Cardiovascular and renal pharmacology Cardiovascular disease is the leading cause of death in the developed world.

Cardiac action potential Many ion channels interact to generate a coordinated cardiac action potential. Depolarisation (0), rapid repolarisation (1), plateau (2), repolarisation (3), resting potential ( ) !ction potential differs in different parts of the heart e.g. in nodes "e"#rane potential only reaches $%0"& (c.f. $'0 to $(0"&) Na channels )ast depolarising stage of action potential *ransiently opened, #eco"ing inactivated !ctivated #y cardiac pace"a+er cells (rather than neurotrans"itter) 3 su#units, , -1, -2 . / 0 % *M1D. 1 / voltage sensor, 1% lines pore (selectivity), 12$1% loop outer entrance of pore3 do"ain 444$4& loop inactivation Local anaesthetics 5 alter for" of action potential #y sta#ilising channels in their inactivated state 5 antidysrhyth"ic Ca channels 2 su#units 1 .2 - 6 7 8$type, large depolarisation re9uired (30"&) to open, found in "ost e0cita#le cells, large single channel conductance, stay open long ti"e, activity enhanced #y phosphorylation 1, responsi#le for plateau phase *$type, open transiently with rapid inactivation, low single channel conductance, s"all depolarisation re9uired to open (10$20"&), present in pace"a+er, trigger *$type "ay sufficiently depolarise cell to activate 8$type. Dihydropyridines nifedipine, 1% in do"ain 444, 12$1% loop in 4&. Doesn:t #loc+ *$type channels Phenylalkylamines verapamil, 12$1% loop in 4& ; affecting selectivity and inactivation Benzothiazepines 5 diltiazem, #loc+ fro" outside (< "odulate nifedipine #inding) Potassium channels = conductance is co"ple0 with several channel types Mutations in &>=C can cause long ?* syndro"e and sudden adult death syndro"e. Dual role, repolarisation at end of !@ and sta#ilisation and "odification of the resting cell "e"#rane potential Voltage gated, peptides "a+e pore. 4nactivation, AB$type: #all and chain vs AC$type: "ove"ent of residues at e0tracellular surface of pore $ slower Inward rectifying, (the action of e0cita#le "e"#ranes to allow electrical i"pulses to #e conducted preferentially in one direction). Cesponsi#le for "aintenance of resting "e"#rane potential (4=1 current). 4f = channels open

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all ti"e then with cardiac plateau would lose "assive a"ount of =. *hey conduct inward = current at hyperpolarised potentials, #ut close at depolarised potentials, preventing outward = current and = loss. *hey have Avalve$li+e: #ehaviour. Mg and polya"ines such as sper"ine are i"plicated in rectification "echanis" KA P channel 5 !*@ sensitive (sulphonylurea sensitive $ inhi#ition). Dypo0ia E reduced !*@ E channels open E hyperpolarisaFon E cardioprotecFon

Pacemaker Bo nervous input initiating each !@ 4ntrinsic rhyth" produced #y spontaneous !@ generated #y nodal tissue. Bodal tissue doesn:t have sta#le resting potential #ut gradually rises until gating potential of &>4C reached. 4f current is responsi#le Ahyperpolarisation activated cyclic nucleotide gated channels (DCB)5 open on hyperpolarisation and close at depolarisation !s per"ea#le to Ba as they are to =, #ut on hyperpolarisation Ba enters. !ctivated directly #y c!M@ rather than through c!M@ "ediated @=! activity Autonomic effects on cardiac physiology 1y"pathetic 5 -1 adrenergic in nodal cells and ventricular "uscle. - phosphorylation .1 su#unit 8$type Ca channels increasing flu0 (via @=! activated #y >s 5 9uite slow, ta+es G30s to reach "a0i"u" current) - sensitise ryanodine receptors, increased Ca release E posiFve inotropic effect - potential at which 4f is activated is positively shifted E posiFve chronotropic effect (via c!M@) - &arious delayed rectifier = channels enhanced leading to accelerated repolarisation and hence positive chronotropic effect @arasy"pathetic 5 M2 channels in nodes only (no inotropic effect) - H @=! and -6 inhi#it Ca current (#ut no effect on force) - potential at which 4f is activated is negatively shifted E negaFve chronotropic effect - 4=!Ch leads to hyperpolarisation

Dysrhythmia Conduction syste" of heart ensures organised and appropriate sti"ulation 1! node initiates nor"al rhyth" (GI0"in$1) 1! node da"age or increased e0cita#ility of another area can lead to JC*K@4C )KC4L@!CJM!=JC. Myocardiu" is a functional syncytiu" and can conduct in any direction !@:s collide at co""on point, e0tinction patern &>4C inactivate upon activation which leads to refractory period preventing re$e0citation inappropriately.

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@ro#le"s include 1! da"age, "yocardiu" da"age (slows conduction so pulse arrives late and can e0cite tissue that would have #een refractory). Most often caused #y M4 E connecFve Fssue low conducFvity. J.g re$entrant dysrhyth"ias Vaughan illiams classi!ication o! anti"dysrhythmics (#ased on the effect of the drug on the action potential rather than the class of drug) Class I !a channel "lock #LA$ - IA %&inidine and procainamide5 affinity for open state, drug lengthens refractory period preventing re$entrant #ehaviour 5 4nter"ediate +inetics - IB Lignocaine 5 (iv) #inds during phase 0, and dissociates in ti"e for ne0t !@, #ut if !@ arrives early, drug still associated and prevents e0citation. @revents pre"ature #eats. Capid +inetics - IC 5 )lecainide 5 slow onset Class II ' adrenoreceptor antagonists - ' #loc+ers reduce sy"pathetic effects. Catechola"ines can act on ischae"ic "yocardiu" which is already lia#le to inappropriate e0citation, and e0ert inotropic and chronotropic effects which leads to suscepti#ility to dysrhyth"ias. J.g. propranolol( atenolol Class III )otalol and amiodarone increase action potential duration possi#ly #y inhi#iting repolarising potassiu" currents Class IV *a channel "lockers - verapamil and diltiazem Ca #loc+ 5 #ut not used when cardiac function is co"pro"ised as "ay inhi#it contractionM

Congestive heart !ailure Deart fails to "aintain ade9uate circulation of the #ody. 4f the heart is una#le to cope, "ore #lood returns than can #e pu"ped, and the venous circulation #eco"es congested. !lthough veins adapta#le increased hydrostatic forces leads to oede"a. Can arise rapidly e.g. due to M4 or streptococcal infection3 #ut "ore nor"ally develops gradually due to chronic e0cessive functional de"ands, e.g. dysrhyth"ias, dia#etes. 1everity of heart failure graded #y the BND! classification 1$ . 1o to treat, increase contractile force of heart 5 positive inotropic effect, and reducing the load #y reducing filling pressure. Cardiac glycosides 5 Digo0in and digito0in. (also oua#ain #ut too powerful) act #y inhi#iting the BaL= !*@ase. *his prevents 3CaL1Ba e0change due to raised intracellular Ba. *his leads to raised Ca. !lso sti"ulates vagus 5 greater

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ti"e for ventricular filling. May also have deleterious effects on sy"pathetic trans"ission so often these are only used when there is also dysrhyth"ias. 1 agonists 5 sy"pathetic sti"ulation leads to positive inotropic effect. OP* this leads to increased cardiac o0ygen de"and, increase heart rate 5 "ay precipitate dysrhyth"ias, "ay precipitateLpotentiate hypertension. Do"&tamine ('+ #loc+ can "a+e severe cardiac failure worse) 1 antagonists cardiac failure leads to chronic sy"pathetic sti"ulation, which can lead to desensitisation of receptors with - receptors disproportionately downregulated and .1 upregulated. *his leads to increased adrenergic output which can result in cardio"yocyte apoptosis. Bisoprolol and carvedilol li"it da"aging effects of chronic catechola"ine sti"ulation and i"prove cardiac function. Inodilators 5 inotropic and vasodilatation. @hosphodiesterase inhi#itors raises c!M@ "i"ic+ing '+ sti"ulation. *ype 444 phosphodiesterase inhi#itors i"portant here, Amrinone #short acting)( milrinone (long acting). DilatationQ ; M8C= phosphorylation decreases action thus no contraction. Methyl anthines 5 caffeine( theophtlline 5 non selective phosphodiester inhi#itors, #ut also adensosine !2 antagonists leading to Ca release fro" stores Calcium sensitisers ! Pimo"endan 5 for canine dilated cardio"yopathy 5 calciu" sensitiser, increase cardiac calciu" #inding efficiency to troponin without a re9uire"ent for "ore energy consu"ption. !lso inhi#it @DJ 444 causing peripheral vasodilaition. 4n hu"ans, levosimendan AC" inhi#itors 5 see later. Ceduce preload (decreasing #ody fluid volu"es) and afterload (reducing peripheral vascular resistance) $iuretics 5 (decrease oede"a) see later $rugs targeting e citation"contraction coupling 5 1JCC!2 gene therapy 5 clinical trials in P= ,ndothelin system Jndothelin$1 derived fro" vascular endotheliu", potent vasoconstrictor, "itogenic and inotropic in "yocardiu". 8arger peptide cleaved #y Aendothelin converting enRy"e:. Jvidence for role of endothelin$1 in disease progression, plas"a levels raised, can contri#ute to e0ercise intolerance. *wo receptors, J*! vascular s"ooth "uscle 5 constriction3 J*O constriction at "uscle, #ut also dilatation at endotheliu". Bosentan non specific antagonist #eing used in trials.

Anticoagulant drugs #i$rinolytic agents M4 e"ergency treat"ent with clot lysis can i"prove survival. Drugs ai" to dissolve clots and li"it necrosis.

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)treptokinase #inds plas"inogen activator generating plas"in protease. *his is antigenic so not suita#le for chronic use Anistreplase plas"inogen and anisoylated strepto+inase 5 "ore prolonged activity -rokinase endogenous protein. 1ingle chain secreted #y +idney. *wo chain plas"inogen activator Alteplase( d&teplase( reteplase reco"#inant singleLdou#le chain hu"an tissue plas"inogen activators. Bote, rane.amic acid can inhi#it fi#rinolysis, #y co"petitively inhi#iting plas"inogen activation, and at higher concentrations, non$co"petitively inhi#its plas"in. %revention o! clot !ormation %eparin activates anti$thro"#in 444, which inactivates serine proteases of the coagulation cascade including Sa. Must #e ad"inistered #y inTection. Inhi#itors of glycoprotein II#&IIIa receptor this receptor is involved in fi#rinogen #ridging #etween platelets causing aggregation. ,ptifi"atide #peptide inhi"itor$( irofi"an #non/peptide inhi"itor$ and A"ci.ima" #monoclonal anti"ody against receptor$ Aspirin irreversi#le inhi#itor of cycloo0ygenase prevent platelet aggregation #y altering #alance of prostacyclin and thro"#o0ane in favour of vasodilatory and anti$ aggregative prostacyclin. Clopidogrel inhi#its platelet aggregation #y inhi#iting #inding of !D@ to its receptors, @2N1 and @2N12. 'arfarin 5 oral anticoagulant. Oloc+s vita"in = epo0ide reductase, an enRy"e in a cycle that is re9uired for ga""a$car#o0ylation of clotting factors 44, &44, 4S and S as well as regulatory proteins C, 1 and U. @ro#le" is that "any drugs interact (through activating or inhi#iting warfarins "eta#olis" and so regular #lood tests re9uired) Da$igatran 5 a thro"#in inhi#itor used as prophyla0is in patients undergoing +nee or hip surgery (D&* prophyla0is) and in patients with atrial fi#rillation < 1 additional ris+ factor for stro+e Vshown to #e 0W #etter than warfarin at reducing ris+X &ivaro'a$an 5 first factor Sa inhi#itor, si"ilar uses as a#ove.

&enal %harmacology $I()"*IC+ Diuretics cause an increased urine output 5 with increased Ba e0cretion (natri&resis). 4e diuretics induce increased e0cretion of solutes and water.

Jason Ali 2013

Jffect, reduces volu"e of e0tracellular fluid co"part"ent. Dence can reduce #lood volu"e and so are useful in congestive heart failure and hypertension (as well as "aintaining renal function in various renal diseases) 1, -oop diuretics !ct on loop of henle Ahigh ceiling: 5 capacity to cause high diuresis ( litres day$1) can #e dangerous if used inappropriately) 0r&semide( "&metanide( piretanide 5 are sulphona"ides Oloc+ Ba$=$2Cl co$transporter in apical "e"#rane of ascending li"# Drugs actively secreted into pro0i"al tu#ule 5 so concentration Yea+ inhi#ition of car#onic anhydrase >iven iv, accelerated effect, putatively attri#uted to venodilatation role Can lead to hypo+alae"ia 5 can #e reversed #y use of slow release = co"pounds given in conTunction !lso "eta#olic al+alosis 5 increased BaLD e0change leads to D loss Ca and Mg loss is increased Pric acid e0cretion decreased (pro"enecid given to reverse #y #loc+ing rea#sorption) ., *hia/ide diuretics 1ydrochlorothiazide( "endrofl&azide( .ipamide lesser effect than loop diuretics. 1o"e inhi#ition of C! !ction in cortical seg"ent of thic+ ascending li"#, or distal tu#ule, #loc+ing the BaLCl co$transporter (#inding to Cl site) 4n later stages also have an effect on vasodilation !gain hypo+alae"ia and "eta#olic acidosis pro#le"s (contraindication with cardiac glycosides, as with low = the action of glycosides is enhanced) Mg loss is increased, uric acid loss decreased. 0, Potassium sparing diuretics Amiloride( triamterene( spironolactone !"iloride and tria"terene, #loc+ the Jndothelial Ba channel in late distal tu#ule. Diuretic effect wea+, #ut = loss reduced. 1pironolactone, antagonises the action of aldosterone. 1pironolactone is "eta#olised in liver to canrenone. Co"petes with aldosterone for #inding to cytoplas"ic receptor (hence reduced synthesis of Ba channels and BaL= !*@ase). Jffect of drug is only significant when distal tu#ule under influence of aldosterone. Oecause re9uires turnover of channels, slow rate of onset. 1, Car#onic anhydrase inhi#itors Acetazolamide. 4nhi#it BaDCK3 rea#sorption in pro0i"al and distal tu#ules C!i reduce availa#ility of D< and so urine pD rises as DCK3$ increases

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OP* Z((W enRy"e "ust #e #loc+ed to achieve an apprecia#le effect 8eads to = loss in distal tu#ule Knly wea+ diuretics, #ut one i"portant use is in glauco"a 2, 3smotic diuretics 1i"plest in action. !rchetypal e0a"ple is mannitol. 1"all "olecular weight su#stance filtered #ut not rea#sor#ed, hence retaining os"otic e9uivalent of water and hence increasing urine volu"e Pseful when urine flow is reduced due to e0cessive rea#sorption, as "aintains urine flow Can reduce rapidly intracranial and intraocular pressure so useful for cere#ral oede"a due to head inTuries

(lood pressure) hypertension )enin angiotensin system Decreased perfusion of renal vessels, and sy"pathetic sti"ulation, leads to release of rennin fro" Tu0taglo"erular apparatus. Cenin cleaves angiotensinogen E angiotensin 4 converted to angiotensin 44 #y !CJ. @revalent on endotheliu" of lung !ngiotensin 44 leads to increased !O@, via vasoconstriction, thirst, aldosteroneQ A*, inhi"itors2 captopril( enalapril (converted to active enalaprilat in liver) usually co"#ined with diuretics. (hypotension is potentially dangerous as ris+ of renal failure is increased since glo"erular efferent cant constrict (ang. 44 "ediated) )aralasin angiotensin 44 partial agonist 5 peptide so not good orally Losartan non peptide angiotensin 44 antagonist )enal kallikrein!kinin system Orady+inin is a short peptide 5 potent natriuretic and renal vasodilator. 4f high Ba reaches distal tu#ule, then +alli+rein released, catalyses +inninogen E #rady+inin, and Ba rea#sorption inhi#ited Atrial natriuretic peptide Celeased fro" heart in response to atrial stretch. !cts via "e"#rane #ound guanylate cyclase receptor !ctions reduce #lood pressure and volu"e, vasodilator, reduces Ba rea#sorption sti"ulatin natriuresis, inhi#its rennin release.

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*+D,C -./0 Antihypertensive chemotherapy Most cases are Aessential: hypertension with un+nown aetiology. Bon phar"acological treat"ents, lose weight, sodiu" restriction, e0ercise etc. $iuretics 5 as a#ove AC" inhi#itors 5 captopril, enalapril. Decreased angiotensin 44 and aldosterone. Psually co"#ined with diuretic. Decreased #rady+inin "eta#olis" "ay lead to dry cough adrenoreceptor antagonists e.g. propranolol, or "ore specific atenolol (prevent #ronchoconstriction) various suggested "odes of action including decreased CK., decreased plas"a renin. 41!adrenoceptor antagonists praRosin. !rterioles tonically constricted via 3+ receptor. Bon selective 3 #loc+ (pheno0y#enRa"ine) gives vasodilatation !BD refle0 tachycardia due to increased sy"pathetic activity (4. nor"ally inhi#it B! release) Yith praRosin lac+ of refle0 tachycardia. Afirst$dose effect: Calcium channel antagonist act on 8$type channels. May also have "ild diuretic effects and "ay #loc+ aldosterone. Most co""only nifedipine. Potassium channel openers 5 lemakalim( pinacidil( mino.idil( diazo.ide( cromakalim. !ct on !*@$sensitive = channels in vascular s"ooth "uscle 5 hyperpolarising. Drugs antagonise the activity of !*@ and sulphonylureas Centrally acting 4.&I1 agonist 5 clonidine( g&anfacine4 &asoconstriction if given topically, vasodilator syste"ically. Kriginally thought to #e due to decreasing B!. Dowever effect now see"s to #e via i"idaRoline receptor 41. circu"stantial evidence, guanficine "ore potent .2 agonist #ut low efficacy as antihypertensive. Alpha!methyldopa 5 centrally acting. Converted to Afalse trans"itter: reducing B! release. +ympatholytics 5&anethidine 6eserpine 5anglion #lockers 1e.amethoni&m rimetaphan

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+odium nitroprusside "eta#olised to BK. in solution hydrolyses to DCB so stored as powder in dar+ %ydrala/ine arteriolar vasodilator "echanis" un+nown.

1ypolipidaemic drugs Ceducing plas"a lipids #eneficial for reducing effects downstrea" of atherosclerosis. )tatins( e4g4 lovastatin inhi#its DM>$Co! reductase (rate li"iting step in cholesterol synthesis), hence liver scavenges fro" #lood *holestyramine anion e0change resin, prevents reupta+e of #ile acids fro" intestine 5 hence liver increases cholesterol "eta#olis" to generate #ile acids *lofi"rate sti"ulates lipoprotein lipase releasing triglycerides fro" &8D8 which can then #e ta+en up for "eta#olis" or storage !icotinic acid inhi#its triglyceride production in liver 0ish oil reduces hypertriglyceridae"ia, and eicosapentanoic acid contained su#stitutes for arachidonic acid in production of @g and *0 which are less effective at causing platelet aggregation.

Angina %ectoris Co""onest "anifestation of ischae"ic heart disease 5 inade9uate #lood flow to the "yocardiu". Can lead to dysrhyth"ias or congestive heart failure. &ariant angina 5 coronary artery spas"s spontaneously 4n systole "yocardiu" receives little #lood. 1y"pathetic sti"ulation causes angina pt to suffer pain, - 4ncreased heart rate (less ti"e in diastole), - increased force of contraction (K2 de"and), - decreased cardiac efficiency 1y"pathetic sti"ulation can also cause dilatation via -2 receptors. Dowever in angina pt resting o0ygen de"and is achieved #y full dilatation and so no additional capacity. Collateral circulation develops 5 for" of adaptation !itrovasodilators 5 glyceryl trinitrate (poor a#sorption so su#lingual)( isosor"ide dinitrate( amyl nitrite. *hey are converted to BK in s"ooth "uscle cells #y "odulation of Ca sensitive eBK1. BK E c>M@ E M8C=. !s coronary vessels fully dilated, #elieved "ain effect is on &JBKP1 dilatation as well as collaterals.

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Dipyridamole 5 another vasodilator sti"ulates adenosine receptors 5 opens all vessels leading to coronary steal. ' antagonists propranolol( atenololQ reduce sy"pathetic sti"ulation. OP* non selective have disadvantage #y revealing .1 "ediated vasoconstriction #y re"oving -2 dilatation. 4n heart failure, sy"pathetic sti"ulation "ust #e "aintained for ade9uate CK, and so partial agonists can #e used, alprenolol *a channel "lock nifedipine acts on vascular s"ooth "uscle Z "yocardiu", leading to vasodilatation. Bifedipine #inds inactivated state ("ore at $%0 of "uscle, than $(0 "yocardiu") Angiogenesis 5 pro"ising recent develop"ent. Most wor+ using &J>). Must li"it duration of e0posure, so use adenoviral or plas"id.

V+23 -./0 Anthelmintics Del"inths, "alnutrition, tissue da"age, anae"ia, lu"inal o#struction, "igratory da"age, carriers of other pathogens, hypersensitivity. Beed to su#vert uni9ue and novel characteristics of hel"inths. Dowever often precise MKD! isn:t +nown for sure. -e6amisole and pyrantel cholinergic agonists !gonists at synaptic and e0trasynaptic nicotinic receptors. Channel per"ea#le to #oth = and Ba. Kpen channel #loc+ade 5 self antagonis" #y drug entering channel Channel penta"eric 5 variation of su#units can lead to resistance

Aldicar# and dichloros anticholinesterases - !Ch #uilds up causing contractions and paralysis. - Drugs car#a"ylate or phosphorylate the !ChJ - Del"inths have "ultiple isofor"s with different distri#utions Paraher7uamide nicotinic antagonist - Causes flaccid paralysis #y inhi#iting depolarisation - !lso inhi#it "otility of wor"s - 1how selectivity for parasite n!ChC Pipera/ine 5ABA agonist - 8igand gated Cl channels 5 causing hyperpolarisation and flaccid paralysis - Digh VCK2X is re9uired 5 as found in gut 5 less active against free living wor"s - Distinct wor" isofor"s of receptor, >!O!n (insensitive to "a""alian >!O!a antagonist #icuculine

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A6ermectins and mil#emycin glutamate gated Cl channel - 4ncreases "uscle Cl per"ea#ility 5 hyperpolarisation and flaccid paralysis - Bovel receptor appears to #e inverte#rate specific - *wo su#unit types, . and - for"ing penta"ers. Drug #inds to . unit whilst gluta"ate #inds - units. - *argets pharyngeal "uscles preventing feeding, also egg laying and "otile "usculature - 8ow VdrugX potentiates gluta"ate3 high V X directly opens Pra/i7uantel Ca permea#ility - Oelieved to increase Ca per"ea#ility #ut the precise channel involved is un+nown - Capid "uscle contraction and thus spastic paralysis - !lso da"ages tegu"ent revealing antigens allowing i""une response - 1chisto - su#unit decreases pea+ Ca current #ut also confers sensitivity to praRi9uantel when coe0pressed with "a""alian .. Ben/imida/oles microtu#ule formation - &esicle traffic+ing, structural integrity, cell division, glucose upta+e - Drugs #ind - tu#ulin and act as Acap: preventing further poly"erisation - Adyna"ic insta#ility: leads to disappearance of "icrotu#ules - leads to a slow starvation - resistance can #e generated #y "utation in tu#ulin, N200) Nitro ynil and closantel proton ionophores - dissociatea#le D< and lipophilic, allows proton gradient to #e dissipated across "itochondrial "e"#ranes - also fall in pD gradient across tegu"ent

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*C4 5 2rue6#alse 5 .egatively mar7ed 1, Ion channels and the cardiac AP a) @hase 2 of the cardiac !@ is rapid repolarisation #) )ast depolarising phase is attri#uted to Ba channels c) 8$type Ca channels re9uire only low depolarisation to #eco"e active d) *$type Ca channels have a low single channel conductance e) &> =< channel co"prises single peptide with do"ains (each with % *M1D) f) 4f is the current responsi#le for initiating the activity of the 1! node ., Autonomic effects a) 1y"pathetic sti"ulation shifts 4f to "ore depolarising potentials #) @arasy"pathetic syste" has #oth negative inotropic and chronotropic effects 0, $ysrhythmias a) Cardiac "uscle can conduct in any direction #) Jctopic pace"a+er is when the 1! node increases its fre9uency c) 8ocal anaesthetics can #e used to treat dysrhyth"ias d) -1 agonists "ay #e used to treat dysrhyth"ias 1, Congesti6e heart failure a) 4f the left side of the hear fails there is pul"onary oede"a #) Chronic e0cessive functional de"ands lead to rapid develop"ent of CD) c) *ype & phosphodiesterase inhi#itors can #e used to treat CD) d) Ceduced endothelin is associated with CD) 2, Angina pectoris a) Dilatation of coronary arteries is a plausi#le "eans of treat"ent #) -1 antagonists are #etter than - non selective for angina treat"ent 8, Clot lysis and hyperlipidaemia a) several drugs target the activation of plas"in to degrade clots #) statins target the rate li"iting step of cholesterol synthesis

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*C4 5 2rue6#alse 5 .egatively mar7ed 1, Ion channels and the cardiac AP g) @hase 2 of the cardiac !@ is rapid repolarisation # %1A3+ 1 h) )ast depolarising phase is attri#uted to Ba channels 2 i) 8$type Ca channels re9uire only low depolarisation to #eco"e active # /A&8+ T) *$type Ca channels have a low single channel conductance 2 +) &> =< channel co"prises single peptide with do"ains (each with % *M1D) # 9 %+%2,D+3 l) 4f is the current responsi#le for initiating the activity of the 1! node 2 ., Autonomic effects c) 1y"pathetic sti"ulation shifts 4f to "ore depolarising potentials 2 d) @arasy"pathetic syste" has #oth negative inotropic and chronotropic effects # .- ,.-2&-%,C (+CA:3+ .- &+C+%2-&3 ,. *:3C/+ 0, $ysrhythmias e) Cardiac "uscle can conduct in any direction 2 f) Jctopic pace"a+er is when the 1! node increases its fre9uency # -21+& %AC+*A;+& <,+ .-2 3A= g) 8ocal anaesthetics can #e used to treat dysrhyth"ias 2 h) -1 agonists "ay #e used to treat dysrhyth"ias # A.2A8-.,323

1+.

1, Congesti6e heart failure e) 4f the left side of the hear fails there is pul"onary oede"a # 3032+*,C +>8> A(D-*,.A/ A3C,2+3 f) Chronic e0cessive functional de"ands lead to rapid develop"ent of CD) # 8&AD:A/ D+V+/-%*+.2 g) *ype & phosphodiesterase inhi#itors can #e used to treat CD) # 20%+ ,,, h) Ceduced endothelin is associated with CD) # &A,3+D 2, Angina pectoris c) Dilatation of coronary arteries is a plausi#le "eans of treat"ent # 21+0 A&+ A/&+AD0 D,/A2+D A2 &+32 d) -1 antagonists are #etter than - non selective for angina treat"ent 2 8, Clot lysis and hyperlipidaemia c) several drugs target the activation of plas"in to degrade clots 2 d= statins target the rate li"iting step of cholesterol synthesis 2

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*C4 5 2rue6#alse 5 .egatively mar7ed 1, $iuretics a) 8oop diuretics #loc+ BaLCl co$transporter #) 8oop diuretics induce hypo+alae"ia and "eta#olic acidosis c) *hiaRide diuretics de"onstrate greater diuresis than loop diuretics d) Z((W car#onic anhydrase "ust #e #loc+ed for efficacy e) os"otic diuretics can #e filtered #ut not rea#sor#ed ., )enal system a) Cenin is induced #y raised renal perfusion pressure #) Cenin converts angiotensin 4 to angiotensin 44 c) !CJ inhi#itors are used as antihypertensives d) Orady+inin reduces the rea#sorption of Ba e) !B@ responses ai" to reduce the !O@ 0, Antihypertensi6es a) .1 agonists can #e used to treat hypertension #) Calciu" channel #loc+ers can #e used to treat hypertension c) Drugs can #e used to antagonise the effect of !*@ on the =!*@ channels to treat hypertension. d) -1 selective agonists are preferred as antihypertensives e) central .2 receptors are targeted #y antihypertensives 1, Anthelmintics a) Bicotinic agonists and antagonists are useful as anthel"intics #) >!O! agonists induce a flaccid paralysis c) >luta"ate gated Ca2< channels are targeted #y anthel"intics d) Cesistance to "icrotu#ule disrupting drugs has not #een recognised yet e) Microtu#ule disrupting drugs +ill wor"s #y starving the"

Jason Ali 2013

*C4 5 2rue6#alse 5 .egatively mar7ed 1, $iuretics a) 8oop diuretics #loc+ BaLCl co$transporter # .a6;62Cl #) 8oop diuretics induce hypo+alae"ia and "eta#olic acidosis # A/;A/-3,3 c) *hiaRide diuretics de"onstrate greater diuresis than loop diuretics # d) Z((W car#onic anhydrase "ust #e #loc+ed for efficacy 2 e) os"otic diuretics can #e filtered #ut not rea#sor#ed 2 ., )enal system a) Cenin is induced #y raised renal perfusion pressure # " /- +&+D #) Cenin converts angiotensin 4 to angiotensin 44 # <AC+= c) !CJ inhi#itors are used as antihypertensives 2 d) Orady+inin reduces the rea#sorption of Ba 2 e) !B@ responses ai" to reduce the !O@ 2 0, antihypertensi6es a) .1 agonists can #e used to treat hypertension # " A.2A8-.,323 #) Calciu" channel #loc+ers can #e used to treat hypertension 2 c) Drugs can #e used to antagonise the effect of !*@ on the =!*@ channels to treat hypertension 2 d) -1 selective agonists are preferred as antihypertensives # A.2A8-.,323 e) central .2 receptors are targeted #y antihypertensives 2 1, Anthelmintics a) Bicotinic agonists and antagonists are useful as anthel"intics 2 #) >!O! agonists induce a flaccid paralysis 2 c) >luta"ate gated Ca2< channels are targeted #y anthel"intics # Cl d) Cesistance to "icrotu#ule disrupting drugs has not #een recognised yet # e) Microtu#ule disrupting drugs +ill wor"s #y starving the" 2

Jason Ali 2013