicacid,chenodeoxycholicacid) o Semisyntheticbileacidderivatives(e.g:dehydrocholicacid) o Sodiumsaltsofbileacids Mechanismofaction o Bilesaltsstimulatecholeresis(bileflow) o Bilesaltsemulsifylipids,enhancingthedigestionofffatsandtheabsorptionoflongchainfattyacids. Uses o Bilesaltsandacidstreatvigorousmaldigestionsyndromescharacterizedbysteatorrhea(e.g: pancreatitisandbilesaltdeficiency). Cholagogues Theseareagentsthatpromotetheflowofbilefromtheliverandgallbladder.Eg:licorice,ursodeoxycholic acid.
Purgatives and laxatives

Purgativesaredrugswhichcausemarkedintensificationofintestinalactivityandresultsintheexpulsionof intestinalcontentfromthecolonandrectum. Thetermsaperientandcatharticarealsoappliedtodescribethepurgatives.Adistinctionismadeaccording totheintensityofaction. Laxativeoraperient:aremilderinaction,eliminationofsoftbutformedstools Purgativesorcathartic:arestrongeractionresultinginmorefluidevacuation. Laxativeandcatharticsareusedfor: o Reliefofacutenondietaryconstipation o Removalpoisonsfromthegastrointestinaltract o Preventionoftenesmusinadvancedpregnancyorprolapse 48|U R V I S H M I S T R Y
49|U R V I S H M I S T R Y o Evacuationofthebowelpriortosurgeryorradiography Manydrugsinlowdosesactaslaxativeandinlargerdosesaspurgatives. Typeofstoolsandlatencyofactionofpurgativesemployedinusuallyrecommendeddoses Softformedfeces Semifluidstools Wateryevacuation (take13days) (take68hours) (within13hours) Bulkforming Docusates Liquidparaffin Lactulose Phenolphthalein Salinepurgatives Bisacodyl Castoroil Senna
Classification

Bulkformingagents:Dietaryfiberlikebran,Psyllium(Plantago),Ispaghula Stoolsofteningagents:Docusates(DioctylSodiumsulfosuccinate) Lubricantagent:Liquidparaffin Stimulant(contact)purgativeagents: o Diphenylmethane,Phenolphthalein,Bisacodyl o Anthroquinones(emodins),Senna,Cascarasagrada o Fixedoils:castoroil Osmoticpurgativeagents: o Magnesiumsalts:sulfate(Epsomsalt),hydroxide,oxide o Sodiumsalts:sulfate(glauberssalt),phosphate o Sodiumpotassiumtartrate o Sodiumphosphateandsodiumtartrate o mixtures(Fleetmixtures) o Lactulose Allpurgativesincreasethewatercontentoffecesby: o Ahydrophilicorosmoticaction,retainingwaterandelectrolytesintheintestinallumenincrease volumeofcoloniccontentandmakeiteasilypropelled. o Actingonintestinalmucosatodecreasenetabsorptionofwaterandelectrolyteintestinaltransitis enhancedindirectlybyfluidbulk o Increasingpropulsivemotilityasprimaryactionallowinglesstimeforabsorptionofsaltandwater asasecondaryeffect Certainpurgativesincreasemotilitythroughanactiononthemyentericplexus. Laxativesmodifythefluiddynamicsofthemucosalcellandmaycausefluidaccumulationingutlumenby oneormoreofthefollowingmechanisms: o inhibitingNa+K+ATPaseofvilluscellsimpairingelectrolyteandwateradsorption o Stimulatingadnylylcyclaseincryptcellsincreasingwaterandelectrolytesecretion o Enhancingprostaglandinsynthesisinmucosawhichincreasessecretion o Structuralinjurytoabsorbingintestinalmucosalcells. Osmoticcatharticsarenonabsorbableorpoorlyabsorbablesaltsorpolymersthatosmoticallyretainwaterin theintestinallumen.Solutesthatarenotabsorbedintheintestineretainwaterosmoticallyanddistendthe bowelincreaseperistalsisindirectly. Allinorganicsaltsusedasosmoticpurgativeshavesimilaractiondifferonlyindose,palatabilityandriskof systemictoxicity. Theyhavearapidonsetofactionthatbeginsinthesmallintestine. Osmoticcatharticsarethecatharticsofchoiceforeliminationofpoisons. Magnesiumsulfateandmagnesiumoxideareadministeredorally515g;bitterintaste Sodiumsulfate1015gisadministeredorallyorviaastomachtubeasa6%solution 49|U R V I S H M I S T R Y
General mechanism of action
Osmotic purgatives
50|U R V I S H M I S T R Y Sodiumphosphate612g Sodiumpotassiumtartrate(Rochellessalt)815g Polytheleneglycolelectrolytesolutionsareadministeredorallypriortocolonoscopy Sodiumphosphateandsodiumtartratemixturesareadministeredrectallytodogs.Incats,theyproduce hyperphosphatemiaandshouldnotbeused. Thesaltsmentionedabovearedissolvedin100200mlofwter,produce12fluidevacuationwithin123 hourswithmildcramping,casuenearlycompleteemptyingofbowels. Smallerdoseshavemilderlaxativeaction. Magnesiumionsreleasecholecystokininwhichmayaidpurgativeactionofmagnesiumsalts. Magnesiumsaltsarecontraindicatedinrenalinsufficiency,whilesodiumsaltsshouldnotbeusedinpatients sufferingformCongestiveHeartFailureandothersodiumretainingstates. Repeateduseofsalinepurgativescancausefluidandelectrolyteimbalance. Lactulose Itisasemisyntheticdisaccharideoffructoseandlactosewhichisnotdigestedorabsorbedformsmall intestinebutretainswater. Itisbrokendowninthecolonbythecolonicbacteriatoosmoticallymoreactiveproducts. Flatulenceiscommon,crampsoccurinfewcases.Nauseamaybeproducedbecsueofunpleasanttaste. Itisnotpreferredforconstipation. Lactulosecausesreductionofbloodammoniaby2550%inpatientswithhepaticencephalopathy. ThebreakdownproductsoflactuloseareacidicandreducethepHofstools. Ammoniaproducedbybacteriaincoloninconvertedtoionizedammoniumandisnotabsorbed.
Irritant purgatives

Irritant/Stimulant/contactcatharatics:(e.g:castoroil,aloes,senna,cascarasagarada) Irritantcatharticsareplantderivatives. Theyarepowerfulpurgativesandoftenproducegriping. Theywerethoughttoirritatetheintestinalmucosaandthusstimulatemotoractivity. Itaccumulateswaterandelectrolytesinthelumenbyalteringabsorptiveandsecretoryactivityofthe mucosalcell. TheyinhibitNa+K+ATPaseatthebasolateralmembraneofvillouscellstransportofNa+andaccompanying waterintotheinterstitiumisreduced. SecretionisenhancedbyactivatedcAMPincryptcellsandbyincreasedprostaglandinsynthesis. Largerdosesofstimulantpurgativescancauseexcespurgation,fluidandelectrolyteimbalance. Hypokalemiacanoccuronregularuse.Routineandlongtermusemustbeavoided,producescolonicatony. Theymayreflexlystimulategraviduterus,hencecontraindicatedinpregnancyandalsoinsubacuteand chronicintestinalobstruction. CastoroilisablandvegetableoilobtainedfromtheseedsofRicinuscommunis. Itiscleavedbypancreaticlipasesinthesmallintestinetoyieldirritantricinoleates,whichstimulate peristalsisandreducefluidabsorption.Thisishydrolyzedintheileumbylipasetoricinoleicacidandglycerol. Ricinoleicacidbeingpolarispoorlyabsorbed. Aloe,sennaandcascarasagradacontainanthroquinoneglycosidesthatarehydrolyzedinthelargeintestine toyieldtoirritantanthraquinonesemodinsSennaismostpopularlyused. Unabsorbedinthesmallintestine,theyarepassedtothecolonwherebacterialiberatetheactiveanthrol formwhicheitheractslocallyorisabsorbedintocirculationexcretedinbiletoactonsmallintestine. Thustheytake67hourstoproduceaction. Theyaresecretedinmilksufficienttocausepurgationinthesucklingyoungones. Itisoneoftheoldestpurgativesused. Itmainlycontainstriglyceridesofricinolenicacidwhichisapolarlongchainfattyacidwhich Itwasbelievedtoirritatethemucosaandstimulateintestinalcontraction. Theprimaryactionhasnowbeenshowntobedecreasedintestinalabsorptionofwaterandelectrolytes,and enhancedsecretionbyadetergentlikeactiononthemucosa. 50|U R V I S H M I S T R Y
51|U R V I S H M I S T R Y Itcausesmorphologicaldamageofvillustipandperistalsisisincreased. Duetoitsunpalatibility,frequentcrampingandviolentaction,possibilityofdehydrationandafter constipationmucosaldamageitisnolongerfavoured. SennaisobtainedfromleavesandpodofcertainCassiasp,whileCascarasagradaisthepowderedbarkof thbuckthorntree. Anthraquinones Anthraquinonesstimulatesmoothmuscleandincreasecolonicmotility. Becausetheyactinthelargeintestine,theironsetofactionisslow.Usuallygivenatnighttimewhichcausea single,softbutformedevacuationgenerallyoccursinthemorning. Crampsandexcessivepurgingoccurissomecases. Theactiveprincipleisbelievedtoactonthemyentricplexustoincreaseperistalsisanddecrease segmentation. Theyalsoinhibitsaltandwaterabsorptioninthecolon. SennaanthraquinonehasbeenfoundtosimulatePGE2intheratintestine. Regularuseagecausescolonicatonyandmucosalpigmentation. Aloeespeciallyreleasestheanthraquinoneemodin,whichhasaffinitytowardsthesigmoidflexureofthe horsesintestine,andproducesthecatharticeffect. Irritantcatharticsareadministeredorallytorelieveacuteconstipationinsmallandlargeanimals. Diphenylmethanes Phenolphthaleinisanindicatorandisinuseaspurgativesinceearlierdays.Itturnsurinepinkifalkaline. Bisacodylisalateradditionandmorepopular. Diphenylmethanesarepartlyabsorbedandreexcretedinbile,enterohepaticcirculationismoreimportant inphenolphthateinwhichcanproduceprotractedaction. Bisacodylisactivatedintheintestinebydeacetylation. Theirprimarysiteofactionisinthecoloninwhichoneortwosemiformedmotionsoccurafter68hours. Phenolphathalein:60130mg:tobeadministeredatnighttime Bisacodyl(Dulcolax)5mg,10mgtablet Adverseeffects Thesedosesofphenolphthaleinproducefluidevacuationsandcramps.Morphologicalalterationsinthe colonicmucosaislikelytooccurandmakesmucosamoreleaky. Bisacodylsuppositoryactsbyirritatingtheanalandrectalmucosaleadingtoreflexincreaseinmotility causingevacuationin2040minutes.Itmaycauseinflammationandmucosaldamage.
Bulk purgatives
Bulklaxatives(e.g:methylcellulose,agar,psyllium,wheatbran) Dietaryfibresconsistsofunabsorbablecellwallandotherconstituentsofvegetablefoodcellulose,pectins, glycoproteinsandotherpolysaccharides. Branisabyproductofflourindustryconsistsof40%dietaryfibre.Itabsorbswaterintheintestines,swells, increaseswatercontentoffeces.softensitandfacilitatescolonictransit. Osmoticallyactiveproductsmaybeformedinthecolonbybacterialdegradationofpectinsetc.,whichactto retainwater. Dietaryfibresupportsbacterialgrowthincolonwhichcontributetothefecalmass. Certaindietaryfibres(gums,lignins,pectins)bindbileacidsandpromotetheirexcretioninfecesleadingto enhancementofdegradationofcholesterolinliverandtherebyplasmaLDLcholesteolislowered. Increasedintakeofdietaryfibresisthemostappropriatemethodforpreventionandtreatmentoffunctional constipation. Itisthefirstlineapproachformostdogsandcatsinthetreatmentofsimpleconstipation. Prolongedintakeofbranandotherbulkformingagentsreducesrectosigmoidintraluminalpressurerelives symptomsofirritableboweldiseaseandcolonicdiverticulosis. Itisalsousefulwhentenesmusatstoolshastobeavoided. Demerits Unpalatable,2040g/dayneedstobeingested. Fulleffectrequiresdailyadministrationforatleast34days. 51|U R V I S H M I S T R Y

52|U R V I S H M I S T R Y Itdoesnotsoftenfecesalreadypresentincolonorrectum. Flatulencemayoccur. Psyllium(Plantago)andIspaghula Containnaturalcolloidmucilage,whichformsagelatinousmassbyabsorbingwater,312gofrefinedhusk freshlymixedwithwaterormilkandtakendailyactsin13days. Itshouldnotbeswalloweddry(mayleadtooesophagealimpaction) Ispaghulahusk(refined) Plantagohusk Methylcelluloseandcarboxymethylcellulosearesemisyntheticcolloidalhydrophilicderivativesofcellulose;46 g/dayissatisfactorytoproducelaxativeeffect. Mechanismofaction Bulklaxativescontainhydrophiliccolloids,whichabsorbwaterandincreaebulk. Bulkstimulativeslargebowelperistalsis Wheatbranisadministeredorallybyaddingtothediet. Thelaxativeeffectoccurswithin13days. Generousamountofwatermustbegivenwithallbulkformingagents. Itshouldnotbeusedinpatientswithgastriculcerations,adhesions,stenosisandwhenfecalimpactionisa possibility
Lubricant purgatives
Lubricants,mineraloil(liquidpetroleum)andwhitepetroleumlubricateandsoftenfeces. Liquidparaffinisaviscousliquid;amixtureofpetroleumhydrocarbons.Itwasintroducedasalaxative earlier.Itispharmacologicallyinert.Whentakenfor23days,itsoftensstoolsandissaidtolubricatehard scybalibycoatingthem. Dose:1530ml/dayoilassuchorinemulsifiedformindog Disadvantages Itwillbeveryblandandunpleasanttoswallowbecauseofoilyconsistency Smallpassesintotheintestinalmucosa,carriedintothelymphandmayproduceforeignbodygranulomain theintestinalsubmucosa,mesentericlymphnodes,liverandspleen. Probalilityofcausinglipidpneumoniabecauseoftricklingintolungswhileswallowing Carriesfatsolublevitaminswithitintothestoolsleadingtodeficiency Leakageoftheoilpastanalsphinctermayembarrassandstainthefloor Mayinterferewithhealingintheanoractalregion. Henceadvisableforoccasionaluseandthattoopostoperatively. Surfactants Docusatesisananionicsurfactantthatactsinthelargeboweltohydrateandsoftenfecesbyanemulsifying action. Itcausesnetwateraccumulationintheintestinallumenbyanactionontheintestinalmucosa.Itemulsifies thecoloniccontents. Beingadetergent,itcandisruptthemucosalbarrierandenhanceabsorptionofmaynonabsorbabledrugs, e.gliquidparaffinshouldnotbecombinedwithit.Eg:Cellubril,Laxiconascapsules Dose:100200mg/day;actsin13days.Itisamildlaxative;speciallyindicatedwhenstrainingaststools mustbeavoided. Crampsandabdominalpaincanoccur.Itisbitterintaste.Liquidpreparationsmaycausenauseaandis hepatotoxiconprolongedusage.

Choice, indications, combinations, abuse of purgatives

Choiceanduseofpurgatives Laxativesareimportantfortheirharmfulnessastheyarefortheirvalueinmedicine. Alllaxativesarecontraindicatedin: o Ananimalofundiagnosedabdominalpain,colicorvomiting o Organicconstipationduetostrictureorobstructioninbowel,hypothryroidism,hypercalcemia, malignanciesanceratindrugslikeopioids,sedatives,,anticholinergicsetc., 52|U R V I S H M I S T R Y
53|U R V I S H M I S T R Y Validindicationsoflaxativesare FunctionalconstipationSpastic(irritablebowel)andAtonic(Sluggishbowel) Recumbentanimals Tenesmus Bowelsurgery,endoscopyu,abdominalXray Afteranthelminticstreatment Food/drugpoisoning. Combinedpreparationsofpurgatives Agarol:Liquidparaffin+Phenolphthalein+Agar Cremaffin:Milkofmagnesia+Liquidparaffin+Phenolphthalein Julax:Bisacodyl+Casanthrol Laxatin:Sennosides+Docusates PursennidIN:Purifiedsennaextract+docusates. Purgativeabuse Chronicuseofpurgativesmustbediscouraged. Oncethepurgativehabitforms,itisdifficulttobreak. Dangersofpurgativeabuseare: o Flairingofintestinalpathology,ruptureofinflamedbowel o Fluidandelectrolyteimbalance,speciallyhypokalemia o Steatorrhoea,malabsorptionsyndrome o Proteinlosingenteropathy o Spasticcolitis
Antidiarrheal
Generalconsiderations o Acutediarrheamayrespondtosymptomatictherapywithantidiarrhealdrugs,butchronicdiarrhea requiresadefinitivediagnosisandspecifictherapy. Oralrehydrationtherapyrepresentsasignificantadvanceintreatingdiarrheaintheabsenceofvomiting. Inadditiontoglucoseoraminoacids,orboth,thesesolutionscontainsodiumchloride,potassiumchloride, sodiumbicarbonate,andpotassiumphosphate. Sodiumglucoseandsodiumaminoacidlinkedabsorptionbytheenterocyteremainintacteveninthe presenceofmoderatedamagetotheintestinalvilli,providingthedrivingforceforwaterandelectrolyte absorptionformthelumentoreplacefecallosses. Opiates o Paregoricisacamphoratedtinctureofopium o Diphenoxylateisasyntheticcongenerofmepridine.Lomotilisdiphenoxylateplusatropine
Opioids
Loperamide Loperamideisasyntheticpiperidineopioid Itisanopiateanaloguewithweakanticholinergicproperty. Becauseofpoorwatersolubilitylittleisabsorbedformtheintestine. Entryintobrainisnegligible. Inadditiontoitsopiatelikeactiononmotility,italsoinhibitssecretion. Itimprovesfecalcontinencebyenhancinganalsphinctertone. Mechanismofaction OpiatesinhibitAChrelease. Theresultantincreasedgastrointestinalrhythmicsegmentationanddecreasedpropulsivemotilityslowthe transittimeofluminalcontentsandincreaseabsorption Inaddition,opiatesdirectlystimulateabsorptionoffluidandelectrolyteviamuopiatereceptorsintheCNS andintestinalmucosa. Codeine 53|U R V I S H M I S T R Y
54|U R V I S H M I S T R Y Antidiarrhealactionisprimarilyattributedtoitsperipheralactiononsmallintestineandcolon. Itdoesnothavecentraleffects,buitproducedependance. Itshouldbeusedonlyforashortperiod. Diphenoxylate Itisanopioidchemicallyrelatedtopethidine:usedexclusivelyasconstipatingagent. Theantidiarrhealactionisprominent,butbecauseitisabsorbedsystemicallyandcrossesbloodbrainbarrier CNSeffectsmayoccur. Atropineisaddedinanonpharmacologicaldosetodiscourageabuse. Abuseliabilityisratedlowandoverdosewillproducedisturbingatropinicsideeffects. Use:Opiatesareeffectiveinthesymptomatictreatmentofacutediarrhea. Administration Paregoricisadministeredorally23timesdailytodogsandcatsoncedailytocalvesandfoals Diphenoxylateisadministeredorally23timesdailytodogsandcats Loperamideisadministeredorally12timesdailytodogsandcats Codeineisadministeredorally23timesdailytodogsandcats. Adverseeffects:bacterialovergrowthintheintestinallumenofanimalswithinfectiousdiarrheamayresult fromslowedintestinaltransittime. Incats,excitatoryreactionsrenderopiateusecontroversial. Paregoricisacamphoratedtinctureofopium. Diphenoxylateisasyntheticcongenerofmepridine. Lomotilisdiphenoxylateplusatropine.
Anticholinergics
Anticholinergicagents Methscopolamine.Otherdrugsincludeaminopentamide,propanthelineandisopropamide,whicharealso effectiveasantiemetics Mechanismofaction Anticholinergicsinhibitpropulsiveandnonpropulsivegastrointestinalmotility. Theyalsoinhibitnormal,cholinergicallymediatedbasalsecretionsofthegastrointestinaltract. Uses Anticholinergicagentsmaybeusedtotreatdiarrhea:however,theyareofquestionablebenefitinthis capacitybecausediarrheaismorecommonlyassociatedwithhypomotilitythanhypermotility Anticholinergicagentsmaybeusedtotreatgastrointestinalspasm Administration Aminopentamideisadministeredorally,intramuscularlyorsubcutaneouslyevery812hours Propanthelineisadministeredorallyevery8hours Isopropamideisadministeredorallyevery12hours Adverseeffects Adverseeffectsofanticholinergicsincludexerostomia,xerophthalmia,lossofvisualaccommodation, tachycardia,urineretention,paralyticileusandconstipation. Anticholinergicsarecontraindicatedinpatientswithglaucoma.
Protectants and adsorbants

Kaolinpectinsuspensions(20%kaolin(hydratedaluminiumsilicate)and1%pectin(apolygalacturonicacid carbohydratepolymer) Bismuthsubsalicylate. Mechanismofaction Protectivesandadsorbentsadsorbtoxinsandprovideaprotectivecoatingoninflamedmucosa. Bismuthsubsalicylatehasanantiprostaglandinactioninadditiontoitsadsorbentproperties. Uses:Protectantsandadsorbentsareusedforthesymptomatictherapyofacutediarrhea.Adsorbentsmay decreasefluidityoffeceswithoutactuallydecreasingfecalwaterloss,therebylimitingtheirusefulness. Adminsitration 54|U R V I S H M I S T R Y
55|U R V I S H M I S T R Y Kaolinpectinsuspensionsareadministeredorallyevery46hours.Kaolinpectiniseffectiveindogs,cats, birds,horses,cattle,sheepandwine. Bismuthsubsalicylateisadministeredorallyevery46hours.Bismuthsubsalicylateisapprovedforusein dogs,horses,cattleandwine.Salicylateshouldnotbeadministeredtocats. Adverseeffects:Bismuthsubsalicylatemayproducedarkfeces,whichshouldnotbeconfusedwithmelena.
Antisecretory drugs

Sulfasalazine(Salicylazosulfapyridine)itisacompoundof5aminosalycylicacid(5ASA)withsulfapyridine linkedthroughanazobond. The5ASAisoflowsolubilityanditispoorlyabsorbedfromtheileum. Theazobondissplitbycolonicbacteiatorelease5ASAandsulfapyridine. Theformerexertsalocalantiinflammatoryeffect,probablybyinhibitingprostaglandinsynthesis(andother mediatorslikeleukotrienes,PAFaswellasmigrationofinflammatorycellsintobowlwall),decreases mucosalsecretionaffordsconsiderablereliefinulcerativecolitisandrelatedinflammatoryboweldisease. Givenduringanexacerbationitreducesnumberofstools,abdominalcrampsandfeverbutislesseffective thancorticosteroids:maybeemployedformildtomoderateexacerbation. Thebeneficialeffectofsulfasalazineisclearlynotduetoanyantibacterialaction(bowelfloraremains largelyunaffected)sulpyridinemoietyonlyservestocarry5ASAtothethecolonwithoutbeingabsorbed proximally. However,partofthereleasedsulfapyridineisabsorbedinthecolonandisresponsibleforadverseeffects likerashes,fever,jointpain,haemolysisandblooddyscrasias. Nausea,vomiting,headacheandanemiaareotherfrequentsideeffects.Maleinfertilityisreported. Sulfasalazinehasalsobeenusedasadiseasemodifyingdruginrheumatoidarthritistheabsorbed sulfapyridineappearstoberesponsibleforthetherapeuticeffect.
Protectants
Adsorbants Ispaghula Psyllium Methylcellulose Sulfasalazine Mesalazine Bismuthsubsalicylate Atropine Octreoxide Irritablebowel Ileostomy/colostomydiearrhea Ulcerativecolitis Otherinflammatoryboweldiseaes Travellersdiarrhea Nervous,druginduceddiaerrhea Carcinoid,VIPsecretingtumour
Antisecretory
Antimotility(opioids) Codeine Noninfectiveormildtravelersdiarrhea Diphenoxylateatropine Idiopathicdiarrhea Lopramide Afteranalsurgery,colostomy.
Rumen pharmacology
Oesophageal groove closure

Theoesophagealgroovereflexiswelldevelopedinsucklingneonatesbutbecomeslessreliableinolder animals. Bypassingtheruminoreticulumcanhaveseveraladvantages. Drugsadministereddirectlyintotheruminoreticulumareabsorbedveryslowlywhencomparedwith abomasaldelivery. Moreoverdrugsmaybedegradedbyruminalmicroflora(eg:chloramphenicolanddigitalisglycoside)orthe drugsmaybeharmfultothebeneficialmicrobes(eg;tetracyclines,penicillinandsulfonamides). Oraladministrationofmedicamentsintendedforthelocalintestinaleffect(eg:purgatives,antidiarrhoeals, contrastmediaandsomeanthelmintics)shouldbeprecededbyadministrationofanappropriateofsalt solutiontoclosethereticulargroovetoavoidruminoreticulardispersion. 55|U R V I S H M I S T R Y
56|U R V I S H M I S T R Y 5%coppersulphate,5%zincsulphate,10%sodiumbicarbonateor10%sodiumsulphatecanbe administeredatdosesof60mltocattletobringaboutclosureofoesophagealgroove. 12%coppersulphateisusefulinsheep.Onsetofreflexresponsetakesabout510secondsandthegroove mayremainclosedforupto60seconds. Sucklingisastrongstimulusforthisreflexeveninadults.Itisbesttoallowsickcalvesandlambstodrink medicatedmilkfromanippletoassureabomasaldeliveryandrapidabsorption. Administrationofliquidmedicationtoruminantsorallymayresultinspontaneousclosureofthereticular grooveinacertainnumberofcalveswhichresultsinancompleteorpartialruminoreticularbypass. Whenstimulated,buccalandpharyngealreceptorsactivateavagalreflexthatclosesthegroovewithing25 seconds:effectslastfor60seconds. Milk,sodiumbicarbonate(10%tocalves)orcoppersulphate(5%tocalves,2%tolambs)butnotwatermay beusedtoinduceesophagealgrooveclosure.
Ruminotorics

Ruminotoricsareagentsandmixturesthatpromoteforestomachfunction(fermentationandmotility). Typicallysuchmixturesconsistbitterslikenuxvomicatostimulatesalivationandperhapsruminal contractions, alkalinizingcompoundslikemagnesiumoxidetoelevatealowruminalfluidpH, galactogenicsubstancelikeglycerol, mineralslikecobaltascofactorsformicrobialenzymefunctionand saltslikephosphateasbufferstomaintainosmolality. Bitters:(e.g:nuxvomica,ginger,capsicum)stimulatesalivationwhichmayenhancerumenfunction, however,theefficacyofbittersisminimal.Bittersareadministeredorally. Cholinergics(e.g:neostigmine,bethenachol)transientlyincreasethefrequency,butnotthestrength,of contractionsinrumenatony.Cholinergicsareadministeredsubcutaneously. Opiateantagonists(e.g:naloxone)stimulateextrinsiccontractionswhenadministeredparenterally.Opiate antagonistsareusefulforthetreatmentofendotoxininducedrumenstasis. RumenfluidtransferOralinoculationofviablerumenbacteriaandprotozoaisthemosteffectivemeansof restoringrumenfunctionfollowingcorrectionoftheprimarycauseofstasis
Rumen antacids
Rumenantacids(e.g:magnesiumoxide,magnesiumcarbonate,aluminiumhydroxide,calciumcarbonate, ammoniumcarbonate) Antacidsareusedtotreatmildcasesoflacticacidiosisresultingformcarbohydrateengorgement. Theseagentsareadministeredorallyevery812hoursSystemicalkalosismayresultfromoverdose especiallyofmagnesiumoxide.
Antizymotics

Antizymoticsareagentsthatusedtocontolfermentationintheruminantforestomach.Whenorally administeredtheseagentsactbyinhibitingmicrobialgrowthintherumen. Theyareofuseinconditionssuchasbloatwheretheeisuncontrolledfermentation.Eg:Formalein, turpentineoil.
Cardiovascular pharmacology
Classes of drugs acting on heart

Drugsactingontheheartcanbeclassifiedinto Drugsthatdirectlyaffectthemyocardialcellswhichincludes o autonomicneurotransmittersandrelateddrugs o cardiacglycosidesandotherinotropicagents o antidysrhythmicorantiarrhythmicdrugs Drugsthataffectthecardiacfunctionindirectlythroughactionselsewhereinthevascularsystemcalcium antagonistsactingbothdirectlyonthemyocardialcellsandindirectlybyrelaxingthearterioles. 56|U R V I S H M I S T R Y
57|U R V I S H M I S T R Y Autonomictransmittersandrelateddrugs Bothsympatheticandparasympatheticsystemsexertatoniceffectontheheartatrest. Themaineffectsofsympatheticactivityontheheartare o positiveinotropiceffect(increasedforceofcontraction) o positivechronotropiceffect(increasedheartrate) o increasedautomaticity o repolarisationandrestorationoffunctionfollowinggeneralisedcardiacdepolarisation o Reducedcardiacefficiency. Theparasympatheticeffectsinclude o cardiacslowingandreducedautomaticity o decreasedforceofcontraction o inhibitionofAVconduction
Effects of drugs acting on heart

Theeffectofdrugsontheheartmaybeexpressedas Inotropiceffectifitaffectsthecontractility Chronotropicifitaffectstherhythmicity Dromotropicifitaffectstheconductivity Bathmotropicifitaffectstheexcitability Tonotropicifitaffectsthetonicity.
Congestive heart failure

Heartfailureisaglobaltermforthephysiologicalstateinwhichcardiacoutputisinsufficientinmeetingthe needsofthebodyandlungs.Oftentermed"congestiveheartfailure"orCHF,thisismostcommonlycaused whencardiacoutputislowandthebodybecomescongestedwithfluid. Commoncausesofheartfailureinclude: myocardialinfarction ischemicheartdisease, hypertension, valvularheartdisease Cardiomyopathy. Itmayalsooccurdueto severeanemia, Gramnegativesepticemia, beriberi(vitaminB1/thiaminedeficiency), thyrotoxicosis, arteriovenousfistulae, arteriovenousmalformations.
Cardiac glycosides
Themainsourceofcardiacglycosidesisfromthefoxglovefamily. Theireffectivenessincardiacfailurewas,describedbyWilliamWitheringin1775.Hepublishedhisclassic monographAnaccountofthefoxgloveandsomeofitsmedicinaluses:withpracticalremarksondropsyon usedbyanoldwomanofShorpshireandotherdiseasesin1785. Initiallykidneywasthoughttobethetargetorgan Thecardiacglycosidesareuniqueinthattheynotonlyimprovethecontractilityofthemyocardium,butalso reducetheheartsdemandforenergyandoxygen. Thesedrugsalsodeceasetheconductionofcertainimpulseswithintheheartandthereforedecreasethe heartrate. Sourceofglycosides DigitalispurpureaorPurplefoxglve(leaf)Digitoxin,Gitoxin,Gitalin DigitalislanataorWhitefoxglove(leaf)Digitoxin,Gitoxin,Digoxin 57|U R V I S H M I S T R Y

58|U R V I S H M I S T R Y Strophanthuskombe(seed)StrophanthinK Strophanthusgratus(seed)StrophanthinG(Ouabain) Thevetianeriifolia(nut)Thevetin ConvallariamajalisConvallotoxin Bufovulgaris(Toadskin)Bufotoxin
Chemistry of cardiac glycosides

Cardiacareglycosidesthatcontainanaglycone(genine)andasugarmoiety.(chemicalstructurepicture hyperlink) Thesugarmoietyconsistsofonetofoursugarresidues. Thepharmacologicalactivityrestswiththeaglyconeandthesugarhelpsinthepharmacokineticproperties. Theaglyconeconsistsofacyclopentanoperhydrophenanthereneringstructureattachedtoa5or6 memberedunsaturatedlactonering.
Mechanism of action on cardiac glycosides
CardiacglycosidesproducetheiractionbyinhibitionofNa+,K+transportsystem(Na+,K+ATPase) InhibitionofthissodiumpumpresultsinincreasedintracellularNa+concentration NormallysodiumisbroughtintothecellinexchangeforCalciumduringtheplateauphase BecauseoftheelevatedintracellularNa+,sodiumcalciumexchangerisnotfunctional,leadingtoelevated intracellularCa++levels Ca++formsacomplexwithtroponinandtropomyosinallowingactinandmyosinfilamentstocometogether Musclecontracts AlteredNa+,K+andCa++levelsarethebasisforboththetherapeuticandtoxiceffectsofthecardiac glycosides.
Pharmacological effects of cardiac glycosides

Positiveinotropiceffectisnoticedbyimprovedemptyingandreductioninsizeofthedilatedfailingheart. Themusclecontractsmorequicklyandmorepowerfullyforthesamefillingstimulusandforthesame oxygenconsumption. Sovenouspressureisreduced,oedemafluidisreabsorbedandbloodpressureincreases. 58|U R V I S H M I S T R Y
59|U R V I S H M I S T R Y Negativechronotropiceffectsbydirectstimulationofthevagalcentreandbyslowingtherateofpassageof impulsesthroughtheconductingsystem. Diureticeffectduetoincreasedbloodflowandincreasedglomerularfiltrationrate.
Pharamacokinetics

Absorptiondiffersamongthedigoxinpreparations. Prepareddigitaliscauseslocalirritationandvomitinginpiganddogandforthesespeciesdigitalisglycoside shouldbegiven. Inruminants,oraladministrationofglycosidesleadstodestructionofthedrugandhenceitispreferableto givethedrugparenterally. Plasmaproteinbindingishighwithdigitoxin. Excretionofthedrugisbythekidneys. Enterohepaticrecyclingincreasesthedurationofactionofthedrug. Theuseofthesedrugsindogsandcatsisnotuncommon. However,theabsorptionofdigoxinfromthegastrointestinaltractthoughadequatemaydiffersomewhat amonganimalsandcanbeinfluencedbyfeedingtimes.
Therapeutic uses of cardiac glycosides

Congestiveheartfailure. ArrhythmiasbydepressingtheAVnodalconductivityandincreasingrefractoriness.
Digitalization
Digitalisglycosideshaveanarrowmarginofsafety. Initialadministrationoflargedoseindivideddoses.(2448hrs) Followedbymaintenancedose. Loadingdoseindogs o Slowmethod5equalpartsfor48hrs o Rapidmethod3equalparts@6hrinterval. o Intensivemethodhalfdoseinitially,onefourthafter6hrsandoneeightheachafter4hrintervals o Digitoxin0.110.22mg/kgtotalloadingdose Maintenancedose0.011mg/kg@12hrintervalsindogs Thereisaconsiderable,individualvariationinresponsetotheseglycosides.

Adverse reactions of cardiac glycosides

Riskoftoxicityisgreaterinpatientswithadvancedheartdisease,inhighdosage,renaldisease,ageand hypothyroidism. Factorsthatincreasemyocardialsensitivitytodigitalistoxicityincludemyocardialdiseaseorischemia, hypokalemia,highserumcalciumandlowserummagnesium. Symptomsoftoxicitycanbegroupedascardiacsymptomsandnoncardiacsymptoms. Cardiacsymptomsoftoxicity o Sinusbradycardia, o SAblock, o AVblock,tachycardia, o prematureventricularcontraction Noncardiacsymptomsoftoxicity gastrointestinaldisturbanceslikeanorexia,nausea,vomitingfatigueandmuscleweakness CNSeffectslikeconfusion,hallucination,restlessness,insomnia,drowsinessandoccasionallyovert psychoses Visualeffectslikehazyvision,difficultyinreading,photophobia,chromatopsia(yelloworgreencolour appearance) gynaecomastia(antiadrenergiceffect).
Treatment of cardiac glycosides toxicity

Withholdcardiacglycosides Withholdpotassiumdepletingdiuretics Administerpotassiumsalts Administerantiarrhythmicsifarrhythmiasappeartobelifethreatening Administeragentslikeactivatedcharcoaltobinddigoxininthegastrointestinaltract.

Precautions and drug interactions

Hypokalemiawillleadtoincreaseddigitalistoxicity Inelderlypatientsandinpatientswithrenalandseverehepaticdiseasethetoxicitywillbehigher Thyrotoxicosisreducestheresponsivenesstodigitalis Myxoedemaincreasestheresponsivenesstodigitalis PartialAVblockmaybeconvertedtocompleteAVblock
Drug interactions

Diureticspotassiumdepletingdiureticsprecipitatedigitalistoxicitywhilepotassiumsparingdiuretics reducetherenalexcretionofdigitalis Calciumprecipitatesdigitalistoxicity Quinidinereducesbindingtoproteinsandtherebyincreasetheconcentrationandtoxicityofdigitalis Verapamilanddiltiazemincreaseplasmaconcentrationsofdigoxin Antacidsandneomycinreduceabsorptionofdigitalis.
Other drugs used in CHF

Phosphodiesteraseinhibitorsliketheophylline. Diureticslikefurosemidetoincreasewaterandsodiumexcretion,decreasepreloadandrelievesymptomsof pulmonaryandsystemiccongestion Vasodilatorslikehydralazine ACEinhibitorslikeenalapril,lisinopriletc. Adrenergicalpha1agonistslikeprazosin Calciumchannelblockerslikenifedipine
Antiarrhythmic drugs
Types of arrhythmia

Sinusbradycardialowsinusrate<60beats/min. Sinustachycardiahighsinusrateof100180beats/minasoccursduringexerciseorotherconditionsthat leadtoincreasedSAnodalfiringrate. Atrialtachycardiaaseriesof3ormoreconsecutiveatrialprematurebeatsoccurringatafrequency >100/min;usuallyduetoabnormalfocuswithintheatriaandparoxysmalinnature.Thistypeofrhythm includesparoxysmalatrialtachycardia(PAT). Atrialfluttersinusrateof250350beats/min. Atrialfibrillationuncoordinatedatrialdepolarizations. JunctionalEscapeRhythmSAnodesuppressioncanresultinAVnodegeneratedrhythmof4060beats/min (notprecededbypwave). AVblocksaconductionblockwithintheAVnode(oroccasionallyinthebundleofhis)thatimpairsimpulse conductionfromtheatriatotheventricles. Supraventriculartachycardia(SVT)usuallycausedbyreentrycurrentswithintheatriaorbetweenventricles andatriaproducinghighheartratesof140250. Ventricularprematurebeats(VPBs)causedbyectopicventricularfoci;characterizedbywidenedQRS. Ventriculartachycardia(VT)highventricularratecausedbyaberrantventricularautomaticityorby intraventricularreentry;canbesustainedornonsustained(paroxysmal);characterizedbywidenedQRS; ratesof100to200beats/min;lifethreatening. 60|U R V I S H M I S T R Y
61|U R V I S H M I S T R Y Ventricularflutterventriculardepolarizations>200/min. Ventricularfibrillationuncoordinatedventriculardepolarizations VentricularfibrilfirstdegreeAVnodalblocktheconductionvelocityisslowedsothatthePRintervalis increasedtogreaterthan0.2seconds.Canbecausedbyenhancedvagaltone,digitalis,betablockers, calciumchannelblockers,orischemicdamage. SeconddegreeAVnodalblocktheconductionvelocityisslowedtothepointwheresomeimpulsesfrom theatriacannotpassthroughtheAVnode.thiscanresultinPwavesthatarenotfollowedbyARS complexes.forexample,1or2PwavesmayoccuralonebeforeoneisfollowedbyaQRS.WhentheQRS followsthePwave,thePRintervalisincreased.Inthistypeofblock,theventricularrhythmwillbelessthan thesinusrhythm. ThirddegreeAVnodalblockconductionthroughtheAVnodeiscompletelyblockedsothatnoimpulsesare abletobetransmittedfromtheatriatotheventricles. QRScomplexeswillstilloccur(escaperhythm),buttheywilloriginatefromwithintheAVnode,bundleof his,orotherventricularregions.Therefore,QRScomplexeswillnotbeprecededbyPwaves. Furthermore,therewillbecompleteasynchronybetweenthePwaveandQRScomplexes. Atrialrhythmmaybecompletelynormal,butventricularrhythmwillbegreatlyreduceddependinguponthe locationofthesitegeneratingtheventricularimpulse. Ventricularratetypicallyrangefrom30to40beats/min. WOLFFPARKINSONSYNDROMEAnaccessorypathway(BundleofKent)thatconnectstheatriaandthe ventricles,inadditiontotheAVnode.Thisaccessorypathwaydoesnotsharetherateslowingpropertiesof theAVnode,andmayconductelectricalactivityatasignificantlyhigherratethantheAVnode
Arrhythmia
Arrythmiaisanyabnormalpatternofelectricalactivityintheheart.Normallythewavesofdepolarization followaspecificsequence,startingintheSAnodeandendingwiththecontractionofthe ventricles.Sometimesanotherareaofthemyocardiumorconductingsystembeginstodepolarizeoutof sequenceormorerapidlythantheSAnode,disruptingthenormalelectricpattern. Arrhythmiasaredividedintotwogeneralgroups:thosethatresultinanincreasedheartrateandthosethat resultinadecreasedheartrate. Arrhythmiasarefurthersubdividedintogroupsaccordingtothelocationoftheectopicfociorlesioncausing arrhythmia. Asupraventriculararrhythmiaindicatedthatthecauseoftheproblemisabovetheventricle. Aventriculararrhythmiaindicatesthattheproblemoriginatesintheventricles. Theabnormalsiteofdepolarizationiscalledanectopicfocus. AnectopicfocusintheventriclesmaybeindicatedontheECGasasinglelargebizarrewave.Multiple prematureventricularcontractionscauseflutter.Iftheconductiondisturbanceissevere,thehearthasno coordinatedcontractionsandtheconditionisreferredtoasventricularfibrillation.
Antiarrhythmic drugs

Antiarrhythmicsareagentsusedtocontrolectopicfociorreversedisorganizedconductionofelectrical impulsesthroughtheheart Althoughresearchhasprovidedsomeinformationregardingthecellularmechanismsofarrhythmiasandthe modeofactionofantiarrhythmicdrugs,thegeneralapproachtotherapyremainsempirical.
Classification
Antiarrhythmicsorantidysrhythmicsareclassifiedasfollows. o ClassIdrugsactbyblockingthesodiumchannel.Theyaresubdividedinto3subgroups,IA,IB,andIC, basedeffectsonphase0deploarizationandrepolarization: SubclassIAdrugshavemoderatepotencyatblockingthesodiumchannelandalsousually prolongrepolarization(increaseQRS)Eg.quinidne,procainamide,disopyramide SubclassIBdrugshavethelowestpotencyassodiumchannelblockers,producelittleifany changeinactionpotentialduration,andusuallyshortenrepolarization.Eg.lidocaine, phenytoin 61|U R V I S H M I S T R Y
62|U R V I S H M I S T R Y SubclassICdrugsarethemostpotentsodiumchannelblockingagents,andhavelittleeffect onrepolarization(increasePR,increaseQRS)Eg.flecainide,encainide o ClassIIdrugsactindirectlyonelectrophysiologicalparametersbyblockingbetaadrenergicreceptors (increasingPR).eg.propranolol o ClassIIIdrugsactbymechanismsthatarenotwellunderstood(interferencewithpotassium conductanceisonepossiblemechanism),butacttoprolongrepolarization(increaserefractoriness), withlittleeffectontherateofdepolarization(QT).eg.sotalol,amiodarone o ClassIVdrugsactbyblockingthevoltagesensitivecalciumchannels.Theyslowtheconductionin theSAandAVnodeswhereactionpotentialpropagationdependsonslowinwardcalciumcurrent. eg.verapamil,nifedipine Inadditiontotheaboveclasses,thereisalsoamiscellaneousgroupofdrugsthatincludesdigoxin, adenosine,andalinidine(achloridechannelblocker). o Drugswithinaclassarenotnecessarilyclinicallysimilar:apatientmayrespondwelltoonedrugina givenclass,butnotanother. o Almostallofthecurrentlyavailabledrugshavemultipleactions;inagivenpatient,itisdifficultto establishwhichactionisresponsiblefortheaction o Themetabolitesofsomedrugscontributetoorareprimarilyresponsiblefortheirantiarrhythmic actions(e.g.procainamideanditsmetabolite,Nacetylprocainamide;encainideanditsmetabolite, 3methoxyOdesmethylencainide)
Actions of sodium channel blockers
Theenhancementofsodiumchannelblockseeninrapidlydepolarizingtissuehasbeentermed"use dependentblockade"andisthoughttoberesponsiblefortheefficacyofthesedrugsinslowingand convertingtachycardiaswithminimaleffectsonconductioninnormaltissuesstimulatedatnormal physiologicalrates. Atheorytoexplainusedependentblockade,termedthemodulatedreceptortheory(MRT),hasbeen proposedandusedtoexplainmanycharacteristicsofthesodiumchannelblockers. ThistheoryisbasedonathreestatemodelforthesodiumchanneloriginallyproposedbyHodgkinand Huxley: Thethreenormalchannelstatesare:Resting,Open(orActivated),andInactive 62|U R V I S H M I S T R Y
63|U R V I S H M I S T R Y o Undernormalrestingconditions,thesodiumchannelsarepredominantlyintheRestingstateand arenonconducting. o Whenthemembraneisdepolarized,thesodiumchannelsOpenandconductsodium,resultinginthe inwardsodiumcurrentthatmakesthemajorcontributiontophase0oftheactionpotential o TheinwardsodiumcurrentrapidlydecaysaschannelsmovetotheInactivestate o ThereturnoftheInactivechanneltotheRestingstateistermedreactivationandisvoltageand timedependent. o Thetheoryassumesthatsodiumchannelblockerdrugsbinddifferentchannelstateswithdifferent affinitiesandthatdrugbindingaltersthetransitionratesbetweendifferentstates. o DrugbindingresultsintransitionstoR*,O*,andI*channelstates.These"*"stateshavedifferent transitionratesbetweenstatesthanthenormalchannelstates. o ThemostclinicallyusefuldrugswouldhaveaffinityfortheOpenand/orInactivestate,andthereby exhibitusedependentblockade. o DrugswithhighaffinityfortheRestingstatewouldbetoxic.
Adrenergic blockers
Thedrugsinthisclasssuppressadrenergicmediatedectopicactivity.Themembersofthegrouplike propranololblockthebetareceptorsofthecardiactissue.ItdecreasesslopeofPhaseIVdepolarizationand automaticityinSAnode. Propranololisusefulintreatingsinustachycardia,extrasystolesprovokedbyexerciseoremotion. SotalolisbetablockerwithalsoClassIIIactivity. Esmololisashortactingdrugforemergencycontrolofventricularrate
Actions on potassium currents

Potassiumcurrents,predominantlythecurrentknownasthedelayedrectifier,areresponsiblefor repolarizingthemembraneduringtheactionpotential. Blockofpotassiumcurrentsduringtheplateauphaseoftheactionpotentialisthoughttobethemechanism ofactionofmanydrugsthatprolongtherefractoryperiod. Drugsthatarethoughttoact,atleastinpart,byinhibitingpotassiumcurrentsincludequinidine,sotalol,N acetylprocainamide,andamiodarone. Thesedrugstendtohaveahigherpropensitytocausetorsadesdepointes(aproarrhythmiaalsoreferredto asdruginducedlongQTsyndrome). Mostoftheavailabledrugsthatprolongrepolarizationexhibitnegativeratedependence,whereaspositive ratedependence(i.e.greaterefficacyintachycardias)istheidealcharacteristicfordrugsusedtoconvert spontaneoustachycardia. Somedrugsusedtotreathypertensionandangina(nicorandil,pinacidil,andseveralotherdrugs)activateor openpotassiumchannelsandtherebyacttoshortenrefractorinessofmyocardialtissuewhichleadsto arrhythmogenicstatesinanimalmodels.
Actions of Ca channel blockers

Mostclinicalventriculararrhythmiasareneitherpreventednorsuppressedbycalciumchannelblockers CalciumchannelblockersareusefulintreatingarrhythmiasinvolvingreentrywithintheAVnodeandinthe rareformsofmonomorphicventriculartachycardiaseeninpatientswithstructurallynormalmyocardium Manyofthecalciumchannelblockersalsohavetheabilitytoblocksodiumchannels,probablyduetothe similarityintheiraminoacidsequences(sequencehomology) Calciumchannelblockadeisenhancedbyverapamil(andtoalesserextentbydiltiazem)asthefrequencyof depolarizationisincreased Diltiazem ForSVTs,hypertension Dose:Dogs0.1250.35mg/kgi.v,chronicmanagement0.51.5mg/kgp.oq8h Cats0.51mg/kgp.o Ferrets(hypertrophiccardiomyopathy)27.5mg/kgp.otwicedaily Verapamil 63|U R V I S H M I S T R Y

64|U R V I S H M I S T R Y Dose:Dogs0.05mg/kgi.vslowly,repeatevery5minutesoral0.52mg/kg.q.8h
Clinical uses of antiarrhythmic drugs
ClassIdrugs:Qunidineandprocainamideareseldomusedinarrhythmiasnowbecauseoftheirsideeffects. Disopyramideisusedinatrialfibrillation.Lignocaineisusedintravenouslytotreatventriculartachycardia andpreventventricularfibrillation.(Preparationscontainingadrenalinealongwithlignocaineshouldnotbe used). ClassIIdrugs:Thesedrugsareusedinpatientsrecoveringfrommyocardialinfarction.Theyarealsoused prophylacticallyagainstrecurrenttachycardia. ClassIIIdrugs:Thesedrugsareusefulinsupraventricularandventriculararrhythmias. ClassIVdrugs:Verapamilisusedtopreventrecurrenceofsupraventriculartachycardia,toreduceventricular rateinpatientswithatrialfibrillation.Thesedrugsaredangerousandineffectiveinventriculararrhythmias.
Adverse effects of Antiarrhythmic drugs
Oneofthemostcommonandseriousadversecardiaceffectsisproarrhythmia(arrhythmiaironically precipitatedbyantiarrhythmictherapy)whichcanoccurin520%ofpatientstreatedwithClassIandClassIII drugs. ClassIdrugs(Sodiumchannelblockers): o Proarrhythmiceffect o Dosedependentnegativeinotropiceffect SubclassIA(especiallyquinidine)Torsadesdepointes("twistingofthepoints"): o Usuallyoccurswithinthefirstweekoftherapy o PreexistingprolongedQTintervalsmaybeindicatorofsusceptibility o Potentiatedbybradycardia o Oftenassociatedwithconcurrentelectrolytedisturbances(hypokalemia,hypomagnesemia) SubclassICVentriculartachycardia ClassIIdrugs(Betablockers): o Sinusbradycardia o Atrioventricularblock o Depressionofleftventricularfunction ClassIIIdrugs(Potassiumchannelblockers): o Sinusbradycardia o Torsadesdepointes ClassIVdrugs(Calciumchannelblockers): o Atrioventricularblock o Negativeinotropicaction
Adverse extra cardiac effects
Oneofthemostcommonandseriousadversecardiaceffectsisproarrhythmia(arrhythmiaironically precipitatedbyantiarrhythmictherapy)whichcanoccurin520%ofpatientstreatedwithClassIandClassIII drugs. ClassIdrugs(Sodiumchannelblockers): o Proarrhythmiceffect o Dosedependentnegativeinotropiceffect SubclassIA(especiallyquinidine)Torsadesdepointes("twistingofthepoints"): o Usuallyoccurswithinthefirstweekoftherapy o PreexistingprolongedQTintervalsmaybeindicatorofsusceptibility o Potentiatedbybradycardia o Oftenassociatedwithconcurrentelectrolytedisturbances(hypokalemia,hypomagnesemia) SubclassICVentriculartachycardia ClassIIdrugs(Betablockers): o Sinusbradycardia o Atrioventricularblock 64|U R V I S H M I S T R Y
65|U R V I S H M I S T R Y o Depressionofleftventricularfunction ClassIIIdrugs(Potassiumchannelblockers): o Sinusbradycardia o Torsadesdepointes ClassIVdrugs(Calciumchannelblockers): o Atrioventricularblock o Negativeinotropicaction
Vasodilators and antihypertensive drugs

Direct acting Vasodilators
Directlyactingvasodilatorsproducetheiractionmainlybyinterferingwiththeavailabilityofcalciumfor vasoconstriction. CalciumentryispreventedeitherbyblockingvoltagedependentCa2+channelsorbycausing hyperpolarization. DrugsproducevasodilatoractivitybyalteringCa2+releasefromthesarcoplasmicreticulumorreuptakeinto itandenzymesthatdetermineCa2+sensitivity. Thesemechanismsareexemplifiedbycalciumantagonists,potassiumchannelactivatorsanddrugsthat influencecytoplasmicconcentrationsofcyclicneucleotides. Nitrates Amylnitrate,isosorbidedinitrate,glyceryltrinitrate(nitroglycerine)areusedasvasodilators. Theseareavailableasoraltablets,buccaltablets,sublingualtablets,inhalationpreparations,topicalpatches (sustainedrelease)andtopicalointment. Nitroglycerinealsohelpstodilatecoronarybloodvessels. Thesedrugscauseadirectrelaxationofarterialandvenoussmoothmusclesbyactingasasourceofnitric oxidewhichisreleasedandcausesdirectrelaxation. Toxicityincludeshypotension,methemoglobinaemiaanddermatitis. Calciumchannelblockers Thesedrugscausegeneralizedvasodilatation,thoughindividualagentsdifferinregionaldistributionofthe effectbyreducingintracellularavailabilityofCalciumions. Drugsunderthiscategoryincludeverapamil,diltiazem,nifedipine,nimodipineandamlodipine. Potassiumchannelactivators ThesedrugsrelaxsmoothmusclesbyselectivelyincreasingthemembranepermeabilitytoK+. Thishyperpolarizesthemembrane,switchingoffvoltagedependentCa2+channelsandinhibitingaction potentialgeneration. Drugsunderthiscategoryincludecromokalin,pinacidil,minoridilanddiazoxide. Agentsthatactbyincreasingcyclicnucleotideconcentration Cyclaseactivation o ManydrugsrelaxvascularsmoothmusclebyincreasingthecellularconcentrationofeithercGMPor cAMP. o Dopaminehasmixedvasodilatorandvasoconstrictoractions,but,isusedtherapeuticallytodilate therenalvasculaturewhereitincreasesthecAMPbyactivatingadenylatecyclase. Nitroprusside o Isaverypowerfulvasodilatorwithlittleeffectsoutsidethevascularsystem. o Itbreaksdownunderphysiologicalconditionstoyieldnitricoxide,whichproducesthe vasodilatationeffect. o Toxicitytonitroprussideincludesexcessivevasodilatationandaccumulationofthiocyanate. o Thisdrugalsohasaveryshorthalflifeandmustbeadministeredbyintravenousrouteasafreshly preparedsolution. Natriureticpeptidescausevasodilatationbyactivatingguanylatecyclase. Phosphodiesteraseinhibitorsliketheophyllinecanalsocausevasodilatation. Vasodilatorswithunknownmechanismofaction 65|U R V I S H M I S T R Y
66|U R V I S H M I S T R Y Hydralazine o Actsmainlyonarteriesandarteriolescausingafallofbloodpressureaccompaniedbyreflex tachycardia. o Thisdrugproducesanincreaseinthestrokevolumeandisusefulinmitralinsufficiency. Ethanol o Dilatescutaneousbloodvesselscausingthefamiliardrunkardsflush.
Indirectly acting vasodilators

Thisconsistsoftwogroupsnamely o Thosethatinhibitsympatheticallymediatedvasoconstriction.Drugscaninhibitsympathetic pathwayatanypointfromthecentralnervoussystemtotheperipheralnervousterminal.Prazosina selective1adrenergicantagonistreducesmeanarterialpressure. o thosethatinhibitrenninangiotensinsystem Renininhibitors Severaldrugsinhibitreleaseofrennin,butthismechanismofactionisnotofimportance. Reninactivityinhibitorslikeenalkirenhavebeendeveloped.Buttheirclinicaluseisnotappreciable. ACEinhibitors CaptoprilwasthefirstACEinhibitortobedeveloped.OtherACEinhibitorsincludeenlapril,lisinopril, ramipril,perindoprilandtrandolaprl. Thesedrugsareusefulinhypertension,cardiacfailure,myocardialinfarction,diabeticnephropathyand progressiverenalfailure. AngiotensinIIreceptorsubtypeantagonists LosartanisaorallyactivepureantagonistofAT1receptor. Theyarebeingtriedinelderlypatientswithheartfailure.
Clinical uses
Clinicalusesofvasodilatorsinclude Hypertension, Cardiacfailureand Shock
Vasoconstrictors

1adrenergicagonistsanddrugsthatreleasenoradrenalinefromthesympatheticnerveterminalsorinhibit itsreuptakecausevasoconstriction. SomeeicosanoidslikethromboxaneAandseveralpeptideslikeendothelin,angiotensinandvasopressinare alsopredominantlyvasoconstrictors.
Clinical uses of vasoconstrictors

Clinicalusesofvasoconstrictorsinclude nasaldecongestion coadministrationwithlocalanaesthetics vasopressinmaybeusedtostopbleedingfromoesophagealvaricesinpatientswithportalhypertension causedbyliverdiseases.
Classification of antihypertensive drugs

Theseareagentsusedtoreducetheelvatebloodpressure.Theycanbeclassifiedbasedonthemechanismofaction asunder: Agentsinterferingwithsympatheticactivity o Alphaadrenergicreceptorblockers:Phentolamine,tolazoline,prazosin, o Betaadrenergicbolckers:Propranolol,Atenolol,Metoprolol o AlphaandBetaadrenergicblocker:Labetalol o Agentsinterferingwithsentralsympatheticactivity:Clonidine Vasodilators 66|U R V I S H M I S T R Y
67|U R V I S H M I S T R Y o Nitrates:Amylnitrate,isosorbidedinitrate,glyceryltrinitrate(nitroglycerine)areusedas vasodilators. o Calciumchannelblockers:Drugsunderthiscategoryincludeverapamil,diltiazem,nifedipine, nimodipineandamlodipine. o Potassiumchannelactivators:Drugsunderthiscategoryincludecromokalin,pinacidil,minoridiland diazoxide. o Agentsthatactbyincreasingcyclicnucleotideconcentration:Nitroprusside o Vasodilatorswithunknownmechanismofaction:Hydralazine o AgentsactingthroughinhibitionofAngiotensin AngiotensinConvertingenzymeinhibtors:Enalapril,Captopril AngiotensinReceptorblocker:Losartan
Antihypertensive drugs
Firstlineantihypertensivedrugs ACEinhibitors AT1antagonists adrenergicblockers Calciumchannelblockers Diuretics Diuretics Thiazidesandrelateddrugsaredrugsofchoiceinuncomplicatedhypertension Thiazidesaremildantihypertensives Effectiveinelderlypatients o TheyareeffectiveinIsolatedsystolichypertension, o lowreninhypertension o Obesewithvolumeoverload Theyareindicatedinhypertensioncomplicatedby o Heartfailure o RiskofCoronaryarterydisease o Diabetes Diureticsshouldbeavoidedin o Patientswithabnormallipidprofile o Pregnancyinducedhypertension ACEInhibitors/AT1blockers Firstchoicedruginallgradesofessentialaswellasrenovascularhypertension ACEinhibitorsshouldbeavoidedin o Bilateralrenalarterystenosis o Pregnancy o Hyperkalaemia Mostappropriateantihypertensivesinpatientswith o Diabetes o Nephropathy/chronickidneydisease o Leftventricularhypertrophy o Congestiveheartfailure o PostMyocardialInfarction o Gout o Dyslipidemia Theyappeartobemoreeffectiveinrelativelyyoungpatients ACEinhibitorsproducepersistentcough(duringthefirsttwoweeks)anddysguesia(lossoftastesensation). blockers Mildantihypertensive Theyareindicatedasantihypertensiveinpatientswith o Stableheartfailure 67|U R V I S H M I S T R Y
68|U R V I S H M I S T R Y o Postmyocardialinfarction o Highcoronaryarterydiseaserisk Highlysuitablefor o Patientswithcoexistinganxietyortachycardia o Relativelyyoungnonobesepatients o Highreninhypertensivepatients o Migrainepatients o Pregnantindividuals Contraindicatedin o Peripheralvasculardisease o Pulmonarydiseaseasthma,COPD o CardiacdiseaseConductiondefects,decompensatedheartfailure o Abnormallipidprofile CalciumChannelblockers Preferredin o Elderlyhypertensivepatientswhohavepoorarterialwallcompliance o Isolatedsystolichypertension o Asthma/COPDpatients o Pregnanthypertensive o Diabetes Preventsrecurrentstroke Verapamilanddiltiazemshouldbeavoidedin o Congestiveheartfailure,cardiacconductiondefects Dihydropyridinesshouldbeavoidedin o Ischaemicheartdisease o Postmyocardialinfarction o Gastroesophagealreflux o Maleswithprostateenlargement
Hematinic, coagulants and anticoagulants

Haematinics
Haematinicsareagentswhichareusedinthetreatmentofanaemiaandgenerallyactbystimulationofhaemoglobin synthesisoferythropoiesis. Iron Ironisnecessaryforhamoglobinformation.Itisavailableinthediet. Howeveroftenitissupplementedforthetreatmentofdeficiencyofironbygivingasoralorparenteral preparation. Oralpreparationshouldbesuppliedasferroussulphate,gluconateandfumarate.Theusualdoseis100300 mg/kgfordogsand50100mg/kgforcats. Parenteralpreparationscanbeadministerediforalpreparationsarenotfeasible.Irondextrancanbegiven asasingleinjectionat23daysofageinneonatalpigs. Copper Copperisutilizedasacofactorinthesynthesisofhaemoglobin.Copperdeficiency,ifsuspectedistreatedby administeringcoppercontainingsaltssuchascoppersulphateorcopperglycinate. Cobalt CobaltisutilizedforthesynthesisofVitaminB12.SupplementationisbysulafateorchlorideofCobalt@0.2 to0.5gm/dayforcattleor0.050.1gm/dayforsowthroughfeedororaldrenching. Folicacid FolicacidisalsoessentialforsynthesisofDNAandRNAandthussynthesisofRBCs.Anaemiaduetofolic aciddeficiencyiscalledmegaloblaticanaemia.Folicacidisalsoavailablebydietfromyeast,liver,vegetables etc.Supplementationoffolicacidcanbegivenasoralsupplements@25mg/kg/day. 68|U R V I S H M I S T R Y
69|U R V I S H M I S T R Y VitaminB12 VitaminB12isessentialforDNAsynthesis.DeficiencyofVitaminB12causesnuclearmaturationanddivision andcausesperniciousanaemia.Supplementationisgivenbyparenteralpreparationsofcyanocobalamin@ 25g/kg. Erythropoietin Itisaglycoproteinhormoneproducedbyrenalperitubularcellsinresponsetohypoxicsignalsreceivedin thekidney.Itisessentialfornormalerythropoiesis.Thisactsonbonemarrowtostimulateerythropoiesis. Erythropoietinisindicatedinanaemiaduetochronicrenalfailure.Thesyntheticformoferythropoietin Epoetinalfaisavailableandisgivensubcutaneousinjections. Anabolicsteroids Thesearetestosteronelikecopoundswithproteinanabolicactivity.TheyincreasecirculatingRBCmass. Theyareindicatedinchronicnonregenerativeanaemias.Nandrolone,Stanozalolareproducysthatare availabletobegivenbyoralroute.
Coagulants
Coagulantsareagentsthatpromotecoagulationofblood.Variouscoagulantsusedare Thromboplastin Thrombopalstin(thrombokinase)isproducednaturallybyplateletsanddamagedtissue. Commercialthromboplastinisanextractofcattlebraininnormalsaline. Itisappliedlocallyasahaemostaticincapillaryoozing,inthetreatmentofepistaxis. Thrombin Thrombinisanenzyme,whichconvertsfibrinogenintofibrin. Bovinethrombinisapowdersuppliedwithsuitablediluent. Itisusedinarrestingcapillaryhaemorrhageandinconjunctionwithfibrinogenorfibrinfoamforthis purpose. Fibrinogen Fibrinogenisusedinassistingtheadhesionofgraftsofskinandmucousmembraneasa2%solution. Fibrin Fibrinisavailableasfibrinfoamintheformofstripsofafinewhitesponge. Thesestripsaresoakedinthrombinsolutionandplacedoverthesiteofhaemorrhageorinthecavity. Coagulationoccursimmediately. Oxidisedcellulose Itshouldbeapplieddryandwhenitswellsformsabrowngelatinousmasswhichmaytakeabout7daysor moretobeabsorbed. Calciumalginate Thisconsistsofcalciumoramixtureofcalciumandsodiumalginates. Itisanabsorbablehaemostatic. Absorbablegelatinsponge Thisispreparedfromgelatinandtreatedwithformaldehyde,heated,whiskedintoafoamandfreezedried. Thisspongeisinsolubleinwater,butcanbewetted. Miscellaneouslocalhaemostaticsincludestrongsolutionofferricchloride,alumandtannicacid. o Freshbloodorplasma o VitaminK VitaminK1(fromplants,fatsoluble)Phytonadione VitaminK2(producedbybacteria)Meanquinone VitaminK3(i)FatsolubleMenadione WatersolubleMenadionesodiumbisulfite,Menadionesodiumdiphosphate o Miscellaneous Fibrinogen Antihaemophilicfactor Tissueextract Adrenochromemonosemicarbazone Rutin
70|U R V I S H M I S T R Y Ethamsylate
Anticoagulants

Anticoagulantsareagentsthatinhibitcoagulationofbloodeitherinvitroorinvivo. Theinvitroanticoagulantsareusefulinthecollectionofbloodforlaboratoryanalysisorforblood transfusion
In vitro anticoagulants
Anticoagulantsusefulforbloodcollectionforlaboratoryuseinclude o Sodiumoxalate20%solutionat0.01ml/mlofblood o Sodiumcitrate25%solutionat0.01ml/mlofblood o Edetatedisodium(EDTA)2%solutionat0.01ml/mlofblood o Heparinsodium75IU/10mlofblood Anticoagulantsusefulforbloodcollectionfortransfusioninclude o Sodiumcitratesolutionat10ml/90mlofbloodcontainingSodiumcitrate2.5g,sodiumchloride0.9 ganddistilledwatertomake100ml o ACDsolutionAcidcitratedextrosesolutionat15ml/100mlofbloodcontainingSodiumcitrate2.5 g,citricacid0.8g,dextrose2.5ganddistilledwatertomake100ml o Heparinsodiumat400to600IU/100mlofwholeblood Inadditiontotheaboveagentsapplyingcoldat2to5Corcollectingbloodinareceptaclehavingsmoothor unwettablewallslikesiliconcoatedreceptaclescanalsobeusedtocollectbloodwithoutcoagulation.
Systemic anticoagulants in vivo

Heparin Heparinisusedbothasinvitroandinvivoanticoagulant.Heparinisusedparenterallyasananticoagulant. Ithasdirectandalmostinstantaneousactiononthecoagulationprocess. Heparinispresentinmastcellsalongwithhistamineandserotoninandispreparedcommerciallyfrom bovinelungandporcineintestinalmucosa. Heparinisahighlynegativelychargedmucopolysaccharidehavinglargermolecularsizeandhenceis administeredparenterally. Heparinprolongstheclottingtimeofbloodbothinvivoandinvitro. Heparinpreventsfibrinformationintheprocessofcoagulation. ItincreasestheactivityofantithrombinIII. AntithrombinIIItheninhibitstheconversionofprothrombintothrombinbythromboplastin. AntithrombinIIIalsodirectlyinactivatesthrombininthepresenceofheparin. Heparindecreasesaldosteronesecretion,increasestheconcentrationoffreethyroxine. Itslowswoundhealinganddepressescellmediatedimmunity.
Clinical uses of anticoagulants

Prophylaxisandtreatmentofvenousthrombosisandpulmonaryoedema Inatrialfibrillationwithembolisation Inthediagnosisandtreatmentofchronicconsumptivecoagulopathies. Asananticoagulantinbloodtransfusion Forthepreventionofclottinginatrialandcardiacsurgery Forpreventionofcerebralthrombosis
Coumarin derivatives

Coumarinisnormallypresentinsomespeciesofsweetcloverandhasnoanticoagulantactivity. Thederivativesofcoumarinnamelydicumarol(bishydroxycoumarin)andwarfarinarecoumarinderivatives. Warfarinsodiumisthedrugofchoiceandistheprototypecoumarinderivativeanticoagulant. Coumarinderivativesareusedasoralanticoagulants. TheyarevitaminKantagonists. Theytakeabout812hourstoproducetheiraction. 70|U R V I S H M I S T R Y
71|U R V I S H M I S T R Y Theyarewidelyusedinsecondaryprophylactictreatmentofvenousthrombosisandpulmonaryembolism. Aspirin,cimetitidine,phenylbutazone,oxyphenbutazone,cotrimoxazole,metronidazoleanddisulfiram increasetheresponsetoanticoagulants.
Heparin antagonist

Protaminesulphateisastronglybasiclowmolecularweightproteinobtainedfromthespermofcertainfish. Givenintravenouslyitneutralizestheheparinweightforweight. Intheabsenceofheparin,protaminesulphateitselfactsasaweakanticoagulant
Respiratory pharmacology expectorants

Expectorants

Expectorantsincreasethefluidityandvolumeofrespiratorysecretions,andintheearlystagesof inflammationrelievespainandtendstoreduceslightlytheincidenceofcoughing. Thecontributionofexpectorantstotherapeuticsuccessisslightandtheirmainroletodayisascomponents ofcompoundcoughremediesfororaladministration. Expectorantsareclassifiedasinhalantexpectorants,ingestedexpectorantsandmucolyticexpectorants.
Inhalant expectorants

Theinhalantsarestillusedalone. Theseagentseitherheatedordissolvedinsteamingwaterareintendedforinhalationinaconfinedair space. Animals,atleastinitially,appeartoresentthestrongodourandthesteam. Thewholeprocedureistroublesome,and,becauseofthesteamgeneratingapparatus,potentially dangerous. Smallanimalsarebestsimplyexposedtosteamforrepeatedshortperiodsortoanaerosolofwater generatedbypumpandfedintoafacemaskorasmall,enclosedcage. Theseproceduresareeffectiveinchronicrespiratorydiseaseandaresupportedbyappropriate physiotherapydesignedtoaidthedrainageandexpulsionoftheliquefiedexudates. Inhalantexpectorantsincludebenzoin,eucalyptusoilandothervolatileoils,andwoodtarsandoilssuchas turpentineoroneofitsrefinedfractions,liketerebene.
Ingested expectorants

Systemicexpectorantsofdiverseoriginsareavailable. Thesearealladministeredbymouth. Somearenauseantsandcaninducevomiting,butareadministeredinsubemeticdoses. Othersareabsorbedfromthegutandareexcreted,atleastinpart,viathebronchialmucosa. Reflexornauseantexpectorantsincludeipecaacuanha,squill,balsamoftoluandcocillana,allofwhichareof vegetableorigin. Ipecacuanhacontainsanemeticalkaloid,emetineandsquillcontainsaglycosidewithemeticand cardiotonicproperties. Bronchialsecretionsarestimulatedasaphysiologicalpreludetovomiting. Locallyacting,systemicallyadministeredexpectorantsofvalueinchronicconditionsarerepresentedby sodiumiodideandpotassiumiodide. Theiodideisrapidlyexcretedthroughthebronchialmucosaandincreasesitssecretoryactivity. Ammoniumchlorideisoneofthemanyammoniumsalts,whichhavebeenusedasexpectorantsdespitelack ofagreementastotheirmodeofaction. GuiacolandGlycerylguiacolate(guaifenesin),aderivativeofguiacolobtainedfromcreosotearecommon stimulantexpectorantsincoughmedications,
Mucolytics
Mucolyticsassistinpreventingorremovingmucusplugsthatcauseatelectasisandthismayprogressto bronchiectasis.Sodiumacetylcysteinesolution20%isinhaledintheformofsprayoraerosol.Thesulphydryl 71|U R V I S H M I S T R Y
72|U R V I S H M I S T R Y groupofacetylcysteinebreaksdisulphidebondsintheglycoproteinsinexudates.Thedrugshareswith DMSOthepropertyofscavenginghydroxylradicals. Itcausesmildirritationtotherespiratorytract,butitsotherwisesafeandsuccessfulineffectingtherapid liquefactionofmucopurulentmaterials. Severalminutesofexposurerepeatedtwoorthreetimesaday,perhapswithpositivepressure,givesthe bestresults. Acetylcysteineisalsousedasanintravenousantidoteforacetaminophentoxicityincats. Bromhexineisofvalueinachievingliquefactionandimprovedflowcharacteristicsofmucusbyincreasingits volumeanddecreasingitsviscidity. Itisavailableinsolutionorasapowder,aloneormixedwithantibacterialagents. Bromhexinebringsaboutanincreaseinthecontentofimmunboglobulinandoxytetracyclineinbronchial secretions,presumablybyincreasingmembranepermeability. Thedrugimproveslysosomalfunctionandthatlysosomalenzymeshydrolysethemucopolysaccharidefibers ofmucous. Thedoserateis1mg/kgbodyweighttwicedailyinsmallanimalsand0.10.25mg/kgbodyweightin horses,eitherorallyorparenterally,for7days. Dembrexineisofvalueintreatingequinesandforitsactiononthesecretoryactivityofserousglandularcells inrespiratorymucosae. Themucusofmodifiedcompositionandhencedecreasedviscosityissecreted. Suchmucusismoreamenabletomucociliaryclearanceandcausespeedierreductionincoughingand cessationofmucusproductionintreatedanimals. Theproductcanbeadministeredintravenouslyorbymouthatadoserateof0.30.5mg/kgtwicedailyfor10 days.
Decongestants and antitussives

Decongestants

TwomajorcategoriesofdrugsusedasdecongestantsaretheH1antagonistsandsympathomimeticdrugs likeephedrine,pseudoephedrineandphenylephrine. Thealphaadrenoceptoragonistscauseshrinkageoftheswollenmucosaofthenasaltractinallergicorviral rhinitis Examplesareoxymetazoline,xylometazolineetc.
Antitussives

Coughsedativesorantitussivescausedepressionofthecoughcentreandreducetheincidenceofcoughing. Theyshouldnotbeusedwhenrespiratorysecretionsarecopiousunlesscoughingisexcessiveandcausing exhaustion(thisstateisuncommoninanimals). Antitussives,whichdiminishthefrequencyofcoughing,areofbenefitwhencoughingispainful,non productive,distressing,exhaustingandlikelytoexacerbateorevencauselungdamage. Theyactbyinterferingwiththecoughreflex,eitheratthelevelofthesensoryendingsintheupper respiratorytract,oratthelevelofcentralnervoussystem. Astrongantitussiveshouldnotbeusedwithanexpectorantbecauseincreasedfluidneedstoberemovedby coughingbuttheantitussivewillreducecoughing. Althoughsomeantitussivessuchasdextromethorphanareusedwithexpectorants,thecoughsuppression producedisnotsufficienttohinderremovalofexcesssecretions.
Directly acting antitussives

Localactionisachievedbydemulcent;thesweet,syrupyvehiclesinwhichothercoughremediesare dissolved. Demulcents(honeyandsyrup)coat,protectandsootheinflamedmucosaeforabriefperiod. Amorespecificactioninclaimedforbenzonatate,anagentthatdepressestheafferentsensorsofthecough reflexandpulmonarystretchreceptors. Localanestheticscanbeusedtocontrolseverecough. 72|U R V I S H M I S T R Y
Centrally acting antitussives

Thecoughcentreislocatedinthemedullaoblongata,incloseassociationwiththerespiratorycentre. Specificneuronsinvolvedincoughcoordinationhaveshowntobesuppressedbyantitussives. Codeine(methylmorphine)isanaturallyoccurringalkaloidandhasbeenthemajorantitussive Itsharesmanyotheractionsofmorphineatalesspotentlevel,eg.itisanalgesicandconstipant. Itcanbeconvertedtomorphineinthebody,butthisdoesnotgiverisetohabituationatthedosesusedfor coughcontrol,althoughaddictiontocodeineispossible. Codeineiswellabsorbedfromthegutandowesitssatisfactorydurationofactiontoaslowermetabolism. Codeinedoesnotcauserespiratorydepressionasdomorphine. Codeineiseffectiveatanoraldoseof12mg/kg. Morphineanddimorphine(heroin)canbeusedascoughsuppressant,theiruseisrestrictedtothecontrolof severecoughinterminalstages. Butorphanolisacentrallyactingopioidcoughdepressantthatcauseslittlesedationascomparedtostronger opioiddrugs. Hydrocodoneisanarcoticdrugthatisusedasanantitussiveinwhichsedationiscommonandlongterm administrationresultsinconstipationwithanoverdoseofhydrocodonecausingsevererespiratoryand cardiovasculardepression. Nonnarcoticantitussiveshavebeendevelopedtoincreasethesafetyoftheseagentsforuseinman,inan attempttoretaintheabilityofcodeinetosuppressthecoughcentrebuttolosetheCNSeffectse.g. respiratorydepression,analgesiaandatendencytohabituation. Pholcodeineisabouttwiceaspotentascodeine,nosacapine(ahistaminereleaserindogs)and dextromethorphanareaboutequipotent,anddextrorphanisabouthalfaspotent. Allsharethemildsedativeeffectofcodeineanditsoccasionaltendencytoinducevomiting. Thelevoisomersofdextrorphananddextromethorphanhavebothanalgesicandaddictiveproperties. Oralrouteisconventionalforcoughremedies;theseagentsmaybegivenparenterally.
Bronchodilators

Bronchodilatorscausethesmoothmuscleoftheairwaystorelaxandcanthereforecontributesignificantly tothereliefofdyspnoeaandtheremovalofthestimulusforcoughing. Bronchodilatorsareoftherapeuticrelevanceinthemanagementofrespiratorydiseaseaccompaniedby coughinganddyspnoea. Mostdrugsthatinducebronchodilatationalsoreduceinflammation. BronchodilatorsreverseairwaysmoothmusclecontractionbyincreasingthecAMP,decreasingcGMPor decreasingcalciumionconcentrations. Inadditionthesedrugsalsodecreasemucosaloedemaandareantiinflammatorybecausetheytendto preventmediatorreleasefrominflammatorycells.
Methyl xanthene

Methylxanthinesincludethealkaloidscaffeine,theobromineandtheophyllinedrugs,whichhavebeenused asCNSstimulants,diuretics,heartstimulantsandsmoothmusclerelaxants. Itisthesmoothmusclerelaxantproperty,whichisresponsibleforthebronchodilatoreffectofthe xanthines. Thesmoothmusclerelaxantactionisattributedtoinhibitionofphosphodiesterase,theintracellularenzyme thatinactivatescAMP. TheCNSstimulantactionofthesedrugsalsocontributestoimprovedrespiratoryfunction,asalso theimprovementincirculatoryandrenalfunctionincardiacasthmaofdogs. Derivativesoftheophyllinewithsuperiorpharmacokineticpropertiesarenowpreferred. Aminophylline,diprophyllineandetamiphyllinegivenbyslowintravenous,intramuscularorsubcutaneous injectionareeffectiveinreducingairwayresistanceinacutebronchoconstriction. Aminophyllineismoresolublethantheophyllineandisbetterabsorbed.
Sympathomimetic

Adrenaline,isoprenalineandalargenumberofagentscapableofstimulatingbeta2adrenoceptorsareused extensivelyinthecontrolofbronchialasthmainman. Adrenalinehasbothalphaandbetaactionsandismoreusefulinsevereanaphylaxis(adrenalinebitartrate 1:1000solutionforinjection;largeanimals24ml,dogs0.10.3mlintravenouslyoruptodoublethesedoses subcutaneously)whileephedrineanditscongenersareusedprophylacticallyinman. Directactingbeta2agonistsarepreferredfortherapy.Suchcompoundsareexemplifiedbysalbutamol, fenoterolandhexoprenaline.Theseselectiveagentsarerelativelyfreeofdangerouscardiacstimulantside effectsoftheformerlyused,mixed1,2agonistssuchasisoprenaline. Thesympathomimeticsareeffectiveinrelievingthebronchoconstriction,whichfollowsthereleaseof histamineand/or5HTfrommastcellswhosesecretoryactivitytheyalsoinhibit. Administrationasanaerosolreducesthedelaytoonsetofeffecttoafewminutes.However,aerosol inhalationisnotaconvenientmeansofadministrationforanimals.Itisrecommendedinthemanagementof chronicallergies,bronchitis,chronicobstructivepulmonarydiseaseandequineinfluenza.
Parasympatholytics spasmolytics

Parasympatholyticssuchasatropinehavebeenusedasabronchodilatorinchronicemphysemainhorses. Therationaleisthatatropineovercomesthemuscariniccholinoceptormediatedbronchoconstriction.The effectisdilationofthelargerairways Atropinederivativese.g.eucatropine,havealsolongbeenusedinpaediatricpreparationsforwhooping cough. Asthesulphate,atropineisroutinelyinjectedpreoperativelytoreduceoreliminatesalivaryandbronchial secretionsduringanesthesia. Thedosebysubcutaneousinjectionis30100mg/kg. Ipratropiumamuscarinicblockingbronchodilator,isusedasanaerosol. Thereductioninvolume,higherviscosityofsecretionsanddecreasedmucociliaryclearance,canbea disadvantage.
Corticosteroids

Thereductionofmucosaledemainbronchiandbronchiolescanbeachievedbyuseofglucocorticoidsto suppresstheinflammatoryresponse. Inmanthecorticosteroidsareusedforsevere,disabling,bronchodilatorresistantasthma. Thesemaybeadministeredorally,parenterallyorasanaerosol. Theirusecarriestherisksofareducedabilitytogightinfectionsandalsotheriskofadrenalcortex suppressioniftheadministrationisprolonged. Theireffectsontheinflammatoryresponseincludemembranestabilization,reducedantibodysynthesis, reducedmediatorreleasefollowingantigenantibodyinteractionsandlessenedfibrosis. Thesedrugsalsoblockuptake2andsoextendthehalflifeofendogenoussympathomimetics. Corticosteroidscanbeusedwithadvantagetocontrolchronicallergictypesummercoughsindogseitherby theoraladministrationofprednisoloneorbytheuseofinjectabledepotpreparations.
NSAIDs

TheintroductionofNSAIDswithhighantiinflammatorypotencyhasmadethisgroupbeneficialasadjuncts alongwithantimicrobials Theylackthesuppressionoftheimmuneresponseseenwiththecorticosteroids. Theirabilitytosuppresstheproductionofthechemicalmediatorsoftheinflammatoryresponseunderlies theirabilitytoreducestructuraldamageandfunctionalimpairmentinthepneumoniclung. Ventilation,gaseousexchangeandpulmonaryhaemodynamicscanallbeimprovedbyNSAIDadministration. Flunixinisespeciallyrecommendedforthispurpose.
Antihistaminics

TheintroductionofNSAIDswithhighantiinflammatorypotencyhasmadethisgroupbeneficialasadjuncts alongwithantimicrobials Theylackthesuppressionoftheimmuneresponseseenwiththecorticosteroids. Theirabilitytosuppresstheproductionofthechemicalmediatorsoftheinflammatoryresponseunderlies theirabilitytoreducestructuraldamageandfunctionalimpairmentinthepneumoniclung. Ventilation,gaseousexchangeandpulmonaryhaemodynamicscanallbeimprovedbyNSAIDadministration. Flunixinisespeciallyrecommendedforthispurpose.
Mast cell stabilizers

Thedrugactsbystabilizingmastcellmembranespreventingdegranulationandthereleaseofchemical mediators(eg.Histamineandleukotrienes)inresponsetoallergens. Adepressantactiononchemosensitiveendingwhichtriggerbronchoconstrictionisalsosuggested. MorerecentlyithasbeenshownalsotopreventthereleaseoftissuedamagingfreeradicalsofIgEactivated platelets. Cromoglycateisnotabronchodilatorandisnoteffectiveintherapidreliefofexistingbronchoconstriction. Ithasgivensufficientimprovementintherespiratoryfunctioninhorseswithchronicobstructivepulmonary disease. 75|U R V I S H M I S T R Y
76|U R V I S H M I S T R Y Adminsitrationisdoneviaaspecialnebulizerandfacemask,80mgoncedailyfor14days.The1015min periodofnebulizationisgenerallywellacceptedbythehorse. Itisavailableasdrugforprotectinghorseswithallergicrespiratorydiseaseagainstpredictableantigen challenge.
Respiratory stimulants
Respiratorystimulantsareagentsusedtoimproverespiration.
Diuretics

Diureticsareagentsthatincreasethesaltandwaterexcretionbyanactiononthekidneys. Diureticseffectiveforthetreatmentofedemahavebeenavailablesincethe16thcenturyandmercurous chloridewasknownbyParacelsustobediuretic. In1930,Swartzdiscoveredthattheantimicrobialsulfanilamidecouldbeusedtotreatedemainpatients withcongestiveheartfailureduetoanincreaseinrenalexcretionofNa+. Mostmoderndiureticsweredevelopedwhensideeffectsofantibacterialdrugswerenoted,whichincluded changesinurinecompositionandoutput. Exceptforspironolactone,diureticsweredevelopedempirically,withoutknowledgeofspecifictransport pathwaysinthenephron. Theyareusedmainlyincasesofcardiacfailure,oedemaandhypertension.
Physiological diuresis
Itisoccasionallydesirabletoprovokediuresisinordertoincreaseurinaryfloworvolumeasinthecaseof treatmentofcystitisortopreventcrystalluriawithsulphonamidetherapy,ratherthanwiththeintentionof reducingbodyfluidvolume. Insuchcasesincreasedwaterintakeissufficient.
Classification of diuretics
Basedontheiractiononthekidneysdiureticsareclassifiedas Diureticsactingdirectlyonthecellsofthenephron o AgentsactingontheascendingloopofHenleEthacrynicacid,frusemide o AgentsactingontheearlydistaltubulesThiazideslikechlorthiazide o AgentsactingontheCollectingtubulesandductsTriamterene,amiloride Diureticsmodifyingthecontentsofthefiltrate o OsmoticdiureticsMannitol o CarbonicanhydraseinhibitorsAcetazolamide Basedontheirmodeofactiondiureticsareclassifiedas o OsmoticdiureticsGlycerine,mannitol,urea,isosorbide o InhibitorsofcarbonicanhydraseAcetazolamide,dichlorphenamidine o InhibitorsofNa+K+2Clsymport(Highceilingloopdiuretics)Frusemide,Ethacrynicacid, Bumetanide o InhibitorsofNa+ClsymportThiazideandthiazidelikedrugs o Potassiumsparingdiuretics InhibitorsofepithelialsodiumchannelsTriamterene,amiloride AntagonistsofaldosteroneSpironolactone o XanthinediureticsTheophylline Itcanalsobeclassifiedas o CardiacdiureticsXanthines o OsmoticdiureticsMannitol,Isosorbide,Urea o NatriureticsMercurials,Thiazides,Acetazolamide
Osmotic diuretics
Theseareinertsubstancesfilteredintotheglomerulus. 76|U R V I S H M I S T R Y
77|U R V I S H M I S T R Y Theirmaineffectisexertedintheproximaltubule,descendinglimbofHenleandthecollectingductwhich arefreelypermeabletowater. Byremaininginthetubularlumen,theseagentscauseanincreaseincolloidosmoticpressureinthetubular lumencausingsuctionofwaterintothetubularlumen. Thereisalsoreducedwaterreabsorptionduetorenalmedullaryhyperemia. ThereisimpairmentofNa+reabsorptionbecausethedilutedsolutioninthelumenreducesthe Na+concentrationgradient,makingitharderforNa+tobereabsorbed. Theyarenotusefulintreatingconditionswithsodiumretention. Thesedrugsareusefulinacutelyraisedintracranialpressureorintraocularpressure. Theyarealsousefulinpreventionofacuterenalfailure. Unwantedeffectsincludetransientexpansionofextracellularfluidvolumeandhyponatraemia,headache andvomiting. Mannitoliscommonlyusedasanosmoticdiureticandhastobeadministeredintravenously. Isosorbidehastheadvantageofbeingabsorbedafteroraladministrationinmonogastricspecies.
Carbonic anhydrase inhibitors

Bicarbonatespenetratetheluminalmembraneonlyveryslowly,anditsabsorptionintheproximaltubuleis heavilydependentonthepresenceofanenzymecarbonicanhydrase. Thisisazinccontainingenzymewhosefunctionistospeeduptheattainmentofequilibriumofthereaction: CO2+H2O>H2CO3 Roleofcarbonicanhydraseindiuresisisthatitiscapableofacceleratingthisreactionineitherdirection. Thisenzymeisfoundwithintheproximaltubulecellsandinassociationwiththeirluminalbrushborder. TheactivatingstepintheprocessofbicarbonateabsorptionisthesecretionofH+intothetubulelumen, whichislargelyresponsibleforthefavourableelectricalgradientdownwhichNa+diffusesintothecell. ThisH+isderivedfromthedissociationofcarbonicacid,whosesupplyisfacilitatedbythepresenceof carbonicanhydrase. Thecarbonicanhydraseinhibitorsinterferewiththeabsorptionofbicarbonatefromtheproximaltubule,by reducingthesupplyofH+tothemembranepumpandbyreducingtherateofabsorptionofcarbonicacid fromthelumen. FilteredbicarbonateisthustrappedintheurinetogetherwithanelectricallyequalamountofNa+andan osmoticallyequivalentamountofwater. Thesedrugscauseanincreasedexcretionofbicarbonatewithaccompanyingsodium,potassiumandwater excretionresultinginanincreasedflowofalkalineurineandmildmetabolicacidosis. TheyarepoordiureticsbecausethereiscompensatoryreabsorptionofNa+isthesegmentsfurtherdownthe nephron. Thesedrugsareusedinglaucomaandinsometypesofepilepsy. Theiractionresultsinadepletionofextracellularbicarbonateandtheireffectisselflimitingastheblood bicarbonatelevelfalls. Sideeffectsaredrowsiness,numbnessandtinglingofthefaceandextremities(duetometabolicacidosis) anddisturbancesofvision. Thisgroupofdrugisrarelyusedasdiuretics. Acetazolamideusedasacarbonicanhydraseinhibitorisaderivativeofasulphonamidebutdoesnotpossess anyantibacterialaction. Acetazolamideisanoncompetitive,irreversibleinhibitorofcarbonicanhydrase.
Loop diuretics

Loopdiuretics(Highceilingdiuretics)arethemosteffectivediuretics AfairlyhighproportionofNa+isalsoreabsorbedintheloopofHenle(22%). TheyareinhibitorsofNa+,K+Clsymport Maineffectofthisgroupofdiureticsisinhibitionofchloridepumpingthroughoutthewholelengthofthe thickascendinglimbofHenle,thusparalysingthekidneysabilitytoconcentrateandtodilutetheurine. 77|U R V I S H M I S T R Y
78|U R V I S H M I S T R Y Theireffectisfromtheluminalsurfaceoftheloopcells. Thesedrugsareextensivelyboundtoplasmaproteinsandrelativelylittleisfilteredintheglomerulus. Theyareactivelysecretedbytheorganicaniontransportersatthesiteofaction.Substances,likeprobenecid whichblockthismechanism,canreducetheirefficacy. ExamplesofLoopdiuretics:Frusemide,BumetanideandEthacrynicacid. Frusemideandbumetamidearesulphonamidederivativeswhileethacrynicacidisnotasulphonamide derivative. Ethacrynicacidmayproduceclinicaldehydrationandacutecirculatorycollapseasitproducessevere diuresisafteradministration. Frusemideproducesrapiddiuresisandhenceisusefulinemergencycases. Itiseasiertocontrolthedegreeofdiuresiswiththisdrugbyvaryingthedoserate. Thereisanincreaseintheexcretionofcalciumandmagnesiumandadecreasedexcretionofuricacid. Theeffectoncalciumismadeuseofinthetreatmentofhypercalcaemia. Theloopdiureticsarereadilyabsorbedfromthegastrointestinaltractandcanalsobeadministered parenterally. Administration Orallyorintravenouslyat15mg/kgindogs. Thiscanbedoubledwithsuccessivedosesuntilaneffectisobtained. Durationofactionis46hours. Inhorsesthedrugisgivenattherateof0.5mg/kgtoreduceincidenceofepistaxis. Incattlegivenorallyat0.51mg/kg,1224hourly.Loopdiureticsareusefulinpatientswithsaltandwater overloadduetoacutepulmonaryoedema,chronicheartfailure,hepaticcirrhosiscomplicatedbyascites, nephroticsyndromeetc. Hypertensionespeciallyifaccompaniedbyrenalimpairment. Acutetreatmentofhypercalcaemia. Untowardeffectsincludepotassiumloss,metabolicalkalosis,depletionofcalciumandmagnesium, hypovolaemiaandhypotension. Localirritationofthegastronintestinaltractandcompetitionwithotherdrugslikedigitalisarenoticed. Aswithotherpotentdiuretics,hyponatraemiacanoccur,butdeafnessisanadverseeffectpeculiartoloop diuretics. Henceconcurrentdosingwithaminoglycosidesiscontraindicated.
Thiazide derivatives
Thiazidediureticsgroupincludeschlorthiazide,hydrochlorthiazide,bendrofluazide,cyclopenthiazide. Thesedrugsaremorepotentthancarbonicanhydrase(CA)inhibitors.Mostthiazidesareweakinhibitorsof CA,butthisisnotthebasisoftheiraction. Siteofactionofthiazidediureticisatthedistaltubule(hencetheyaremediumactingdiuretics)wherethere isonlyasmallamountofreabsorptionofsodiumsincemostoftheNa+isalreadyabsorbedintheearlier partsofthenephron. Inthedistaltubule,Na+isreabsorbedviaaNa+Clcotransport. Thiazidesinhibitthiscotransportmechanism,thuspreventingNa+frombeingreabsorbed. ThiazidesmayalsoinhibittheNa+K+ATPaseindirectly. DuetoNa+K+counterexchangeatthecollectingtubule,potassiumlossmaybeinducedbythesedrugs leadingtoserioushypokalemia. Thethiazidesareactivebymouthaswellasbyparenteraladministration. Theireffectsarefairlyslowinonset. Thiazidesareusedinthetreatmentofoedemaincardiacfailure.Inhepaticcirrhosis,muchK+lossisnot appreciable. HencethiazidesaregiveninconjunctionwithK+tabletsorwithaK+sparingdiuretic. Thiazidesaresecretedinthekidneyviatheorganicacidsecretarysystem. Sideeffects Hypokalemia Increaseinbloodsugar(hyperglycemia),especiallyindiabetics, 78|U R V I S H M I S T R Y

79|U R V I S H M I S T R Y Reducedinsulinalsocausesincreasedglycogenolysisandreducedglycogenesis. Thiazidesmaycauseareducedexcretionofuricacid,leadingtogout.Thethiazidesaresulphonamides,and sosharecrossreactivitywithotherdrugsofthisgroup. Therefore,ifapatientisallergictoasulphonamide,chancesarethatthepatientwillalsobeallergicto thiazides. Photosensitivityandhaemolyticanaemiamayoccur.
Potassium sparing diuretic

Thereare2groupsofdrugsinthiscategory. Theonlything,theyhaveincommonistheirsiteofaction(latedistaltubuleandcollectingduct). Howevertheirmechanismofactionisquitedifferent. o InhibitionofaldosteroneSpiranolactone o InhibitionoftheNa+K+exchangeinthecollectingductTriamterene,Amiloride Aldosteroneantagonists Aldosterone(asteroidhormone)enterstubularcellsandbindstoamineralocorticoidreceptorinthe cytoplasm. ThishormonereceptorcomplexbindstoaresponseelementontheDNA. Bindingresultsintheexpressionofaldosteroneinducedproteinsleadingtoactivationofsilent Na+channels/pumps,alterationofthecyclingofthechannelsandpumps,increasedexpressionofchannels andpumpsandalteredpermeabilityofthetightjunction(zonulaoccludens). AlltheaboveeffectsresultinanincreaseinNa+conductance(reabsorption)andsecretionofK+(Oneofthe complicationsofexcessaldosteronesecretionishypokalemia). Spiranolactonebindstothemineralocorticoidreceptorandpreventsaldosteronefrombinding. Spiranolactoneatruecompetitiveantagonistofaldosteroneenhancesdirectreabsorptionofsodiumin moreproximalareasofthedistaltubules. Thisdrughasaveryslowonsetofaction,whichisnotdosedependent. Itmayexertoestrogenlikeactivity Itisusedincombinationwiththiazidediuretics. Spiranolactoneisnoteffectiveinthepresenceoflowlevelsofaldosterone. Itisavailableonlyfororaladministration. Ifhyperkalemiaoccursasaresultofspiranolactonetoxicity,thiazidediureticscanbeadministered. Triamtereneandamiloride Thesedrugshavealimiteddiureticefficacy. Theyactonthecollectingtubulesandcollectingducts,inhibitingsodiumreabsorptionanddecreasing potassiumexcretion. TriamtereneinhibitsaldosteronespecificATPase. But,isnotdependentonaldosteronelevels. AmilorideblocksNa+channelsintheluminalmembraneaffectingNa+permeability. Boththedrugspromoteexcretionofuricacid. Themainimportanceofthesedrugsliesintheirpotassiumsparingability. Theycanbegivenwithpotassiumlosingdiureticslikethiazidestomaintainpotassiumbalance. TheyareusefulinconditionswhereK+losscannotbetolerated(oftenusedinconjunctionwiththiazides) InhypertensionandcongestiveheartfailureIfapersonisbeingtreatedwithdigoxinfortheirheartfailure, lossofK+canenhancethetoxicityofdigoxin(cardiacglycoside). IfK+isreduced,theactionsofdigoxinareenhancedbecausenormally,digoxinmustcompetewithK+forthe Na+K+ATPase. Byusingthedrugsincombination,thereisanenhanceddiureticeffectandtheaddedbenefitofnotlosing K+. Spironolactoneisusedinprimaryhyperaldosteronism(tumoroftheadrenals)orsecondary hyperaldosteronism(cardiacfailure,hepaticcirrhosis). Sideeffects Hyperkalemia, Metabolicacidosis, 79|U R V I S H M I S T R Y

80|U R V I S H M I S T R Y Gynaecomastia, Impotence, Decreasedlibido, Hirsuitismand Gastricupsets.
Xanthines and mercurial

Xanthines Thesedrugsstimulatecardiacfunctions.Theirdiureticactivitymaystemfromtheresultantincreaseinrenal bloodflowandtherebyanincreaseinglomerularfiltrationrate. Theyalsoexertadirectactionontherenaltubule.Renalresponseismanifestedbyanincreaseinlevelsof sodiumandchlorideinurine. ThereisnosignificantchangeintheurinepHandpotassiumexcretionappearstoberelativelyunaffected. Examplesare:Caffeine,Theophylline Mercurials Diureticactionofmercurialsisassociatedwithsulphydrylgroupsandsotheyinactivatethesodium transportmechanismofthenephron. Forclinicaluse,mercurialsareobsolete
Drugs acting on urogenital systems

Alkalization of urine
AlterationofurinepH Alterationissometimesdesirableasinthecaseofpoisoningandintheexcretionofsomedrugstopreventside effects. Alkalinisationofurine Alkalinisingagentsreducetheirritationofaninflamedurinarytractanddiscouragethegrowthofcertain organismslikeE.coli. Urinecanbemadealkalinebysodiumbicarbonateintravenousadministrationorbypotassiumcitrateoral administration. Sodiumorpotassiumcitrateismetabolisedtoformastablecation(Na+orK+)andalabileanion(citrate). CitrateistakenupforusebytheTCA.TheNa+orK+isexcretedwiththemostcommonanion(HCO3. Hence,therewillbealkalineurine. Administrationanduse Todecreasetheadverseeffectsofsulphonamidesalkalinisationisuseful.Sulphonamidesaregenerally insolubleinacidurine.Theymaythusprecipitateoutandcrystallise.Therefore,toincreasesolubility,the urineismademorealkaline. ToincreasetheexcretionofacidicdrugslikeAspirin,salicylatesandbarbiturates. Alkalinisationofurineincreasestheantibacterialactivityofaminoglycosidesinurinarytractinfection. Alkalinisationoftheurineinusuallyrecommendedtopreventtherecurrenceofuratestonesindogsafter cystotomy.Sodiumbicarbonateat0.5to1.0gisgivenorallythricedaily.
Acidification of urine
Acidificationofurineisusedasatestforrenaltubularacidosis.Acidificationhelpsintheexcretionofcertain drugslikeamphetamine,phencyclidine,quinineetc. Ammoniumchloride,ascorbicacidorcalciumchloridecanbeusedtoacidifyurine. Ammoniumchloride(NH4Cl)ismetabolisedinthelivertoNH4+andCl. TheClisexcretedalongwithNa+. ThebaseconservingmechanismssecreteH+andNH4+intotheurine. Administrationanduses Acidificationincreasesactionofhexamine,penicillinsandtetracyclinesinthetreatmentofurinarytract infections. AcidificationincreasesexcretionofbasicdrugslikePethidineandamphetamine 80|U R V I S H M I S T R Y
Ecbolics

Theseareagentsthatbringaboutincreaseinuterinecontractions. Oxytocin:Itishormoneoftheposteriorpituitaryreceivedfromthehypothalamus.Ithasamajor physiologicalroleinmilkletdownandlaborinitiation. o Clinicalusesofoxytocin: Forlaborinduction.GivenbyslowI/vindextrosesolution. FormIlkletdown.Onlyinagalacticanimals Fortreatmentofuterineinertiaandforrapdinvolutionofuterus. Toarrestpostparturienthaemorrhage. Forexpulsionofretainedplacenta. o Thedoseofoxytocinis525unitsinbitch,75100unitsincow/mareand3050unitsinsow/ ewe. Oxytocics:Otheragentswhichperformsimilarfunctionsarealsocalledoxytocics. Ergotalkaloids:AlkaloidsfromthefungusClavivepspurpureaviz.ergometrine,ergonovinehaveprominent effectontheuterus.Notpreferredforinductionoflabour.Generallyindicatedforpostparturient haemorrhage,rapidinvolutionofuterus,retainedplacenta. PGF2alpha:Exertspotentstimulantactiononmyometrium.Itisalsopopularlyusedforitsluteolyticeffect.
Tocolytics

Theseareagentsthatinhibituterinecontractions.Theyrelaxuterinesmmothmuscleandmaybeusedto delaylaborandtostopthreatenedabortion. Beta2agonists:Salbutamol,terbutaline,isoxsuprine Calciumchannelblockers:Nifedipine,diltiazem Oxytocinantagonist:Atosiban
Fluid therapy
Fluidtherapyreferstoadministrationoffluidstocompensatethelossoffluidsfromthebodyduetoa varietyofconditionsleadingtodehydration.Fluidlossinthebodycanleadtoshockandcanbecomefatalif unattendedto. Thepurposeoffluidtherapyistocorrectdehydrationoroverhydration,elctrolyteimbalanceand/oracid baseimbalance. Itisalsoindicatedtocorrectacidosis/alkalosis,treatshock,giveparenteralnourishmentorevenstimulate organfunctionsuchaskidney. Fluidvolumeandtype Thetypeofsolutionistobedictatedbyhistory,clinicalsignsandlaboratoryexamination. Thevolumeoffluidisdeterminedtheneedformaintenanceaswellastheneedforreplacementoflost fluid. Fornormalmaintenance,athumbruleof65ml/kg/24hrforadultsand130ml/kg/24hrforyoungonesis calculated. Basedonthis,anormalmaturedogof20kgwouldrequire1300mlfor24hrperiod. Replacementoffluidlossmustbeinadditiontothemaintenancerequirement. Tocalculatefluidlossonemustestimatethedegreeofdehydration. Tocalculatethefluidforreplacementonemustcalculatethedegreeofdehydration. Degreeof dehydration 4% 6% Clinicalsigns historyoffluidloss,leatheryskin,mucousmembranestillmoistand evidenceofthirst skinstillleathery,whenliftedtheskinwillpeakandreturntonormal slowly,haircoatdull,mucousmembranedrybutthetonguestill moist 81|U R V I S H M I S T R Y
82|U R V I S H M I S T R Y 8% Skinwillshowlackofpliabilityandelasticity,theskinlosesturgor (whenliftedwillpeakandstay,mucousmembraneandtonguedry, eyeballswillbesoftandsunken. Signsofcirculatorycollapse SymptomsofAcuteshock
12% 15%
Fluidvolumetoreplace Thevolumeoffluidtoreplacelossoffluidiscalculatethebodyweightmultipliedbydegreeofdehydration. Foreg.,adogweighing20kgwith6%dehydrationisgiven20kgx0.061200mlor1.2liters. Thisisapartfromthemaintenancerequirementof20x65=1300ml. Ratesandadministration Therateofreplacementoffluidsshouldparalleltheseverityofdehydration.Fluidsshouldbeadministered rapidlyatfirstfollowedbydecreasingrates. Mostcommonlyitisagreedthat15ml/kg/hrisareasonablerate.Inseverelydehydratedcasesthiscango upto50ml/kg/hr.Higherratescanoverloadthesystemandmayevencauseoverhydration. Routeofadministration Theroutedependsonthetypeofillness,severity,degreeofdehydration,patientcondition,timeand equipmentavailable. Themostcommonandoverlookedoneistheoralornasogastric.Itistheleastdangerous,withoutstrict asepsis. Perrectaladministrationcanalsobeconsidered.Itmaybedifficulttoretainthefluidespeciallyinthe presenceofgastrointestinaldisease. TheIVrouteisthemostversatile.Itisindicatedforemergencies,severecases.Ithastheadvantageoflarge volumeofadministration.Butmaintenanceofindwellingcatheter,clottingandhematomaandlocationof veinaresomeofthedrawbacks. TheSCrouteishandyincasesofsmallanimalswherelargervolumesneedtobegivebutitisdifficultto locatethevein.Itisirritatingandcanbepainful.Fluidabsorptionismoreslow. IProutealsosuffersformthedrawbackofeasypredispositiontoperitonitis.
Choice of fluid
ProperselectionoffluidbeginsbydeterminingthetypeofdeficitandchoiceoffluidsColloid,crystalloidor combinationofboth Fluid Isotonicsaline (Normalsaline,0.9%) Indications Tocorrectmetabolicacidosis,especiallyaftervomiting
Isotonicdextrosesaline Maintenancetherapy,hypertonicdehydration (0.18%NaCl+4.3%Dextrose) Darrowssolution (0.4%NaCl+0.27%KCl+ 0.58%Sodiumlactate) 5%Dextrose Metabolicacidosisassociatedwithdiarrheal dehydrationandpotassiumloss Hypertonicdehydrationresultingfromwater deprivationorheatstroke;usedinemergencyto providetransientalleviationofhypoglycaemia Metabolicacidosis, Replacementoflossesowingtogastrointestinal dysfunction(vomiting,diarrhea),haemorrhage,burns
CompoundSodiumLactate (Hartmannssolutionor Ringerslactate)
83|U R V I S H M I S T R Y ClinicalCondition Choiceoffluid Vomiting NormalSaline DextroseSaline Ringerssolution LactatedRingers Darrowsfluid(InchroniccaseswithK+loss)
Diarrhea
Bowelobstruction LactatedRingers(+colloidforshock) Hemorrhage Wholeblood LactatedRingers Colloid Colloid LactatedRingers Dextran+Hartmanns RingersLactate GelatinColloid Foremergencytreatmentofdehydrationand hypoglycaemia SevereAcidosis Replacementforbloodlossintreatinganaemia Effectiveinrestorationofbloodvolumeincasesof hemorrhageorshock. Hypovolemicshock,burns,bloodlossanddiarrhea
Peritonitis Shock
DextroseSaline(0.9%NaCl+ 5%Dextrose) Sodiumbicarbonate(1.3%) Wholeblood Plasmaexpanders Dextran Gelatincolloidalsolution
Pharmacotheraputics of Hormones
Administration of hormones
Administrationofhormonesfallsintotwocategories: o Replacementtherapyand o Additivetherapy Replacementtherapyistheadministrationofthehormonesatphysiologicallevels.Forexampleinsulin, thyroxine,vasopressin,gonadotrophinsandACTHareadministeredatphysiologicallevels. Additivetherapyistheadministrationofthehormonesatpharmacologicallevels(notusuallyrelatedto naturalmetabolicfunctions).Administrationatpharmacologicallevelsmayproducesideeffectsoruntoward effects.Forexampleandrogensandglucocorticoidsareadministeredatpharmacologicallevels. Augmentationistheprocessofincreasingdurationofactionofahormonebycombiningtheprotein hormoneswithcopper,zincorironofheme.
Corticotrophins and related peptides

Corticotrophinreleasinghormone ThishormonestimulatessynthesisandsecretionofACTHbypituitarycorticotrophs. ThishormoneappearstoexertitseffectonACTHreleasethroughbothadenylatecyclaseandcalcium calmodulinsignaltransductionsystems. 83|U R V I S H M I S T R Y
84|U R V I S H M I S T R Y Adrenocorticotrophin ACTHstimulatesthesecretionofglucocorticoids,mineralocorticoidsandadrenalandrogens Itactsbyincreasingtheactivityoftheratelimitingagentinsteroidsynthesisandconvertscholesterolto pregnonolone. ACTHalsostimulatesadrenalhypertrophyandhyperplasia. CorticotrpinandACTHareusedasdiagnostictoolstotestadrenocorticotrophandadrenalfunction reserve.ACTHcanbeusedforallthepurposesforwhichglucocorticoidsarerecommended. TheadvantageofACTHisthatitleadstosuppressionofpituitaryovertimewhileglucocorticoidssuppress thepituitaryandadrenalcortexquickly. ACTHgelpreparationsarederivedfrompigpituitaries.BothporcineandsyntheticACTHarewellabsorbed afterintramuscularadministration. However,itsdisadvantageisthatitcannotbeadministeredbyoralrouteunlikeglucocorticoids.
Insulin
Endocrinepancreas TheBetacellsoftheisletsoflangerhanssecretethepeptidehormoneinsulin. Insulinissecretedinresponsetogastrointestinalpeptidehormones,plasmaconcentrationsofglucose, aminoacidsorfattyacidsandotherlocal(glucagons)orsystemic(acetylcholineandbetaagonists)chemical messengersordrugs(sulphonylureas). Diabetesmellitusisaconditionduetolackofinsulinandischaracterizedbysweeturine,polydipisia,wasting oftissues,developmentofketocidosis,hypersomolarcomaanddeath. In1921BantingandBestextractedtheactivecompoundfrompancreasthatcontrolledhyperglycemiain diabeticdogsandhuman. TherearetwotypesofdiabetesinhumanandtheyareIDDMorTYPEI(Insulindependentdiabetesmellitus) andNIDDMorTypeII(NoninsulindependentDiabetesmellitus). InIDDMthereislackofinsulinandinNIDDMthereisresistancetoinsulin.
Pharmacological actions of insulin

Pharmacologicalactions Insulinbindstospecificcellmembranelocatedreceptors. Thisfacilitatestheentryofglucose,aminoacidsandpotassiumionsintomostcells. Thisreversesthehyperglycemiaofdiabetesmellitusbyallowingexcessglucosetobecomeintracellular. Insidethecell,proteinsynthesisisincreasedandglucoseisphosphorylatedbyATPandhexokinaseandis usedtoderiveenergyorforincorporationintoglycogen. Thestorageofcarbohydrateisfurtheraidedbytheinhibitionoftheactionoftheenzymesofglycogenolysis. Proteinsynthesisisaidedbytheimpairmentofgluconeogenesis. Insulinalsofacilitatesfatdepositionandstronglyinhibitslipolysis. Actionsofinsulininclude o Increasedglucoseuptakeintomuscleandfat o Increasedglycogenesis o Decreasedglycogenolysis o Decreasedgluconeogenesis o Stimulationofgrowth(anabolic) o Decreasedlipolysis o Decreasedproteinbreakdown
Preparations of insulin

Insulinwasoriginallyderivedfromthepancreasofeitherpigoftheox. Thestandardpreparationcontains20,40and80unitsofinsulininonemilliliteroftheinjection. Therateofabsorptionofinsulinanditsdurationofactiondependsonthephysicalstate(crystallineor amorphous,proportionofzinc,solutionorsuspension)andtherouteofinjectionofthechosenformulation.
85|U R V I S H M I S T R Y Thecomplexedsolutionie.Protaminezincinsulinandglobinofzincinsulinareeffectiveforabout48hours and24hours.But,theplaininsuliniseffectiveonlyfor8hoursandlenteinsuliniseffectivefor1820hours duration. Humaninsulin(Humulin)isaDNArecombinantderivedpreparationofinsulin. Thespecializeddeliverydevicesforinsulinincludeinsulinsyringes,pendevices,inhalationdevices,pumps andimplantablepreparations. Uses o Diabetesmellitusindogs o Acetonemiaincattle(Insulinisapowerfulantiketoticagent.Itisparticularlyusefulinketosisthat occurswithinthefirstweekoflactationandisnonresponsivetoglucoseorglucocorticoidstherapy alone) o Pregnancytoxemiainsheep.
Oral hypoglycemic drugs

Sulphonylureas Theseareagentsthatwerefirstintroducedasoralhypoglycemicagents. Therearetwogroupsofsulphonamidesnamelyfirstandsecondgenerationsulphonylureas. Firstgenerationincludestolbutamide,chlorpropamide,acetohexamideandtolazanide. Secondgenerationincludesglibenclamide,glipizideandgliclazide. Inthepancreaticbetacells,sulphonylureasdecreaseATPdependentpotassiumchannelsintheplasma membrane. Thisresultsindepolarizationandreleaseofinsulin. Presenceofatleast30%functionalbetacellsisessentialfortheactionofsulphonylureas. Thisgroupofdrugsisoftenusedincombinationwithmetformin. Theyareboundtoplasmaproteins,metabolisedbytheliverandexcretedbythekidney. Theycancrosstheplacenta(hencenotusedinpregnancy)andaretobetakenbeforeameal. Sideeffectsincludehypoglycemia,GITeffects,rashandincreasedweight. ThereisinteractionwithNSAIDsandsulphonamides(makinghypoglycemiamorelikely). Ifusedwithalcoholtheywillcauseseverehypoglycemia. Biguanides Thisgroupincludesphenforminandmetformin. Theycauselittleornohypoglycemiainnondiabeticsubjectsanddonotstimulatepancreaticbetacells. Presenceofinsulinisessentialfortheiraction. Theysuppresshepaticgluconeogenesisandglucoseoutputfromtheliver,enhancebindingofinsulintoits receptorsandstimulateinsulinmediatedglucosedisposal. Theyincreaseglucoseuptakeintoskeletalmuscleandmaydecreasetheabsorptionofglucose. Thisgroupofdrugshaveashorthalflifeandareexcretedbythekidney. Sideeffectsincludehypoglycemia,nausea,vomitinganddiarrhea. Meglitidineanalogs Repaglinidelowersbloodglucosebystimulatingthereleaseofinsulinfromthepancreas.Itachievesthisby closingATPdependentpotassiumchannelsinthemembraneofthebetacells.Thisdepolarizesthebeta cells,openingthecells'calciumchannels,andtheresultingcalciuminfluxinducesinsulinsecretion.Eg: repaglinide Thiazolidinediones Itworksasaninsulinsensitizer,bybindingtotheproxisomeproliferatoractivatedreceptors(PPARs)infat cellsandmakingthecellsmoreresponsivetoinsulin.Eg:rosglitazone glucosidaseinhibitor Itisastarchblocker,andinhibitsalphaglucosidase,anintestinalenzymethatreleasesglucosefrom largercarbohydrates.Eg:acarbose
Thyroid hormone
Thethyroidglandsecretesthreemainhormones:thyroxine,triiodothyronineandcalcitonin. 85|U R V I S H M I S T R Y
86|U R V I S H M I S T R Y Thyroxineandtriiodothyronineproducedinthethyroidfolliclesarecriticallyimportantforthenormal growthanddevelopmentandfortheenergymetabolism. Calcitoninproducedintheinterfollicularcellsisinvolvedinthecontrolofplasmacalcium. Thestepsinthyroidhormonesynthesis,storageandsecretioninclude: o uptakeofiodinebythefolliclecells o oxidationofiodineandiodinationoftyrosineresiduesofthyroglobulin o secretionofthyroidhormone Thyroidhormoneisessentialforthenormalgrowthanddevelopment. Deficiencyresultsincretinism. Theyhaveamarkedeffectonthelipid,carbohydrateandproteinmetabolism. BothT3andT4areusedtotreatthyroidhormonedeficiency Lthyroxinesodiumisusedfororaladministration. Itsabsorptionisinfluencedbythepresenceoffoodinthestomach,suralfate,ironandcalcium. Enzymeinducerslikephenytoin,rifampin,carbamazepineincreasethemetabolism
Thyroid inhibitors

Theseareusefulinthetreatmentofthyrotoxicosis,hyperthyroidism,Grave'sdisease Inhibithormonesynthesis(Antithyroid)Propylthiouracil,methimazole,carbimazole InhibitiodinetrappingThiocyanates,perchlorates,nitrates Inhibithormonereleaseiodine,iodidesofsodiumandpotassium,organic,iodine DestroythyroidtissueRadioactiveiodine
General principles in corticosteroids therapy

1. Glucocorticoidsareonlypalliativeanddonotprovidecompletecure 2. Individualvariationsoccurbetweenpatientsintheirresponsetoglucocorticoidstherapyandhencedose needstobeindividualized. 3. Initialdosedependsonseverityofthedisease.Startwithahighdoseinsevereillnessandgraduallyreduce asclinicalsignssubsidewhileinmildcasesstartwiththelowestdoseandenhancethedoseasperneed. 4. Prolongedtherapyathighdosesforseveralweeksmaycauseadrenalatrophy. 5. GlucocorticoidsevenatphysiologicaldosagemayresultinsuppressionofHypothalamopituitaryadrenal axis 6. Itshouldpreferablybeadministeredlocallyratherthansystemicallysincelowsystemiclevelminimally interfereswithcorticalativity. 86|U R V I S H M I S T R Y
87|U R V I S H M I S T R Y 7. Glucocorticoidtherapyshouldnotbeterminatedabruptlysinceitmayinducehypoadrenocorticism.Dosage shouldbeterminatedgraduallyoveraperiodof2weeks. 8. Antiinflammatoryandantiallergytherapy o Largeproportionofdrugsareusedinveterinarypracticetocombatinflammationorallergy o Valuableinthetreatmentofchronicdiseaseoccurringperiodicallyandintheabsenceofknown causes o Usedinthetreatmentofchronicarthritis,tendonitis,bursitis,conjunctivitis,dermatitis,pruritic dermatoses,allergicpulmonarydiseaseandallergicgastroenteritis. o Maybeusedforshortperiodsforshortperiodsinanaphylaxis,angioneuroticedema,urticariaand serumsickness. 9. Itshouldbeusedwithcautionincaseofinfectiousdisease,sinceglucocorticoidswillpromotedissemination ofinfectiousorganismthroughoutthebodyresultinginfulminatinginfectiouscondition.Itisindicatedalong withantibioticsthatareeffectiveinthetreatmentofunderlyinginfection. 10. Glucocorticoidreducescollagensynthesisandtherebyreducestherateofwoundhealing.Glucocorticoids areindicatedinthetreatmentoftraumaticwoundofprepuceofbullssoastopreventrapidhealingthat wouldleadtostrictureformation. 11. AsaphysiologicalreplacementitisusedfortreatmentofAddisonsdisease(Chronicadrenalinsufficiency) andacuteadrenalinsufficiencyinhumanbeings. 12. Glucocorticoidsathighdoseinducesparturitionandcanbeusedtoinduceparturitionincows,ewesetc. However,sincetheyhaveteratogeniceffectsduringearlypregnancy,itshouldbeusedwithcautionin pregnantanimals. 13. Therapyofshock:Earlytreatmentofglucocorticoidimproveshemodynamicsandenhancessurvivalin hemorrhagicandsepticshockbutcontraindicatedinchronicsepsisbecauseofitsimmunosuppressive effects 14. Itcanbeusedtotreatdepressivestatesofpetanimalsandeventemperamentaldairycowssinceitinduces euphoria. 15. Itdepressesimmunesystem.ItsuppressesBlymphocytesproliferationandTlymphocytesactivation. Immunemediatedthrombocytopenia,autoimmunehaemolyticanaemia,collagendiseaselikesystemic lupuserythematosus,polyarteritisnodosarespondtoglucocorticoidtherapy.Forthesamereason,itis contraindicatedduringvaccination o Corticoidsareusedinlargenumberofinflammatoryoculardiseasesuchasallergicconjunctivitis, iritis,iridocyclitis,keratitisastopicalinstillation. o Systemictherapyisusefulinthetreatmentofretinitis,opticneuritis,uveitis. o Contraindicatedincornealulcerssincetheyslowtheprocessofreepithelialisationofcornea. 16. Corticosteroidscanbeusedalongwithotherimmunosuppressantstopreventrejectionreactionduring organtransplantationandskinallograft.
Anti-inflammatory and sodium retaining potencies of Glucocorticoids

Corticosteroid Shortacting(halflife12h) Hydrocortisone Cortisone Fludrocortisone Antiinflammatorypotency Sodiumretainingpotency 1 0.8 10 1 0.8 125 0.8 0.8 0.5 87|U R V I S H M I S T R Y
Intermediateacting(halflife1236h) Prednisone Prednisolone Methylprednisolone 4 5 5
88|U R V I S H M I S T R Y Triamcinolone Longacting(Halflife3672h) Paramethasone Betamethasone Dexamethasone Flumethasone 5 10 10 10 10 0 0 0 0 0
Reproductive hormones and Vitamins

Hormones influencing reproductive functions
Gonadotrophinreleasinghormone(GnRH) Effects AdministrationofGnRHreleasesLHandFSHfromtheanteriorpituitarygland.TheeffectsofGnRHon LH/FSHreleasearedependenton o thedoseandrouteofadministration o theendocrinestatusoftheanimalatthetimeoftreatmentand o thefrequencyofinjection GenerallythereleaseofLHandFSHarehigherfollowingGnRHinjectionwhentheanimalisunderthe influenceofestrogenandlowerinprogesteronedominatedanimals. Uses InjectionofasinglelargequantityofGnRHduringthefollicularphaseoftheestrouscyclestimulates ovulation2448hourslater. o Injectionattheendofasynchronizationscheduleinordertocontrolthetimeofovulationfor schedulingtimesofinsemination o Toovercomedelayedovulationindairycows,particularlyinhighyieldingpostpartumcowsbred within60daysofparturition o Injectionofmaresduringtheestroustotimetheovulationandcoveringinordertomaximizethe chancesofconception o Injectionofcowsatthetimeofinseminationtoincreaseconceptionrate GnRHstimulatesLHandFSHinthemaleandmayhaveauseinanimalswithpoorsemenproducingability. SyntheticGnRHlikegonadorelin,buserelinandfertirelinhavebeenproducedwhichstimulatereleaseof bothFSHandLH. BuserelinwasdevelopedbysubstitutingtwoaminoacidsinnaturalGnRH. Thismodificationhelpedinincreasingresistancetoenzymaticdegradationandanincreasedplasma concentrationofFSHandLHwhichpersistedforseveralhourswasnoticedinmaresandcowsattherapeutic concentrations.
Anterior pituitary gonadotropins

BothLHandFSHareglycoproteinhormones. Theyaresecretedfromthegonadotrophcellsoftheanteriorpituitarygland. Theyconsistoftwopolypeptidesubunits. Thegonadotrophichormonescontroltheestrouscycleofthefemaleandmodulatetesticularfunctionsin themale. Inthefemale,FSHisresponsiblemainlyforgrowthofthefolliclebybindingtogranulosacellsand stimulatingestradiolproduction. 88|U R V I S H M I S T R Y
Effects

89|U R V I S H M I S T R Y LHisresponsibleforfinalmaturationandovulationbybindingtothethecalcellsofthedevelopingfollicle andstimulatingthesynthesisofandrogens. Inthemale,LHbindstoleydigcellsorinterstitialcellslocatedintheconnectivetissuestromaofthetestis andstimulateandrogenproduction. Thegonadotrophinsareavailableasapowderwhichcanbeeasilyreconstitutedbytheadditionofsterile water,salineorappropriatebuffer. Onceintheliquidformtheymustbestoredat4degreecentrigradeandnotsubjectedtoexcessiveagitation topreventdenaturationofprotein. Uses TheusesofLHare o toinduceovulationofamaturefollicle o toleutinizefollicularcysts o toinducefolliculargrowthandovulation. TheusesofFSHare: o toincreasethenumberofovashedinthecattleforsuperovulatorypurposeand o toincreasethelittersizebyincreasingtheovulation.
Placental gonadotropins

Themaintenanceofthecorpusleuteumofpregnancyinsomespeciesisfavouredbytheproductionof chorionicgonadotropin(CG)eg.human(hCG)fromday8 inthemaretheendomaterialcupsproduceahormone(eCG)fromday40toaboutday150(previously calledpregnantmareserumgonadotropin(PMSG)). hCGcontainsmoreofLHthanFSH,whileeCGcontainsmoreofFSHthanLH. hCGismainlyleutienising.Infemaleanimalsthisinducesovulationandreinforcesthesecretionof progesteronebytheovary. hCGwillbindtoLHreceptorsonthegranulos,thecaandlutealcellswithhighaffinityandspecificity. eCGhasLHlikeactivityonlyinthemare,butintheotherspeciesithasmainlyFSHlikeactivity. Inthemareitonlyleutinizefolliclesalreadypresentintheovarybut,intheotherspeciesitstimulates folliculargrowthandovulation. Serumgonadotrophinhasbeenusedtoincreasethenumberofdevelopingfollicleandovulationandoestrus andthusincreasetheincidenceoftwinsincattle. Itisusedtocontrolthetimeofovulationinmaresbecauseintheseanimalsovulationnormallyoccurs towardstheendofalongestralperiod. Itiswidelyusedinthetreatmentofcysticovariandiseaseespeciallywherenymphomaniaispresentand sometimesinthetreatmentofcyrptorchidism. Inmaleanimalschorionicgonadotropinisusedtostimulatethesecretionoftestosteronebythetestes.
Effects

Uses

Estrogens

Thereareanumberofsourcesofestrogensproducedinthebody Theyareproducedfromthegranulosecellsofthefollicle,thecorpusluteumofprimates,theplacentathe adrenalsandthetestes. Oestrogensinfluencethefemalesexcharacteristicssuchasanincreaseinthegrowth,proteinsynthesisand fluidsecretionsofoviduct,uterus,cervixandvagina. Theyalsoaffectmammarydevelopment. Theyinducetheexpressionofbehaviouralestrusinthefemaleandlibidointhemale. Oestrogensalsohavemanyeffectsongeneralbodymetabolismincludingfatdistributionandcontentwithin thebody,mineralmetabolism,bonegrowthandproteinsynthesisinmaytissuesincludingthemuscle. Theyinfluencegonadotrophinsecretionandatlowconcentrationshaveanegativefeedbackeffectonthe hypothalamus,whileathighdoses,intheabsenceofprogesteronetheyhaveapositivefeedbackeffectin femalesresultinginthepreovulatorysurgeingonadotrophinoutput. 89|U R V I S H M I S T R Y
90|U R V I S H M I S T R Y Thetestesofboththeboarandthestallionproduceoestrogensinhighquantitiesandpregnantmares produceawiderangeofestrogenslikeequilin,hippulinandequilenin. Equinemaleurineandtestescontainenormousquantitiesofestrogens. Thenaturalestrogensinclude17betaestradiol,estroneandestriol. Theyhaveloworalactivity. Syntheticsteroidalestrogensincludesimpleesterssuchasestradiolbenzoateorvalerate. Themostcommonnonsteroidalestrogens,whichhaveahighaffinityfortheestradiolreceptor,arethe stilbenes. Theyareorallyactive,highlypotentandarenoteasilymetabolized. Somearegenotoxiccarcinogensandhencetheiruseisprohibited. Clinicaluses Misallianceinthebitch Inductionofoestrusandovulationinanoestrusanimals Controlofthetimeofovulation Controloflifespanofthecorpusluteum Treatmentofpyometraandmummifiedfoetus Obesityduetohypogonadisminbitches Urinaryincontinenceinoldandspayedbitches Analoedemaindogs Regressionofhypertrophiedprostrateglands Caponizationofyoungandoldcockerels Sideeffects Thisincludesgastrointestinalupsets,feminizationinmale,sodiumretentionandoedema. Inchronicoverdosagegenitalerythema,irritation,polydipsiaandpolyuriaarenoticed.
Progesterone

Themainfunctionofprogesteroneistoestablishandmaintainpreganacy,bypreparingtheuterine endometriumforimplantationandbypreventingmyometrialuterinecontractionsduringpregnancy. ItalsoactsasanegativefeedbackhormoneduringtheovariancyclesuppressingLHandFSHsecretion, oestrusandovulation. Insomespecies,itprimesbehaviouralcentresinthebrainandsoallowsestradioltoinducebehavioural estrus. Itisproducedmainlyfromthecorpusluetumandtheplacentaandtoalesserextentfromtheadrenalgland. Inthepregnantanimal,thecorpusleuteumismaintainedforthedurationofpregnancy,exceptinthemare. Insomespeciessuchasthesowandthegoat,thelutealprogesteroneisrequiredthroughoutpregnancy:in otherspeciessuchasthemareandtheewe,theplacentalprogesteroneistheprimarysourceafterday100 inthemareandday55intheewe.
Uses Controlofovulation Inductionofovulation Reduceembryonicloss. Syntheticprogesterones Medroxyprogesterone(MAP)usedtocontrolestrusandovulationinthecyclicewesandtoinduceestrus inanoestrousewes.Itcanbeusedinbitchestosuppresstheonsetofnextestrus. Flurogesteroneacetate(FGA)usedtocontrolorinduceestrousinewes. Melengesterolacetate(MGA)usedtosuppressestrusinheifers Norgestometusedtocontrolorinduceovulation Proligestoneusedtocontrolestrousinbitches.

Androgens

Androgensaresubstanceswhichstimulatethemaleaccessoryorgansandproducethesecondarysex characteristics. Themajorandrogensofimportancearetestosterone,dihydrotestosteroneandandrostenedione. 90|U R V I S H M I S T R Y
91|U R V I S H M I S T R Y Testosteroneisconvertedto: o dihydrotestosteronewhichhasbiologicalactivitywithintestesand o toestradiolwithinthebraintoinducemalelibido. Androgensareproducedintheleydigcellsofthetestesandtestosteroneisalsoproducedintheepididymis ofthestallion. Inthemaleandrogensstimulatespermatogenesis,growth,anddevelopmentandfluidsecretionsofthe testes,secondarymalecharacteristicsandmuscledevelopment. Inthefemale,theyarethemainprecursorsofestrogensynthesiswithinthefollicle. TheyalsoactaspartofthenegativefeedbacksystemtocontrolLHandFSHsecretion. Inanimals,thereareonlylimitedusesofandrogenstocontrolreproduction. Testosteronehasanaboliceffectsleadingtoincreasedproteinsynthesis,retentionofpotassiumand phosphorus,increasedbonegrowth,cartilageandothertissuesandincreasederythropoiesisbysecreting erythropoietin. Theyareusedtotreatinfertilityandimpotencywithvaryingsuccess. Androgensarealsoadministeredtocowsandheiferstousethemasdetectorsofoestrus.
Anabolic steroids

Compoundsstructurallyrelatedtotestosteronebutpossessingproteinanabolicactivitywithminimal androgenicactivityarecalledanabolicsteroids. Thesedrugsareusedmainlyintherapeuticallydebilitatedanimals. Themetabolicactivitiesinclude o Proteinanabolismwithpositivenitrogenbalance o Increasedmusclemassduetoincreasedproteinandglycogencontent o Highretentionofcalciumandphosphorus. Drugsusedarenandroloneandstanozalol. Antiandrogenslikedelmadinoneacetateareusedtocontrolhypersexualityindogsandcats,relieve prostatehypertrophy,tumoursandbehavioralproblemsindogsandcats.
Posterior pituitary hormones

Therearetwoknownposteriorpituitaryhormones: o Vasopressin(ADH)andoxytocin. o Posteriorpituitaryhormonesaresynthesizedinthehypothalamusandtransportedtotheposterior pituitary,wheretheyarereleasedintocirculation. Antidiuretichormone(Vasopresssin) Thishormoneregulateswaterpermeabilityinthedistaltubulesandcollectingductofthenephron. Itisalsoavasoconstrictorandinfluencescardiovascularfunctions. Itisusedinthetreatmentofdiabetesinsipidusandprophylacticallyagainstbleedinginhaemophilia. Oxytocin Oxytocinisproducedinneuronalbodiesinthesupraopticandparaventricularnucleiofthehypothalamus. OytocinstimulatessmoothmusclecontractionsandalsoincludesPGF2alphareleasewhichcausesluteolysis. Uses Speedingtheexpulsionoffoetuswhenuterineinertiaisdiagnosed Aidsintheexpulsionofplacentaldebrisandpromotesinvolutionoftheuterus Inuterineprolapseinjectionofoxytocinatseveralplacesintheorganreducestheengorgementand contractstheeverteduterus.Thushelpsinthereplacementmoreeasily Functionalagalactiaincows Inmastitisincattletoexpeltheinfectedmilkbeforeusinganyantibacterialagents.
Pharmacotherapeutics of fat soluble vitamins

Vitaminsareessentialnutrientspresentinminutequantitiesinfoods.Ifthereisadeficiencyinsupplyof vitamins,deficiencydiseasesoccur.Insuchascenario,supplementationofvitaminsisindicated. Fatsolublevitamins 91|U R V I S H M I S T R Y
92|U R V I S H M I S T R Y Vitamin Deficiencysigns A Keratinizationofepithelium,night blindness,fetalresorption,lowegg prduction,poorhatchability Treatment Farmanimals:100200units /kg/day Poultry:0.070.22gm/kgfeed
Ricketsinyoungandosteomalaciainadults Farmanimals:50100IU/kg/ day Dog:200400IU/kg/day Chicks150300IU/kg/day Musculardystrophyinyoungandwhite musclediseaseorstifflambdiseasein cattle Allyoungstock40mg/kg/day PO; 25mg/kg/dayScorIM OralSwine500mg;Dog30mg /kgandpoultry350mg/bird/ day
Delayedclotting,spontanoushaemorrhage Menadione/Menaphthone Forwarfarinpisoning5mg/kg IM ForSweetcloverpoisoning1.2 mg/kgIM Fordeficiency:Smallanimals2 10mg/dayPO LargeAnimals:100400mg/ dayPO Poultry12gm/tonoffeed
Pharmacotherapeutics of water soluble vitamins

Vitamin B1Thiamine Deficiencysign Brackenfernpoisoning Nervoussigns Treatment Calf550mg Sheep20200mg Cat120mg Dog550mg Horse/Ox100 1000mg POorIMorSC Pig5mg/day Horse40mg/day infeed
B2Riboflavin
Curledtoeparalysisinchicken,anaemia, dermatitis,csoursincalves,lowfertility, eyedischarge,photophobiainhorse
B3pyridoxine
Acrodynia(dermatitis,hyperkeratinization) Sameasthiamine indogs,degenerationofspinaland peripheralnerves Pellagra,Blacktongueindog,roughskin, Oralulcers,diarrhoea,dermatitis Dog510mg/ kgIM Cat1030mg/kg IM Calf25mg/daySC Pig0.10.3gmSC 92|U R V I S H M I S T R Y
Nicotinicacid
93|U R V I S H M I S T R Y or0.20.9gm orally B12 Hydroxycobalamin Biotin Choline Bushsickness,hindlimbweakness, incoordination,hairorwoolloss,stunted growth,anaemia Fattyliveriffedentirelyonwheatration EggwhitecontainsantibiotinfactorAvidin Perosis(slippedtendon)inpoultry Ataxiaindogs,catsandpigs DogandCat24 g/kg/dayIM 100g/chick/day PO Dog550mg/day PO CAt2550mg/kg dayPOorSC Alsoinmilkfeveror ketosisincattleand buffaloes Horse24gmSC Bull12gmSc Cow12gmIVorSC beforemating Dog2575mg/ dayPOorSC
Ascorbicacid (VitaminC)
Nodefinitesigns
Drugs acting on skin and mucous membranes

Counterirritants
Theseareagentsthatarethoughttoactbyproducinganirritantactionontheskinwhichenablesincreased bloodflowtotheappliedarea.Whenanirritantsubstanceproducespainfulstimulusontheskin,itisableto maskthepainfromdeepertissues. Theyalsobringaboutanantiinflammatoryresponseduetoenhancedbloodsupplyandishelpfulintreating localisedconditionssuchastrauma,swelling,painetc. Counterirritantsareverycommonlyemployedinreducingpainandinflammationintraumaticand musculoskeletalconditions. Dependingontheintensityofirritationproduced,counterirritantsareclassifiedasfollows. Rubefacient:Agentsthatproduceamildincreaseinbloodflowatthesiteofapplication. Eg:Iodineointment Vesicant:Agentsthatproduceastifferirritationtoformvesicantsunderneaththeskinwhicharefilledwith serousfluid.Eg:Cantharidine Pustulant:Agentsthatproduceamuchstrongerirritationwhichreachestheunderlyingstructuresandform pustuleswhicharefilledwithpus.Eg.Crotonoil Caustic:Agentsthatproduceveryintenseformofirritationsothattheycorrodetheskinandunderlying structures.Eg:Causticsoda,causticpotash
Penetration enhancers
Chemicalpenetrationenhancersactbyimprovingpenetrationbyreversiblydamagingstratumcorneumor byalteringthestratumcorneumtoreducetheresistancetodiffusion. o Azone&derivates o Ureaandderivatives1dodecylurea,1,3decylurea,propyleneglycol o Terpenecarrone,pulegone,menthone o AproticsolventsDMSO,2pyrrolidone o Surfactantssuchaspolyethyleneglycol 93|U R V I S H M I S T R Y
94|U R V I S H M I S T R Y Suitableuseofpenetrationenhancerswouldhelpincreasethebioavailabilityofagentsgivenintradermally.
Adsorbants

Adsorbantsaresubstanceswhichcanbindnoxiousandirritantsubstances.Whenappliedontheskin,they lessentheirritationandaffordprotectiontotheskin. Example: o Dustingpowder o Starch,Zincoxide,CaCO3 o Boricacidandtalc o Collodion o Dimethicone
Demulcents
(demulcereTosmooth) Theseareinertagentsthatsoothendamagesmucosabypreventingcontactwithairorotherirritants. Highmolecularweightwatersolublecompounds o AlleviatingirritationwithinherentpropertiestoreduceirritationE.g.Glycerin,gelatin,hydroxyl propylcellulose,methylcellulose Glycerin o Lowconcentrationhydratesskin.Howeverinhighconcentration,itdehydratesskin Propyleneglycol o Hygroscopic,bacteriostatic,fungistatic Gumacacia o Colloidalplantcarbohydratesthatswellinwater,formingmucilaginoussolutions.
Emollients

Emollientsareblandoilymaterialsthatsoftenskin Decreasetransepidermalwaterlossandthushelpfulindryskinandcrackedskin Examples o Vegetableoils:Almondoil,Cottonseedoil,Oliveoil,Peanutoil,Cocobutter o Animaloils:Lard,Lanolin,Spermaceti(fromspermwhale) o Petroleumproducts:Liquidparaffin,paraffin
Astringents

Emollientsareblandoilymaterialsthatsoftenskin Decreasetransepidermalwaterlossandthushelpfulindryskinandcrackedskin Examples o Vegetableoils:Almondoil,Cottonseedoil,Oliveoil,Peanutoil,Cocobutter o Animaloils:Lard,Lanolin,Spermaceti(fromspermwhale) o Petroleumproducts:Liquidparaffin,paraffin
Other agents used on skins

Besidestheaboveanumberofotheragentsareusedontheskin.Thesedrugswillbediscussedunderappropriate headings. Keratolytics Theseagentscausetheouterlayeroftheskintoloosenandshed.Theycansoftenkeratinandusedinteh treatmentofdandruffandseborrheicdermatitisEg.Zincpyrithione,sulfurandsalicylicacid Antibacterial Antifungals Corticosteroids Vasodilators Fibrinolytic Antiinflammatoryagents 94|U R V I S H M I S T R Y
95|U R V I S H M I S T R Y Vehicles
Bioenhancers, immunostimulants and immunosuppressors

Bioenhancers
Bioenhancersareagentsthatatlowdosespromoteandaugmentthebioavailabilityorbiologicalactivityof drugs. Herbalbioenhancersareagentsofherbaloriginoranyphytomolecule,whichiscapableofenhancing bioavailabilityand/orbioefficacyofaspecifieddrugornutrientatthelowdosebutitdonotshowtypical pharmacologicalactivity. Theconceptofbioenhancers(herbalorigin)canbetrackedbacktoAyurvedasystemofmedicine.'Trikatu' meaningthreeacidsisanAyurvedicpreparationcontainingblackpepper,longpepperandginger,whichare prescribedroutinelyforavarietyofdiseasesaspartofamultidrugprescription. Herbalbioenhancershavepropertieslikenontoxictohumansandanimals,effectiveatlowconcentrations, easytoformulateandenhanceabsorptionandbioactivityofthedrugornutrient.Herbalbioenhancersare suggestedtoactthroughseveralmechanismsofaction.Variousmechanismsofactionpostulatedforherbal bioenhancersinclude o increaseingastrointestinalbloodsupplyandreductioninhydrochloricacidsecretion, o inhibitionofgastricemptyingtime,gastrointestinaltransitandintestinalmotility, o modificationsinGITepithelialcellmembranepermeability, o cholagogouseffect, o thermogenicandbioenergeticsproperties, o Inhibitionofdrugmetabolizingenzymesandsuppressionoffirstpassmetabolismandstimulationof gammaglutamyltranspeptidase(GGT)activitywhichenhancesuptakeofaminoacids. ImportantIndianHerbalBioenhancers Longpepper(Piperlongum), Blackpepper(Pipernigrum), Ginger(Zingiberofficinale), Liquorice(Glycyrrhizaglabra), Blackcumin(Cuminumcyminum), Cumin/Caraway(Carumcarvi), Garlic(Alliumsativum)and IndianAloe(Aloevera) Thedevelopmentofplantbasedbioenhancersistobetargetedfordrugsthatarepoorlybioavailable,givenfor longerperiodoftime,highlytoxicandexpensive.Further,researchshouldbecarriedouttoevaluateclinical applicationofherbalbioenhancersinmodernhumanandveterinarytherapeutics.
Immunostimulants

Theseareagentsthathavebeenusedtoenhanceanimmuneresponseandarehelpfulasadjunctagentsfor therapy. Mostcommonuseindogsisforthetreamentofchronicrecurrentstaphylococcalpyoderma. StaphagelysateisapreparationofS.aureusandstaphylococcalbacteriophage.ItisbelievedtostimulateT lymphocytesandactivatephagocyticcells. Staphylococcalbacterintoxoidhasbeenusedwithsomesuccessincaninebacterialhypersensitivity. Oneofthemostcommonlyusedimmunomodulatorinveterinarypracticeistheanthelminticlevamisole, whichisadvocatedatonethirdtheanthelminticdoseforimmunomodulatoryactivityforgeneralised immunityenhancementasisrequiredpostvaccination.
Immunosuppressant
Theseareagentsknowntosuppresstheimmuneresponseonadministration.Inhumanbeingstheyarevery commonlyusedintransplantstopreventgraftrejectionandinthetreatmentofautoimmunediseases.In veterinarypracticetoo,theyareveryuseful. 95|U R V I S H M I S T R Y
96|U R V I S H M I S T R Y Glucocorticoidsarethemostcommonlyusedimmunosuppressiveagents.Itisusedforimmunemediated skindisorders. Cyclophosphamide,analkylatingagent,isusedincombinationwithglucocorticoidsforseverecasesof autoimmnunediseasessuchassystemiclupuserythematosus,pempighus,rheumatoidarthritis.Theside effectsincludehaemorrhagiccystitis,fibrosisofthebladder,bonemarrowsuppressionetc. Chlorambucilissloweractingandlesstoxic.Itisadministeredalternatelywithglucocorticoids. Azathioprineismorecommonlyusedforpemphigus. Cyclosporinewhichismostcommonlyusedinmanforgraftrejection,mayalsobeusedinanimalsto preventpempighus,lupusetc.Itispotentiallynephrotoxic,hepatotoxic,toxictoalimentarytract,andbone marrowsuppression.ItblockstheproliferationofactivatedTlymphocytes,byinhibitinginterleukin2,gene activationandRNAtranscription.ItcanbeusedforKeratoconjunctivitissiccaindogs. Dapsoneusedasanantibacterialfortreatingleprosyinman,hasbeenfoundtoinhibtchemotaxis, degranulationofmastcellsandinhibitIgG,IgA,prostaglandinsandalsoTcellresponses.Itisalsousedfor caninepemphigusandlupuserythematosusandallowsfordecreaseinthedoseofglucocorticoids.

Veterinary Pharmacology Course Overview

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Veterinary Pharmacology Course Overview

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General and Systemic Veterinary Pharmacology

Pre- Christian era

Terms and definitions

Drug related terms

Dose related terms

12|U R V I S H M I S T R Y Alkaloidsshouldbeadministeredinsmallquantitiesandwhengiveninexcesstheymayproducedeath withoutmuchpostmortemchangesfordiagnosis.(Adrenalineisconsideredasanimalalkaloid).

Animal source of drugs

13|U R V I S H M I S T R Y oilsandfats(usuallyfixed),suchascodliveroil enzymes,whichareproducedbylivingcellsandactascatalysts,suchaspancreatinandpepsin vaccines,whichincludesuspensionsofkilled,modified,orattenuatedmicroorganisms,orantigenic materialsobtainedfromthese.

Synthetic sources of drugs

Microbial source of drugs

Pharmacokinetics: principles of drug activity

Subcutaneous and intramuscular routes

Other parenteral routes

Structure of biological membranes

Passage of drugs across membranes

Carrier mediated transfusion

Pinocytosis and phagocytosis

Absorption of drugs from GI tract

Role of ionization and lipid solubility in drug absorption

Henderson and Heselbelch equation

Absorption of drugs after parenteral administration

Absorption of drugs after inhalation or topical administration

Plasma protein binding of drugs

Plasma protein binding

Drugswithinthesamegroupbindvariably Eg.Sulfonamides: Sulfamethazine30%,Sulfadiazine50% Sulfamethoxazole60%,Sulfisoxazole90%

Tissue storage of drugs

Barriers to drug distribution

Biotransformation of drugs/xenobiotics: drug metabolism

Sequelae of biotransformation reactions

Phase-I Biotransformation - oxidation reactions and others

26|U R V I S H M I S T R Y Deaminationofamine Desulfuration Hydrolysisofestersandamides Reduction a.Azoreduction b.Nitroreductionhloramphenicol

Amphetamine Thiobarbital,parathion Procaine Prontosil Chloramphenicol

Nonmicrosomalreactions MonoAmineOxidase(forbiogenicandotheramines) Esterases(forcholineanddietaryesters) Dehydrogenases(foralcoholsandaldehydes)

Phase II reactions - synthetic reactions

Enzyme induction and inhibition

Hepatic and other routes of administration

Important pharmacokinetic parameters

Principles of Drug activity Pharmacodynamics

Enzyme mediated drug action

Receptor mediated drug action

Terms related to drug receptor binding

Receptors - structure and function

Second messenger systems

Dose response curve

Asthenameindicatesthisreferstotheplottingofthedosevsresponse,withthedoseinXaxisand responseinsomemeasurableunitsintheYaxis. Thefeaturesofthecurvesoobtainedwillprovideusefulinformationabouttheactionofthedrugorin comparisonamongdrugs.

Features of dose response curve

Quantal dose response curve

Factors modifying drug action

Adverse effects of drugs

Types of adverse effects

Drug screening and drug discovery

Preclinical safety and toxicity testing

42|U R V I S H M I S T R Y Futuremassbioprospectingendeavorsmusttakeheedofthelessonslearnedfrompastandpresent experiencesintheplanningforasuccessfulmassbioprospectingventure.

Biopharmaceuticals and gene therapy

Gastro intestinal pharmacology

Histamine receptors H2 antagonist

Proton pump antagonists

Digestants and purgatives

Purgatives and laxatives

General mechanism of action

Choice, indications, combinations, abuse of purgatives

Protectants and adsorbants