3 Cardiovascular Pharmacology

8/12/2019 3 Cardiovascular Pharmacology

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Jason Ali 2013

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"#ranepotential 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 / % *MD. / voltage sensor, % lines pore (selectivity), $% loop

outer entrance of pore do"ain 444$4& loop inactivation

Local anaesthetics5 alter for" of action potential #y sta#ilising channels intheir inactivated state 5 antidysrhyth"ic

Ca channels

su#units 12- 6 7 8$type large depolarisation re9uired (30"&) to open, found in "ost ecita#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 % in do"ain 444, $% loop in 4&. Doesn:t #loc+*$type channels

Phenylalkylamines verapamil $% loop in 4& ; affecting selectivity andinactivation

Benzothiazepines5 diltiazem #loc+ fro" outside (< "odulate nifedipine#inding)

Potassium channels

= conductance is co"ple 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 ofthe resting cell "e"#rane potential

Voltage gated peptides "a+e pore. 4nactivation AB$type: #all and chain vsAC$type: "ove"ent of residues at etracellular surface of pore $ slower

Inward rectifying (the action of ecita#le "e"#ranes to allow electricali"pulses to #e conducted preferentially in one direction). esponsi#le for"aintenance of resting "e"#rane potential (4=1current). 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"

KAPchannel 5 !*@ sensitive (sulphonylurea sensitive $ inhi#ition). ypoia Ereduced !*@ 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.

4fcurrent is responsi#le Ahyperpolarisation activated cyclic nucleotide gatedchannels (CB)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

y"pathetic 5 -1adrenergic in nodal cells and ventricular "uscle.- phosphorylation 1su#unit 8$type Ca channels increasing flu (via @=!

activated #y >s5 9uite slow, ta+es G30s to reach "ai"u" current)

- sensitise ryanodine receptors, increased Ca release E posiFveinotropic effect

- potential at which 4fis activated is positively shifted E posiFvechronotropic effect (via c!M@)

- &arious delayed rectifier = channels enhanced leading to acceleratedrepolarisation 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 4fis activated is negatively shifted E negaFve

chronotropic effect

- 4=!Chleads to hyperpolarisation

Dysrhythmia

Conduction syste" of heart ensures organised and appropriate sti"ulation ! node initiates nor"al rhyth" (GI0"in$1) ! node da"age or increased ecita#ility of another area can lead to

JC*K@4C KC4L@!CJM!=J.

Myocardiu" is a functional syncytiu" and can conduct in any direction !@:s collide at co""on point etinction patern &>4C inactivate upon activation which leads to refractory period preventingre$ecitation inappropriately.


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Jason Ali 2013

@ro#le"s include ! da"age, "yocardiu" da"age (slows conduction sopulse arrives late and can ecite 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 ofthe drug on the action potential rather than the class of drug)

Class I!a channel "lock #LA$

- IA %&inidineandprocainamide5 affinity for open state, druglengthens refractory period preventing re$entrant #ehaviour 5

4nter"ediate +inetics

- IB Lignocaine5 (iv) #inds during phase 0, and dissociates in ti"e fornet !@, #ut if !@ arrives early, drug still associated and prevents

ecitation. @revents pre"ature #eats. apid +inetics

- IC5 lecainide 5 slow onset Class II

' adrenoreceptor antagonists

- '#loc+ers reduce sy"pathetic effects. Catechola"ines can act onischae"ic "yocardiu" which is already lia#le to inappropriate

ecitation, and eert 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 diltiazemCa #loc+ 5 #ut not used when cardiacfunction is co"pro"ised as "ay inhi#it contraction

Congestive heart !ailure

eart 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 infection #ut "ore nor"ally

develops gradually due to chronic ecessive functional de"ands, e.g. dysrhyth"ias,

dia#etes. everity of heart failure graded #y the BN! classification 1$.

o to treat increase contractile force of heart 5 positive inotropic effect, and

reducing the load #y reducing filling pressure.

Cardiac glycosides5 Digoin and digitoin. (also oua#ain #ut too powerful)act #y inhi#iting the BaL= !*@ase. *his prevents 3CaL1Ba echange due toraised 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.

1agonists5 sy"pathetic sti"ulation leads to positive inotropic effect. OP*this leads to increased cardiac oygen de"and, increase heart rate 5 "ay

precipitate dysrhyth"ias, "ay precipitateLpotentiate hypertension.

Do"&tamine('+#loc+ can "a+e severe cardiac failure worse)

1antagonists cardiac failure leads to chronic sy"pathetic sti"ulation,which can lead to desensitisation of receptors with - receptors

disproportionately downregulated and 1upregulated. *his leads to

increased adrenergic output which can result in cardio"yocyte apoptosis.

Bisoprolol and carvedilolli"it da"aging effects of chronic catechola"ine

sti"ulation and i"prove cardiac function.

Inodilators5 inotropic and vasodilatation. @hosphodiesterase inhi#itors raises c!M@ "i"ic+ing '+sti"ulation. *ype 444 phosphodiesterase inhi#itors

i"portant hereAmrinone #short acting)( milrinone(long acting). DilatationQ

; M8C= phosphorylation decreases action thus no contraction. Methylanthines5 caffeine( theophtlline5 non selective phosphodiester

inhi#itors, #ut also adensosine !2antagonists leading to Ca release fro"

stores

Calcium sensitisers ! Pimo"endan5 for canine dilated cardio"yopathy 5calciu" 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#itors5 see later. educe preload (decreasing #ody fluid volu"es)and afterload (reducing peripheral vascular resistance)

$iuretics5 (decrease oede"a) see later $rugs targeting ecitation"contraction coupling5 JC!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 eercise intolerance. *wo receptors J*!vascular s"ooth

"uscle 5 constriction J*Oconstriction at "uscle, #ut also dilatation at endotheliu".

Bosentannon 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 prolongedactivity

-rokinase endogenous protein. ingle chain secreted #y +idney. *wo chainplas"inogen activator

Alteplase( d&teplase( reteplase reco"#inant singleLdou#le chain hu"antissue plas"inogen activators.

Bote, rane.amic acidcan 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 thecoagulation 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$andA"ci.ima" #monoclonal anti"ody against

receptor$

Aspirinirreversi#le inhi#itor of cyclooygenase prevent platelet aggregation #y

altering #alance of prostacyclin and thro"#oane in favour of vasodilatory and anti$

aggregative prostacyclin.

Clopidogrel inhi#its platelet aggregation #y inhi#iting #inding of !D@ to its

receptors @2N1and @2N12.

'arfarin5 oral anticoagulant. Oloc+s vita"in = epoide reductase, an enRy"e in a

cycle that is re9uired for ga""a$car#oylation of clotting factors 44, &44, 4S and S as

well as regulatory proteins C, and U. @ro#le" is that "any drugs interact (through

activating or inhi#iting warfarins "eta#olis" and so regular #lood tests re9uired)

Da$igatran5 a thro"#in inhi#itor used as prophylais in patients undergoing +neeor hip surgery (D&* prophylais) 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$an5 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 ecretion (natri&resis).4e diuretics induce increased ecretion of solutes and water.


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Jason Ali 2013

Jffect reduces volu"e of etracellular fluid co"part"ent.

ence 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( piretanide5 are sulphona"ides Oloc+ Ba$=$2Cl co$transporter in apical "e"#rane of ascending li"# Drugs actively secreted into proi"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 BaL echange leads to loss Ca and Mg loss is increased Pric acid ecretion decreased (pro"enecid given to reverse #y #loc+ing

rea#sorption)

., *hia/ide diuretics

1ydrochlorothiazide( "endrofl&azide( .ipamide lesser effect than loop diuretics. o"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 distaltu#ule. Diuretic effect wea+, #ut = loss reduced. pironolactone antagonises the action of aldosterone. pironolactone 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.

, Car#onic anhydrase inhi#itors

Acetazolamide.

4nhi#it BaCK3rea#sorption in proi"al and distal tu#ules C!i reduce availa#ility of


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Jason Ali 2013

OP* ZW 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

i"plest in action. !rchetypal ea"ple is mannitol. "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 ecessive rea#sorption, as"aintains urine flow

Can reduce rapidly intracranial and intraocular pressure so useful for cere#raloede"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" Tutaglo"erular apparatus. enin 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

eleased 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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*+DC -./

Antihypertensive chemotherapy

Most cases are Aessential: hypertension with un+nown aetiology.

Bon phar"acological treat"ents lose weight, sodiu" restriction, eercise etc.

$iuretics5 as a#ove

AC" inhi#itors5 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+ (phenoy#enRa"ine) gives vasodilatation !BD refle

tachycardia due to increased sy"pathetic activity (4.nor"ally inhi#it B! release)

Yith praRosin lac+ of refle 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 openers5 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.&I1agonist5 clonidine( g&anfacine4 &asoconstriction if given

topically, vasodilator syste"ically. Kriginally thought to #e due to decreasing B!.

owever effect now see"s to #e via i"idaRoline receptor 41. circu"stantial evidence

guanficine "ore potent 2agonist #ut low efficacy as antihypertensive.

Alpha!methyldopa5 centrally acting. Converted to Afalse trans"itter: reducing B!release.

+ympatholytics

5&anethidine 6eserpine

5anglion #lockers

1e.amethoni&m rimetaphan


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Jason Ali 2013

+odium nitroprusside "eta#olised to BK. in solution hydrolyses to CB so stored

as powder in dar+

%ydrala/ine arteriolar vasodilator "echanis" un+nown.

ypolipidaemic drugs

educing plas"a lipids #eneficial for reducing effects downstrea" of atherosclerosis.

)tatins( e4g4 lovastatin inhi#its M>$Co! reductase (rate li"iting step incholesterol synthesis), hence liver scavenges fro" #lood

*holestyramine anion echange 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" &8D8which 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 * 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. y"pathetic sti"ulation causes angina

pt to suffer pain

- 4ncreased heart rate (less ti"e in diastole),- increased force of contraction (K2de"and),- decreased cardiac efficiency

y"pathetic sti"ulation can also cause dilatation via -2receptors. owever in

angina pt resting oygen de"and is achieved #y full dilatation and so no additional

capacity.

Collateral circulation develops 5 for" of adaptation

!itrovasodilators5 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 eBK. BK E c>M@ E M8C=. !s coronary

vessels fully dilated, #elieved "ain effect is on &JBKP dilatation as well ascollaterals.


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Jason Ali 2013

Dipyridamole5 another vasodilator sti"ulates adenosine receptors 5 opensall 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 -2dilatation. 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")

Angiogenesis5 pro"ising recent develop"ent. Most wor+ using &J>. Mustli"it duration of eposure, so use adenoviral or plas"id.

V+ -./

Anthelmintics

el"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. owever often

precise MKD! isn:t +nown for sure.

-e6amisole and pyrantel cholinergic agonists

- !gonists at synaptic and etrasynaptic nicotinic receptors. Channelper"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- el"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- how selectivity for parasite n!Ch

Pipera/ine 5ABA agonist

- 8igand gated Cl channels 5 causing hyperpolarisation and flaccidparalysis

- igh VCK2X is re9uired 5 as found in gut 5 less active against free livingwor"s

- Distinct wor" isofor"s of receptor >!O!n(insensitive to "a""alian>!O!aantagonist #icuculine


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Jason Ali 2013

*C4 5 rue6#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 channelsc) 8$type Ca channels re9uire only low depolarisation to #eco"e actived) *$type Ca channels have a low single channel conductancee) &> =


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Jason Ali 2013


1, Ion channels and the cardiac AP

g) @hase 2 of the cardiac !@ is rapid repolarisation # %A+ 1h) ast depolarising phase is attri#uted to Ba channels 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 +) &> =8>A(D-*.A/ AC+

f) Chronic ecessive functional de"ands lead to rapid develop"ent of C #8&AD:A/ D+V+/-%*+.

g) *ype & phosphodiesterase inhi#itors can #e used to treat C # %+ h) educed endothelin is associated with C # &A+D

2, Angina pectoris

c) Dilatation of coronary arteries is a plausi#le "eans of treat"ent # + A&+A/&+AD D/A+D A &+d) -1antagonists are #etter than - non selective for angina treat"ent

8, Clot lysis and hyperlipidaemia

c) several drugs target the activation of plas"in to degrade clots d= statins target the rate li"iting step of cholesterol synthesis


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1, $iuretics

a) 8oop diuretics #loc+ BaLCl co$transporter# .a6;62Cl#) 8oop diuretics induce hypo+alae"ia and "eta#olic acidosis # A/;A/-c) *hiaRide diuretics de"onstrate greater diuresis than loop diuretics #d) ZW car#onic anhydrase "ust #e #loc+ed for efficacy e) os"otic diuretics can #e filtered #ut not rea#sor#ed

., )enal system

a) enin is induced #y raised renal perfusion pressure # " /-+&+D#) enin converts angiotensin 4 to angiotensin 44 # !O! agonists induce a flaccid paralysis c) >luta"ate gated Ca2

Documents

3 Cardiovascular Pharmacology