Discuss the drug use in the mechanism of asthma and explain their mechanisms of action?

How do they differ in their abilities to control an acute effect? August 94 Describe the different drugs used in the treatment of asthma, with particular reference to their anti-inflammatory effects where appropriate. FP 01 rep Discuss the drug treatment of asthma with particular reference to the antiinflammatory agents. FP 02 Classes of agents (1st 3 Mechanism of action Side effects bronchodilators, last 3 antiinflammatory) B2 receptor agonist increase sympathetic- relax tremor, palpitations and (salbutamol, terbutaline, bronchial SM- increase in hypokalemia (result from salmeterol) cAMP alkalosis) Muscarinic antagonists inhibits parasympathetic/ ipratropium bromide Ach at M1, M2, M3 muscarinic receptorsbronchodilatation and reduce mucous secretion. Slower acting Xanthines phosphodiesterase inhibitor (Aminophyline, theophyline(caffeine)) relax muscle by inhibiting phosphodiesterase resulting in increased cAMP and cGMP. Also can be anti inflammatory(inhibits late phase) Corticosteroid 1.binds to cytosolic (Budesonide, fluticasone, glucocorticoids receptor prednisolone(orally), etc). 2.inhibit transciption of COX 2, interleukins and TNFa (inflammatory cytokines) 3.induce lipocortin which phopholipase A2 4.reduce synthesis of PG and LT Cromones reduce eosinophil, Ig E and Nedrocromil and sodium inflammatory mediators cromogylate. production Anti-leukitrienes (zafirlukast and zileuton) 1. receptor antagonists for CysLT1 ( additive of B2 agonist effect) 2. inhibitors for 5lipoxygenase(enzyme in the production of leukotrienes) low therapeutic rangeGIT, CV, CNS. Drug interactions in alcohol (reduce NADPH(, heart and liver failure.

1. Dysphonia myopathy of laryngeal muscles 2. Oral candidiasisinfection (immune suppressant)

few-suitable for children

few, GIT n headaches

3. brochodilatation and reduced inflammation .An eight year-old boy is complaining of recurrent breathlessness and

wheeze. His general practitioner diagnoses asthma. Discuss the mechanisms whereby manipulation of the autonomic nervous system may relieve this bronchospasm. FP 05
Parasympathetic: Predominant inner ation of airway smooth muscle - !agus "#th$ %ccupation of &' receptors by (ch causes bronchoconstriction and increased mucous secretion. (utoinhibitory &2 receptors occupied by ()h and switch off its release. *ympathetic: +o direct sympathetic supply of smooth muscle. )irculating adrenaline acts at ,2 adrenoceptors on airway smooth muscle, and inhibits bronchoconstriction. ( 10 year-old boy is brought into the hospital (ccident - .mergency Department with an acute e/acerbation of asthma. 0is initial treatment includes an inhaled beta-2 adrenoceptor agonist and an inhaled muscarinic receptor antagonist. Discuss the ad antages of local deli ery of these drugs in comparison to systemic "oral or intra enous$ administration. FP 01 ( 10 year-old girl is brought into the (ccident - .mergency Department with an acute e/acerbation of asthma. 0er initial treatment includes an inhaled nebulised beta-2 adrenoceptor agonist and an inhaled nebulised muscarinic receptor antagonist. Discuss the ad antages of local deli ery of these drugs by comparison to systemic administration "oral or intra enous route$. FP 02rep (d antages: 3ocali4ation of effect- selecti ely acting on the receptors of bronchioles ( oid ad erse effect- systemic administration produce unwanted effects such as tremor and tachycardia for ,2 agonist and atropine-li5e-side effects for & antagonist. 6apid effect- a oid first pass metabolism and gut absorption compared to oral administeration. (sthma Prophyla/is of 6ecurrent (ttac5s. .(637 8+96%D:)98%+ %F (+988+F3(&&(9%67 90.6(P7 ( oidance of allergens and irritants *tep 1 - 8nhaled b2 agonists *tep 2 - (ddition of inhaled steroids or cromones "children$ *tep ' - 0igh dose inhaled steroids or low dose inhaled steroids with long acting b2 agonists *tep 1 - (s step ' plus se;uential trial of 1. %ral theophylline 2. 8nhaled antimuscarinic agent '. 8nhaled cromone

1. 3eu5otriene receptor antagonist *tep 2 - %ral steroids )%PD &(+(<.&.+9 ).**(98%+ %F *&%=8+< ( oid occupational inhaled pollutants (ntibiotics for acute e/acerbations with purulent sputum ,ronchodilators ,2 adrenoreceptor agonists &uscarinic "&'$ antagonists #anthines (nti-inflammatory Drugs <lucocorticoids *electi e PD.1 inhibitors "6oflumilast, )ilomilast$ %/ygen therapy > low dose 21? "contraindicated in smo5ers$ !entilatory support during e/acerbations +asal intermittent positi e pressure entilation "+8PP!$ (+989:**8!. Centrally acting > opioids increase the threshold for stimulation of neurons in the medullary cough centre. 9hey are effecti e at doses below those necessary for pain relief. "can cause addiction$ )odeine: good cough suppressant but mucociliary clearance and decreases secretions. De/tromethorphan: synthetic opioid. Does not cause addiction, mucociliary clearance or constipation. Peripherally acting drugs reduce sensiti ity of cough receptors 3ocal anaethetics ",ronchoscopy, nebulised for chronic cough$ &enthol apor - lo4enges "strepsils$ impregnated with menthol or eucalyptus oil !(*):3(6 .+D%90.38:&

HEA ! "A#$% E Definition: 9he pathological state in which the heart is unable to pump enough blood for the needs of metabolising tissues 9he initial adapti e mechanisms that wor5 in the short term cause problems in the long term. 9he adapti e mechanisms include 8ntrinsic cardiac compression: Decreased renal blood flow causes renal asoconstriction. 9his acti ates the renin-angiotensin a/is. (ldosterone is released and results in +a@ and water retention 3ow blood pressure can increase sympathetic tone which can increase afterload.

9hese adapti e mechanisms wor5 in the short term. 3ong term leads to heart failure as e entually the heart fails. myocardial hypertrophy acti ation of neurohumoral mechanisms: increase in sympathetic tone and may increase the down regulation of beta receptor e/pression in response to the chronically ele ated sympathetic tone that occurs in heart failure Drug Diuretics "loop and thia4ide$ (ngiotensincon erting en4yme "().$ inhibitors )aptopril, .nalopril, 3isonopril &ech of actionA indication +a@ e/cretion in the 5idney ascular olume and preload (88 le els peripheral ascular resistance afterload Pre ent release of aldosterone and hence +a@ and water retention " preload$ 6educe noradrenaline release (s (). "bloc5 (91receptor$ 8 > (). cough, heart failure !asodilate both arterial and enous smooth muscle. 9hought to produce ascular rela/ation by enhancement of c<&P acti ity. %rganic nitrates > decrease cardiac preload rela/ the smooth muscle in &etabolismA drug interaction *ide effectA contraindication 3oss of electrolytes, especially =@, +a@, &g@@, )a@@. )ough 0ypotension 6enal dysfunction 0yper5alemia

8 > with +*(8D, stops prostaglandin mediated asodilation of the renal efferent arteriole

(ngiotensin 2 receptor "(91$ bloc5ers "losartan, cardosartan$ +itrates

) - pregnancy, retino ascular d4

0eadache, hypotension

0ydrala4ine

8neffecti e alone in heart

precapillary resistance essels

failure "8t causes a refle/ increase in heart rate "myocardial o/ygen consumption$ and a druginduced lupus li5e syndrome$ :sed with nitrates "3ong term heart failure patient: downregulation of ,1receptor$

,-,loc5ers "&etoprolol, bisoprolol, car eldilol$

Positi e 8notropes "digo/in$

Phophodieste rase inhibitors "&ilrinone$ ,eta1 adrenoceptor agonists "Dobutamine, dopamine$ )ardiac (ffect the electrical glycosides acti ity of the heart "digo/in$ by: agal ner e acti ity slows firing of *( node slows conduction through the (! node.

force and rate of contraction conduction elocity may reduce the down regulation of beta receptor 8nhibit +aA= (9Pase. intracellular +a, intracytoplasmic calcium contractility. 9his is described as a positi e inotropic effect. )%

3ow therapeutic ratio. 9o/icity e/acerbated by hypo5alemia. 9o/icity treated with a specific antibody to digo/in.

<astrointestinal disturbance, nausea, omiting, diarrhoea )+* effects, include isual hallucinations 9o/icity can cause disordered electrical acti ity "arrhythmia$

07P.69.+*8%+

Drug

&ech of actionA indication

&etabolismA drug interaction

*ide effectA contraindication ) >gout

9hia4ide diuretic "hydrochlorothia4ide$ , bloc5er 06 )% 8nhibit rennin secretion 8 - &8, angina, heart failure )a channel bloc5er "nifedipine - short acting, amlodipine > long acting$ (). inhibitor "captopril > short, lisinopril > long$ )a influ/ rela/ *& asodilatation (88 formation peripheral ascular resistance afterload brady5inin brea5down (s (). "bloc5 (91receptor$ 8 > (). cough, heart failure ,loc5 asodilate 8 - prostatism

(ngiotensin 2 receptor "(91$ bloc5ers "losartan, cardosartan$ 1 bloc5er "do/a4osin, pra4osin$

- e inotropy, bronchospasm, )+* effect, dyslipidaemia, impotence ) > asthma, heart bloc5 0eadache Flushing %edema 9achycardia )onstipation 8 > with )ough +*(8D, stops 0ypotension prostaglandin 6enal mediated dysfunction asodilation of 0yper5alemia the renal efferent arteriole ) - pregnancy, retino ascular d4 Fatigue, postural hypotension ) > urinary incontinance

2 adrenoceptor agonist 6enin inhibitor "enal5iren$ D1 agonist "fenoldopam$ 82 agonist "mo/onidine$ (+<8+( P.)9%68* (ngina Pectoris : &ismatch between myocardial o/ygen supply and demand. *ymptom: 6etrosternal discomfort, pressure li5e, occurs with e/ertion, relie ed by rest, may radiate down arm or into nec5.

&etabolismA drug interaction %rganic nitrates 9olerance +% acti ate "<lyceryltrinitrat guanylate ,cos e$ cyclase c<&P, supero/ide production acti ate protein nitrate 5inase free 21-h intracellular )a rela/ation preload, asodilation 8 > angina, &8, heart failure -bloc5er 1-heart ratecontractilit y 2- contract *& "blood essel and bronchi$ 1- smooth muscle rela/ation )a channel )a influ/ bloc5er rela/ *& "nifedipine - short contractility acting, amlodipine > long acting$ =@channel (cti ate (9P acti ator channel "nicorandil$ +itro asodilator "+% donor$ action (). inhibitor (88 formation 8 > with "captopril > short, peripheral +*(8D, lisinopril > long$ stops ascular prostaglandin resistance mediated afterload asodilation brady5inin of the renal brea5down efferent arteriole <ene therapy new essel formation "eg:!<.F$ 0ormone replacement therapy, antio/idant, fish oil, re antiplatelet

Drug

&ech of actionA indication

*ide effectA contraindication 0eadache, hypotension, methaemoglobinaemi a

,ronchoconstriction, - e inotrophy, bradycardia, impotence, fatigue, dyslipidaemia ) > asthma, heart bloc5

0eadache, di44iness Flushing %edema 9achycardia )onstipation 0ypotension 0eadache, flushing, di44iness "due to dilatation$ )ough 0ypotension 6enal dysfunction 0yper5alemia

ascularisation,

(+98 (660790&8)*, 07P%38P8D(.&8)* Drug &ech of actionA &etabolismA drug indication interaction )lass 1a - )ardiac *lows phase 0 depressant A ",loc5s fast +a Decreased channel > automaticity increases relati e refractory period$ *lows phase 1 ",loc5 oltage dependent +a channels - (cts on atrial, entricular muscle cells,pur5inBe fibres and (! node$ 8 - !entricular arrhythmias and *!9 ,loc5 the +a 6apidly channels metaboli4ed A0alf 8 - !entricular life C '0 mins arrhythmias ,loc5 the fast +a channel"li5e other class 1$ +o effect on action potential duration 8 - *!9 and !entricular arrhythmias (ct on *( and (! nodes predominantly

*ide effectA contraindication Disopyramide: (nticholinergic effects: +ausea, omiting, dry mouth, urinary retention Procainamide: (ssociated with +@!, 6ash, (rthralgia

Class &b Drugs "3ignocaine: 8!$ Class &c Drugs

0igh plasma le els cause drowsiness, paresthesia and sei4ure acti ity

)lass 88 ,eta bloc5ers *..s: ,ronchoconstriction, 0eart bloc5, 0eart 8 - *!9 and failure !entricular arrhythmias )lass 888 (ct by slowing (miodarone mainly repolarisation effects the pur5inBe "phase '$, fibres and prolonging the entricular muscle action potential cells. duration.

,ronchoconstriction, - e inotrophy, bradycardia, impotence, fatigue, dyslipidaemia ) > asthma, heart bloc5 9hyroid disorders, photosensiti ity, li er damage and pulmonary al eolitis

)lass 8! )alcium channel bloc5er !erapamil and Diltia4em Positi e inotropes 6ate controlling agent

8 - *!9 and !entricular arrhythmias ,loc5 the 3 subtype of )a@@ channels (ct on (! node "+,: )a@@ influ/ only$ 8 - *!9 8ncreases central agal acti ity *lows conduction thruD (!+ and ,undle of 0is

interacts with beta bloc5ers

))F

Drug 0&<-)o ( reductase inhibitors *tatins "*im astatin, Pra astatin, 3o astatin, (tor astatin, Flu astatin, )eri astatin$ ,ile (cid binding resins ")holestyramine and colestipol$

&ech of actionA &etabolismA drug *ide effectA indication interaction contraindication 8nhibit 6D* <8 upset 0epatitis "0&<)o(&e alonic &uscle aches acid$ &yositis (ngio-oedema *leep disturbance

Fibrates ")lofibrate, Fenofibrate, ,e4afibrate, <emfibro4il$

(nion e/change resins Pre ent resorption thruD terminal ileum of bile salts and e/ogenous cholesterol "enterohepatic circulation$ 8ncreased con ersion of endogenous chol to bile salts 8ncreased 3D3 receptor e/pression A decreased 3D3 8ncrease acti ity of peripheral lipoprotein lipase 6educe !3D3 production, increase

Drug malabsorption: including folic acid and statins "gi e other drugs 1 hour before A 1hours after

(bdominal fullness )onstipation +ausea 6educe absorption of !itamin ( - D 0ypertriglyceridemia

:sed in combination with other lipidlowering drugs in patients with

(bdominal pain, nausea &yositis "8n combination with *tatins$

hepatic 3D3 upta5e

treatmentresistant dyslipidemia

6aised li er en4ymes, gallstones Flushing in 10 ?, rash, <8 upset

+icotinic acid

Fish oils

8nhibits mobili4ation of free fatty acids from peripheral tissues 6educes hepatic triglyceride synthesis, secretion of !3D3 and thus indirectly 3D3 "10-22?$ 8ncreases 0D3 "12'2?$ w-' fatty acids containing eicosapentaenoic acid cause reduced !3D3 synthesis triglycerides but E3D3F +o pro en benefit, not used routinely 3owers 3D3 and E0D3F in plasma (ncillary effects antio/idant lower 0D3 +ot prescribed 8nhibit cholesterol absorption in intestine as ester "sterol ester$ reduces total cholesterol by 10?, 3D3 cholesterol by 12? no clinical data

Probucol

<8 disturbances in 10? patients *udden death

Plant sterols and stanols )holesterol li5e plant e/tracts