Pharmacology

Answers
2012
By: Aviad Nachmany.
Nadav Bitton.
Civita Davide Francesco.
Natasha Barabash.
4GM

1. What is pharmacology. Subdivisions of pharmacology:

Pharmacology is a branch in medicine or biology that concern to the study of drugs and its
interactions within a biological system to affect its function.
A drug can be defined as a man-made (synthetic) or naturally occurring substance that excretes
a biochemical and/or physiological over a cell, tissue, organ or the organism as a whole.
More specifically it can be defined as the study of interactions between a living organism and a
chemical substance that affects normal or abnormal functions.
There are 2 main areas in pharmacology:

Pahrmacokinetics: is the study of the fate of the drug, or the effects of the organism over the
drug, composed of absorption, distribution, metabolism and excretion (last 2 are called also
elimination).

Pharmacodynamics: it is the effect of the drug over the organism, or the drug action,
mechanism of drug action.

Medicine - is a plant or animal substance or even a synthetic substance or a mixture of drugs

combined with other substances (vehicle) to make it stable, edible and useful for therapy.

Agent is a collective name for group of drugs (antihypertensive, antipyretics, etc.).

subdivisions in pharmacology:

clinical pharmacology: medication effects on humans and animals.

Neuropharmacology: effects of a drug over the nervous system.

Psychoparmacology: effects of a drug over the human brain.

Toxicology: study the harmful or toxic effects of a given drug.

Theoretical pharmacology: study theories in pharmacology.

Environmental pharmacology: gene-environment interactions.

Posology: also can be called doseology, is a branch studying how medicine is dosed.

2. Historical development of pharmacology, Drug names.

Pharmacology as an independent branch stated developing somewhere in the 19th century

but there are evidence of pharmacological therapy all the way to 6 B.C and written evidence
from the 4th or 5th century in india.
In ancient Egypt, various papyrus recorded pharmacological knowledge as far as the 16th
century B.C.
In ancient Greece, history of parmacotherapy dates to the 4th century B.C when there was a

group of experts in medicinal plants.

In Baghdad during the 8th century, there was a network of state-regulated pharmacies during
the Islamic golden era and in Europe it was recorder somewhere in the 12th century.

milestones in pharmacology:

1805: isolation of Morphine by Sertirner.

1860: synthesis of Salicylic acid by Kolbe and Lautemann.

1874: synthesis of Acetysalicylic acid.

1904: barbiturates.

1928: Penicillin was discovered by Fleming.

WW2: the first use of sulfonamides as antimicrobial although discovered way earlier.

1960: Propranolol: developed by Black.

Drug names: a drug is given 2 names, the first one is a generic name which is the name that
appear in the pharmacopeia and can vary among nations (paracetamol-acetaminophen).
The second name will be the commercial name of the drug that was given to it by the
manufacturer, most of the times is easier to remember and pronounce.

3. Mechanisms of drug passage across the membranes:

Also called absorption, a drug can pass across a biological membrane in 2 main ways:

passive diffusion.

active diffusion.

Passive diffusion will be a process in which the drug, or the substance cross the membrane
along the concentration gradient. In order to achieve that the drug must be liposoluble and
non ionized (charged molecules cannot cross membranes passively) which is achieved due
to the drug's pKA. No specific carrier is required and the substance can pass through
channels (for ionized forms). Weak acid will cross membrane easily in an acidic
environment and weak bases in alkali environment.
Molecules larger than a certain size (100-200 Dalton) will not pass through pores.

fascilitated diffusion- passage of a molecule through special proteins (i.e ion channels) that
do not require energy.

active transport is a process that require energy and involves a specific carrier molecule or a

pump (Na+/K+ pump) in order to move substances against their concentration gradient.

the transport can be uniport (one substance, one way) symport (2 substances together, one
way i.e glucose and sodium in the intestines) and antiport (one substance one way the
other substance to the other way, i.e sodium/calcium pump).

4. Routes of drug administration :

The route of administration of a drug may be crucial for its activity or alter the absorption and
the bioavailability of given drug.
Typical routes of administration include parenteral, enteral and other:

Enteral (through the GIT):

P.O. - It is the most common method of administration, given as a pill, a capsule or lozenge
(loz = )which is easy for the patient and does not require any instruments or medical
staff, but undergo biotransforamtion in the stomach and in the liver (first pass effect) thus
the bioavailability is decreased.

S.L. - sub-lingual administration is administration of a drug under the tongue that go straight
to the capillary network and thus bypass the liver and the stomach.

Parenteral (not from the GIT): used for drugs that are poorly absorbed from the GIT
(heparin), unstable in the GIT (insulin) and in patients that require rapid onset.
This methods have the highest bioavailability, because they do not pass through the GIT or
the hepatic circulation.

I.M. - intra-muscular injection is a method with a rapid absorption of water soluble

substances, can be given as emulsions (lipids+water) or suspension (water+powder) as well,
it is necessary to aspirate to make sure the drug is in the muscle and not vein or artery,
relatively painful or scary for the patient and may be prone for infections.

I.V. - intra-venous injection is the only method with 100% bioavailability of water soluble
substances.

S.C. - absorption of lipid soluble materials through the sub-cutaneous tissue.

Other:

Inhalation fast method with intense effect, but can be irritating to the respiratory system.

Transdermal slow sustained release of substances from the skin to the systemic
circulation which may lead to local irritation.

Topical creams or lotions or powder preparations that can be given topically on the skin.

P.R. - per rectum is administration through mucous membrane (anus) and can decrease the
first pass effect by 50%, because 50% of the absorbed drug bypass the hepatic circulation,
can be given in cases such as vomiting or to infants, but can be uncomfortable.

Intrathecal / Intraventricular- administration of a drug directly to the CSF.

Intranasal usually nasal decongestants and is the administration of drug directly to the
nose.

5. Absorption of drugs.
Absorption is the transfer of a drug from its site of administration to the blood stream which
may be influenced by many factors.

the route of administration only I.V has 100% bioavailability, because it is directly to the
blood.

The pH and the pKa most drugs are either weak base or weak acid, acidic (HA) is non
ionized in acidic environment (HA H+ + A-) and basic is non ionized in alkali
environment (BH+ B +H+), a drug passes the membrane when it is uncharged.

Blood flow in the absorption site, surface area and contact at the absorption time.

Food and drink can influence the absorption rate and biotransformation of a drug

The absorption can be either via passive diffusion (through membrane or pores), active (through
pumps and transport molecules) or via endo/exocytosis (for very large molecules).

6. Bioavailability. Factors influencing bioavailability:

It is the fraction of administered drug that reaches the systemic circulation in a chemically
unchanged form.

It is determined by comparing the plasma levels of a drug after a particular route of

administration (oral, P.R, etc) with plasma drug levels achieved by an IV injection.
Mathematically it is defined as the area under the curve, plotted over time of a given dose (oral,
PR, etc) divided by area under the curve of an injected dose, multiple 100 for percentage.
Bioavailability = AUC route / AUC injected x 100 = ?

Bioequivalence: 2 related drugs that show comparable bioavailability and similar times to
achieve peak levels.

Theraputic equivalent: 2 similar drugs with comparable efficacy and safety.

Factors influencing bioavailability:

first pass effect: drug absorbed from the GIT enters the portal circulation before entering the
systemic circulation where it is metabolized in the liver (p450) reducing the amount in the
systemic circulation.

Solubility of a drug.

Chemical instability: degradation in the GIT.

Other: coating, size, crystal formation, etc.

7. Distribution of drugs, Binding of drugs to proteins:

It is the process by which a drug reversibly leaves the bloodstream and enters the interstitium
(extra-cellular fluid) and/or to the cells.
It primarily depends on:

blood flow: there is unequal distribution of blood in the body (brain, liver and kidneys gets
the highest amount of the blood) leading to fast action over the brain for example.

Capillary permeability: determined by the capillary structure (tight junctions in BBB) and
the chemical nature of the drug (liposolubility transfer through biologic membranes)

binding to plasma proteins: albumin is the main binding protein.

Volume of distribution:

A hypothetical volume of fluid into which a drug is distributed, the higher the Vd the more drug

is within body compartments. Also known as the partition coefficient of a drug between body
body compartments and the plasma.
Vd will be equal to the amount of drug administered (Dose) divided by the plasma
concentration (Vd = D / C =?). In reality C is not constant and should be considered as a logC
(adding the elimination factor).

Binding of drugs to proteins:

In the systemic circulation the drug may be free or protein-bound (fractions). Only free drug can
interact with target molecule and pass membranes. When some amount of the free drug is
spent some bound drug molecules are released and become free (balance). Plasma proteins to
which the drugs are bound to are Albumins (mainly acidic and lipophilic drugs) Globulins and
glycoproteins (basic drugs). Binding depends on: drug concentration, protein concentration and
binding capacity, drug affinity (drug displacement).

8. Drug metabolism:
Drugs are most often eliminated by biotransformation and/or excretion into the bile or urine.
This process involves usually transformation of a lipophilic drug into a polar water soluble
substance that is more easily excreted.
The liver is the major organ for biotransformation, but also the kidney and intestines play a role
for some drugs (some drugs are pro-drugs, and must be metabolized to become active).

Zero order kinetics: the rate of metabolism remains constant (enzyme is saturated).

First order kinetics: metabolism is directly proportional to the concentration of free drug,
meaning that a constant fraction of drug is metabolized over time.

There are 2 main types of reactions of drug metabolism:

Phase 1: convert lipophilic molecules into more polar molecules by introducing or

unmasking a polar group (i.e OH). This mainly involves the cytochrome p450 system
(microsomal mixed function oxidase) which is located in the smooth endoplasmic
reticulum, mainly that of the liver cells, but there are also non-CYP450 phase 1 reactions
(alcohol dehydrogenation, hydrolysis, esterases).
So we can say phase 1 involves oxidation, reduction and/or hydrolysis. Following phase 1

reaction the drug can be activated, unchanged or inactivated.

CYP P450: important for the metabolism of endogenous substances and the
biotransformation of exogenous substances, there are many isoforms of the enzyme and 4
are the most important: CYP3A4 (60%), CYP2D6 (25%), CYP2C9/10 (15%), CYP2C19
(15%) - {yes I know it is more than 100%, the reason is one substrate can be for more than
1 enzyme). CYP3A4 is also located in the intestinal mucosa, and all these enzyme exhibit
genetic polymorphism (fast and slow metabolism).

Inducers: major site for drug interactions (phenobarbital and rifampin are able to increase
the synthesis of CYP isoenzymes) resulting in increased biotransformation.

Inhibitors: the most common form is competition for the same isoenzyme. Grapefruit juice
inhibits CYP3A4 thus never to be taken with any drug.

Phase 2 reaction: this phase is the conjugation reaction phase with endogenous substances,
such as Glucuronic acid, Sulfuric acid, Acetic acid or Amino acid result in polar, water
soluble substance. Neonates are deficient in the conjugation system thus particularly
vulnerably to drugs such as chloramphenicol and have neonatal jaundice. {note, that some
drugs can enter phase 2 directly and skip phase 1, but they got to have a polar group}.

9. Drug excretion:
Occur via number of routes, such as the hepatic (bile), intestines, lungs (breath), lactation,but by
far the most important is the renal clearance.

Renal excretion: removal of water soluble molecules (lipophilic are reabsorbed) which
result from 3 processes:

Glomerular filtration free drug flows the the capillary slits into the Bowman's capsule,
normal rate is 125 ml/min.

Proximal tubular secretion occur primarily by 2 energy requiring processes, anion system
and cation system, which can transport many compounds, thus competition for these
systems can occur between drugs.

Distal tubular reabsorption if the drug is uncharged it diffuses through the membrane,
thus weak acids may be eliminated by alkalization of the urine and vice versa (known as ion

trapping).

Factors that may influence secretion are: age, pathologic processes and drug interactions.

clearance of a drug is via the sum of the routes of elimination, meaning

Cl total = CL renal + CL hepatic + CL pulmonary+ CL other = KeVd
CL total = KeVd
(Ke = elimination constant and Vd equal the volume of distribution and both are usually
known).

GIT excretion - in liver there is a similar transport system as in renal tubules, and then the
substance is transported into bile. Also exist transport systems from steroids and similar
substances. Bile is excreted to intestine, it could be reabsorbed (enterohepatic circulation)
thus prolonging the effect of the drug (e.g. digoxin, morphine)

10. Molecular aspects, drug-receptor interaction, second messengers:

In general we can say that no drug is 100% specific toward a single molecule or receptor, thus
increasing the concentration of the drug will influence other targets too. The binding of the drug
to its receptor is usually reversible, but in some instances can be covalent and irreversible.
Drugs exert their action by several different mechanisms:

Indirect: on the basis of their physiochemical properties with no specific binding site, i.e
osmotic diuretics.

Direct: interact with a specific target molecule, which can be:

Enzymes mainly inhibitors, such as MAO or COX or ACE inhibitors.

Ion channel blockers or modulators, such as calcium channel blockers, PPI's.

Carrier molecules such as reuptake of neurotransmitters (SSRI- selective serotonin

reuptake inhibitor), glucose transporters.

Receptors - Most of the drugs exert their effect by interacting with receptors which are
present on the cell surface or intracellularly.

Drug-receptor interactions: interaction of receptors and ligands invloves the formation of

chemical bonds,such as hydrogen, Van Der Waals and elcrostatic bonds. These are weak

bonds, thus require short distance between the atoms for proper bonding, hence the
specificity, the old theory states that there is a lock and key fit between the ligand and
receptor (good for understanding) but the newer theory is the induced fit model which
state that the receptor undergo conformational changes in the presence of the ligand.
There are 4 major types of receptors:

Ligand gated ion channels: responsible for the regulation of the flow of ions across cell
membranes, it is regulated by the binding of the ligand to the channel, important
representatives of this group are nicotinic receptors and GABA receptors.

G protein-coupled receptors: comprised of a single peptide with 7 different membranespanning regions which is linked to a G protein, which has 3 subunits (alpha, beta, gamma).
G protein can be stimulatory (Gs) or inhibitory (Gi), by binding to a ligand there is a
conformational change of the receptor which then interact with the alpha subunit of the G
protein, which in turn binds GTP and activate adenylyl cyclase which change the
concentration of the second messenger in the cell.

Enzyme linked receptors: having cytosolic enzyme activity as an integral part of their
structure or function (insulin receptor), binding of a ligand to the receptor will activate or
inhibit the enzyme.
The most common receptors are those having Tyrosine kinase, which when activated
phosphorilates tyrosine residues of proteins.

Intracellular receptors: the ligand must diffuse into the cell to interact with the receptor,
thus the ligand must be lipid soluble and for this reason it is transported through the plasma
bound to serum proteins (such as albumin), example for such are steroid hormones (cortisol)
and thyroid hormones. The activated ligand-receptor complex migrate to the nucleus and
bind to specific DNA sequence, resulting in regulation of gene expression.

Drug can be agonists (bind to receptor and produce response), partial agonist and antagonist
(occupy receptor without producing a response)
antagonist can be competitive (displace agonist- i.e propranolol for beta receptors) or bind
irreversibly to the receptor.

Second messenger: compounds which conduct signals from G-protein coupled receptors.

Adenyl cyclase - activated by alpha GTP subunit, result in production of cAMP regulates
protein phosphorylation.

Phospholipase C responsible for the genertaion of diacylglycerol and IP3 (inositol

triphosphate), which responsible for the regulation of intracellular free calcium
concentration (increase).

Guanylyl cyclase convert GTP to cGMP that stimulate cGMP protein kinase (in intestinal
mucosa and vascular smooth muscle).

11. dose response quantitation. Therapeutic index:

The magnitude of a drug action increases as the concentration of a drug increases at the receptor
site.

Potency: a measure of the amount of drug necessary to produce an effect of a given

magnitude. EC50 is used in order to determine potency (drug dose that show fifty percent of
maximal response). Semilogarithmic plots are used, using log {drug concentration} as the X
axis and percentage of maximal effect as the Y axis.
An important factor that reduces EC50 is the drug affinity to the receptor, thus the higher
the affinity the lower the EC50 and the higher the potency.

Efficacy: the ability of the drug to illicit physiologic response when it interacts with a
receptor. It depends on the number of drug-receptor complexes formed and the efficiency of
the coupling for cellular response. E-max is an analogue to the enzyme catalyzed reactions
and is rate limiting, meaning there is maximum activity possible efficacy is more
therapeutically beneficial than potency.

Drug-receptor binding: Needed to determine the affinity according to the amount of drug
applied and amount of receptors bound.

affinity is described as the strength of the interaction between a ligand and a receptor, high
affinity means strong connection.

Down regulation is when long term application of agonist to receptor there is down
regulation of receptors i.e. in sensitivity and in amount on membrane=tolerance to
drugs.

Up regulation is when long term application of antagonist to receptor there is up regulation

of receptors i.e. in sensitivity and in amount on membrane (sudden breaking of therapy
e.g. - blockers).

Agonist: binding of a drug to receptor mimics the biologic response of the endogenous
ligand.

partial agonist have efficacy to the receptor, but lower than the true agonist, cannot produce
E-max.

Antagonist: drugs that decrease the action of another drug or endogenous ligand, can be
competitive (on the same receptor), allosteric (non-competitive, on a different site) or even
functional (on another site than the receptor or different receptor).

Therapeutic index:

It is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or
effective response, thus is defines as T.I = TD50/ED50. It is a measure of drug's safety because
a large number indicate wide margin between toxic and effective doses.
It is found in clinical trials, and is the toxic dose in 50% of the subjects / the effective dose in
50% of the subjects.

12. Harmful effects of drugs. Drug allergy:

Can be also called side effects and is any response to the drug which is unexpected and
damaging the organism which can be caused by the pharmacochemical or pharmacodynamic
properties of the drug, thus they are predictable and dose dependent or due to reactive
metabolites (toxic effect).
The harmful effect can be classified into 5 categories:

Type A Augmented reaction: it is the most common, pharmacologically predictable, dose

dependent and usually cause low mortality, can occur on normal dosage and tend to resolve
or improve with lowered dose. Associated with low mortality.
It can be avoidable by assessing the predisposing factors (e.g. genetics), start with the
lowest dose possible and adjust in case of renal or hepatic problems.

Type B Bizarre: it is not predictable, not dose dependent, will occur in some individuals
and associated with high mortality. It include allergic reactions and genetic abnormalities
(e.g. G6PD). May be minimized by taking good history (drug and family) and avoiding
certain drugs in certain disease states. If occur the drug must be stopped.

Type C Continuous: due to long term use (up regulation), for example tardive diskynesias.

Type D Delayed: teratogenicity, carcinogenesis.

Type E End of use: appearance of symptoms that were not present at the beginning of
use withdrawal symptoms.

side effects can be mild, moderate or severe, in the last one cessation of the drug is
mandatory.

Drug allergy:

It differ than toxicity in that the reaction appear in only part of the population, it is not dosedependent, the symptoms differ from pharmacological effect and the presence of circulating
antibodies. It can be:

acute anaphylaxis, circulating antibodies, fever, haemolysis, fever, etc.

it is a delayed type hypersensitivity, or type 1 hypersensitivity (IgE mediated), meaning that

there has to be prior sensitization by an allergen in order to cause an allergic reaction.

13. Drug abuse:

It is a serious social, medical and financial problem that occur in any state and all the levels of
society and is an habitual use of substance in order to alter one's mood, emotion or state of
conscious. Can also be defined as the use of drug not for a non-therapeutic effect.

Cannabis: a psychoactive drug in which the active substance is THC (tetrahydrocanabiol)

which is usually smoked, but can be also ingested (hush cakes), leading to euphoria,
relaxation and amplification of senses.

Sort term effects: increased appetite, tachycardia, redness of the eye, impaired intellectual,
may lead to panic, anxiety, hallucinations or psychosis.

Long term effects: tolerance, psychological dependance, lung cancer, etc.

medical use: anti-emetic (cancer), appetizer (AIDS), lower intraocular pressure, decrease
muscle spasms.

Coca: from the plant erythroxylon, the psychoactive substance is cocaine, can be chewed,
smoked, ingested, injected or sniffed (the most common). Can lead to euphoria, alertness
and postponed hunger and fatigue, but tolerance develops rapidly and it may lead to serious
side effects: tachycardia, tachypnea, hypertension, midriasis, violent behavior,
hallucinations, restlessness, psychosis, convulsions and nasal septal defect (typical nose
bleeding from a weak membranous circular part on the septum).
It is used in medicine as a local anesthetic in surgery.

Opium: from the poppy flower (Papaver), the main substances are morphine, codeine,
papaverine (used medically) and Heroin (semi synthetic abuse drug).

leading to euphoria and analgesia.

Hallmark of intoxication is pin point pupils (severe miosis).

Causes also constipation, malnutrition and rapid tolerance and has severe withdrawal
symptoms (nalaxone is antagonist).

Medically used as anti-tussive (codein), for abdominal pain (papaverine), anti-diarrheal in

some countries and as analgestic (morphine).

CNS depressants: benzodiazepins and barbiturates.

They relief tension, anxiety and stress but can lead to depression, ataxia, confusion,
amnesia, insomnia, tolerance and dependance.
Used in medicine as anxiolytics, sedatives, myorelaxants and antiepileptic.

CNS stimulants:

Amphetamines: similar action to cocaine, stimulant, may cause the same problems as
cocaine, but is used medically in: ADD, narcolepsy, nasal congestion.

Ecstasy: fascilitate empathy, closeness to others, sociability, increase physical and emotional
energy, but may lead to depression, anxiety, visual and auditory hallucinations, stroke.

Hallucinogens: best known is LSD, its effects are extremely variable and largely depend on
the abuser state of mind.

It leads to alterations in though, mood and sensory perception + similar to ecstasy.

Side effects are: paranoia, distorted perception, prolonged anxiety, hallucinations,
flashbacks and depression.

14. Effects of age and disease on drug disposition, Genetic factors influencing drug action:
There are may factors that may influence the metabolism of a drug in the body, age and disease
state are 2 of those factors.

Age: it is relevant for 2 age groups mainly, to the pediatric (mainly newborns) and geriatric
patients.

Pediatric patients there are insufficient liver functions, glucoronization is insufficient,

there is high amount of extra-cellular fluid and decreased renal functions and glomerular
filtration, all these lead to decreased metabolism of a drug, and to decrease excretion of a
drug (elimination).
Some examples include chloramphenicol leading to gray baby syndrome and aspirin
leading to Reye's syndrome.

Elderly patients there is an age dependent decrease in liver functions, associated with
normal aging, disease state, substance abuse, co-morbidities.
In patients > 70 years of a age the drugs accumulate in the kidney due to decrease in GFR
and tubular secretion, together with the decrease in liver function, requiring dose adjustment
of the drug in order to reach the therapeutic effect and not the toxic effect.
There is also decrease in other factors, such as platelet count or RBC, requiring decrease in
agent such as Warfarin.

Disease state: in systemic diseases that damage the kidneys, liver or heart there is a
possibility for accumulation of harmful substances in the body with decrease elimination,
thus all patient with a severe disease state require dose adjustment.

Renal failure uremia increased BBB penetration drugs accumulate in the kidney
intoxication.

Cardiac failure decreased tissue perfusion decreased elimination activation of RAS

elevated plasma levels of a drug toxicity.

Liver disease impaired metabolism and glucoronization intoxication.

Liver disease may also lead to decreased albumin production, increasing the free drug in the
plasma, leading to side effects. As well there is a reduction in clotting factors, leading to
bleeding tendencies (think about it before giving Warfarin).

Genetic factors: pharmacogenetics is a branch in pharmacology that study the effect of

genetic polymorphism, or genetic variations over the drug activity, or the activity of the
drug over the body.

genetic polymorphism variations of genes coding for various proteins in a population, in

pharmacology it can affect pharmacokinetics (transport, protein binding, metabolism) and
pharmacodynamics (ion channels, receptor variations, enzymatic problems, etc).
The best studied is the metabolism at the P450 enzymatic location, on the smooth ER of the
liver cells which can affect large spectrum of metabolizing enzymes.

From the point of view of metabolism, the CYP450 has 60 genes with only 8 relevant in
pharmacology. The enzyme with the biggest polymorphism in the society is CYP2D6, the
second biggest enzyme system responsible for the metabolism of 20% of the drugs, its
function is to catalyze hydroxylation of demethylation (beta blockers, antiarrhythmics,
analgestics).
There are 3 types of metabolizers in the society: extensive metabolizers (EM most of the
society), poor metabolizers (accumulation of drugs), ultra extensive metabolizers (lower
effect of drug mostly Saudi Arabians).

From pharmacodynamic point of view, there can be receptor polymorphism (can decrease or
increase reaction to drug), enzymatic problems (G6PD- haemolytic anemia), etc.

15. Drug interactions:

Drug interactions can occur on the pharmacokinetic or pharmacodynamic level, they can be a
significant cause of drug related problems and contribute to both morbidity and mortality.

High risk patients for drug interactions are the elderly, because they usually have comorbidity, reduced metabolism and accumulation of substances together with the fact that
they are usually on more than one drug.
Children are also in increased risk.

High risk drugs for drug interactions will be those with low therapeutic index, due to the
fact that any increase in their plasma concentration is dangerous (i.e Digoxin, Warfarin).

Pharmacodynamic interactions: these are competition at the site of activity (receptor

level). It can be antagonist, synergist (additive) or indirect (diuretics increase plasma levels
of digoxin).

Pharmacokinetic interactions: it is when one drug affects the absorption, distribution,

metabolism or excretion of another drug, thus leading to change in its blood concentration
and effect.

Absorption: most of the time it is decrease in absorption, due to chelating agents, changes in
gastric pH, dysmicrobia and by side effects, such as vomiting, of a given drug.

Distribution: usually due to competition for binding to plasma proteins (Warfarin +

NSAID's) usually insignificant due to the fact that the increase is usually transient only
and there is increased metabolism in order to compensate the increased plasma levels.

Metabolism: some drugs are either inducers or inhibitors of enzymes, mainly in the P450
system, leading to altered metabolism and possible harmful effects.

Substrate: a drug which is metabolized by the enzyme system.

Inducer: a drug, or substance, that causes an increased activity of the CYP system by
causing increased synthesis, thus increasing the velocity of drug metabolism Rifampin
is a potent inducer.

Inhibitor: drug binds to the CYP isoenzyme and prevents binding (and therefore
metabolism) of the substrate drug. For most drug interactions the inhibition is due to
reversible, competitive binding.
For example: Grapefruit juice inhibits CYP3A4, Cimentidine inhibits the metabolism
of propranolol, Amiodarone inhibits the metabolism of digoxin.

Excretion: may be influenced by change in the active excretion by competing for the same
transport mechanism, may lead to change in the urine pH (used for treatment of salicylate or
barbiturate poisoning) and thus the ionization of a drug and/or may change the renal blood
flow.

16. Discovery of drugs. Evaluation of drugs:

Drug discovery: it is the process by which drugs are discovered and designed.

In the past, most drugs were discovered by identifying the active substance from traditional
remedies ( ) or by screening of thousands of naturally occurring substances for
biological effect.
Today, as scientists and doctors are well aware of the molecular basis of disease and its
pathophysiology there is the possibility to synthesize specific compounds to interact in the
molecular level. The process of drug discovery involves the identification of candidates,
synthesis, characterization, screening, and assays for therapeutic efficacy. Once a compound has
shown its value in these tests, it will begin the process of drug development prior to clinical
trials.

Evaluation of drugs: or drug development is the process that come after the process of
drug discovery and include pre-clinical research (microorganisms/animals) and clinical
trials as well as the approval for drug safety and marketing.
pre-clinical research:
little is known after drug discovery about the pharmacokinetics, safety, toxicity of the newly
discovered drug, so this is why these trials are conducted as well as to determine the dose
and dosing intervals.
It is conducted on animal subjects (rats, mice, monkeys, dogs) and is used mainly to
determine the dose, route of administration, type of drug (tab., lozz., capsule, etc), toxicity,
major organ toxicity, lethality, etc.
it evaluates:

acute toxicity: by calculating LD50 (lethal dose for 50% of the subjects).

Sub-actue toxicity: toxic manifestations in lower doses.

Chronic manifestation: to determine carcinogenesis or teratogenicity properties.

Therapeutic index: TD50 / ED50.

Pharmacokinetic and metabolic processes.

 Clinical trials:
Involve 3 steps of evaluation + the 4th step of marketing approval.

Phase 1: explorative evaluation: usually done on healthy individuals and is made in order to
define the safety and dosing, best route of administration and pharmacokinetics.

Phase 2: controlled clinical evaluation, used to study the toxicity and efficacy of a drug
compared to placebo drug and/or other drugs.

Phase 3: extended clinical evaluation, involve large group of people, last many years and
study the chronic use and the risk:benefit ratio.

After all these stages of evaluation are finished, it is possible to send a request for
approval of the drug for marketing.

Phase 4: post marketing surveillance, collection of data regarding efficacy and adverse
reactions (usually for the rare adverse reaction that did not came up during the clinical
trials).

Part 2

1. Basic principles in peripheral neurotransmission:

Neurotransmission is when a substance called neurotransmitter is released from the nerve
ending to bind to a receptor and elicit a response.
In the periphery the relevant neurotransmission systems are the sensory, motor (somatic) and
autonomic nervous system, which is made out of 2 sub-systems, the sympathetic and the
parasympathetic.
The autonomic nervous system has a central part and a peripheral part.

central part of the sympathetic nervous system is located in the thoraco-lumbar spine and
the central part for the parasympathetic is located in the cervico-sacral parts of the spine.

The sympathetic and parasympathetic give dual innervation to organs, thus can be considered
being antagonists to one another, meaning that decrease in one's innervation will lead to relative
increase in the second (can be utilized therapeutically).

Sweat glands, pilomotor muscles, kidney and adrenal medulla receive only sympathetic
innervation.

Neurotransmission can only occur in the presence of nerve fibers, hormones are not
neurotransmitters although they can lead to response.

Important note is that in the autonomic nervous system there is a post ganglionic neuron
between the nerve and the effector organ. This is not found in the somatic system.

somatic transmission:
Nerve impulse Ca++ influx at the nerve ending release of Ach to the synaptic cleft
binding to nicotinic receptors (Nm) increase sodium influx depolarization.

Ach is either degraded by Ach esterase or undergo reuptake.

Sympathetic:
Impulse running through the preganglionic neuron influx of Ca++ at the nerve
ending > Ach release binding to post ganglionic nicotinic receptor (Nn) impulse
running in the post ganglionic neuron Ca++ influx release of Noradrenalin to the
synaptic cleft binding to alpha or beta receptors.

Noradrenalin undergo reuptake or degraded by MAO (mono-amino oxidase) or COMT

(cathecol O methyl transferase)

parasympathetic:
Impulse running through the preganglionic neuron influx of Ca ++ release of Ach
binding to Nicotinic receptors nerve impulse Ca++ influx Ach release to the

synaptic cleft binding to muscarinic (M) receptors.

The removal is the same as in somatic.

sympathetic activity: fight or flight: Pupil (mydriasis (1)), Bronchi (dilation (2)), Heart (
rate, force, contractility (positive chrono, ino, dromotropic effect) (1+2)), GI tract (
peristalsis, blood flow, sphincter tone( 2+ 1)), Stomach (Decrease function,
motility(2)) Liver (glycogenlysis and gluconeogenesis (2)), Blood vessels (skeletal
muscle (2) vasodilatation, skin and viscera (1) vasoconstriction), Saliva ( flow,
viscosity(1)), Uterus ( contraction, relaxation(2)), increased sweating (M).

Parasympathetic activity: rest and digest: Pupils (myosis), Bronchi (constriction,

secretion), Heart ( rate, force, contractility (negative chrono, ino, dromotropic effect)
(M2)), GI tract ( peristalsis, blood flow, HCL secretion, sphincter tone), Bladder (
sphincter tone), Blood vessels (vasodilatation (M3)), Saliva ( flow, viscosity).

2. Pharmacological effects of adrenergic neurotransmitters:

The sympathetic nervous system is activated in response to stressful stimuli (trauma, fear,
hypoglycemia, etc) and lead to secretion of noradrenalin (norepinephrine) from nerve terminals
which in turn lead to the fight or flight response.
The sympathetic nervous system works almost predominantly on alpha and beta receptor, but on
the skin it works over Muscarinic receptors to increase sweat gland thermoregulation.

Alpha 1 mydriasis, vasoconstriction, sphincters contraction, ejaculation, uterus

contraction, pilomotor muscle contraction.

Alpha 2 inhibition of norepinephrin and insulin release.

Beta 1 tachycardia (SA node), positive inotropic, renin release, lipolysis.

Beta 2 vasodilation, bronchodilation, relaxed uterus, gluconeogenesis & glycogenolysis.

sympathetic activity: fight or flight: Pupil (mydriasis (1)), Bronchi (dilation (2)), Heart (
rate, force, contractility (positive chrono, ino, dromotropic effect) (1+2)), GI tract (
peristalsis, blood flow, sphincter tone( 2+ 1)), Stomach (Decrease function,
motility(2)) Liver (glycogenlysis and gluconeogenesis (2)), Blood vessels (skeletal
muscle (2) vasodilatation, skin and viscera (1) vasoconstriction), Saliva ( flow,
viscosity(1)), Uterus ( contraction, relaxation(2)), increased sweating (M).

3. Drugs affecting adrenergic neurotransmission:

The adrenergic nervous system secrete norepinephrine (NE), thus the drugs affecting its
neurotransmission by either binding to the receptors (direct acting) or by interfering with
secretion or degradation of NE.
Drugs that activate the adrenoreceptors (alpha, beta) are termed sympathomimetic while drugs
that block the receptor action are known as sympatholytic.

Adrenergic agonists:

these can be either direct acting drugs (not requiring nerve terminal) that bind directly to the
receptor to elicit a response, or indirectly acting drugs, which modulate the levels of free NE by
inhibiting the enzymes (COMT, MAO), influence the release of NE or influence the reuptake.

Direct acting: epineperine, NE, dopamine, isoproterenol, albuterol, phenyepherine,

salmeterol.

Indirect acting: amphetamine, cocaine.

Mixed (direct + indirect): ephedrine and pseudoephedrine.

Adrenergic antagonists:

these agents can again be direct or indirect, although most of the drugs are direct.

blockers: these drugs profoundly affect blood pressure, due to the fact that the
vasculature is solely under control of the sympathetic nervous system, thus blockade of the
alpha 1 receptors will lead to reduced sympathetic tone and vasodilation which will lead to
reflex tachycardia that must be dealt before giving alpha blockers.
Examples: phenoxybenzamine, phentolamine, terazosin, doxazosin.

antagonists: known also as beta blockers (all end with -olol), they are competitive
antagonists and can be selective or cardioselective {selective beta 1 blockers- there are no
clinically effective beta 2 blockers}, these drugs will bind to beta receptors and antagonize
their action thus increase the parasympathetic activity and will lead to bronchoconstriction.
Decreased cardiac output, etc.
these drugs can be with or without ISA (intrinsic sympathomimetic activity) which
describes the partial beta adrenergic response elicited by a series of beta blockers.

Selective beta 1 with ISA acebutolol.

Non selective beta blocker with ISA pindolol.

Non selective beta blockers without ISA - propranolol, timololcarvedilol.

selective beta 1 blockers without ISA atenolol, metroprolol.

indirectly acting: Guanethidine, Reserpine these drugs influence reuptake or release of

NE.

4. Adrenergic agonists (sympathomimetics):

Sympathomimetics by definition are drugs that mimic the reactions of the endogenous
norepinepherine (NE), either by directly binding to the receptor or by indirectly acting, thus
influencing the levels of endogenous NE.

synthesis, release and metabolism of NE:

The process involves 5 steps: synthesis, storage, release, receptor binding, metabolism.

Synthesis: Tyrosine is transported to the cell where it is hydroxylated to DOPA (rate

limiting step) which is then decarboxylated to form Dopamine.

Storage: Dopamine enters a vesicle and converted to NE.

Release: calcium influx after an action potential, leading to vesicular fusion and release of
NE.

Receptor binding: binds to either post synaptic receptor (1, 1,2) or presynaptic (2), thus
to formation of second messengers (cAMP, ISP3) or negative feedback.

Metabolism: NE can be removed and diffuse into general circulation, reuptaked into the
neuron, methylated by COMT (cathecol O methyl transferase) or oxidized by MAO
(mono-amino oxidaze).

Direct acting adrenergic agonists: binds directly to the receptor.

Epinephrine (adrenaline): a cathecolamine, synthesized from tyrosine in the adrenal
medulla, it has positive inotropic and chronotropic on the heart, bronchodilation (beta
2), increased glycogenolysis (beta 2).
the drug is used in broncospasm, open angle glaucoma (vasoconstriction), anaphylactic
shock, cardiac arrest, anesthetic solution (to cause vasodilation).
Rapid onset, brief duration, it is metabolized by COMT and MAO. Can be given SC, IV,
inhalation and topically.

side effects: CNS disturbances, arrhythmias, pulmonary edema.

NE: mostly alpha response, leading to vasoconstriction, thus leading to increased BP.
Used to treat shock (only indication), given IV, similar metabolism and side effects as
adrenaline. Leads to reflex bradicardia.

 Isoproterenol: predominantly stimulate beta receptors (1 and 2) thus it is not used

therapeutically, but can be used in emergencies to stimulate the heart.
Dopamine: stimulate alpha, beta and Dopamine receptors, thus it acts on the heart with
positive inotropic and chronotropic effects, vasodilator, as well as on the renal and
splanchnic arteries leading to vasodilation.
Used in shock states by continuous infusion. Short lived side effects.
Oxymetazoline: stimulate alpha 1 and 2 receptors, used primarily as a nasal
decongestant (otrivin) or eye vasoconstrictor (stilla) rebound congestion with long
term use.
Dobutamine: beta 1 agonist, used in cardiology in congestive heart failure to increase
cardiac output.
Phenylepherine: alpha 1 agonist, used mainly as nasal decongestant and produce
prolonged vasoconstriction.
Albuterol, Salmeterol: short acting beta 2 agonist, used as bronchodilator.

Indirect acting: cause NE release or inhibit uptake.

Amphetamine: marked CNS stimulation, leading to inhibition of NE uptake, used to

treat narcolepsy and hyperactivity in children.

Cocaine: block reuptake of NE by blocking Na/K pump leading to accumulation of NE

in the synaptic cleft.

Mixed action: induce release of NE and activate adrenegic receptors.

Ephedrine and pseudoephedrine: are plant alkaloids with long duration of action,
absorbed well orally, used for asthma treatment and as nasal decongestant.

typical side effects for all sympathomimetics are: arrhythmias, headache, nausea, tremor,
insomnia, hyperactivity.

5. Adrenergic antagonists (sympatholytics):

Sympatholytics, or blockers, bind to adrenoreceptors ( or ) but do not trigger a response and
act by binding either reversibly or irreversibly.
They can be alpha blockers, beta blockers or affect the uptake or release.

Alpha blockers: affect blood pressure by blocking alpha 1 receptors, leading to

vasodilation and decreased peripheral resistance, which in turn will lead to reflex
tachycardia.

Prazosin, Terazosin, Doxazosin, Tamsulosin: selective competitive alpha 1 blockers, the

first 3 are used to treat hypertension while the last is used for benign prostatic hyperplasia.
May lead to orthostatic hypotension, tachycardia, vertigo and sexual dysfunction

Phenoxybenzamine: a non selective alpha blocker, bind covalently to alpha receptors

(irreversible), thus decrease peripheral resistance leading to reflex tachycardia.
Not really used today, but is used only in the treatment of pheochromocytoma (adrenaline
producing tumor in the adrenal medulla).

Phentolamine: same as phenoxybenzamine, but competitive rather than irreversible.

Beta blockers (all end with olol): can be non selective or beta 1 selective
(cardioselective) only. Can be with or without ISA.

Cardioselective: through beta 1 receptors.

Atenolol, Metoprolol, Acebutolol: cardioselective beta blockers, lower BP, have low
effect or even none on pulmonary functions, peripheral resistance and carbohydrate
metabolism.

Non selective:

Propanolol: prototype beta blocker, used to treat hypertension, glaucoma, migraine,

hyperthyroidism, angina pectoris and M.I.
It may lead to bronchoconstriction (beta 2), arrhythmias, sexual impairment (unclear
why)

Timolol and Nadolol: more potent than propranolol, the rest is the same.

antagonists with ISA:

Acebutolol written above, a selective beta blocker, but has ability to stimulate beta
receptors (partial agonists), effective in hypertension.

Pindolol non selective beta blocker with ISA.

Mixed antagonists (alpha and beta):

Carvedilol and Labetalol: used for hypertension and congestive heart failure, can lead to
orthostatic hypotention.

drugs affecting uptake and release:

Reserpine: plant alkaloid, blocks the moving of NE, dopamine and serotoin to the
storage vesicles in the adrenergic nerves, leading to depletion.
Guanethidine: block the release of stored NE and displaces NE from storage vesicles,
leading to depletion.

6. Acetylcholine as a cholinergic neurotransmitter:

All preganglionic fibers, the post ganglionic fibers of parasympathetic system, and the
muscarinic fibers use acetylcholine as a neurotransmitter.
Acetylcholine neurotransmittion has 6 steps:
Synthesis of Ach:
choline is transported from the extracellular fluid into the cytoplasm together with sodium (can
be inhibited with hemicholinium) formation of Ach from choline and acetyl CoA with the
enzyme choline acetyl transferase).
Storage: uptake into storage vesicles.
Release: influx of calcium ions in response to AP leading to vesicular fusion inhibited by
butulinum toxin and aggravated with spider venum.
Binding to receptor: Ach diffuse across the synaptic cleft, binds to either Nicotinic or
Muscarinic receptor, thus leading to biological response.
Degradation: cleavage of Ach to choline (which gets reuptaked) and acetate
Recycling: recaptured by sodium-coupled uptake system (require energy) due to the constant
charge (ionization) of the choline molecule.
there are 2 major families of receptors that react to acetylcholine, these are the muscarinic
recptors which are designated from M1-M5 but only M1-M3 are clinically relevant, and
nicotinic receptors that are located on the surface of the ganglionic neurons and the surface of
the striated muscle.
On muscarinic receptor the response will be G protein coupled and will lead to formation of
second messengers (cAMP, phospholipase C, IP3) and on the striated muscles it will lead to
influx of sodium ions and action potential (ligand gated ion cannel).

7. Cholinergic agonists (parasympathomimetics):

Drugs that act on the cholinergic nervous system and can be direct and indirect acting.

Direct acting agonists:

do not need nerve ending and act directly on the level of the receptor.
They can be Ach, synthetic choline esters (carbachol, bethanechol) and natural alkaloids
(pilocarpin).

Ach therapeutically not important, can activate everything basically, and is rapidly
inactivated by AchE.

Bethanechol not hydrolized by AchE, lacks nicotinic action but has strong muscarinic
action. Its main action is on smooth musculature (bladder and GIT). It is used for
treatment of urinary retention.

Carbachol not hydrolized by AchE, has strong effect over the CVS and GIT thus rarely
used therapeutically except the eyes as a miotic agent, leading to miosis due to
contraction of the circular muscle and lead to spasms of accomodation (only cholinergic
drugs causes contraction of the ciliary muscles leading to iris accommodation and
blurred vision).

Pilocarpin alkaloid, uncharged (penetrate CNS), used primarily in ophthalmology to

reduce intraocular pressure in closed and open angle glaucoma, lead to miosis and
contaction of ciliary muscle (opposite to atropine).

Sjorgern's syndrome dry mouth and lack of tears is treated with this agent.

Indirect acting agonists:

Work by binding to AchE, either reversibly or irreversibly (echothiopate), thus terminate its
action and prolong the life of Ach in the synaptic cleft.
Physostigmine found naturally in plants which bind reversibly to AchE (competitive
inhibition). Used therapeutically to increase intestinal and bladder motility, reduce
pressure in glaucoma.
Neostigmine reversibly inhibits AchE, but more polar than physostigmine and cannot
penetrate the BBB, used to stimulate the bladder and the GIT.
Rivastigmine used in Alzheimer's disease, can only delay the disease.
Demecarium and Edrophonium AchE inhibitors. Edrophonium is a very short acting
drug that is used in the diagnosis of Myasthenia Gravis only.
Echothiophate it is an organophosphate that binds covalently to AchE. It is impossible

to reactivate the enzyme after its aging (loss of ethyl group). In case of intoxication with
insecticides we can use ASAP atropine or pralidoxime (any oxime will do).

side effects of cholinergic agonists are nausea, vomiting, diarrhea, salivation, sweating,
hypotension, miosis, bronchoconstriction and flush.

8. Cholinergic antagonists (parasympatholytics):

There are generally speaking 2 types of cholinergic antagonists, the first being antimuscarinic
agents and the second antinicotinic agents (ganglionic blockers- the next question,
neuromuscular blockers).

Muscarinic blockers: block muscarinic receptors , causing inhibition of muscarinic

functions, have no action on neuromuscular transmission or autonomic ganglia.

Atropine: an alkaloid from the plant atropa belldona with high affinity to muscarinic
receptors, binds competitively and acts centrally and peripherally.
Used in ophthalmology to cause mydriasis (for eye tests). Used as antispasmodic agent ,
antisecretory (prior to respiratory surgery) and to tread organophosphate poisoning.
May lead to tachycardia, constipation, blurred vision, xerostomia and dry eyes as well as
confusion and hallucinations.

Scopolamine: belladona alkaloid, has peripheral effects similar to atropine but higher
effects over the CNS, thus is one of the most effective motion sickness drugs and has
amnestic properties (brief loss of short term memory- great for surgery).

Ipratropium: used in inhalation, useful in treating asthma and COPD.

Ganglionic blockers: Nicotine and Mecamylamine next topic !!!!!

Neuromuscular blocking drugs: Succinilcholine, curarine, etc..discussed on the next

topic !!!

9. Ganglionic blocking agents and myorelaxants:

Ganglionic blockers: specifically act on nicotinic receptors at the ganglia of SNS and
PSNS, these drugs block the entire output of the ANS and only serve as a tool in
experimental pharmacology.

Nicotine a poison, with no therapeutic benefit and many unwanted effects. The only use of
nicotine is to eliminate the nicotine craving of smokers.
Causes tachycardia, high BP, increased peristalsis increased secretions (both SNS and

PSNS). Its worse side effect is that it may lead to pheochromocytoma in the future due to
repetitive stimulation of the adrenal medulla.

Myorelaxants: also known as neuromuscular blocking agents, they block the transmission
between motor nerve endings and the nicotinic receptors on the neuromuscular end of
skeletal muscule. These are structural analogues of Ach and act either as an agonist or
antagonist.
They are clinically useful in surgery and in facilitated intubation.

Antagonist blockers (competitive nondepolarizing): significantly increased the safety of

anesthesia (less anesthetics are required). The first drug historically is Tubocurarine,
synthesized from the curarine the native amazonians use to hunt with.
Mechanism: competitive binding over the nicotinic receptor, thus inhibiting muscle
contraction (can be displaced with neostigmine or other AchE inhibitors).
Injected IV, do not cross BBB, not metabolized (excreted unchanged) or undergo
spontaneous metabolism. Side effects are: may induce histamine release and reduced BP.
Examples: Mivacurium, Cistacurium, Tubocurarine, Metocurine, Rocuronium,
Pipercuronium.

Agonist agents (depolarizing agents): the only relevant drug is Succinylcholine which acts
as Ach, but is bot destroyed by by AchE, thus leading to desensitization of the receptor
(incapable transmitting further impulses) and flaccid paralysis.
Its is very fast in onset and very short in duration, thus very good for endotracheal
intubation.
Side effects: malignant hyperthermia (treated by cooling and dantrolene), apnea,
hypekalemia.

10.BASIC PRINCIPLES IN NEUROTRANSMISSION IN CNS:

Differences between ANS and CNS:
1. More NT: 10-50 (ANS 2). 2. More synapses 3. Inhibitory network. 4. Most transmission
done through ion channels and not with 2nd messenger.
Excitatory pathways: depolarization of neuron. Ach/Glutamate bind to postsynaptic
membrane influx of Na ions depolarization.

Inhibitory Pathways: Results in hyprepolarization. GABA or Glycine post synaptic

membrane Influx Cl hypopolarization
NOA (norepinephrine) Large amounts in hypothalamus and limbic system. Receptors: 1,
2, 1, 2, 3. High NOA = Mania. Low NOA = Narcolepsy Blood pressure regulation:
Binding to 1 = BP. NOA = Low BP. 2 agonist have sympatolytic effectNOA release.
Dopamine EPS rich in dopamine. neurons lack dopamine-hydroxylasecant transform
dopamine into NOA. Motor System: Parkinson = Lack of dopamine Parkinsonism = long
term antipsychotic drug. (rigidity, tremor, hypokinesia). Behavioral Effects Schizophrenia =
Dopamine hyper activity. Long term amphetamine use (release of NOA and DP)schizophrenia.
Ant. Pituitary: Dopamine = in prolactin secretion DP = GH. (can treat acromegaly
paradoxicaly) Vomiting DP release = nausea and vomiting D-antagonists = Anti emetic.
ACETYLCHOLINE M or N receptors. M receptors cause Ach release (act presynaptically
negative feedback) M - antagonist = Ach release. Dementia + Alzheimer Loss of
cholinergic neurons are found in dementia. Choline or Ach esterase inhibitors = Ach =
Temporary treatment. Parkinson and Huntington Hyperactivity of Ach causes Dopamine
levels. Low levels of Achhigh levels of DP = hyperkinetic Chorea.
SEROTONIN Large amounts in hypothalamus and limbic system. Receptors = 5-HT (1-7).
Hallucination effect loss of serotonin = hallucinations. LSD = Serotonin antagonist =
Hallucinogen. Sleep, Mood serotonin = No sleep, application of serotonin doesnt help treat
insomnia. Depression = serotonin Mania = serotonin. Sensory transmission serotonin
= High stimuli to pain. Serotonin inhibits pain transmission. Autonomic&Endocrine Temp.
reg. BP control Sexual Function control Effects secretion of hormones from hypothalamus.
GABA Main inhibitor in the brain. GABA - A = Connect to Cl channel (alcohol,
barbiturates) hyperpolarization. GABA - B = presynaptic G protein linkedinh. of NT release.
Used to treat: Insomnia, Anxiety, Alcohol withdrawal, Spasticity, Epilepsy.
Glutamate and Aspartate (excitatory AA) Synthesized in Krebs cycle. Receptors: NMDA,
AMPA NMDA: Long term potentiation = long term memory. Excitotoxicity = cause
neuronal damage if not inhibited. Epilepsy - high concentration of glutamate in epileptic
focus.

11.ANTYPSYCHOTIC DRUGS (NEUROLEPTICS):

Used to treat SCHIZOPHRENIA and other disorders (MANIA, DEPRESSION) or

GRANDIOSITY, PARANOIA. HALLUCINATIONS and DELIRIUM.

SCHIZOPHRENIA(type of psychosis) has excitatory effects like: hallucinations, delusion,

thinking and speech disorders and negative symptoms such as no emotions and social
contact problems.

The cause of schizophrenia is combined with genetic and environmental factors that affects
several brain areas causing: a dysfunction of the MESOLIMBIC or MESOCORTICAL
DOPAMINERGIC neurons.

The Dopamine Theory

A) The use of amphetamine or D agonists can cause schizophrenia and elevate the symptoms
and the use of DP antagonists decrease the symptoms of schizophrenia.
B) Hyperactivity of DP neurons = Schizophrenia.
Classification of Drugs
1.(Classical) TYPICAL NEUROLEPTIC competitive inhibitors of DOPAMINE
receptors
LOW POTENCY: CHLORPROMAZINE; PROCHLORPERAZINE; THIORIDAZINE;
HIGH POTENCY: HALOPERIDOL; FLUPHENAZINE; (PIMOZIDE; THIOTHIXENE) effect tegmentum main extrapyramidal effect.
2. (new) Atypical NEUROLEPTIC blockade both serotonin and dopamine receptors,
lower tendency to motor side effects + effective against negative symptoms. They also block:
D2, , M receptors. High affinity with D4 receptor and low affinity with D2.
CLOZAPINEhigh affinity to D4 Receptor + nonselective D1,D2 affinity.
RISPERIDONEblocks serotonin greater than D2.
OLANZAPINEblocks serotonin greater than D2.
QUETIAPINEblocks D2 receptors more potently than 5-HT 2a receptors.
Mechanism:
Blockage of DP receptors in the brain, occupying the receptor intracellular response.

 The newer agents are more selective to D2 then D1. Initially they cause increase of DP and
increase activity of midbrain. Later there is a decline in activity and reaching a steady level
after 3 weeks.
D1 and D5 receptorsactivate adenylyl cyclase
D2,D3 and D4 receptorsinhibit adenylyl cyclase
Effects of ANTILEPTICS
Apathy Slow response to stimuli. Inhibits aggressively. Anti emetic No loss of
intellectual functions, no cognitive impairment and motor incoordination is minimal(in this
point they differ mostly from CNS depressant like BARBITURATES).
Unwanted effects
Extra-pyramidal effects - Tremors, chorea excessive Ach,dystonia, tardive dyskinesia,
Parkinson-like symptoms due to chronic treatment; But Atypical neuroleptics exhibit a lower
incidence of these symptoms.
Anti-muscarinic effects - Blurred vision, dry mouth, constipation, but the effect may counteract
the motor disturbances (CLOZAPINE) Sedation (H1) Orthostatic hypotension (alpha)
Weight gain (SEROTONIN).
Antiemetic effects - with the exception of ARIPIPRAZOLE and THIORIDAZINE most of the
neuroleptic drugs have antiemetic effects that are mediated by blocking D2-dopaminiergic
receptors of the chemoreceptor trigger zone of the medulla. Basically combats NAUSEA!
Adverse effects: tremors, postural hypotension, constipation, urinary retention, confusion,
sexual dysfunction.

12.ANTIDEPRESSANTS:
DEPRESSION = Intense feeling of sadness + hopelessness + no pleasure in usual activities
+ sleep disorders + no concentration + suicide thoughts. While MANIA is characterized by
the opposite behavior (enthusiasm rapid thought and speech patterns, extreme selfconfidence and impaired judgment)
Theory of Monoamine NT: NOA + 5-HT main NT in charge of mood. alterations causes
mood change. can be caused by loss of sensitivity of inhibition of receptors. Serotonin is the

main mediator.
Problem of the theory: Lag Period of 2 weeks between start of the treatment and effect, but the
amount of NT rise immediately.
New theory: The antidepressent drugs inhibit the reuptke of 5-HT serotonin in the synaptic
cleft Down regulation of the presynaptic rec. over 2-3 wks postsynaptic response
because of more secretion and less negative feedback.

Note: The onset of therapeutic effects of the major antidepressant drugs requires several
weeks 1)at the administration time (still persist DEPRESSION); 2) after 2 to 12 weeks
the effects manifest!

MAO inhibitors: PHENELZINE is the First clinically active agent. It inhibits the MAO
(irreversibly) preventing the inactivation of monoamines within the neuron cause more
molecules to be secreted into the cleft and an excess of neurotransmission.
It is not selective and affects MAO all over the body and also levels of Nor Adrenaline =
sympathetic activity = hypertension.
Contraindications:
High interaction with food that contain tyramine (hard cheese, red wine) can cause
hypertension, headache, MI, intracranial bleeding.
Should not be given together with SSRI serotonin syndrome life threatening.
RIMA (reversible inhibitors of MAO): Moclobenide
Less effect on tyramine.
side effects of NOA: nausea, headache, nervousness.
Tricyclic Antidepressants (TCA): lead to inhibition of re-uptake of noradrenaline (NOA) and
serotonin (5-HT) and to Blockage of M, H, 1 receptors (side effects).
M=Dry mouth, constipation.
M+1=Tachycardia, hypertension.
H=Sedative effect, weight gain.
Adverse effects: DRY MOUTH, CONSTIPATION, URINARY RETENTION, BLURRED
VISION, TACHYCARDIA, ARRHYTMIAS, NAUSEA, DROWSINESS.

Drugs: IMIPRAMINE (Good GIT absorption) MITRIPTYLINE, CLOMIPRAMINE,

DOXEPIN, TRIMIPRA MINE.
Selective Serotonin Re-uptake Inhibitors SSRI: these drugs BLOCK THE RE-UPTAKE
OF SEROTONIN, thus leading to concentration of neurotransmitters in the synaptic cleft and
to greater postsynaptic neuronal activity.
No inhibition of Noradrenalin reuptake. Mild blockage of M, H, 1 receptors. (side
effects= same as TCA).
Pharmacokinetics: well absorbed ORALLY; peak levels are seen in 2-8h; food has little effect
on absorption(except for SERTRALINE); plasma half life of 16-36 h; methabolism by P-450
dependent enzymes and glucuronide.
Contraindications:
not given together with MAO serotonin syndrome, life threatening (tremor, abdominal pain,
HT, tachycardia and collapse)

List of main drugs:

FLUOXETINE (PROZAK) for BULIMIA NERVOSA (this is the indication approved for) most frequently used. Fluoxentine and paroxentine are potent inhibitors of a hepatic cytochrome
P-450 responsible for elimination of: tryciclic antidepressant drugs, neuroleptics and
antiarrhytmic.

CITALOPRAM - No affinity to M, H, R. - less side effects (nausea, insomnia)

ESCITALOPRAM,FLUVOXAMINE- for OBSESSIVE-COMPULSIVE DISORDERS

Adverse effects: NAUSEA, ANXIETY, DROWSINESS, INSOMNIA, SEXUAL

DYSFUNCTION, DRUG INTERACTIONS, DISCONTINUATION SYNDROME.
NEW ANTIDEPRESANTS

NOA Reuptake Inhibitors (NRI): REBOXETINE (depression, narcolepsy and panic).

NOA and Dopamine Reuptake Inhibitors (NDRI): BUPROPION - weak inhibitor (as a
pro-drug), when metabolized is a strong inhibitor. Given when SSRI is not tolerated.
Treatment of nicotine withdrawal. CI in epilepsy

Serotonin and NOA Reuptke Inhibitors (SNRI): VENLAFAXINE, Like TCA, without

M, H, effect. DULOXETINE (not administer with hepatic and renal insufficiency!)

NOA and specific serotoninergic antidepressant (NASSA): MIRTAZAPINE - block

presynaptic alpha 2 receptor. It is an H1 receptor antagonist as well - cause sedation and
weight gain.

Serotonin 2A antagonist reuptake inhibitor (SARI): NEFAZODONE - CI in patient with

liver disease.

ANTI-MANIA (BIPOLAR DISORDER): LITHIUM SALTS - Unknown mechanism.

Lead to prevention in acute manic episode. 95% of it excreted in urine. Its side effects are:
First days - tremor, polyuria, nausea, thirst. Intoxication - vomiting, diarrhea, mm weakness
Tinnitus, ataxia in high doses.

VALPROIC ACID CARBAMAZEPINE

13.ANTIANXIETY AND HYPNOTIC DRUGS:

Anxiety is sympathetic activation with symptoms such as fear / tachycardia / dyspnoea /
sweating, etc.
Both in the same category:
Sedation = Suppression of response to stimuli.
Hypnotic = Prolonged depression of CNS, dose from sedative causes hypnotic effect.
1st Generation - Barbiturates - not used anymore. 2nd Generation Benzodiazepines 3rd
Generation - Zolpidem, Zaleplon. NB!! Only symptomatic drugs, doesn't treat the anxiety.
A)BENZODIAZEPINES
Targets the GABA-A receptors. both affinity to GABA and influx of Cl- into the cell
hyperpolarization. This causes inhibition of the sympathetic neurons. Well absorbed p.o.
passes the BBB, fast onset Strongly bind to plasma proteins.

MAIN EFFECTS:
ANTI-ANXIETY: TRIAZOLAM can produce aggression in some individuals.
ANTI-CONVULSANT: CLONAZEPAM used to treat epilepsy.

 DIAZEPAM: STATUS EPILEPTICUS control of life threatening seizures.

EFFECTS: Sedation and induction of sleep. Reduction of muscle tone and coordination. - used
to treat spasms.

SIDE EFFECTS:
Affects Manuel skill - driving
Can enhance depressant action of other drugs
Overdose - Severe CNS and respiratory depression if combined with: Alcohol, Barbiturates
and/or Narcotics (Antidote = FLUMAZENIL)

TOLERANCE: via down regulation of receptors tolerance in all BZD.

DEPENDANCE: When stopping the drug it causes in anxiety with tremor and dizziness.

B)SEROTONIN DRUGS
1)BUSPIRONE: Strong anxiolytic effect without sedative or muscle relaxant effect. It is and
Agonist of 5-HT receptor.
PHARMACOKINETICS: Metabolized quickly in liver - grapefruit juice effect.
Disadvantage = slow onset of action.
2)HYDROXYZINE: It is an antihistamine with antiemetic activity (used for dental and
surgical procedures, in patients with anxiety.

Side effects: DROWSINESS

3)ANTIDEPRESSANT: for managing chronic anxiety disorders (SSRIs, TCAs,

VENLAFAXINE, DULOXETINE, MAO-Is)
C)NEW DRUGS
1) ZOLPIDEM: Same effect as BZD with minimal muscle relaxant and anti-convulsant
activity, possess a small risk of tolerance and dependance.
2) ZALEPLON: Rapid onset and short duration. It is good for people that have trouble
sleeping.

14.STIMULANTS OF CNS:
There are 2 groups of drugs that act primarily to stimulate the CNS:
A)PSYCHOMOTOR STIMULANTS - Excitement, Euphoria, Fatigue, Motor Activity.
B)PSYCHOTOMIMETIC drugs or HALLUCINOGENS - Change Of Thinking, Mood
And Perceptual state (dream like).
A )PSYCHOMOTOR STIMULANTS
METHYLXANTINES - Caffeine, Theophylline (tea), Theobromine (cocoa)

Mechanism of action:

1)influx of Ca.
2) in cAMP and cGMP (by inhibition of phospodiesterase + blockade of adenosine receptors).
CNS - (cortex stimulation): Allertness, in fatigue.
In high doses may lead to anxiety and tremors. Tolerance develops fast with withdrawal
syndromes (caffeine) - fatigue and sedation.
CVS - HR and contractility(positive inotropic and chronotropic effects on the heart). In
higher dose can cause arrythmia and tachycardia.
Mild diuretic action -urinary output of Cl-, NA+, K+.
GIT - Stimulates secretion of HCl from gastric mucosa acidity.
Relaxation of SM of bronchioles - treatment of asthma in the past;now B2 agonists or
corticosteroids!
PHARMACOKINETICS: well absorbed orally (can across placenta and accumulate in the
mothers milk) metabolized in the liver and excreted in the urine.

SIDE EFFECTS: INSOMNIA DEPENDANCE LETHAL DOSE AT 10g (100 CUPS

OF COFFEE)!!!!

NICOTINE - (induce the highest dependence)- At low doses cause ganglionic stimulation by
depolarization leading toAROUSAL and RELAXATION.
At high doses it causes ganglionic blockade leading to RESPIRATORY PARALYSIS and
HYPOTENSION due to MEDULLARY PARALYSIS!

 CNS - some degree of Euphoria, Arousal and relaxation; severe hypotension and respiratory
paralysis in high doses for medullary paralysis.
Peripheral - stimulation of sympathetic ganglia and adrenal medulla leading to:

BP.

HR + Vasoconstriction of blood vessels like coronary aa.

bowel activity.

at high doses- BP falls and all Motility stops, dependance, addiction, tolerance. The
lethal dose is 60 mg

PHARMACOKINETICS:lipid soluble= absorption can occur via oral mucosa, lungs, GIT
mucosa and skin; (mothers milk accumulation) > methabolism of lung and liver excreted
by urine.
SIDE EFFECTS: TREMOR, INTESTINAL CRAMPS, HYPERTENSION.
COCAINE: Block of reuptake of monoamine: norepinephrine, epinephrine, serotonin and
dopamine(Do),connecting to the monoaminergic reuptake transporters potentiates and
prolongs the CNS and peripheral actions:
1)prolongs dopaminergic effects on limbic system intense euphoria;
2) chronic intake of dopamine: dopamine
CNS - Well being, euphoria, feeling of greatness.
Sympathetic nervous system - Fight or flight response( typical adrenergic stimulation).
Hyperthermia!!! (impairs sweating and cutaneous vasodilatation).
THERAPEUTIC USES: - Local anesthetic on: eye, ear, nose, throat surgery.
Major effects of cocaine use: euphoria + tachycardia + tachypnea > agitation + hypertension +
dyspnea seizure + arrhythmias + respiratory failure DEATH!!!!
PHARMACOKINETICS: often self administered by chewing, intranasal snorting (powder),
smoking (crack) or I.V.; intranasal intake manifests effects after 15-20 min and lasts for 1-1.5 h
while IV has a faster onset of the effects but shorter duration. Then it is de-esterified and
demethylated excreted in the urine.

SIDE EFFECTS: ANXIETY DEPRESSION SEIZURES TOXIC EFFECTS and CARDIAC

ARRHYTHMIAS. Anatomically the damage is due to the VASOCONSTRICTION
NECROSIS AND PERFORATION of the NASAL SEPTUM seen by chronic inhalation of
cocaine powder!
AMPHETAMINE it is a non-catecholaminergic sympathetic amine with effects clinical and
neurological like cocaine, 2 main drugs are used: METHAMPHETAMINE and
DEXTROAMPHETAMINE.
Inhibitor of MAO (monoamine oxydase) amount of cathecholamine neurotransmitters in
the synaptic space, like norepinephrine, serotonin and dopamine response of action on
CNS and in periphery amphetamine acts on the adrenergic system, indirectly stimulating the
receptors through norepinephrine release!
CNS - ALLERTNESS, FATIGUE and APETITE CONTROL.
THERAPEUTIC USE: ADHD (is also used methylphenidate - known also as RITALIN);
NARCOLEPSY.
SIDE EFFECTS: DEPENDENCY/TOLERANCE SCHIZOPHRENIA HYPERTENSION
ANOREXIA NAUSEA, VOMITING; CONFUSION, INSOMNIA, DIARRHEA,VERTIGO.
PHARMACOKINETICS: completely absorbed from the GIT metabolized in the LIVER
excreted in the URINE
B) PSYCHOTOMIMETIC drugs or HALLUCINOGENS:
LSD (LYSERGIC ACID DIETHYLAMINE): stimulates serotonin (5-HT 1 and 2) Receptors
activation of sympathetic nervous system PUPULARY DILITATION, BP, BODY
TEMP, PILOERECTION. May lead to:

HALLUCINATIONS with brilliant colors + MOOD ALTERATION (at LOW doses of LSD)
HALOPERIDOL and other neuroleptics (antidote for hallucinations induced by LSD).

Tolerance and physical dependence (true one is rare);

SIDE EFFECTS: HYPERREFLEXIA, NAUSEA and MUSCULAR WEAKNESS.

THC (marihuana): THC=TETRAIDROCANNABINOL available as DRONABINOL.

Lead to EUPHORIA(first) DROWSINESS and RELAXATION(second).

Other effects are: appetite stimulation, xerostomia, visual hallucinations, delusions and in
sensory activity.
PHARMACOKINETICS: the THC effects appear immediately after the drug is smoked,
maximum effect takes about 20 min and lasts for 3h! DRONABINOL (oral admin. Has peak
effect in 2 to 4 h and lasts even for 6 h, but appetite persists fro 24 h)
SIDE EFFECTS: Tachycardia, Hypertension, Hallucinations, Anxiety, Panic in long term use.
USAGE: Treat emesis in chemotherapy, appetite in HIV patients and in Glaucoma.

15.ANTIEPILEPTICS
EPILEPSY: SYMPTOMATIC EPILEPSY, IDIOPATIC EPILEPSY (young adults 75%);
Trigger mechanism of epilepsy: hyperpyrexia (infections), CNS infections, Metabolic
disorders, Toxic agents, Brain hypoxia, Expanding process (tumor, haemorrhage), CNS
developmental disorder, Brain traum, Anaphylactic reaction.
Main goal of drug: the ideal anti-epileptic drug is non-sedative.
Drugs in different forms of epilepsy:

Grand mal(tonic-clonic): CARBAMAZEPINE, PHENYTOIN, VALPROATE.

Petit mal (ABSENCE): ETHOSUXIMIDE, VALPROATE.

Partial complex: CARBAMAZEPINE, PHENYTOIN, PRIMIDON and VALPROATE.

Atonic and myoclonic: VALPROATE, CLONAZEPAM.

Acute epileptic attack: DIAZEPAM, LORAZEPAM.

Phenobarbital Acts on GABA - A receptors Prolong Cl opening.

High doses block Ca channels Rarely used (sedative effect + danger of overdose and
toxicity.) for Grand mal or partial seizures.

Phenytoin > Na channel blocker. Used for partial attacks or generalized tonic-clonic seizures.
Side Effects: Nystagum (depression of cerebellum), Hyperplasia of gingiva, Teratogenic effect,
Allergies, Osteoporosis.

 Carbamazepine Effect similar to phenytoin. Na+ channel blockers!!!, inhibits synaptic

transmission. It is the drug of choice in partial attacks and used against painful seizures in DM
or trigeminal neuralgia.
Side Effects: Diplopia, ataxia, restlesness, GIT intolerance, elderly aplastic anemia Inducers of
enzymes.
Ethosuximide Inhibits T-type calcium channels. Used for petit mal seizures
Side Effects: GIT, Fatigue, headache.
Benzodiazepines Targets the (gamma- aminobutyric acid) GABA-A receptors.(GABA is the
major inhibitory neurotransmitter in the CNS).
3 main steps of action on Benzodiazepine-GABA-chloride ion channel complex:
1) RECEPTOR EMPTY (no agonist) receptor is inactive and the coupled chloride channel
is closed.
2) RECEPTOR binding GABA causes the opening of chloride ion channel
hyperpolarization of cell.
3) RECEPTOR binding GABA and Benzodiazepine binding of GABA is by
benzodiazepine greater entry of chloride ion > hyperpolarization of the cell and making it
more difficult to depolarize neural excitability.
( both affinity to GABA and influx of Cl- into the cell hyperpolarization inhibition of the
sympathetic neurons)
ROUTE: Well absorbed p.o. - passes the BBB, fast onset. Strongly bind to plasma proteins.
Main Effects:
A) TRIAZOLAM: Anti-anxiety - (aggression in some individuals).
B) CLONAZEPAM: long acting, absences, myoclonic seizures, highly effective anti-epileptic
drug.
C) DIAZEPAM: Status epilepticus.
D) LORAZEPAM - more effective then diazepam Sedation and induction of sleep + treat
spasms.
Side Effects: 1)Affects manual skill 2) enhance depressant action of other drugs 3) Overdose

4) Severe CNS and resp. depression if combined with: Barbiturates, Narcotics

Antidote=Flumazenil
Tolerance: There is a down regulation of receptors in all BZD.
Dependance: When stopping after a long time use in anxiety with tremor and dizziness.
Addiction is not a major problem!
Valproic acid The mechanism of action is not fully understood, but generally it inhibits
GABA transaminase (enzyme that degrades GABA) and also aspartate level in brain.

Effects: propagation of abnormal impulses in brain.

Adverse effects: nausea, vomiting, ataxia, sedation, hepatotoxicity, teratogen.

Clinical use: myoclonic seizures, incidence and severity of tonic-clonic seizure.

NEWER DRUGS: Vigabatrin, Lamotrigine, Gabapentine(GABA analogue), Felbamate,

Topiramate

16.TREATMENT OF PARKINSON DISEASE:

DEFINITION: Parkinsonism is a progressive neurological disorder of muscle involvement,

characterized by: TREMORS, MUSCULAR RIGIDITY, BRADYKINESIA and
HYPERTONIA, + POSTURAL and GAIT ABNORMALITIES.

ETIOLOGY: is related with destruction of DOPAMINERGIC NEURONS IN THE

SUBSTANTIA NIGRA with a consequent REDUCTION OF DOPAMINE ACTIONS IN
THE CORPUS STRIATUM(basal ganglia); clinical manifest. Occurs when the dopamine
depletion of 60-80%!

SECONDARY PARKINSONISM is caused by drugs: HALLOPERIDOL and

PENOTHIAZINES, which work pharmacologically by BLOCKING OF DOPAMINERGIC
RECEPTORS in the brain. (they shouldnt be used in Parkinsonian patients).

ROLE OF SUBSTANTIA NIGRA in PARKINSONS disease:

SN is a part of extra-pyramidal system is the source of DOPAMINERGIC neurons (works as a

TONIC support and influence on the motor activity) that end in the NEUROSTRIATUM which

has cell neurons that end in SN and that secrete INIBITORY TRANSMITTER GABA!

PATHOPHYSIOLOGY:
1) cell death results in less dopamine release in the neurostriatum,
2)loss of the inhibitory effect of dopamine results in Ach triggers a chain of ABNORMAL
SIGNALING leading to IMPAIRED MOTILITY!

DRUGS USED IN PARKINSON: Main goal: temporary relief from the symptoms of the
disorder but they dont arrest or reverse the neuronal degeneration of the disease.
A)LEVODOPA (precursor of dopamine, can cross BBB), used to restore dopaminergic
neurotransmission in the striatum by DOPAMINE SYNTHESIS IN THE SURVIVING and
HEALTHY NEURONS of the SN.
Problem: DOSES of LEVODOPA because much of the drug is DECARBOXYLATED to
DOPAMINE already in the periphery, causing:
1) side effects: vomiting, nausea, cardiac arrhytmia., tachycardia, psychiatric problems
(levodopa exacerbate the symptoms of psychiatric patients), hypotension and dyskinesias.
2)waste of drug effect when combines with VIT. B6 (pyridoxine)!
Solution: use a combination of LEVODOPA + CARBIDOPA (a dopa decarboxylase inhibitor,
decrease the metabolism of levodopa in the periphery)!
B) SELEGINE and RASAGILINE(agents dopamine effect)

SELEGINE DOPAMINE levels in the brain. LEVODOPA actions when those drugs
are combined. required dose of LEVODOPA.

1) at low/moderate doses, inhibits selectively MAO type B (metabolizes DOPAMINE).

2) doesnt inhibit MAO type A(metabolizes NOREPINEPHRINE and SEROTONIN).
SIDE EFFECTS:
1) at recommended doses can cause SEVERE HYPERTENSION.
2) selegine is metabolized to amphetamine and methamphetamin producing: INSOMNIA.

RASAGILINE is an irreversible and selective inhibitor of brain (MAO type B); x5 times the
selegine potency; it is NOT methabolized to any amphetamine-like substance!
C) CATHECOL-O-METHYLTRANSFERASE(COMT) INHIBITORS:
The combination LEVODOPA+CARBIDOPA works for the purpose already explained before,
but when carbidopa inhibits the peripheral decarboxylation of the levodopa it formes a new
metabolite in significant concentration that is the 3-O-methyldopa which competes with
levodopa for the active transport in the CNS.
The inhibition of COMT by ENTACAPONE or TOLCAPONE plasma [c] of 3-Omethyldopa restoring the central uptake of LEVODOPA!
TOLCAPONE differs from ENTACAPONE in its long duration and the fact that it crosses
BBB for inhibition in CNS of the COMT, but both excreted by feces and urine.
ENTACAPONE is not toxic to the liver in respect to TOLCAPONE!
SIDE EFFECTS: diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations
and sleep disorders.
D) DOPAMINE-RECEPTOR AGONISTS
The group includes: BROMOCRIPTINE (ERGOTAMINE derivative, which is a
vasoconstrictive alkaloid) and ROPINIROLE, PRAMIPEXOLE and ROTIGOTINE.

BROMOCRIPTINE: is the 2nd drug of choice and is an agonist of D2 presynaptic

receptors.
It has longer duration of action then Levodopa. And can be combined with L-dopa to
prolong the tolerance effect.

S.E.: Nausea, Vomiting Hypotension Diskinesia Confusion and hallucinations.

ROPINIROL, CARBEGOLINE, PRAMIPEXOL: 2nd generation of agonists.

monotherapy, in severe cases combined with L-dopa, MAO Inhibitors.
E) AMANTIDINE (influenza anti-viral drug) that may increase release of dopamine and block
choolinergic receptors.
F) BIPERIDOL, PROCYCLINE, TRIHEXYFENIDIL - acethylcholine blocking agents

17.Analgetic-antipyretic drugs

PAIN( for analgesic action): the sensation of painful stimuli depends on nerve ending
transmission. Prostaglandins (PGE2) sensitize nerve endings to effect of pain mediators
(mainly bradykinin, histamine). We may treat pain either by:

1) lowering PGs level( PGE2 synthesis) by ASPIRIN and other NSAIDs;

2) by inhibition of pain transmission and perception in the CNS (OPIOID ANALGETICS).

FEVER: PGE2 has a direct pyrogenic effect on neurons in the hypothalamus. its level has
a beneficial anti-pyretic effect.

PROSTAGLANDINS: are synthesized by the enzyme COX1 (physiologic prostaglandins)

and COX2 (prostaglandins in inflammation) from arachidonic acid found in cell
membranes. The COX pathway is responsible for production of thromboxans and
prostacyclines, while the LOX pathway produces leukotrines.

Main strategy of reducing pain, fever, inflammation is the inhibition of COX pathway in
order to amount of PGs. Some drugs posses analgetic-antipyretic properties while other
posses more anti-inflammatory properties.

Drugs used to treat pain and fever (mainly NSAID's and Paracetamol):
1. NSAIDs: all NSAID's are able to inhibit COX, lowering PGs level.
Classification:

Salicyclates aspirin (ASA): irreversibly inhibits COX non-selective.

Effects (dose): 1) Anti-agreggatory ( platelet aggregation).2) Anti-pyretic; 3)Analgesic 4).
Anti-inflammatory 5). Possibly anti-cancer
Adverse effects: Gastric ulcer ( protective function of PGs in stomach), Allergy,
tachypnea in higher doses (respiratory alkalosis), Reyes syndrome: in children after viral
infection and children under 12 is CI, paracetamol should be used, tinnitus and fever.

Propionic acid derivatives (IBUPROFEN): Reversible COX inhibitors.

Effects: Analgetic, Anti-pyretic, Anti-inflamatory (Less side effects than aspirin - dyspepsia,
bleeding are the most commn).

Acetic acid derivatives (indometacine, diclofinac): Rev. COX inh, not anti-pyretics.
Effects: analgetic, anti-inflammatory.

Adverse effects: mostly GI. Arthritis and gout (urea accumulation).

COX2 selective NSAIDs (COXibs) - CELECOXIB: Reversibly inhibit COX2.

Lower risk of GI bleeding. Doesnt inhibit platelet aggregation.
CI: IHD or stroke ( level of prostacyclines platelet aggregation)
2. Non-narcotic analgetics (PARACETAMOL / ACETAMINOPHEN)
MECHANISM OF ACTION: block COX in CNS only and have no effect on peripheral COX.
Only analgetic and antipyretic properties. No GI side effects.
ADVERSE EFFECTS: allergy. In high doses: glutathione in liver is depleted paracetamol
exert toxic effects on hepatocytes liver necrosis
TREATMENT: N-ACETYLCYSTEIN.
ACETAMINOPHEN has STRONG ANALGESIC and ANTIPYRETIC effect, but WEAK
ANTI-INFLAMMATORY effect.

18. Nonsteroidal anti-inflammatory drugs (NSAID's):

Inflammation is a protective response to tissue injury and repair. Inflammation may be triggered
by non-harmful agents (pollen), or as an autoimmune reaction (rheumatoid arthritis).
Anti inflammatory/immunosuppressive drugs are used to suppress the reactions. Main chemical
mediators: PGs and LTs. Inflammatory disease will improve when treated with anti
inflammatory drugs. Immune-suppressants (corticosteroids and methotrexate) may be used to
counteract inflammation.
all NSAID's are able to inhibit COX, lowering PGs level.
Classification:
a) Acetyl-Salycilic acid (ASA): rapidly and irreversibly inhibits COX non-selective. Aspirin
resets thermostat of the body the heat dissipation.

Effects (dose): ANTI-AGREGGATORY ( platelet aggregation), TIAs and strokes,

death due to ischemic attack or myocardial infarction and neonatal m.i. or unstable angina
pectoris, cardiovascular risk with revascularization procedures; ANTI-PYRETIC;
ANALGESIC PGE2 synthesis (headache, arthralgia, myalgia); ANTI-

INFLAMATORY(gout, RF, RA, osteoarthritis); P OSSIBLY ANTI-CANCER; external

applications: topically for corns, calluses and warts.

Effect on platelets: (TXA2 platelet aggregation while PGI2 it).

Low doses of aspirin inhibit thromboxane production in platelets via acetylation of the
cyclooxygenase > platelet aggregationanticoagulant effect with prolonged bleeding.

Actions on the kidney: COX- inhibitors prevent synthesis of PGE-2 and PGI-2; these
prostaglandins are responsible for maintaining renal blood flow in the presence of circulating
vasoconstrictors Pgs retention of sodium and water cause EDEMA and
HYPERKALEMIA.

Adverse effects:
1) Gastric ulcer ( protective function of PGs in stomach);
2) respiratory depression + (respiratory and metabolic acidosis);
3) In very high doses tinnitus, fever, hyperthermia.
4) Hypersensitivity: 15% of patients taking aspiringet hypersensitivity reactions (allergy,
urticaria, bronchoconstriction, angioedema)
5) Reyes syndrome: fulminating hepatitis with cerebral edema when child gets salycilates.

Contraindications: to avoid in PREGNANCY and BREAST-FEEDING time, exclude any

drug interaction with WARFARIN, PHENYTOIN or VALPROIC ACID, avoid chronic aspirin
in patient which already receive PROBENECID or SULFINPYRAZONE; to avoid for at least 6
weeks in children that received live varicella virus vaccine prevent REYES syndrome.

Pharmacokinetics:
A) oral administration (unionized salicyclates) - passively absorbed from the stomach and the
small intestine/ liver/ kidney, half life 3.5h.
B) rectal absorption slow and unreliable, but useful for vomiting children.

Dosage: 2 tablets x 325 mg x 4times daily = ANALGESIA; 12-20 tablets x day = analgesic and
anti-inflammatory activity.

b) PROPIONIC ACID derivatives (IBUPROFEN): Reversible COX inhibitors - inhibits the

synthesis of prostaglandins but not of leukotrienes.
(others: naproxen, fenoprofen, ketoprofen, flurbiprofen and oxaprozin).
Effects: ANALGESIC, ANTI-PYRETIC, ANTI-INFLAMMATORY, + they can alter platelet

function and prolong bleeding time.

Pharmacokinetics: oral administration, bound to serum albumin, liver/kidney excretion.
Adverse effects: Less side effects than aspirin, GI (dyspepsia, bleeding) is most common.
Side effects: CNS involvement like headache, tinnitus, dizziness.

c) ACETIC ACID derivatives (INDOMETACINE, SULINDAC, ETODOLAC): Reversibly

inhibiting the COX. (not used for low fever!)
Effects: ANALGESIC, ANTI-INFLAMMATORY and ANTI-PYRETICS.
Used for: treatment reserved for ACUTE GOUTY ARTHRITIS, AKYLOSING
SPONDYLITIS and OSTEOARTHRITIS OF THE HIP due to its toxicity.
Adverse effects: similar to NSAIDs, less common GI problems and toxicity.

d) COX2 selective NSAIDs (COXibs) CELECOXIB: REVERSIBLE and TIME

DEPENDENT inhibition of COX2.
Effects: treatment of RA, OSTEOARTHRITIS and PAIN; Lower risk of GI bleeding and
Dyspepsia,(lost when added ASPIRIN)
Doesnt inhibit platelet aggregation and doesnt bleeding time!
Pharmacokinetics: colecoxib is readily absorbed, half-life:11h, peak in 3h, metabolized in the
LIVER by cyt. P-450, excreted by feces and urine.
CI: IHD or STROKE ( level of prostacyclines platelet aggregation);, moderate hepatic
impairment(reduced to 50%), avoid in severe hepatic and renal disease. Contraindicated in
patients with allergies to sulfonamides.
Adverse effects: headache, dyspepsia, diarrhea and abdominal pain.
19. Anti-rheumatic drugs and Drug used to treat Gout:

Rheumatoid arthritis is a systemic inflammatory disease which attacks the synovial joints.

There is no known cure for rheumatoid arthritis, but there are treatments that may alleviate
symptoms. For this we can use: NSAID's, corticosteroids, disease modifying agents and
biological treatment.

Disease Modifying Antirheumatic Agents (DMARA): it is a class of drugs that slows down
the progression of the disease and prevent further destruction of joints and bones.

These drugs are contraindicated in pregnancy and are used for the treatment of the disease
rather than the symptoms.

Methotrexate an immunosuppressive agent, used to decrease WBC count and the

inflammation. It is the 1st line drug, or the drug of choice for treating RA and psoriasis and is
used in mono-therapy or with other drugs in this class.
May lead to PUD, nausea, vomiting, cytopenia, hepatotoxicity.

Leflunomide stop lymphocytic replication, used in combination with methotrexate.

It is an immunomodulatory agent that decrease pain and inflammation, thus slowing the
progression of pain and structural damage.

Hydroxychloroquine it is an anti-malarial drug, that proved beneficial in mild RA, but only in
combination with methotrexate.

D-penicillamine cysteine analogue, immunomodulator and is given together with NSAID's or

corticosteroids, not to be used long term because it may lead to Wilson's, aplastic anemia, etc.

Gold salts slow acting immunomodulators, but may lead to heavy metal intoxication.

Biological treatments: we can use immune agents such as TNF's or IL's and monoclonal Ab.

TNF alpha blockers infliximab, adalimumab, etanercept.

IL-1 blockers anakinra.

Monoclonal antibody rituximab.

T cell blocker Abatacept.

Treatment of Gout:

Gout is a metabolic disease characterized by increased Uric acid in the blood which lead to
deposition of sodium-urate crystals in the kidneys and joints and inflammatory response.

for the treatment of acute gout we use NSAID's, intrasynovial glucocorticoids and
Colchicine.

For the treatment of chronic gout is to increase uric acid secretion and inhibition of uric acid
synthesis.

Colchicine inhibit movement/proliferation of leukocytes, stop the secretion of LT. Given

orally, may lead to agranulocytosis and aplastic anemia as well as alopecia.

Allopurinole inhibit uric acid synthesis by competitive inhibition, has to be with Colchicine
because it may lead to acute gout.

Probenecid and Sulfinpyrazone promote renal clearance of uric acid, given also with
antibiotics to reduce its renal clearance.

20. Opioid analgestics:

The primary use of opioid analgesics is to relieve intense and chronic pain and anxiety that
accompanies it (surgery, injury, cancer). It acts by binding to specific opioid receptors in the
CNS and mimic the effect of endorphins, enkephalins and dynorphins.

Pharmacodynamics:

The major effect is mediated by 3 main receptors - ,

, . (mu, kappa, delta) from the G-

protein-coupled receptor family. Binding to an opioid receptor will cause:

1. Inhibition - cAMP content is reduced.
2. Opening of K channels. (postsynaptic K+ efflux hyperpolarization).
3. Inhibits the opening of Ca channels. (presynaptic Ca++ influx).
4. Receptors on spinal cord affect the release of substance P (decrease).
This causes hyperpolarization and in NeuroTransmitter release.

Classes of opioids:

Full agonists: Morphine, hydromorphine, Methadone, fentanyl, oxycodon, Heroin - binds to

receptor.

Moderate Agonist: Codeine, Propoxyphene.

Mixed agonist/antagonist: Buprenorphine binds to receptor in dorsal horn. Pentazocine suppresses , activates .

Full antagonists: Naloxone - treat overdose of opioids.

Other analgesics: Tramadol - -opioid receptor

Therapeutic Uses of Opioids:pain relied, terminal illnesses, pre/post operative, lead to

constipation, relives dyspnea ( pulmonary edema) and cough.

Side effects: sedation, constipation, nausea, urinary retention, addiction, respiratory

depression.

Full agonists:

MORPHINE: acts on receptors in the dorsal horn Substance P release (substance P

modulates pain perception in the spinal cord) and inhibits NT release from nociceptive nerve
ending carrying terminals.
Actions: Analgesia (raises pain threshold), Euphoria, Respiration depression, Anti-tussive,
Miosis (pinpoint pupils), Constipation, Urinary retention, Sedation, Histamine release,
Hormonal changes (ACTH, GTH, CTH, LH, FSH, -ENDORPHIN and GH,PROLACTIN,
ADH).
Therapeutic uses: Analgesia, Treat. of diarrhea, Relief of cough, Treat. Acute pulmonary edema.
Pharmacokinetics: well absorbed by IM, IV, SC injections.
Toxicity: Acute coma, cyanosis, shock death.
Treatment: naloxone.
Chronic: dependence, tolerance, withdrawal symptoms (flu like symptoms with insomnia),
irritability involuntary movements, HT. Treatment: methadone.
Morphine has very high first pass effect should be administered parenteraly and not P.O.

METHADONE(-receptor) is synthetic! orally effective opioid equal to the potency of

morphine but induce less euphoria and longer duration of action, used for weaning the addicted
to heroin or morphine, as substitute for injected opioid.

FENTANYL - chemically related to meperidine, x100 the analgesic potency of morphine,

lipophilic, short duration of time, injected (IV) epidurally or intrathecally. Used during and
postoperatively, also used in cardiac surgery.

OXYCODONE - semi-synthetic derivative of morphine. orally active, combined often with

aspirin or acetaminophen.

Heroin - not a natural product! obtained by diacetylation of morphine x3 its potency, lipid
soluble= across BBB more than morphine; Converted to morphine in the body (no medical use).

MODERATE AGONISTS:

CODEINE - used for its DRY-COUGH/ANTI-TUSSIVE activity.

 MIXED AGONIST/ANTAGONIST:

PENTAZOCINE- acts as an agonist on receptors and is a weak agonist of and . Causes

less euphoria than morphine, but in higher doses can lead to respiratory and GIT activity
depression, b.p., hallucinations, nightmares, dysphoria, tachycardia and dizziness, work load
of the heart. can induce tolerance and dependence.

BUPRENORPHINE- partial agonist, on receptor. Use in opiate detoxification coz it has less
severe and shorter duration of withdrawal symptoms compared to methadone. Indicated for the
treatment of opioid dependence.

OTHER ANALGESICS:

TRAMADOL- analgesic centrally acting by binds to -opioid receptor. For management of

moderate to severe pain. Extensive metabolism. Not to be used in patients taking MAO
inhibitors.
21. Local anesthetics:
Generally applied locally and block nerve conduction of sensory impulses from the periphery to
the CNS. Reversible loss of sensation. Works on the pathway to dorsal horn. GA on the pathway
to cortex.
It selectively binds to the intracellular surface of Na channels and blocks the entry of Na
causing block of depolarization.

Weak base:

non ionized = able to cross membranes, in acidosis LA becomes ionized and are unable to
cross the membrane.

After penetration to the cell, the LA becomes ionized and trapped in the cytosol.

Action of various nerves: works faster in small diameter nerves, rather than large diameter.

Fiber A - pain, thermal and tactile sensation: largest and last to be influenced.

Fiber B - Autonomic paralysis (causes vasodilatation): preganglionic.

Fiber C Touch, Itchy pain. (smallest diameter, influenced first): postganglionic.

Note: local anesthetics are always combined with adrenaline to promote vasoconstriction and to
prevent the absorption of the drug to the systemic circulation, unless given intrathecally.

Classification:

Esters: Procaine, Tetracaine (cocaine derivatives) Metabolized in plasma by

pseudocholine esterase, they have high allergic profile and short half-life.

Amides: Lidocaine, Ropivacaine, Mevicaine. These can be hepatotoxic.

Methods of application:

Topical -Skin or mucosa. Nasal, eye, rectum. May use higher concentration because no
systemic absorption (Tetracaine, Lidocaine).

Infilative (under the skin injection) -Near nerve endings. Lower concentration. (Lidocaine.
Bupivacaine).

Plexus block - Near nerve trunks - Procaine, Lidocaine.

Intrathecal can be subarachnoid or subdural.

I.V. - paradoxical, used only when it is impossible to get to systemic circulation.

Side effects: Allergy, systemic absorption (arrhythmia, tachy/bradycardia), tremor,

convulsions, respiratory depression.

22. General anesthetics:

General anesthetics are drugs used in order to prepare a patient for surgery and to induce
sedation, amnesia, anesthesia and to promote coma or altered mental state as well as
myorelaxation and elimination of reflexes, can be with or without analgesic effect.

Pre-medication will be:

Myorelaxants for intubation or for pre-surgical use.

BZD anxiolytics, hypnotic, sedatives.

Parasympatholytics atropine is used to prevent tachyarrhythmia.

Analgestics for pain suppression, most commonly opioids.

PPI's decrease gastric acid secretion and prevent stress ulcer.

Each anesthesia has 3 stages: induction (depth of anesthesia), maintenance (monitor and
balance) and recovery (reverse of induction).

Depth of anesthesia:
1) analgesia loss of pain.
2) Excitement combative behavior, increased B.P and respiration.
3) Surgical regular state of relaxation.
4) Medullary paralysis leads to death due to depression of the respiratory center.

Inhalation anesthesia:
These drugs work by increasing the sensitivity of GABA receptors to GABA, leading to
decreased excitability of the neuron post-synaptically (Cl channel blockers).

if there is malignant hyperthermia due to succinylcholine (muscle relaxant) use Dantrolene

(antidote).

Halothane it is a weak analgesic, thus usually co-administered with nitrous oxide.

May lead to brady/tachycardia, vasodilation, malignant hyperthermia (antidote is Dantrolene).

Isoflurane it is the drug of 1st choice, it doesn't induce arrhythmia, but leads to hypotension,
and increase the oxygen consumption as well as coronary blood flow.

Sevoflurane used in children.

Nitrous oxide a strong analgesic but weak anesthetic (in-fact can never induce full
anesthesia), used mainly for analgesia in dental work or in combination with other anesthetic
due to its high analgesic properties.

Intravenous anesthesia:

Thiopental a barbiturate that quickly induce anesthesia, it is a potent anesthetic but weak
analgesic, very lipid soluble and short acting (lipophilic).
May lead to cough, laryngospasm, bronchospasm, apnea, Never to be combined with alcohol.
Administered with other drugs, such as BZD (Lorazepam, Diazepam sedation), opioids, NO,
etc.
Propofol known also as Michael Jackson's milk (because he died from it and it is white and

viscous). It is an I.V hypnotic/sedative for the induction and maintenance of anesthesia with
very rapid onset (40 seconds), has poor analgesic effect.
Ketamine A short acting, non barbiturate anesthetic which lead to sedation, amnesia and
immobilit, analgesia.
It increases cardiac output and B.P and it cross the BBB, thus can lead to hallucinations.

23. Drugs used in the treatment of neoplastic diseases:

Tumor cells are characterized by an uncontrolled proliferation, differentiation and loss of
function, they can be invasive and to metastasize and lead to angiogenesis.
The tumor cells arise from over activity of oncogenes or under activity of tumor suppressor
genes (p53, p16) and it may arise due to radiation, viruses, bacterial infection, chemicals, free
radicals and drugs.
Tumors may be divided into:

Chemo-sensitive.

Intermediate chemo-sensitive.

Chemo-resistant.

Response to chemotherapy depends on: fraction of proliferating cells, tumor mass, cell cycle
rate, synchronization of cell cycle within the tumor, resistance of tumor cells (deactivation,
DNA repair, efflux).
Anti cancer drugs are divided according their mechanism of action to:
Alkylating agents:

Cyclophosphamide after activation in the liver (prodrug) it cross link with the DNA to
damage it, given orally and may lead to alopecia, nausea, vomiting, bone marrow
depression, etc.

Anti-metabolite: structural analogs of purines and pyrimidines causing synthesis of defective

nucleic acids and folic acid.

Methotrexate antagonist of folic acid, work by inhibiting DiHydroFolate Reductase

(DHFR), thus inhibiting folic acid from becoming tertahydrofolic acid (FH4).
May lead to stomatitis, myelosuppression, erythema, rash, urticaria and alopecia
(preventable with Leucovorin), nephrotoxicity, hepatotoxicity, pulmonary toxicity and
neurotoxicity.
Cytotoxic ATB's: cytotoxic action, primarily by interactions with the DNA, leading to
disruption of DNA function and inhibiting topoisomerase 1 and 2 (uncoiling) free radicals.

Bleomycin.

Dactomycin.

Mitosis inhibitors (microtubules): derivatives from a plant called Vinca Rosea, thus they are
vinca alkaloids, interfere with microtubular apparatus. May lead to cellulitis and phlebitis.
Drugs are: Vincristine and Vinblastine.
Topoisomerase inhibitors: Topotecan.
Hormones: tumor can be hormone responsive, hormone dependent or both.

Glucocorticoids prednisone.

Tamoxifen - estrogen antagonis, in estrogen dependent breast cancer.

Protein kinase inhibitors Imatinib, against growth factor.

Monoclonal antibodies: effects the angiogenesis or direct against tumor cells.
Drugs: Bevacizumab, Rituximab, Cetuximab.
May lead to myelosuppression, bleeding, susceptibility for infections, alopecia, nausea,
vomiting and many more.

24. Histamine-antihistaminics:
Histamine is a chemical messenger that mediate cellular responses as allergy, HCL secretion
and neurotransmitter in some parts of the brain. It is found in high concentration in mast cells
and basophils, synthesized from histidine and stored in intracellular granules, it is released by
destruction of cells (trauma, cold) and as a response to an allergen (type 1 hypersensitivity).
Histamine binds to the one of the receptor H1-H4, while H1 and H2 are most widely expressed,

the histamine receptors are G protein type. H1 mediated smooth muscle contraction and
increase capillary permeability while H2 are important for gastric acid secretion.

H1 antihistamines: this is what people mean when the say antihistamines, they are H1
receptor blockers and divided into first and second generations.

1st generation: still widely used, but they penetrate CNS and cause sedation
(chlorphenyramine, diphenhydramine, promethazine).

2nd generation: specific H1 that to not penetrate the CNS (loratadine, fexofenadine).

These drugs are used against allergy, motion sickness and nausea (1st generation) and insomnia
(1st generation- sedatives). 1st generation can bind cholinergic, alpha adrenergic and
serotoninergic receptors leading to side effects.
Side effects: cholinergic (xerostomia, urinary retention, tachycardia), adrenergic (hypotension,
reflex tachycardia), serotonin (increased appetite), histamine (sedation).

H2 antihistamines: antagonists to H2 receptors in the stomach and inhibit the binding of

histamine to H2 receptors, thus inhibiting the production of HCL for the treatment of ulcers
and reflux. By binding the receptor they competitively decrease the levels of cAMP and
secretion of gastric acid.
These drugs are less potent then PPI's and are less commonly used today, because they do
not inhibit gastrin receptors or Ach receptor so there is still some degree of acid production.

Drugs: cimentidine, ranitidine, femotidine.

25. antiserotonic drugs:

Serotonin, or 5-HT is a monoamine neurotransmitter which is derived from tryptophan and
mainly found in the GIT, platelets and CNS associated with gut motility, regulation of mood,
appetite, sleep, memory and learning.
The excreted serotonin in the CNS binds to 5-HT receptor and is rapidly degraded by
MonoAmino Oxidase (MAO), the serotonin excreted in the GIT binds to the receptor and lead
to increased GI motility, if in high levels will lead to diarrhea and vomiting, it is absorbed to the
blood stream and taken by the platelets where it is stored, released as a vasoconstrictor.
It is associated with many diseases, such as migraine, depression, anxiety, schizophrenia, eating
disorders, vomiting, diarrhea.
There are 7 types of 5-HT receptors in the body, all but 5-HT3 are G coupled, while 5-HT3 is
ligand gated ion channel.

serotonin antagonists are used in medicine in order to treat serotonin syndrome (too much
serotonin in the body, can only occur from combination of drugs, as antiemetics and as
atypical antipsychotics and against migraines.

Drugs used:

cyproheptadine used to tread carcinoid kideny tumor producing serotonin and to treat
serotonin syndrome. It has antihistaminic, anticholinergic, antiserotoninergic and local
anesthetic properties, used also against migraine.

Clozapine, olanzapine 5-HT2 antagonists which have antipsychotic properties, also

inhibit dopaminergic receptors.

Kitaserine, ritanserine 5-HT2 blockers.

Graniesetron, dolasetron 5-HT3 blockers, used as antiemetics, used together with

antineoplastic drugs.

26. Antivomiting drugs (anti-emetics):

In chemotherapy emesis must be controlled, uncontrolled emesis can produce dehydration,
rejection of curative drug, metabolic imbalance and nutrient depletion.
There are 2 brainstem sites that have keyrole in vomiting as well as the peripheral receptors:

the chemoreceptor trigger zone in the 4th ventricl.

The vomiting center, located in the reticular formation and coordinates motor mechanisms
of vomiting.

The receptors will be: 5-HT3, M1 D2 and H1

Drugs effective against emesis are:

Phenothiazines: act by blocking dopamine receptors, effective against low to moderate emesis
drug is prochlorperazine.

5-HT3 receptor blockers: they have long duration of action and are very effective against
vomiting, they are metabolized in the liver and excreted in the urine all drugs end with -setron
(granisetron, dolasetron).

Butyrophenones: act by blocking dopmine receptor prototype drug is Halloperidol.

Benzodiazepines: have low anti-emetic properties, mostly sedatives, anxiolytics and amnestics
prototype drug is Lorazepam.

Corticosteroids: used in drug combination, effective against emesis but their mechanism of
action is unknown drugs: methylprednisone, dexamethasone.

Cannabinoids: effective, but can cause hallucination, sedation, dependance, etc... can be used as
medicinal marijuana or as marijuana derivatives dronabinol.

Substance P/neurokinin-1 receptor blocker: blocks the neurokinin receptor in the CNS and
block its action drug is Aprepitant.

of course almost any disease can cause vomiting, so we need to treat the underlying cause,
either GIT, ICH, infection, or motion sickness with the appropriate drugs, such as diuretics,
chelating agents or anti motion sickness (scopolamine).

27. Cardiac glycosides:

This is an important class of naturally occurring whose actions are both beneficial and toxic to
the heart. To these agents, the clinically relevant are Digoxin and strophantin, but digoxin is
almost solely used.
The Digoxin enhance the cardiac muscle contractillity (positive inotropic) and thus increase the
cardiac output, it does so by increasing the intracellular calcium concentration.
Digoxin is a naturally occuring substance from the plant Digitalis purpurae (fox-glove
) which influence the sodium and calcium ion flow into the cardiac muscle.

it is a very toxic substance with very low therapeutic index .

Digoxin acts by inhibiting the ability of the myocyte to actively pump sodium from the cell
ant the ability to move calcium out of the cell by working on the Na+/K+ and Na+/Ca2+
exchangers.

It is administered only to patients with severe left ventricular systolic dysfunction, thus is
used only in left heart failure, it can also useful in treating arrhythmias but can lead to
dangerous arrhythmias.

Side effects: cardiac toxicity, arrhythmia (bradyarrhythmia, SA/AV block), nausea,

vomiting, blurred vision.

Contraindicated in case of arrhythmia or IV calcium application.

Risk factors: electrolyte disturbances, diuretics, warfarin (competition for albumin), renal
failure, myocarditis.

Treatment: antiarrhythmic (lidocaine mainly), drug cessation, digoxin antibodies (digoxine

immune Fab).

28. Antianginal drugs:

Angina pectoris is a sudden, severe chest pain radiating to the neck, jaw, back and arm (left).
It is caused by insufficient coronary blood flow and ischemia.
There are several types of angina pectoris:

stable: called also typical angina, characterized by a burning, heavy feeling in the chest due
to reduction of coronary perfusion with fixed obstruction from coronary atherosclerosis.
Occur in workout or any increased demand, relieved by nitoglycerin (NG).

Unstable angina: chest pain from progressively less or even absent effort, not relieved by
nitroglycerine (NG) and require hospital admission to prevent M.I.

Vasospastic angina: occur at rest and sue to vasospasm, respond well to NG.

Drugs used to treat angina are:

Organic nitrates: cause relaxation of coronary arteries and relax veins, thus reducing preload
and oxygen demand. Thought to act by intracellular conversion to nitric oxide (NO) which
activate guanylate cyclase, increases intracellular cAMP and leading to smooth muscle
relaxation and vasodilation.
Drug of choice is Nitroglycerine which is given sub-lingual or transdermal patch (due to major
first pass effect), may lead to headache, postural hypotension and tachycardia. Has to be given
in intervals because of the rapid development of toelrance.

Beta blockers: have negative inotropic effect, block beta 1 receptors.

Atenolol (thus preferred) is cardioselective while propranolol is not cardioselective.
Contraindications for non selective are asthma, COPD, DM and severe bradycardia.

Calcium channel blockers: decrease muscle tone and vascular resistance, drugs used are
mainly:
1. Verapamil: diphenyalkylamine slows conduction.
2. Nifedipine: dihydropyridine arterial vasodilator.
3. Dilitazem: Benzothiazepine.

29. Antidysrhytmic drugs:

Arrhythmia is a dysfunction which causes abnormalities in impulse formation and/or
conduction. It can be either tachy or brady arrhythmia and with or without a sinus rhythm.
Impulses originating from sites other than the SA node, or traveling along accessory pathways
(Reentry, Wolff -Parkinson White syndrome).

Arrhythmias are classified as:

Atrial

atrial flutter: propranolol, verapamil, digoxin.

Atrial fibrillation: propranolol, amioderon, anticoagulants.

Supra-ventricular:

AV nodal reentry: propranolol, verapamil, digoxin.

Acute supra-ventricular tachycardia: verapamil, adenosine.

Ventricular tachycardia:

acute ventricular tachycardia: lidocaine, amioderone.

Ventricular fibrillations: lidocaine, amioderone, epinephrine.

The etiology can be abnormal automaticity, drug effect, conduction abnormalities and for
treatment we have 4 classes of drugs:
Class 1 anti arrhythmic (sodium channel blockers):
block sodium channels, via the same mechanism as local anesthetics, by binding to open or
inactivated sodium channels rather than fully re-polarized, thus they are good in tachycardia.
This property is called state-dependance and it enables the blockade of abnormally high
frequency discharging cells, without interfering with normal cells. Has 3 sub-classes:

1a slow phase 0 depolarization (quinidine, procaineamide), bind to sodium channels and

prevent sodium influx (also inhibits potassium channels), used to maintain sinus rhythm in
tachycardia. May lead to arrhythmia by itself !!!!!

1b shortens phase 3 (lidocaine), thus the cell is unable to fire another action potential
leading to decreased heart rate.

1c markedly slows phase 0 depolarization (propafenone, flecainide), show major effect

even on normal heart, slowly dissociates from resting sodium channels.

Class 2 antiarrhythmics (beta blockers):

Diminish phase 4 repolarization, thus depressing automaticity, prolong AV conduction and
decrease the heart rate and contractility. It is very useful in tacharrhythmias caused by increased
sympathetic tone propranolol, metoprolol, esmolol.
Class 3 antiarrhythmics (potassium channel blockers):
Diminish the outward potassium current during repolarization (phase 3) and prolong the
duration of the AP, all drugs in this class are dangerous and may lead to arrhythmia.

amioderone effective in treating sever refractory tachyarrhythmias, has a very long half
life (weeks) and the effect achieved only after 6 months, causes severe side effects
(pulmonary fibrosis, tremor, hepatotoxicity) in around 50% of the patients.

Sotalol may lead to torsades de pointes () , it is a dangerous ventricular

fibrillation showing abnormal ECG with different heights of R wave, if you will draw a line
it will look like a snake.

Dofetilide recommended for treatment of atrial fibrillation (the only one).

Class 4 antiarrhythmics (calcium channel blockers):

decrease the inward calcium current, resulting in decreased rate of phase 4 spontaneous
repolarization. Bind only to open depolarized channels, thus prevent repolarization and does not
effect the normal heart tissue, but has negative inotropic effect and vasodilatory properties so it
may lead to decreased stroke volume, reduced BP, edema and congestion formaion.
Drugs used: verapamil and Diltiazem.
Other antiarrhythmics:

Digoxin: may lead to ectopic ventricular beat.

Adenosine: decreases conduction velocity, prolong the refractory period and decrease
automaticity in the AV nod, but has to be in high doses.

30. Diuretics:
These drugs are useful in relieving pulmonary congestion and peripheral edema, also useful in
reducing volume overload symptoms (decrease preload and afterload).

Thiazide diuretics:

The most widely used, derivatives of sulfonamides and are relatively weak diuretics. They
affect the distal tubule to decrease the reabsorption of sodium, they work on Na/Cl cotransporter
on the luminal membrane, produces hyperosmolar urine, but does not change the acid-base
balance of the body. Used in HF, hypertension, diabetes insipidus.

Drugs: Chlorthiazide, Chlorthalidone and Metolazone.

Loop diuretics:

Work on the ascending loop of Henle and are the most potent diuretics, they work by decreasing
the reabsorption of Na/K/2Cl in the luminal membrane and are used as the drug of choice for
reducing pulmonary edema in HF, but they are effective for only 2-4 hours.

Drugs: Bumetanide, Furosemide, Torsemide.

Potassium spearing diuretics:

Act on the collecting tubule, they inhibit sodium reabsorption and potassium excretion.

Drugs: Spitolactone (aldosterone antagonist), Amiloride.

Carbonic anhydrase inhibitors:

Not really used as a diuretic.... inhibit carbonic anhydrase located intracellularly at the proximal
tubule carbonic anhydrase catalyzes CO2 and H2O, leading to H2CO3. Mainly used in
glaucoma patients and prophylaxis of mountain sickness.

Drugs: Acetazolamide.

Osmotic diuretics:

Result in some degree of diuresis because they are osmotically active.

Drugs: Manitol and Urea.

31. Antihypertensive drugs:

Hypertension is a very common disorder, named also the silent killer and defined as more
than 140/90 mmHg. In the treatment of hypertension, lack of patient compliance is the biggest
problem.
Drugs that are used as antihypertensives are:

Diuretics: first line drugs in hypertension therapy (thiazide, loop and spironolactone).

Beta blockers:

Decreased activation of B1 receptors decreased cardiac output.

Decreased renin decreased angiotensin 2 decreased peripheral resistance.

Decreased angiotensin 2 decreased aldosterone decreased water and sodium retention

decreased blood volume.

To summerize they decrease cardiac output, decrease renin production and decrease aldosterone
production.
They are used more in young white people, may lead to bradycardia, hypotension, fatigue,
insomnia and sexual dysfunctions.

RAS inhibitors: renin-angiotensin system inhibitors, devided to ACE And ARB.

ACE inhibitors: angiotensin converting enzyme inhibitors are indicated as the 3rd line of
therapy, they reduce peripheral vascular resistance by inhibiting ACE (which is also
responsible for the breakdown of bradykinin, thus when inhibited there is dry persistent

cough), may also be effective in the management of diabetic nephropathy.

All these drugs end with pril.... prototype is captopril, ramipril, etc..

ARB's: angiotensin receptor blockers block only AT1 receptor (angiotensin 1), thus they
work the same as ACE, but do not cause the irritating cough (no bradykinin breakdown
inhibition).
All these drugs end with sartan.... prototype is Losartan, valsartan, etc...

Renin inhibitors:

Directly inhibits renin, there is only 1 drug Aliskiren. Which is contraindicated in pregnancy.

Calcium channel blockers:

verapamil, dilitazem and amlopidine are useful and are good for treating patients with comorbidities (angina, arrhythmia).

Alpha blockers: produce competitive block of alpha 1 adrenoreceptors, thus decrease

peripheral resistance. All drugs end with osin lead to reflex tachycardia.

Drugs: doxazosin, prazosin.

Other drugs: clonidine (alpha 2 blocker), alpha-methyl dopa (alpha 2 agonist), minoxidil
(dilation of persistent vessels).

32. Lipid-lowering drugs:

Some agents decrease production of lipoprotein carriers of cholesterol or triglycerides, or
increase the degradation of lipoproteins. There are also drugs to decrease cholesterol absorption
or to increase its removal.

Statins: HMG CoA reductase inhibitors (statins) inhibit the first committed enzymatic step
of cholesterol synthesis, thus inhibiting De-Novo synthesis of cholesterol and depleting the
cell cholesterol supply, leading to increase in LDL receptors further removing LDL from the
blood. It is used in elevated LDL levels.
Drugs: Lovastatin, Pravastatin.
Side effects: liver function abnormalities, myopathy, rhabdomyolysis.

Niacin (nicotinic acid): reduces LDL and increases HDL by inhibiting lipolysis in adipose
tissue, thus decreasing the levels of triglycerides and LDL, very good for familial
hyperlipidemia (lack of LDL receptors).

Side effects: flush, pruritus, hyperuricemia (leading to gaut).

Fibrates: lower serum triacylglycerol and increae HDL levels by binding to PPAR's
(peroxisome proliferator activated receptor) which regulates the expression of genes
encoding for proteins involved in lipoprotein structure and function.
Side effects: GI disturbances, cholecystolithiasis, myositis, myopathy.

Bile acid-binding resins: has significant LDL cholesterol lowering effects.

These are anion exchange resins ( )that bind negatively charged bile acids and bile salts
in the small intestines, causing the liver to produce more bile and use the cholesterol. May
impair the absorption of fat soluble vitamins (A,D,E,K).

Cholesterol absorption inhibitors: selectively inhibits intestinal absorption of dietary and

biliary cholesterol to the liver, metabolized by glucoronic cnjugation.

The only drug here is Ezetimibe.

Part 3

1. Mechanism of action of antibiotics, resistance, classification:

Antibiotic therapy utilizes the differences that exist between humans and microorganisms or
simply put they have the ability to injure or kill invading microbes without hurting the patient
(selevtive toxicity not absolute).
The differences are cell wall, different ribosomes, different enzymes (e.g. topoisomrases), etc..
For the appropriate selection of antibiotics we need knowledge of the organism, its
susceptibility, the main site of infection, the patient factors, the safety of an agent and its cost.
a) Identification gram stain, PCR, culture, FISH, serology, etc....
b) Empiric therapy an educated guess, used in critically ill patients, take sample and
immediately initiate therapy.
c) Antimicrobial susceptibility obtained after culture, can be bacteriostatic (arrest growth) or
bacteriocidal (kill bacteria).

MIC the minimal inhibitory concentration that inhibits bacterial growth.

MBC the minimal bacteriocidal concentration.

d) Physical factors lipid solubility, size, ionization, protein binding of a drug.

e) Patient factors immune state, co-morbidities, pregnancy, age, renal or hepatic dysfunction.
Drug can be administered IV, IM, SC, PR, PO, SL, PV (per vagina) and the dose is based on the
pharmacological properties of the drug and the patient factors.
The spectrum of the drug can be:

Narrow spectrum single or limited microbes (penicillins).

Extended spectrum effective agains G+ and G- bacteria (cefepime).

Broad spectrum wide range of activity (chloramphenicol, tetracyclins).

Complications of antimicrobial therapy can be hypersensitivity, toxicity or super -infection.

Drug resistance:

bacteria is resistant to an antibiotics if the maximal level of that antibiotic that can be tolerated
by the patient does not stop their growth. They do so by several mechanisms:

spontaneous DNA mutations (e.g. insertions, deletions or substitutions).

DNA transfer of drug resistance from 1 bacteria to another (e.g. plasmid and F-pilli).

Modification of target sites (e.g. alterations of binding proteins).

Decreased accumulation by decreased uptake or increase efflux (porins and efflux pumps).

Enzymatic inactivation (e.g. beta lactams, acetyl transferase or esterases).

Classification:

Cell wall inhibitors: most important are beta lactam antibiotics (penicillin, cephalosporins,
monobactam and carbapenem).

Beta lactamase inhibitors clavulonic acid, sulbactam suicide drugs.

protein synthesis inhibitors tetracyclins, aminoglycosides, macrolides, chloramphenicol.

Folic acid antagonists, DNA inhibitors fluoroquinolones, sulfonamides.

2. penicilins. penicillins with broader spectrum:

Cell wall in composed of peptidoglycan chain consist of NAM (N-acetyl muramic acid) and
NAG (N-acetyl glucoseamine).
The most widely effective and least toxic among the cell wall inhibitors, but has high resistance
profile which keeps increasing all the time.
Penicillins interfere with the last step of cell wall synthesis (cross-linkage), thus resulting in cell
lysis. They are only effective against rapidly growing organisms and act by binding to
penicillin-binding proteins (transpeptidase), which are the bacterial enzymes involved in the
synthesis of cell wall, and disable them.

1st generation: also called natural penicillinis, obtained from penicillium chysogenum
(mold) and has only 2 subtypes:

PNG: penicillin G (benzylpenicilline), effective against G + and G cocci, G + bacilli and

spirochetes, but susceptible to inactivation by penicillinase.

PNV penicillin V same as G, but with higher MBC.

2nd generation: called also penicillinase resistant penicillins, used in penicillinase producing
staphylococci infection only (methicillin is used only in laboratories due to high toxicity).

Drugs: Oxacillin, Nafcillin, Dicloxacillin, Methicillin (theory only).

3rd generation: same spectrum as PNC G, with extra effectiveness against G- bacilli,
usually given with beta lactamase inhibitors.

Drugs: Amoxicillin, Ampicillin (Augmentin amoxicillin + Clavulonic acid).

4th generation: also called anti-pseudomonal, effective against many G- rods and
pseudomona aeroguinosa, broad spectrum. The only one given IV.

Drugs: Pipercarcillin, Ticarcilline, Carbenicillin.

Administered orally or IV, incomplete absorption, secreted in the urine.

Side effects: allergy, diarrhea, nephritis.

3. Cephalosporins:
Semisynthetic antibiotic with the same mode of action as penicillin, but they are little bit more
resistant to beta lactamase. There are 4 generations of cephalosporis.

1st generation: act as PNC G substitute, resistant to staphylococcal penicillinase and has
activity against E.Coli and Klebsiella pneumonia.

Drugs: Cefazoline, cephalexin.

2nd generation: greater activity against G-, but activity agains G+ is weaker.

Drugs: cefuroxime, cefoxitin.

3rd generation: inhanced activity against G- bacilli, and even P. aeroguinosa.

Drugs: ceftriaxone, ceftazidime, cefixime, cefotaxime.

4th generation: must be administered parenterally only !!!!! and has wide antimicrobial
spectrum.

Drugs: Cefepime.

These drugs administered mostly IM or IV, but some can be given orally, all but the 3rd
generation do not cross BBB and do not reach therapeutic value in the CSF, excreted by the
kidney (beside ceftriaxone- eliminated in the bile).
Its main side effect is allergy, but it may also lead to pseudomembranous colitis (C.difficile) due
to dysmicrobia.
4. Aminoglycosides:
It is the old mainstay treatment for series of G- bacilli which was replaced by 3rd generation
cephalosporins due to its serious toxicity.
There are several drugs in this family: Streptomycin (used also in mycobacterial infection) ,
Gentamicin, Tubramycin and Neomycin.

These drugs diffuse into the microbe via porin channels or via oxygen dependent system.
It binds the 30S ribosome leading to misread or wrong ribosome formation.

They are very effective against G- bacilli, including P. aeroguinosa, they are often combined
with Beta lactam antibiotic. Although this drug inhibit cell growth and should not really
destroy the bacteria, it is bacteriocidal (unknown why) and it only affects aerobic bacteria.

The highly polar, polycationic structure of the aminoglycoside is poorly absorbed orally,
thus given parenterally.

Resistance is via decreased uptake, plasmin associated production of enzymes.

Side effects: have very high nephro and ototoxicity (accumulate in the renal cortex and
perilymph of the inner ear), neuromuscular paralysis (neostigmine will alter this) and
allergy.

Note: neomycin is very toxic, thus given only topically !!!!!!!!!!!!!!!!

5. Tetracyclines:
As its name indicate, it is composed of 4 fused rings with a system of conjugated double bonds.
The drugs in this group are: Tetracycline, Doxycycline, and Minocycline.

The drug diffuses into the cell or enter via energy dependent transport protein mechanism,
then it binds to the 30S ribosome, thus blocking tRNA from binding to mRNA (same idea as
aminoglycosides). It is a protein synthesis inhibitor.

It is a broad spectrum antibiotic, works as a bacteriostatic drug and is effective against G+

and G- bacteria.

Resistance is via active Mg +2 active efflux or enzymatic breakdown.

Absorbed well after oral administration, concentrate in the liver, kidney, spleen and skin.

Metabolized and conjugated in the liver, excreted by the bile and kidney.

Side effects: gastric discomforts, hepatotoxicity, phototoxicity (accumulate in the skin),

superinfection, vestibular toxicity.

Contraindicated in liver or kidney failure.

6. Macrolides, lincosamides:

Macrolides: bind irreversibly to the 50S ribosomal sub-unit and is considered to be

bacteriostatic protein synthesis inhibitor.
There are 4 drugs that belong to this group:

Erythromycin: same spectrum as PNC G, thus given to patients with PNC allergy.

Clarithromycin: has activity against intracellular pathogens (chlamydia, legionella,

moraxella).

Azithromycin: for respiratory tract infection (Streptococcus pneumonia, Klebssiella).

Telithromycin: used when the other macrolides are ineffective.

These drugs are given orally, absorbed well, distributed well (except CSF), diffuses also to the
prostate and uniquely accumulate in Macrophages.
It is metabolized in the liver, the metabolite is excreted in the bile (active) and urine (inactive).

side effects are: epigastric pain, cholestatic jaundice, ototoxicity.

Lincosamides: to this group belong Clindamycin. Its mechanism of action is exactly the
same as erythromycin (meaning bind to 50S sub-unit).
The only difference is that is used for the treatment of anaerobic infections, such as
bacteroides fragilis.
Well absorbed orally, distribute well (except CSF), metabolized and excreted into the bile
and urine.
Its major side effect is that it may lead to fatal pseudomembranous colitis, thus usually
given with metronidazole or vancomycin (allways start with metronidazole)

7. Sulphonamides and quinolones:

Fluroquinolones: has 4 generation of drugs with increased activity against G+ microbes.

These drugs diffuse into the cell via porins, inhibit DNA replication by inhibiting DNA
gyrase (Topoisomerase) inhibit uncoiling. It is considered to be bacterocidal and generally
speaking is very effective against gram negative microorganisms.

1st generation: Nalidixic acid not used, lab only.

2nd generation: Ciprofloxacin G+ cocci, G- rods, intracellular bacteria.

3rd generation: Levofloxacin better than 2nd generation, but generally the same.

4th generation: Moxifloxacin G+ cocci and bacilli, G- rods and anaerobes.

Resistance is via mutations of the DNA gyrase and porins.

Absorbed well orally, accumulate in Macrophages and PMN's, thus good for intracellular
bacteria.
Side effects: nausea, vomiting, allergy, diarrhea, headache, phototoxicity (accumulate in the
skin).

Sulfonamides: these are inhibitors if folate synthesis. Folate is essential for the synthesis of
purines and pyrimidines (G,C,A,T,U) and this is why in its absence the cell will not be able
to grow or divide.
These drugs inhibit the De-novo synthesis of folate by competing with the bacterial enzyme.
For the former mentioned reasons, these drugs are bacteriostatic.

active against enterobacteria in the U.T and drugs of choice for toxoplasmosis and malaria.

Administered orally, bind to serum albumin, penetrate into CSF, acetylated in the liver, and
may lead to crystaluria (due to its toxic metabolite).

Side effects: crystaluria (nephrotoxicity), allergy, hemolytic anemia (G6PD deficincy),

kernicterus (in newborns).

Contraindicated in neonates, pregnant women and G6PD patients.

Drugs: Sulfamethoxazole, Sulfadiazine, Sulfacetamide......

8. Antistaphylococcal ATB:
Staphylococcus is a gram positive round shaped bacteria in an arrangement like a cluster of
grapes, the relevant types are S.aureus, S.epidermitis, S. saprofiticus and S.haemolyticus.
Some of the staphylococcal species, mainly S.aureus produce penicillinases and can be
penicillin resistant, meticilline resistant and even there are already few strains which are
vancomycin resistant.
In general we can use cell wall inhibitors.

for penicillin sensitive infections, such as strep throat (usually type A is sensitive), we can
use PNC V.

for penicillinase producin Staphylococcal infections we use 2nd generation penicillins, such
as oxacillin, nafcillin, dicloxacillin. It is possible to give 3rd generation penicillin, such as
amoxicillin or ampicillin, usually with clavulonic acid or sulbactam (Augmentin).

Cephalosporins, such as cefdinir and cefazolin may be effective.

Azithromycin may also be used (macrolide).

If all of the above has failed, we can bring the big gun and use Vancomycin, which bind to
D-Ala-D-Ala side chain in the cell wall, preventing the elongation. It is very effective
against both staphylococcal infections and clostridium difficile.
Note: today there are some strains that are even vancomycin resistant, use with caution.

In case vancomysin is insufficient...... we use Daptomycin, which disrupts the cell

membrane function and DNA/protein synthesis, really an all around drug, reserved
specifically for MRSA or VRSA or VRE (vancomycin resistant enterococci).

9. Antimycobacterial agents:
Mycobacterium is a rod shaped bacteria with a lipid-rich wall, stained by an acid-fast stain and
leads to Tuberculosis or Leprosy. It is a n intracellular infection, resulting in granulomatous
lesions. Mycobacterium grow very slowly, thus treatment is for 6 months to 2 years and require
multi- drug therapy due to high resistance profile.

 For the treatment of Mycobacterium Tuberculosis we use:

1st line drugs:

Izoniazid a prodrug, activated by a mycobacterial cataslae-peroxidase and its function is to

d ecrease the production of mycolic acid. This drug is used only in TB and is bacteriostatic.
Administered orally, diffuses very well into caseous necrosis tissue, metabolized via
acetylation, excreted in the urine.
Its main side effects are: allergy, hepatotoxicity, peripheral neuritis.

Rifampin derived from streptomyces (like streptomycin), never given as a mono-therapy.

It inhibits mRNA synthesis by suppressing the initiation step (interact with bacterial RNA
polymerase). Used for M.Tuberculosis and M.Leprosy.
Administered orally, eliminated via bile/urine (the bodily secretion will be stained in red,
inform the patient so they will not be scarred).

Pyrazinamide - a synthetic, orally administered, bacteriocidal antitubercular agent with an

unknown mechanism of action.

Ethambutol inhibits araninosyl transferase, thus inhibiting the synthesis of mycobacterial

arabinogalactam cell wall (same idea as vancomycin just different substrate).
Administered orally, excreted in the urine, can lead to optic neuritis and gout (due to
decreased urea secretion).

2nd line drugs:

Streptomycin an aminoglycoside.

Cycloserine orally effective, tuberculostatic agent.

Fluoroquinolons inhibit DNA gyrase.

Macrolides bacteriostatic protein synthesis inhibitors (bind to 50S)- erythromycin,

clarythromicinm, azithromycin.
Leprosy: 70% of the cases occur in India. The bacilli enter the recipient from the host's
skin lesion or nasal discharges via broken skin or respiratory tract.
Leprosy is treated with a triple drug regime of Rifampin, Dapsone and Clofazimine.

Dapsone sulfonamide-like drug which inhibit folate synthesis, thus bacteriostatic. Good
for pneumocystis jirovicy (carinii) in HIV pateint and has same side effects as sulfonamide
(crystaluria, haemolytic anemia, allergy).

Clofazimine binds to DNA and prevent future DNA replication, may lead to red-brown
discoloration of the skin.

10. Antiviral and antifungal drugs:

Antiviral drugs:

Viruses lack cell wall and cell membrane and they do not carry out metabolic processes, thus
they use the host's cell machienary for their own needs (replication, metabolism) and therefor
the clinical symptoms appear relatively late, only after the virus replicated and budded
Antiviral drugs work by one of the following mechanisms:

block virus attachment to the cell.

Block uncoating of the virus Amantidine, Rimatidine.

Inhibit viral protein synthesis interferons.

Inhibit specific virus enzymes.

Inhibit virus assembly.

Inhibit virus release.

Stimulate host immune response.

For respiratory infections: for influenza, respiratory syncitial virus (RSV) and
orthomyxovirus we can use:

neuraminidase inhibitors Zanamivir, lead to virion accumulation

inhibitors of viral uncoating amantidine, ranitidine.
Ribavirin synthetic guanisine analogue.

For hepatic infections:

interferons immune modulators & antiviral, given only by S.C route for HCV and HBV.
Adefovir nucleotide analogue.
Entecavir guanosine analogue

For herpes virus:

Acyclovir can be oral or topical, specific for herpes virus. It is a protease inhibitor which
inhibit viral DNA polymerase.
Ganciclovir acyclovir analogue, but better against CMV.
Penciclovir nucleoside derivative, inhibit DNA polymerase.

For HIV infections: we use HAART (highly active antiretroviral therapy).

NRTI nucleotide reverse transcriptase inhibitors (zidovudine, stavudine).

NNRTI non-nucleotide reverse transcriptase inhibitors (Nevirapine).
Protease inhibitors result in production of non infectious virions (Indinavir, ritonavir).

 Integrase inhibitors prevent entry of HIV into the cell (Raltegravir).

Antifungal drugs:

Infectious diseases which are caused by fungi are termed mycoses, it is caused by eukaryot with
a rigid cell wall made of chitin (NAG polymer) with cell membrane that contain ergosterols
(rather than cholesterol) they are most often chronic infections that resistant to many forms of
ATB's. The differences between fungi and human cells are utilized clinically.
There are 3 classes of antifungal drugs:
Polyenes:

Amphotericine & Nystatin cell membrane ergosterol binding drug leading to pore
formation, these are fungicidal drugs. Amphotericine is usef for almost all infections, while
nystatin is used topically in oral candidiasis, vaginal mycosis and topical mycosis.

Griseofulvin nucleic acid synthesis inhibitor, a fungistatic drug used for onychomycosis.

Azoles: they work by decreasing ergosterol synthesis by fungal CYP450 binding, can be
administered topically or orally, even IV if needed.
- representatives: Chlotrimazole, Ketonazole, Fluconazole, Itraconazole.
Other: work the same as azoles, it is a synthetic pyrimidine antimetabolite, thus disrupt DNA
synthesis. Has good CNS penetration, used mainly for systemic candidosis or cryptococcosis.

to this belong only Flucytosine. May lead to GIT, hematologic and hepatal disturbances.

11. Antiprotozoal and antihelmintic drugs:

Antiprotozoal: drugs that are being used to treat parasitic infections such as: Malaria,
amebiasis, leishmaniasis, giardiasis, trichomoniasia.
It is harder to treat protozoal infections than bacterial infections and usually takes more time
while causing serious toxic effects on the host.

Anti-Malarial drugs: malaria is an acute inflammation caused by the genus Plasmodium, it is

transmitted by a mosquito (Anophelos) vector which lives in humid swampy areas.
Admission of the protozoa liver maturation invade RBC multiply and rupture
RBC, then pass to infect other RBC (some become gametocytes) female mosquito picks
up gametocytes to pass to another host.
There are several drugs used for malaria:

Primaquine prevent the transmission of the disease and kill the parasite, effective against
parasites outside the RBC.

Chloroquine kills the intracellular (RBC) parasites by preventing the enzymatic change
of Heme (toxic to the parasite) to a non toxic substance.

Pyrimethamine effective against the gametocyte form and free blood plasmodium.

Mefloquine, Quinine, Artemisinin same as Chloroquine, but are used in therapy resistant
(which spreads very fast) plasmodium.

Chloramphenicol is also an option for treating Malaria.

All are given orally, hepatic metabolism.

Side effects are: Hemolytic anemia, GI disturbances (rare), rash and headache safe agents.

Anti-Amebiasis drugs: it's an infection of intestinal tract caused by Entamoeba histolytica. The
diagnosis is done by isolating E. hestolytica from feces, can form cysts (mainly in the liver).
The best agents used for treatment of amebiasis are:

Paramomycin work only in the intestines.

Metronidazole mixed action, systemic and luminal and is the best known drug.

Chloroquine - used to treat the liver abscesses formed by the cysts (also anti-Malarial).

Emetine same as chloroquine.

Side effects may include GI disturbances, rash and headache.

Anti-Trichomoniasis for the treatment of the STD caused by T.Vaginalis we use

metronidazole.

Anti-trionosomiasis fatal disease (known as sleeping disease) caused by the agent T.brucei or
T. gamebiasis, which invade the CNS and cause inflammation of the brain and spinal cord thus
producing lethargy and continuous sleep. The vector for it is the Tse-Tse fly.
Drugs used are:

Nifurtimox for the T. crusi infection (Chaga's disease), produces free radicals and may
lead to hypersensitivity.

Suramine, Pentamidine and Melarsoprol they inhibit the agents enzymes, decrease
DNA synthesis and lead to energy metabolism disorders.

Side effects: nausea, vomiting, hypotension, ferility, purpura.

Anti-Leishmaniasis caused by leishmania transmitted by the sand fly vector and can be
cutaneous and visceral. The agent invades Macrophages multiply and destroy them
invade new Ma.

Drug: Sodium stibogluconate inhibit the parasites glycolysis.

Anti-Helmitic: these drugs use as narcotizing & paralytic agents for the worm, leading to
inability of the worm to adhere to the intestinal wall thus removed in the feces.
Other mechanisms are inhibition of protein secretion & glucose transport or interference
with microtubular arrangement.
The worm can be either in the intestines or in the tissue in the cystic form (mainly liver and
muscles), thus require usually also careful surgery.
Effective drugs are:

Benzimidazole -used for helmitoses in general.

Ivermectin - used for onchocerciasis (liver blindness)

Praziquantel used for schistosomiasis

All anti-helmitic drugs are contraindicated in pregnancy !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

12. Drugs used in respiratory tract diseases (antiasthmatics, antitussics):

Asthma: an inflammatory condition affecting the bronchi leading to increased mucous

secretion and muscle spasms which in turn lead to narrowing of the lumen and to airflow
obstruction. The main symptoms are dyspnea, wheezing, cough and tachypnea.
The goal of the therapy is to maintain normal activity levels and to minimize the need for an
emergency unit.
It is an obstructive lung disease, probably related to to exposure to an antigen or inhaled
irritants, leading to bronchial hyperreactivity and inflammation of the airway mucosa.
Drug used to treat asthma are:

Adrenergic agonists: inhaled Beta 2 agonists are the drugs of choice for mild asthma.

short acting: not be used alone, unless it is exercise induced asthma, they have rapid onsed
of action and provide relief for 4-6 hours. Drugs are: Salbutamol (albuterol).

Long acting: same as salbutamol, but provide relief for 12 hours with a slow onset of
action, thus cannot be used for quick relief. Drug is Salmeterol.

Corticosteroids: drugs of choice in any degree of persistent asthma, glucocorticoids must be

taken continuously for effective control of the inflammation. It reverses mucosal edema,
decrease capillary permeability and inhibit leukotrien release.
Administered by inhalation or spacers and even oral (only in status asthmaticus) and may lead
to oral candidosis and hoarsness usually they do not produce systemic effect and maintain
their action bound to the respiratory tract.

Alternative treatment: leukotriens antagonist (Zileuton), leukotrien receptor blockers

(Cromolyn), cholinergic antagonist (Ipratropium) and monoclonal antibody (Omalizumab).

Allergic Rhinitis: an inflammation of the mucous membranes of the nose which is

characterized by sneezing, itchy nose/eyes, rhinorrhea and nasal congention.
Allergen production IgE mediated response release of Histamine, leukotriens and
chemotactiv factors.
For the treatment we use combination therapy of antihistamines and nasal decongestants.

Anti-histamines: H1 receptor blocker as Diphenylhydramine, Chlorpheniramine and

Loratidine are useful.

Decongestants: can be nasal spray containing corticosteroids or nasal spray containing alpha
adrenergic antagonist (phenylepherine, oxymetazoline) which should not be used more than
4 days.

Anti-tussives: these are drugs against cough, technically speaking we can use 2 types of
drugs, the first will lead to central inhibition of the cough (in case of dry cough) while the
second will lead to decreased mucous viscosity (in productive cough).

Mucokinetic agents: divided into expectorants (Guaifenesin), which are a universal

component of cough sirup, leading to increased hydration of secretion lowering its viscosity
and to mucolytics (Acetyl-cysteine, Bromhexin) which dissolve the thick mucous.
These agents are used in productive cough (cough with mucous).

Central inhibitors: opiates are used to decrease the cough center sensitivity in the CNS and
to decrease mucous secretion (Codeine, hysrocodon) and is used in dry cough (irritative
cough)

.
13. Drugs affecting gastrointestinal tract (treatment of gastric ulcer, diarrhoe, constipation):
Peptic ulcer, GERD, diarrhea and constipation are common problems of the GIT.

Peptic ulcer disease: NSAID's, H.pylori, increased HCL secretion and inadequate mucosal
defense against gastric acid are associated with PUD.

Antimicrobial therapy: eradication of H.pylori, after histologic approval or positive urea

breath test we use Amoxicillin + Clarythromycin + PPI or PPI + Metronidazole +
Tetracyclines.

H2 receptor agonists: inhibit histamine binding to H2 receptor, thus decrease HCL

production by decreasing the level of intracellular cAMP Ranitidie, Cimetidine,
Femotidine, Amantidine. PPI are better than H2 blockers !!!!!!!!!!!!!

PPI's: suppress secretion of HCL by inhibiting the Hydrogen proton pump, may lead to B12
absorption problems and to pseudomembranous colitis Omeprazole.

Prostaglandins: PGE2 inhibits secretion of HCL and stimulate secretion of mucous and
bicarbonate. Misoprostol is an PG analogue approved for NSAID's induced PUD.

Antacids: weak bases that react with gastric acid to form water and salt (sodium
bicarbonate, magnesium hydroxide, aluminum hydroxide) usually combination therapy
of aluminum hydroxide and magnesium hydroxide (constipation+diarrhea = normal).

Mucosal protecting agents: bismuth subsalicylate and sucralfate.

Antidiarrheal:

Antimotility agents: Loperamide HCL is the prototype drug, has opioid like actions on the
gut (constipation), activating presynaptic opioid receptors in the enteric nervous system to
inhibit Ach release.

Absorbents: Methylcellulos, aluminum hydroxide and bismuth subsalicylate are used to

control diarrhea, they absorb intestinal toxins and microbes.

Electrolyte transport modifiers: Bismuth subsalicylate decrease fluid secretion in the

bowel.

Laxatives: potentiate the risk for abuse.

Irritants and stimulants: Senna ( ) is a very common laxative as well as Bisacodyl

(),they act directly on nerve fibers in the mucosa of the colon.
Castor oil ( ) is an irritant which increase peristalsis.

Bulk laxatives: Hydrophylic colloids, Methylcellulose and Bran ( )from food.

Osmotic laxatives: PEG (poly-ethyl-glycerol), sodium phosphate, magnesium citrate.

Stool softeners: surface active agents Docusate Sodium/Calcium/Potassium.

Lubricant laxatives: Paraffin oil, Glycerin.

14. Antithyroid drugs:

The thyroid gland regulates normal growth and maturation by maintaining a level of
metabolism in the tissue by secreting T3 or T4. The thyroid gland also produces calcitonin, for
the regulation of blood calcium.
Thyroid hormones synthesis is regulated by TSH (Thyroid stimulating hormone), which is
synthesized by anterior pituitary.
TSH action iodide (I-) uptake oxidation to iodine (I2) by peroxidase iodination of
thyrosines on thyroglobulin.
The mechanism: to enter the cell T3, T4 must disconnect from thyroxin binding plasma
proteins in the cell T4 enzymatically deionated to T3 T3 enters the nucleus and attaches to
the specific receptors formation of RNA and protein synthesis.

Hypothyroidism bradycardia, poor resistance to cold, mental and physical slowing

(creatinism- in children).

Hyperthyroidism tachycardia, cardiac arrhythmias, body wasting, nervousness, tremor,

excess heat production.

NSAID's, Glucocorticoids and adrenergic antagonists (beta blockers, alpha blockers) are all
known to cause drug induced hypothyroidism.

Hypothyroidism treatment: usually results from an autoimmune thyroid destruction

(Hasshimoto thyroiditis) and is diagnosed by the elevated levels of TSH and normal/reduced
levels of T3,T4.

Treatment would be Thyroxin (T4) which is given usually once daily thanks to long half
life of the drug, starts to affect after 9 days and intoxication will lead to hyperthyroidism
like symptoms.

Hyperthyroidism treatment: usually a result of Graves-Basedow disease, adenoma, etc. it

is diagnosed by elevated serum level of T3 and T4 with decrease in TSH levels.
Treatment is by removing the affected part of the thyroid (lobectomy) or the entire thyroid
(thyroidectomy) or:

Inhibit the synthesis of the hormone: by thiomides (methimazole, propylthiouracil), they

have no effect on the preexisting hormone levels and may lead to agranulocytosis, rash and
edema.

Blocking the release of the hormone from the follicles: Iodine, but it is efficient only for
several days and used primarily in thyroid storm.

In thyroid storm we use: Propranolol, Propylthiouracil, (PTU), iodine, calcium channel

blockers (verapamil, nifedipine) and glucocorticoids.

15. Steroids, androgens:

The adrenal gland is composed of 2 parts: the medulla secrets epinephrine, and the cortex
which is composed of Zona glomerulasa (Minerocoritcoids), Zona fasciculata (Corticosteroids)
and Zona reticularis (sex hormones).
Mediated by the hypothalamo-pituitary-adrenal axis.

Glucocorticoids: fluctuate according to the circadian rhythm (high in the morning) and is
considered a stress hormone, it binds to intracellular receptors and promote protein
production. Its main actions are:

Anti-inflammatory: decrease immune proliferation, decrease level of complement, direct

cytotoxicity for immune cells, inhibit phospholipase A2 (prevent breakdown to arachidonic
acid- decrease levels of PG and LT).

Metabolic: increase gluconeogenesis, decrease protein synthesis, inhibit osteoblast activity

and decrease calcium absorption, increase lipolysis.

Main uses of glucocorticoids are anti-inflammatory, immunosupressant .

Drugs used are: Cortisol, Prednisone, Dexamethasone, Hydrocortisone.

Side effects: osteoporosis, immune supression, iatrogenic Cushing syndrome, adrenocortical

supression, hyperglycemia, DM, PUD, hirsutism.

Minerocorticoids: Aldosterone is the only one, responsible for water and sodium
reabsorption from the distal tubules. Hyperaldosteronemia can occur due to Conn's disease
(primary adenoma) while Hypoaldosteronemia from Addisson's disease.
- for hyper we use Spironolactone aldosterone antagonist, used as diuretic.
- for hypo we use Fludrocortisone, Ketoconazole

Sex hormones: mediated by the hypothalamus pituitary gonadal axis.

All sex hormones bind to intracellular receptor over the nuclear envelope.

- GnRH receptor agonists Goserelin, Nafreline.

Estrogens: Produced by developing follicles in the ovaries, corpus luteum, and the placenta;
small amounts in the liver, adrenal gland and breasts.

Estradiol is produced and secreted by the ovary (ethinyl estradiol is synthetic estradiol) and
is used in ovarian hypofunction, as oral contraceptive, uterine bleeding, breast/prostate
cancer (contraindicated in estrogen dependent breast cancer).
increase the risk for CVS diseases, stroke, decrease the risk for osteoporosis and colon
cancer and prevent sex organ atrophy.

Tamoxifen, Raloxifen are partial estrogen antagonists which are uses in estrogen dependent
breast cancer.

Progesterone: produced in corpus luteum and adrenal gland (during pregnancy also the
placenta), used as contraceptive or to induce abortion (antiprogestine)
drugs: Norethindrone, Levonorgestrel, Norgestimate, Drospirenone.
Androgens: there are several androgens, one of them is testosterone, the rest are synthesized in
the zona reticularis of the adrenal cortex and include DHEA (dihydroepiandrogen) which is the
primary precursor of estrogen, DHEA-S (dihydroepiandrogen sulfate), DHT
(dihydrotestosterone) which is stronger than testosterone.
They are important for the development of male organs and secondary male characteristics.

Testosterone is produced in the Leydig cells in the testis, as well as in the adrenal cortex
and the ovary (in women) in small amount. Responsible for secondary sex characteristics,
male organ development and spermatogenesis as well as muscle synthesis (hence the abused
anabolic steroids). Lead to enlarged sex organs, hair growth, increase RBC number, muscle
buildup. Therapeutically used for delayed puberty, cryptorchidism, breast cancer.
Side effects: in women leads to hirsutism and musculization, voice deepening and acne.

Antiandrogens: Flutamid, used in women for excess testosterone and in men for prostate
cancer.

16. Oral contraceptives:

These drugs decrease fertility by: preventing ovulation, impairing gametogenesis/gamet
maturation, interfering with gestation.
The estrogen provides a negative feedback on the release of LH and FSH by the pituitary
preventing ovulation. The progestin inhibits LH release and thickens the cervical mucus
blocking the transport of sperm.
Major classes of oral contraceptive (or anti-baby pills according to proph. Shulla).

Combined oral contraceptives (estrogen + progesterone) the most common:

The estrogens decrease the FSH release will lead to decreased ovarian follicle development.
The progesterone decrease the LH release block of ovulation.
The dose is taken for 21 days and mimic the normal menstural cycle (constant estrogen and
progesterone), with a 7 days hormone free period.
This will lead to change in the cervical mucin properties and decrease in sperm penetration, the
hormones influence the endometrium making it not suitable for egg implantation.
Ethinyl estradiol, Norethidrone.

Progesterone alone:

The effect is over the cervical mucin, leading to decreased egg implantation by effecting the
endometrium, motility and secretion of ovarial tubes (Fellopian tubes). It is by far less effective
than the combined therapy and may lead also to irregular bleeding.

Postcoital: it is what called the day after pill, it reduces the chances of pregnancy for
around 1% and less. It is considered to be an emergency pill, used up to 72 hours after
unprotected sex and is composed of high levels of estrogen and progestin (Levonogestrel +
ethinyl estradiol). Second pill should be taken 12 hours after the 1st one. For maximum
efficiency it is advised to take the drug as soon as possible.

Other classes: these are non oral contraceptives and are Vaginal ring, transderal patch, or
progestine intrauterine device (last for 3 years).

Side effects: CVS problems (thromboembolism, stroke), breast fullness, fluid retention,
headache, nausea and vomiting. Contraindicated in estrogen dependent neoplasm and CVD.

17. Corticosteroids and Antidiabetic drugs:

Corticosteroids:

Although the adrenal gland cortex produce minerocorticoids, glucocorticoids and sex hormones
the use of the word corticosteroids usually refers to glucocorticoids which are used in medicine
due to their antiinflammatory and immunosuppressive properties. The major drugs used are
Prednison, Methylprednisone, Cortisol, Hydrocortisone, Prednoisolone, Dexamethasone.
Non the less we still need to speak here about minerocorticoids, so for it read question 15.

Functions:

glycogenolysis and gluconeogenesis glycemia.

protein catabolism and protein synthesis as well as lipolysis.

WBC, immunity, inflammation (by inhibiting phospholipase A2, thus blocking the
production of PGE2 and Leukotriens).

Calcium absorption, osteoblast activity and osteoclast activity.

Mechanism:
It is highly lipid soluble, bound in the plasma to cortisol binding protein or albumin,
diffuses easily through the membrane and bind to the glucocorticoid receptor located on the
nuclear envelope, this will initiate translocation of the receptor and the hormone to initiate
lipocortin and gene expression.
Glucocorticoid levels are according to the circadian rhythm with the highest peak around 4
am and another peak around 4 pm.

Therapeutic use: a replacement therapy in adrenal insufficiency (surgery, drugs, tumor), as

an antiinflammatory drug (asthma, anaphylaxis), as an immunosupressant (arthritis, SLE,
autoimmune, organ transplantation) and generally said to be used whenever we have no idea
what to give.

Side effects: immunosupression (may lead to opportunistic infections), osteoporosis, peptic

ulcer disease (decrease PGE2), growth retardation, hyperglycemia, DM,Cushing syndrome,
hirsutism, etc.

Anti-Diabetic drugs:

There are generally 2 types of DM, with several other sub-types, there is the Type 1 DM (insulin
dependent- juvenile type) and Type 2 DM (insulin resistance).
The sub types would be gestational (also called type 3 DM) and LADA (Late Autoimmune
Diabetes of Adults).
A good way to differentiate between type 1 and 2 is C-peptide, which will be present in type 2
but will be absent in type 1. the blood sugar level is mediated via to hormones which are
secreted from the pancreas, these are the Glucagon (alpha cells) and Insulin (beta cells).

Glucagon increase blood sugar level via glycogenolysis.

Insulin promote intake of glucose into the cells, thus deceasing blood sugar level.

Mechanism of insulin secretion:

blood glucose levels the uptake of glucose (by GLUT2 transporter) glycolytic
phosphorylation (rise in ADP : ATP ratio) inactivation of K+ channels (ATP dependent)
depolarization of the membrane Ca+2 channel opening, exocytotic release of insulin.
Insulin mediated glucose uptake: insulin binds to insulin receptor on the cell surface
glucose transported through GLUT4 into the cell of hepatic glucose release.

Actions of insulin: Regulates glucose metabolism, stimulates lipogenesis, diminishes

lipolysis, AA transport into the cells, modulates transcription, stimulates growth, DNA
synthesis and cell replication (together with IGF and relaxin).

There are several types of recombinant human insulin.

short acting insulin: insulin lispro (2-4 hours).

Long acting: insulin glargine (16-24 hours).

Taking insulin may lead to hypoglycemia and lipodystrophy or even down regulation of the
receptors due to insulin overdose, can occur in type 1 diabetics and athletes (anabolic drug).

Hypoglycemic oral medications for use in DM2:

Sulfonylureas: + channel blockers, the drug has an effect on the pancreatic Beta islet cells
to allow an influx of Ca+2 into the cell in the release of insulin. Drugs used are only the 2nd

generation- Glibenclamide, Glyburide, Glipizide, Glicazide, Glimepiride .

Biguanids (methformin): Anti hyperglycemic, they do not stimulate endogenous insulin

secretion (hypoglycemia will not occur when they are used alone). Works by excessive
hepatic glucose production and glucose utilization in peripheral tissues. LDL/HDL Weight
loss/no gain

Alpha Glucosidase Inhibitors (AGI): Acarbose is the prototype, slow down the breakdown of
disaccharides, polysaccharides, other carbohydrates into monosaccharides.

Meglitinides: Repaglinide is the prototype, useful as a Sulpanylurea replacement.

Thiazolidinediones: primary effect is peripheral ( insulin sensitivity and glucose uptake),

hepatic glucose uptake and hepatic sensitivity to glucose blood glucose levels, they DO
NOT stimulate the pancreas to produce more insulin.
Drugs: Rosiglitazone, Pioglitazone

18. drugs influencing plasmatic calcium concentration:

Calcium is an essential element with many functions in the body, such as depolarization,
contraction of smooth and striated muscles, hormonal secretion, activation of enzymes such as
A2 phospholipase or various proteases.
Plasma levels of calcium are between 2.2-2.6 mmol/liter and half of it (1.1-1.25) is unbound to
plasma proteins.
The extracellular concentration of calcium is very high, 1000 to 10 000 times higher than its
intracellular concentration. This concentration is maintained within a narrow range by
parathyroid hormone and, to a less degree, by calcitonin and vitamin D. Intracellularly the
calcium is stored in storage vesicles in the endoplasmic reticulum.

in cases that the calcium levels are too low, for example due to nutritional habits, there are
preparations that contain calcium which are given to the patient.

Diuretics that work with sodium/calcium pumps, such as thiazide diuretics and loop
diuretics can substantially change the calcium concentration in the plasma.

Digitalis (digoxin) increases the calcium flow into the cell, thus increasing the intracellular
calcium while lowering the extracellular.

Calcium channel blockers decrease the inward current of calcium into the cardiomyocytes.

Some resins used as cationic chelating agents can bind calcium in the intestines and
decrease its absorption.

Bisphosphonates (against osteoporosis) cause inhibition of osteoclasts and activation of

osteoblast.

Calcitonin counteract PTH by lowering serum calcium by inhibiting absorption, inhibiting

osteoclasts and inhibiting tubular absorption.

PTH terparatide is a recombinant segment of human parathyroid hormone, leading to

increased serum calcium.

Glucocorticoids inhibit osteoblasts and activate osteoclasts, thus leading to increased levels
of calcium.

Antacids: calcium bicarbonate.

Laxatives.

All drugs that provoke vomiting may lead to metabolic abnormalities.

Really I have no other idea what can influence calcium levels !!!!!!!
19. Drug affecting hemostasis (anticoagulants , antiaggregatory drugs), antianemic drugs:
1. Drugs affecting haemostasis:

Haemostasis is a stopping of blood loss, essential for survival

Thrombosis pathologic formation of haemostatic plug inside of blood vessels, without

bleeding.
Arterial thrombosis (white) atherosclerosis, platelets and leukocytes
Venous thrombosis (red) stasis, white "head" + red "tail"

Thrombophilia hereditary increased coagulation

Drugs for venous and arterial thrombosis:

A. Oral anticoagulants:

Warfarin, Ximelagatran

Warfarin:
Mechanism:
Competitive inhibitor of vit.K (from oxidized to reduced form) reduced form participates in
the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII
carboxylation binding to phospholipid surface activation.

Pharmacokinetics: fast and complete GI absorption, strong albumin binding small

VD , Cmax up to 1 h., effect after 48 h (results from T1/2 of inhibited factors, effect
lasts 4-5 days, liver metabolism P450.

Effect modifying factors (increase):

1) Drugs:
- inhibitors of liver metabolism (cimetidine, imipramine, cotrimoxazol, ciprofloxacin,
amiodaron)
-platelet inhibitors (NSAIDs, moxalactame, carbenicilline, ASA)
- inhibition of vit. K reduction (cephalosporines)
- in vit. K supply
2) Hepatopathies

Effect modifying factors (inhibition):

1) Drugs:
- liver metabolism inducers (rifamicin, carbamazepin, barbiturates, grizeofulvine)
- agents decreasing absorption (cholesteramin)
2) synthesis, degradation of coagulation factors (pregnancy, hypothyroidism).

Side effects: bleeding (vit.K, fresh plasma, coagulating factors); teratogenity (6-14
week); in protein C synthesis procoagulatory state thrombosis of venules
necrosis of soft tissues (heparin before warfarin).

Contraindications: bleeding, coagulations, GI bleeding, anaemia, surgery or CNS

trauma, malignant hypertension, pregnancy.

Clinical uses: lung embolism; deep vein thrombosis (DVT); thromboembolism

prevention.

Ximelagatran

Direct thrombin inhibition, bio-conversion to active Melagatran, no food or drug

interactions, monitoring not needed.

Clinical uses: thromboembolism (prevention and therapy), prevention of stroke

in patients with atrial fibrillation.

B. Injection anticoagulants ("red" thrombi):

Heparin (H), Low molecular weight (LMW), Heparin (LMWH)

Heparin (H) and LMWH

H: m.w.: up to 40,000; LMWH: 4,000 15,000

Mechanism: ATIII activation thrombin (IIa) and other serine proteases binds to
IIa and ATIII (H in size > 18 polysaccharide residues; LMWH in size < 18
polysaccharide residues, binds only ATIII) effect of ATIII to factor Xa but NOT IIa.
Clinical result: similar effect in venous thrombosis prevention and therapy with lower
risk of bleeding complications.

Pharmacokinetics:
H I.V, S.C; onset: I.V. immediately, S.C up to 60 min
LMWH S.C., twice longer T1/2 (4h.), bioavailability S.C. 90% vs. 20% in H (lower
binding to endotel and macrophages); lower binding to plasma albumines (more
predictable effect).

Side effects:
- bleeding
- thrombocytopenia and thrombosis (paradoxically, caused by IgM or IgG against
complex heparin/platelet F4, which binds Fc receptors of platelets activates F4
release thrombocytopenia)
- osteoporosis (long term therapy activation of osteoclasts)
- hypoaldosteronism (extremely rare)

Clinical uses: prophylaxis of venous thrombosis, therapy of thromembolic disorders,

haemodialysis

C. Oral antiplatelet drugs/Antiaggregants ("white" thrombi):

Acetylsalicylic acid (ASA), Ticlopidin, Dipyridamol, Clopidogrel

Mechanism:

- ASA: COX (irreversible), thromboxan synthesis (TXA2), thrombocyte activation

- Ticlopidin, Clopidogrel: of ADP-dependent activation of GP IIb/IIIa receptor (after
platelet aggregation), all pathways of platelet activation.
- Dipyridamol: PDE

Side effects:
- ASA: risk of bleeding
- Ticlopidin: neutropenia (long term treatment), rash, diarrhea.
- Clopidogrel: nausea, vomiting.
- Dipyridamol: headache, DOES NOT the risk of bleeding.

Clinical uses: prevention of MI, prevention of cerebral ischemia, therapy of "unstable

angina pectoris", maintenance of coronary artery passage after angioplasty (ticlopidin),
combination (ticlopidin + ASA, dipyridamol + ASA) has an addictive effect!

D. Fibrinolytics ("white" thrombi)

1. Streptokinase (streptococcal enzyme, Ag)
Urokinase (human kidney, non-antigenic)
tPA (isolated from tissues, recombinant tissue plasminogen activator r-tPA (alteptase)).
2. All I.V. infusions
3. Mechanism: streptokinase plasminogen plasmin fibrin fibrin breakdown
4. Side effects:
- Streptokinase: Hypersensitivity, decrease of fibrinolytic effect; bleeding
- Urokinase: bleeding
- tPA: bleeding, incidence of reoclusion
5. Clinical uses: arterial thrombosis, DVT, acute lung embolism, acute MI.

strepto- and urokinase act only in new-formed thrombi.

reoclusion after tPA can be prevented by ASA.

2. Antianemic drugs:

Major causes of anemia:

Low count of RBC, abnormality of RBC, abnormality of the haemoglibin.

Reason for low count of RBC: blood loss, inadequate production of blood, excessive
breakdown of RBC, or all 3 factors.

Inadequate production of blood:

- microcytic iron deficiency anaemia: most common, inadequate Hb production, less ability to
absorb/store iron.
- megaloblastic anaemia (pernicious anaemia/B12 defficiency anaemia; folic acid deficiency
anaemia).
- aplastic anaemia idiopathic, toxic, radiation, viral..
A. Therapy for Iron deficiency anemia - Iron supplements:

Ferrous sulfate 37% iron (ferrous gluconate only 13%)

1 tablet/day, dosage depends on the iron needs.

Side effects: stomach and intestinal problems (cramps, constipation, diarrhea,

nausea, vomiting, heartburn, urine discoloration); frequency and severity with the
dosage.

Interactions:
- ATBs (Tetracycline, quinolone) iron their effectiveness.
- Levodopa - iron its effectiveness.
- With Mg, Trisilicate, an antacid, penicillamine good interaction
- Vit. C - the absorption of iron (with no in side effects).

B. Therapy for Pernicious anemia (low RBC count and Lack of Hb):

Vitamin B12 (Cyanocobalamine)

Responsible for many functions in the body (incl. NS)

Anemia should always be treated with S.C. or I.M.

10 g/day for 6-7 days, if improvement is seen reduce the dose, after that
monthly injection.

Side effects: diarrhea and itching, severe allergy (very rare!)

Interactions:
- Aminosalicylic acid and cochicine may the effectiveness of B12
- Alcohol may affect the efficacy of vit. B12.

C. Therapy for Folic acid deficiency anemia:

Folic acid

Found in many common foods (liver, dried peas, lentils, oranges, whole wheat
products, asparagus, beets)

1 mg/day dose

Folic acid in patients with B12 deficiency improves RBC count, but the nerve
damage continues to progress.

Side effects: safe! On rare cases allergy

Interactions: Phenytoins ( of phenytoin effectiveness);

Trimethoprom and Methotrexate ( the metabolism of folic acid).

D. Bone marrow stimulation for erythrocyte production

Epoetin alfa synthetic form of erythropoietin (produced by kidney, stimulates RBC

production and release).

Useful because: anemia ass. with kidney failure, Zidovudine therapy in HIV
patients, cancer patients on chemotherapy, in RBC in surgical patients,
prematurity, sickle-cell anemia, rheumathoid arthritis.

Dosage individualized, 50-100 units/kg 3x a weeks, NOT in patients with

uncontrolled Hypertension!!!

Adverse effects: joint pain, chest pain, diarrhea, swelling, fatigue, fever, weakness,
headache, BP, nausea

E. Aplastic anemia therapy Anabolic steroids: Nandrolone, Oxymetholone

Nandrolone for treatment with kidney failure anemia.

Oxymetholone treats aplastic anemia, 1-2 mg/day, slow response, long side effects
(acne, urinary frequency, breast growth in males, breast pain, masculinization in
women).

F. Hemolitic anemia therapy : excessive break-down of RBC

Causes: intrinsic(hereditary)/Extrinsic factors

Types: Hemolysis, Inherited hemolytic anemia, hemolytic transfusion reaction.

Folic acid, Iron replacement, corticosteroids - depends on the type of cause.

Blood transfusion/splenemectomy in emergencies.

20. principles of genotherapy:

The use of DNA as a pharmaceutical agent for treating disease. most commonly, the use of
DNA that encodes functional therapeutic gene in order to replace a mutated gene. there are
other forms, they involve directly correcting a mutation or using DNA that encodes a
therapeutic protein drug (rather than a natural human gene) to provide treatment. these alterred
genes are packed in a "vector" (a way of inserting these genes into the cells), making them part
of the cell's machinery.
gene therapy had success in treating ADA-SCID, adrenoleukodystrophy and Parkinson's
disease.
First logical approach was to treat single-gene defects (such as cystic fibrosis, haemophilia,
muscular dystrophy and sickle cell anemia). this approach was proved difficult (primarily
because of problems carrying large DNA sections and delivering them to the correct site).
Types:
Somatic Gene Therapy - therapeutic genes are introduced into the somatic cells of the patients,
so the effects are restricted to the individual patient only (not inherited by the patient's
offspring). mainstream line of current basic and clinical research, where mRNA is used to treat
the disease in patients.
germ line gene therapy - restricted for a variety of technical and ethical reasons.
vectors:

viruses - this is a plausible strategy for gene therapy. a number of viruses have been used retrovirus, adenovirus, lentivirus, herpes simplex, vaccinia, pox virus

non viral - have certain advantages over viral methods (such as large scale production and
low host immunogenicity). several methods - injection of naked DNA, electroporation, the
gene gun, sonoporation, magnetofection and others.

Major development in gene therapy:

first used in 1990 to treat a genetic defect that left a 4 year old girl with a defective immune
system. the effects were temporary but successful.
the 1999 death of a patient resulted in a significant setback to gene therapy research.

Problems with gene therapy:

short lived nature of gene therapy - due to rapidly dividing nature of many cells, they
prevent therapy from reaching a long term affect. patients will have to undergo multiple
rounds of gene therapy.

immune response to invaders makes it hard to treat with gene therapy (especially a second
time).

problems with viruses - causing inflammation, toxicity and immune response. there is
always a risk that once inside the patient, may recover its ability to cause disease.

mutations that arise from a single gene defects are best candidates for gene therapy.

chance of inducing tumor. DNA integrated into the wrong place could induce tumors
(occured in trails for X-linked severe combined immunodeficiency patients).

Preventive gene therapy: repairing a gene with a mutation associated with progressive disease.
21. treatment of drug poisoning. Drug interaction:
definition: the study of adverse effects of chemicals on living organisms. All chemicals have
some degree of toxicity. The right dose differentiates a poison from a remedy
common target tissues lungs, liver and tissues with high blood flow (brain or kidneys).

Non selective actions some chemicals (such as corrosive compounds) lead to local
irritation and\or causing effects that are non-selective. Example exposure to strongly
alkaline or acidic substances, causing injury by denaturation.

Selective by interfering with functions of specific biochemical pathway or

macromolecules within tissues. Example warfarin inhibits the vitamin K-dependent
posttranslational modification of certain clotting factors by the liver.

Immediate and delayed actions AchE inhibitors and asbestos.

Occupational and Specific Environmental Toxins: halogenated hydrocarbons (carbon

tetrachloride, chloroform), aromatic hydrocarbons (benzene, toluene), alcohols (methanol,

isopropanol), pesticides (organophosphates, pyrethroids), rodenticides (warfarin), heavy

metals (lead, mercury), gases and inhaled particles (carbon monoxide, cyanide, silica,
asbestos).
Antidotes: exist for only a small class of chemicals. The following strategies are the basis of
treatment:

Pharmcologically antagonize toxic action atropine vs. anticholinesterases

Accelerate detoxification of toxic agent acetaminophen at very high dosease will produce
liver necrosis as a result of its metabolic activation by P450. Administration of Nacetylcysteine will serve as a substitute for glutathione by binding to and inactivating the
reactive metabolites produced. Must be given within 8-10 hours.

Provide alternative target cyanide is treated in 2 steps sodium nitrite is administered to

induce the oxidation of hemoglobin to methemoglobin. The second step is to accelerate its
detoxification.

Reduce metabolic activation after metabolism of methanol by alcohol dehydrogenase, there

is formation of formic acid. Fomepizole inhibits alcohol dehydrogenase, reducing the
metabolism (and the rate of formic acid production) protecting the patient from the toxic
affects.

Chelators drugs that will form covalent bonds with cationic metals, then, the complex is
excreted in urine. Unfortunately,this is not specific to heavy metals, and may react with
essential metals as well (such as zinc).