CARDIOVASCULAR AND RENAL PHARMACOLOGY

Question 1

Abciximab

Answer 1

1 - a MAB against the glycoprotein 2b/3 receptor, inhibits the fibrinogen bridging necessary for platelet aggregation.
2 - also binds the vitronectin receptor on platelets, endothelial cells and VSMCs - involved in cell adhesion and haemostasis.
3 - used with coronary angioplasty to prevent coronary artery thrombosis.

Question 2

Acetazolamide

Answer 2

1 - Carbonic anhydrase inhibitor diuretic
2 - largely obsolete as a class
3 - inhibit reabsorption of NaHCO3 in PCT and DCT (80%) in PCT
4 - exchange utilises Na/H exchanger on the apical membrane driven by the Na pump
5 - urine pH rises
6 - weak diuretics, >99% of the enzyme must be inhibited for an appreciable effect
7 - main clinical use is in glaucoma, suppresses HCO3- secretion which is an important part of aqueous humour formation
8 - can help acclimatisation and reduce mountain sickness and alleviate sleep apnoea at high altitudes.

Question 3

Alteplase

Answer 3

1 - single chain recombinant human tissue plasminogen activators
2 - greater action of plasminogen bound to fibrin in clots therefore localised action

Question 4

Amiloride

Answer 4

1 - a potassium sparing diuretic
2 - blocks apical Na channels in the late distal tubule, less Na driven out basement membrane hence less K into cell hence less K out channel into lumen. diuresis is weak but spares K.

Question 5

Aminocaproic Acid

Answer 5

1 - chemically similar to lysine
2 - competitively inhibts plasminogen activation
3 - prevents excessive clots lysis which would cause severe bleeding

Question 6

Amiodarone

Answer 6

1 - class 3 antidysrhytmic
2 - prolongs the cardiac AP (complex mech) and thus also the refractory period. amiodarone is the best known example.
3 - can be used for ventricular dysrhythmias and reentrants that dont respond to class 1.
4 - prolongs phase 3 (repolarisation but also has beta blocker and K channel blocker like effects at the SA and AV nodes.

Question 7

Amrinone

Answer 7

Fill

Question 8

Anistreplase

Answer 8

combined plasminogen and anisoylated streptokinase
2 - streptokinase is inactive until the anisoyl group is removed, this hapens slowly in the blood
2 - the result is more prolonged activity (4-6hrs) than streptokinase alone.

Question 9

Aspirin

Answer 9

1 - reduces thrombosis
2 - low dose often combined with clopidogrel to improve morbidity and mortility in patients with a wide range of heart disease
3 - prophylaxis is approx a quarter of a tablet a day but only suitable due to the side effects for elderly people or those who’ve had a CV incident.
4 - inhibits production of thromboxane which helps aggregate platelets.

Question 10

Atenolol

Answer 10

1 - selective β1 antagonist
2 - its selectivity reduces risk of bronchorestriction
3 - class 2 antidysrhythmic
4 - can be used with phenoxybenzamine to block the effects of a large release of catecholamines when a phaeochromocytoma is removed
5 - The mainstay of treatment for LQTS, unless there is an identifiable reversible cause, is lifestyle modification and beta-blocker therapy with the implantation of a cardioverter-defibrillator (ICD) in patients who have had a previous cardiac arrest and in those continuing to have symptoms despite beta-blockade. LQTS is the principle cause of SADS.

Question 11

Bisoprolol

Answer 11

1 - a “3rd generation” β1 blocker.
2 - currently in clinical use in the UK for stable heart failure
3 - danger of over-inhibition so doses have to be carefully titrated whilst cardiac function is monitored.

Question 12

Bosentan

Answer 12

1 - new, non-specific endothelin receptor antagonist. used for pulmonary arterial hypertension. endothelin-1 (of 3) is a potent vasoconstrictor but as ETb receptor mediates both constriction of VSMCs and dilation of endothelial cells (via NO) the use of the class of drugs is disputed.

Question 13

Caffeine

Answer 13

1 - A1 (acts via Gi/o) antagonist (hence diuresis via decreased renin?) (also an A2 antagonist)
2 - nonselectively inhibits PDEs so potentiates cAMP signalling and hence rate and force of cardiac contraction along with more disposed to dysrhythmias.
3 - adenosine acts via A1 Rs in the brain to presynaptically inhibits glutamate releasing neurons causing decreased motor activity, respiration, anxiety and to induce sleep. Caffeine inhibits this.
a methylxanthine.
CNS effects due to adenosine antagonism

Question 14

Captopril

Answer 14

1 - an ACE inhibitor
2 - decreases pre and afterload on the heart, the aim is to reduce vascular resistance in heart failure.
3 - almost always combined with diuretics
4 - reduction in aldosterone should, in principle, help avoid hypokalaemia.
5 - ACE also known as kininase 2 which breaks down bradykinin. inhibiting it raises bradykinin levels which acts as an irritant and causes a dry cough (ie not caused by secretions) which can be intolerable to some patients. captopril is especially bad.
6 - hypotension is a dangerous with any ACE inhibitor as risk of renal failure is increased by the block of angiotensin 2 which normally mediates glomerular efferent arteriolar constriction.

Question 15

Carvedilol

Answer 15

1 - a “3rd generation” β1 blocker.
2 - currently in clinical use in the UK for stable heart failure
3 - danger of over-inhibition so doses have to be carefully titrated whilst cardiac function is monitored.

Question 16

Clonidine

Answer 16

1 - α2 (and α1) agonist

2 - antihypertensive but can cause rebound hypertension if a dose is missed. acts via hindbrain receptors

Question 17

Clopidogrel

Answer 17

1 - inhibits platelet aggregation by inhibiting the binding of ADP to its platelet receptor
2 - given with a low dose of aspirin

Question 18

Digoxin

Answer 18

1 - a caridac glycoside that inhibits the sodium pump
2 - commonly used as an antidysrhytmic, but not alone. can also be used in heart failure.
3 - like ouabain but ouabain is too potent for clinical use
4 - dont use with thiazide diuretics as the significant drop in plasma K conc will compound the effect of cardiac glycosides in reducing the activity of the Na pump.

Question 19

Diltiazem

Answer 19

1 - blocks L type Ca channel but distinct site to DHP. enhances their binding.
2 - greater use dependence and more prolonged than DHPs.
3 - preferential to cardiac hence antidysrhytmic (type 4), Acts preferentially at the nodes where the AP depends upon the L and T type current hence slowing conduction.
4 - a benzothiazepine.
5 - more effect on S.M. than verapamil.
6 - well absorbed by GI, extensively metabolised.
7 - side effects - flushing and headache,

Question 20

Dipyridamole

Answer 20

PDE5 (cGMP specific) inhibitor like sildenafil.

an inodilator.

Question 21

Dobutamine

Answer 21

1 - analogue of dopamine
2 - β1 agonist. greater ionotroph than chronotroph.
3 - used in acute cardiogenic shock to raise HR and CO, given IV.
4 - increases HR and O2 demand so arrhythmogenic
5 - can be used to treat heart failure in the absence of hypertension, and improve CO after open heart surgery.

Question 22

Duteplase

Answer 22

1 - double chain recombinant human tissue plasminogen activator
2 - greater action on plasminogen bound to fibrin in clots therefore localised action. plasminogen being the precursor for the serum protease plasmin which breaks down both fibrinogen and fibrin.

Question 23

Enalapril

Answer 23

1 - an ACE inhibitor
2 - the inactive form. converted to the active enalaprilat in the liver
3 - decreases pre and afterload on the heart
4 - almost always combined with a diuretic but the reduction in aldosterone should, in principle, help avoid hypokalaemia.
5 - ACE also known as kininase 2 which breaks down bradykinin. inhibiting it raises bradykinin levels which acts as an irritant and causes a dry cough (ie not caused by secretions) which can be intolerable to some patients. captopril is especially bad.
6 - hypotension is a dangerous with any ACE inhibitor as risk of renal failure is increased by the block of angiotensin 2 which normally mediates glomerular efferent arteriolar constriction.

Question 24

Eptifibatide

Answer 24

1 - a cyclic heptapeptide that binds to and inhibits the glycoprotein 2b/3a receptor. a receptor key to fibrinogen bridging and platelet aggregation.

Question 25

Furosemide

Answer 25

1 - a sulphonamide loop diuretic like bumetanide, causes a v.high rate of diuresis.
2 - blocks the NKCC in the apical membrane of the thick ascending limb.
3 - actively secreted into the proximal tubule hence PCT conc is 10-30 times that of the plasma.
4 - acts on heart failure within 10 mins if given IV as it causes venodilation and hence a drop to AFP before the diuresis. large reduction in fluid vol makes them useful in acute heart failure.
5 - weakly inhibits carbonic anhydrase
6 - can cause hypokalaemia due to increased DCT Na load, and metabolic alkalosis due to increased Na/H exchange and stimulated renal synth of NH3.
7 - also increases Ca and Mg loss
8 - decreases uric acid excretion and hence can cause gout
9 - IV = 10mins, oral = 1-1.5hrs

Question 26

Heparin

Answer 26

1 - a naturally occuring anticoagulant produced by basophils and mast cells.
2 - binds antithrombin 3 causing a conformational change to expose the active site. this activates thrombin and other clotting proteases including factor Xa.
3 - used to treat unstable angina, after myocardial infarcts, to treat DVT and as a prophylactic following surgery.
4 - given IV (hence not very good prophylactic)

Question 27

Hydrochlorothiazide

Answer 27

1 - a thiazide diuretic like bendroflumethiazide.
2 - weakly inhibits carbonic anhydrase
3 - primary action is to block the Na/Cl cotransporter in the early distal tubule
4 - some vasodilator effects
5 - side effects of metabolic alkalosis and hypokalaemia
6 - causes an average fall in plams K of 0.7mM which is significant and hence must not be used with cardiac glycosides

Question 28

Isobutylmethylxanthine (IBMX)

Answer 28

1 - a methylxanthine like caffeine and theophylline.

2 - both a nonselective inhibitor of PDEs (competitive) and Adenosine receptors.

Question 29

Levosimendan

Answer 29

1 - one of the calcium sensitising inodilators
2 - only drug of this particular type that has an significant use in human clinical practice. for heart failure but not licensed in the UK.

Question 30

Lidocaine

Answer 30

1 - local anaesthetic, pd gated Na channels.
2 - pKa 8-9
3 - stabilises inactivated state by blocking channel
4 - an amineester
5 - neutral crosses membrane, protonated form blocks.
6 - inhibits C and Aδ fibres first
7 - use dependent for high rates of stimulation. class 1b antidysrhythmic w/ v.fast association/dissociation.
8 - neuropathic pain.
9 - amides metabolised in the liver.
10 - increases proportion of inactive channels at any pd.

Question 31

Losartan

Answer 31

1 - and non-peptide angiotensin 2 antagonist
2 - acts on AT1 not AT2 receptors
3 - AT1 involved in thirst, aldosterone secretion and vasoconstriction, but AT2 involved more in vasodilation via NO generation and subsequent rise in cGMP. A2 binding AT2 actually inhibits, in certain cells, proliferation but will mediate neural tissue differentiation and can induce apoptosis.

Question 32

Mannitol

Answer 32

1 - an osmotic diuretic
2 - filtered but not reabsorbed hence increases the osmotic gradient and urine volume. also decreases Na reabsorption by lowering its conc in the filtrate
3 - useful for maintaining urine flow and preventing kidney damage by low flow rates
4 - doesnt cross the BBB so useful to rapidly reduce intracranial and intraocular pressure in cerebral oedema

Question 33

α-methylNA

Answer 33

Fill

Question 34

Milrinone

Answer 34

1 - PDE3 (cGMP inhibited) inhibitor. this raises cAMP which in cardiac M makes it an inotroph (ino-).
2 - an inodilator most often used in heart failure. limited use as can cause dysrhythmias so confined to short term treatment of severe heart failure unresponsive to other therapy.
3 - the rise in cAMP in S.M. causes vasodilation and decreases after load on the heart. (-Dilator)
4 - the inodilator most often used in heart failure.

Question 35

Minoxidil

Answer 35

1 - pd gated K channel opener.
2 - vasodilate hence hypertension.
3 - side effect of hirsutism, hence treat alopecia.

Question 36

Ouabain

Answer 36

1 - a cadiac glycoside like digoxin and digitoxin that inhibits the sodium pump
2 - too potent to be used clinically but used experimentally.

Question 37

Nicotine

Answer 37

1 - NACHR antagonist

Question 38

Nifedipine

Answer 38

1 - DHP L type antagonist.
2 - aromatic, highly lipid soluble, accesses channel via lipid phase.
3 - favours mode 0, closed.
4 - Causes peripheral and coronary vasodilation hence treats hypertension and angina.
5 - causes reflex tachycardia.
6 - more active on vascular Ca channels as inactive channels dominate due to the less negative resting pd.
7 - usually combined with a β blocker to combat reflex tachycardia.

Question 39

Pimobendan

Answer 39

1 - an inodilator
2 - a calcium sensitiser, improving binding of Ca2+ to troponin in cardiac muscle without a requirement of more energy.
3 - peripheral vasodilation via PDE3 (cGMP inhibited) inhibition.
4 - used in dogs to treat canine dilated cardiomyopathy and advanced canine mitral valve regurgitation

Question 40

Propranolol

Answer 40

1 - non specific β antagonist. replaced by atenolol.
2 - class 2 antidysrhythmic
3 - non-selective so can cause bronchoconstriction
4 - β1 is linked to Gs causing a rise of cAMP, increases likelihood of opening of L types and T types hence ionotrophic and chronotrophic.

Question 41

Reserpine

Answer 41

1 - blocks NA and DA transport into vesicle by tightly binding amine binding site of VMAT-2 (vesicular monoamine transporter). also causes long term NA (and 5HT in brain) depletion as they leak out of vesicles and are metabolised by MAO.
2 - acts in periphery and brain.
3 - used as antihypertensive but discontinued due to profound psychological depression
4 - recovery requires synthesis of new vesicles

Question 42

Saralasin

Answer 42

1 - an angiotensin 2 partial agonist

2 - a peptide so cant be given orally and hence not competitive with other antihypertensives.

Question 43

Sildenafil

Answer 43

1 - an inodilator that inhibits PDE5 (cGMP specific). increased cAMP in SM caues dilation.

Question 44

Spironolactone

Answer 44

1 - an aldosterone antagonist and hence K sparing diuretic
2 - competes for the cytoplasmic steroid receptor
3 - metabolised to canerone which, along with its K salt potassium canrenoate acts as a K sparing diuretic
4 - effect is only significant when distal tubule cells are under the influence of aldosterone. As the mech depends on channel turnover the rate of onset is slow.
5 - can be used with loop or thiazide diruetics to counteract hypokalaemia.

Question 45

Streptokinase

Answer 45

1 - from haemolytic streptococci
2 - binds plasminogen activator to cause plasmin generation. plasmin being a protease that hydrolyses arg-lys bonds.
3- leads to the degredation of fibrin in clots (and clotting factors 2, 5 and 7)
4 - 47kDa.

Question 46

Tirofiban

Answer 46

1 - a non-peptide inhibitor of the glycoprotein 2b/3 receptor. blocks the fibrinogen bridging that causes platelet aggregation in clot formation.
2 - used to prevent myocardial infarcts in patients with unstable angina or in those who’ve recently had certain types of myocardial infarc.

Question 47

Tranexamic Acid

Answer 47

1 - an analogue of aminocaproic acid.
2 - chemically similar to lysine
3 - competitively inhibts plasminogen activation
4 - prevents excessive clots lysis which would cause severe bleeding

Question 48

Triamterene

Answer 48

1 - a K sparing diuretic
2 - blocks apical Na channels in the late distal tubule, less Na driven out basement membrane hence less K into cell hence less K out channel into lumen.
3 - diuresis is weak but spares K.

Question 49

Warfarin

Answer 49

1 - given orally
2 - an anticoagulant as it inhibits the synthesis of clotting factors 2, 7, 9 and 10 as well as regulatory factors prteins c, s and z.
3 - similar uses as heparin but also used to prevent clotting on prosthetic heart valves or reoccurance of clots.
4 - dosing is complicated as it interacts with many other drugs and foodstuffs.
5 - can be used as a rodenticide but resistance is appearing.

Question 50

Probenecid

Answer 50

1 - inhibits uric acid reabsorption by competing for the same carrier in the PCT
2 - used to treat gout which results from the deposition of sodium urate crystals in the synovial tissue of joints.

Question 51

procainamide

Answer 51

1 - class 1A antidysrhythmic
2 - increases AP duration by blocking pd gated Na channel with intermediate rate of association/dissociation.

Question 52

Flecainide

Answer 52

1 - class 1C antidysrhythmic
2 - no affect on AP but v slow association/dissociation
3 - only used for unusual conditons such as Paroxysmal Supraventricular Tachycardia
(PSVT)

Question 53

Rolipram

Answer 53

1 - an inodilator that blocks PDE4 (cAMP specific)

Question 54

Dabigatran

Answer 54

1 - a thrombin inhibitor.
2 - approved by NICE in October 2012 for patients with atrial fibrillation and one other risk factor for stroke.
3 - evidence that it can reduce risk by up to 40% vs warfarin
4 - the issue is it’s far more expensive - £2.30 a day rather than 3 pence for warfarin.

Question 55

Aliskiren

Answer 55

1 - new renin inhibitor hence blocks angiotensinogen to angiotensin 1