Cardiovacular and Renal Pharmacology

Question 1

Lidocaine

Answer 1

Local anaesthetic that stabilizes V-gated Na+ channels in their inactivated state and make it harder for them to reactivate. These drugs can also be used as Class 1B antidysrhyrhic stop modify the form of the cardiac action potential. It has very fast association and dissociation properties, causing decreased AP duration.

Question 2

Nifedipine

Answer 2

Dihydropyradine that acts on the α subunit of the Ca2+ channel. Photo-affinity labeling reveals 2 binding sites: 1. At segment 6 and S5/S6 loop on domain III2. At S5/S6 loop on domain IV.

Question 3

Verapamil

Answer 3

A phenylalkylamine that acts on V-gated Ca2+ channels. Its binding site has been shown to be the 42αα region that makes up S6 and part of S5/6 loop in domain IV. Also a class IV antidysrhythmic. It is cardioselective, reducing Ca2+ entry. It has limited use as it can compromise excitation-coupling process.

Question 4

Diltiazam

Answer 4

A benzothiazipine that actas in a similar manner to phenylalkylamines, but binds at a separate site. They do modulate DHP binding

Question 5

Spermine (Not a pharmaceutical agent but still bold)

Answer 5

Endogenous intracellular tetravalent polyamine that is important in the occlusion of inward rectifying K+ channels.

Question 6

Quinidine

Answer 6

Class 1A Antidysrhythmic that has an intermediate rate of association and dissociation. Causes increased action potential duration.

Question 7

Procainamide

Answer 7

Class 1A Antidysrhythmic that has an intermediate rate of association and dissociation. Causes increased action potential duration.

Question 8

Flecainide

Answer 8

Class 1C Antidysrhythmic that has no effect on the AP with slow rates of association/dissociation.

Question 9

Propranolol

Answer 9

Class II antidysrhythmic, sympathetic antagonist. General all-round use in cardiac pathologies

Question 10

Atenolol

Answer 10

Class II antidysrhythmic, sympathetic antagonist. General all-round use in cardiac pathologies

Question 11

Amiodarone

Answer 11

Class III antidysrhythmic with a complex mode of action. It prolongs the AP and thus also the refractory period. It us used to treat re-entrant or ventricular dysrhythmias.

Question 12

Digoxin

Answer 12

Cardiac glycoside. Inhibits the Na+/K+ ATPase which leads to a reduction in the Na+ gradient lowering the driving force for Ca2+ extrusion, resulting in increased intracellular calcium levels and increased contractile force. Digoxin and digitoxin are the most commonly used clinically.

Question 13

Oubain

Answer 13

Cardiac glycoside. Inhibits the Na+/K+ ATPase which leads to a reduction in the Na+ gradient lowering the driving force for Ca2+ extrusion, resulting in increased intracellular calcium levels and increased contractile force. Oubain is too powerful to be used clinically, but useful experimentally.

Question 14

Dobutamine

Answer 14

β1-selective agonist. Analogue of dopamine. It is used intravenously for rapid effect. Its ionotropic effect is greater than its chronotropic effect. It is used in cardiogenic shock and open heart surgery.

Question 15

Bisoprolol

Answer 15

3rd generation β1 antagonist (also: Carvedilol). Used to limit the damaging effects of chronic stimulation by catecholines and to improve cardiac function. Used to treat stable heart failure. Overinhibition is a big danger, so drug doses need to be carefully titrated and cardiac function carefully monitored.

Question 16

Carvedilol

Answer 16

3rd generation β1 antagonist (also: Bisoprolol). Used to limit the damaging effects of chronic stimulation by catecholines and to improve cardiac function. Used to treat stable heart failure. Overinhibition is a big danger, so drug doses need to be carefully titrated and cardiac function carefully monitored.

Question 17

Milrinone

Answer 17

Phosphodiesterase type III inhibitor, aka an inodilator. Intracellular cAMP levels rise and mimic the effects of β adrenoreceptor stimulation, so may lead to dysrhythmics. Its use is limited to short term treatment of severe heart failure unresponsive to more conventional therapies.

Question 18

Dipyridamole

Answer 18

Phosphodiesterase Type V inhibitor

Question 19

Sildenafil

Answer 19

Phosphodiesterase Type V inhibitor (aka viagra)

Question 20

Caffeine

Answer 20

Methylxanthine that acts as a non-selective PDE inhibitor. Also an A1 and A2 receptor antagonist, and can cause release of Ca2+ from intracellular stores. The combination of the PDE inhibition and adenosine antagonism produces positive inotropic and chronotropic effects, so methylxanthines increase the likelihood of dysrhythmias developing.

Question 21

IBMX (Isobutylmethylxanthine)

Answer 21

Methylxanthine that acts as a non-selective PDE inhibitor. Also an A1 and A2 receptor antagonist, and can cause release of Ca2+ from intracellular stores. The combination of the PDE inhibition and adenosine antagonism produces positive inotropic and chronotropic effects, so methylxanthines increase the likelihood of dysrhythmias developing.

Question 22

Pimobendan

Answer 22

A “calcium sensitizer”. It sensitises and increases the cardiac Ca2+ binding effiency without a requirement for more energy consumption. It also cause peripheral vasodilation by inhibiting PDE type III. It is used to treat canine dilated cardiomyopathy.

Question 23

Levosimendan

Answer 23

A calcium sensitizer. It sensitises and increases the cardiac Ca2+ binding effiency without a requirement for more energy consumption. It also cause peripheral vasodilation by inhibiting PDE type III. Used in hospitals outside the UK for heart failure.

Question 24

Streptokinase

Answer 24

47kDa protein that causes the generation of plasmin by binding to a plasminogen activator. This leads to the degradation of the fibrin in clots (as well as the breakdown of clotting factors II, V and VII). The protein is produced by haemolytic streptococci, which can cause haemolytic anaemia.

Question 25

Anistreplase

Answer 25

A combination drug of plasminogen and anisoylated streptokinase. The streptokinase is inactive until the anisoyl group is removed in the blood, which happens relatively slowly- it has a half life of 2 hours.This gives the drug a more prolonged effect than streptokinase alone.

Question 26

Alteplase

Answer 26

A single chain recombinant human tissue plasminogen activator. These have a greater preference for plasminogen bound to fibrin, so action is localised.

Question 27

Duteplase

Answer 27

A double chain recombinant human tissue plasminogen activator. It has greater activity on plasminogen bound to fibrin in clots, so its action is localised.

Question 28

Aspirin

Answer 28

Given in low oral dose alongside plasminogen activators to prevent further thrombosis, limiting platelet aggregation. It is given at a much lower dose (1/4 tablet) than when used as a painkiller, so as to avoid severe gastric irritation and ulcer formation.

Question 29

Clopidogrel

Answer 29

When combined with low dose aspirin it can improve morbidity and mortality. In inhibits platelet aggregation by inhibiting the binding of ADP to its receptor on platelets.

Question 30

Eptifibatide

Answer 30

Cyclic heptapeptide inhibitor of the glycoprotein IIb/IIIa receptor, which is needed for the fibrinogen binding between platelets that causes aggregation. used for the prevention of MI or in patients who have recently suffered an MI.

Question 31

Tirofiban

Answer 31

Non-peptide inhibitor of the glycoprotein IIb/IIIa receptor, which is needed for the fibrinogen binding between platelets that causes aggregation. It is used frequently for common conditions such as unstable angina.

Question 32

Abciximab

Answer 32

A monoclonal antibody against the receptor which also binds to the vitronectin (a molecule involved in in cell adhesion and haemostasis) receptor on platelets, endothelial cells and vascular smooth muscle cells. Its use is limited to coronary angioplasty for coronary artery throbosive as its so expensive.

Question 33

Heparin

Answer 33

A naturally occurring anticoagulant produced by basophils and mast cells. It binds to the enzyme inhibitor antithrombin III causing a conformational changes, activating it. Antithrombin III inactivates thrombin and other proteases involved in blood clotting. It can be used for unstable angina after myocardial infarction and also prophylactically for DVT and clot formation during surgery.

Question 34

Warfarin

Answer 34

A drug that inhibits clotting and can be given orally. In inhibits the synthesis of clotting factors II, VII, IX and X as well as regulatory factors protein C, S and Z. It is used for people with increased tendency for thrombosis or individuals who have already formed a blood clot. Also to prevent slot formation on prosthetic heart valves. Warfarin levels need to be carefully monitored as other commonly used drugs or chemicals in foods can interfere with wafarin’s coagulation effect.

Question 35

Dabigatran

Answer 35

A thrombin inhibitor. It’s used in patients with atrial fibrillation and stroke risk factors. It’s administered prophylactically to prevent thromboembolism in individuals who have had recent knee and hip replacement surgery as these individuals are at increased risk of thromboembolism.

Question 36

Rivaroxaban

Answer 36

Factor Xa inhibitor with similar uses to dabigatran.

Question 37

Aminocaproic Acid

Answer 37

Inhibits excessive clot lysis (which can leads to severe bleeding) it completely inhibits plasminogen activation.

Question 38

Tranexamic Acid

Answer 38

An analogue of aminocaproic acid with the same effects - inhibition of excessive clot lysis through inhibition of plasminogen activation.

Question 39

Furosemide

Answer 39

Sulphanomide loop diuretic (aka high ceiling diuretic as it has the capactiy to cause a high rate of urine flow). it blocks the Na+/K+/2Cl- co-transport in the apical membrane of cells in the thick ascending limb. It is actively secreted in the proximal tubule, so its concentration in the thick ascending limb is 10-30x than in the plasma. also a weak inhibitor of carbonic anhydrase. It can cause 15-25% of filtrate to be excreted. The large reduction in fluid volume they produce is advantageous in the treatment of heart failure. It acts within 10 mins when given intravenously. it also cause venodilation, decreasing the atrial filling pressure. However it does have several side effects that are associated with loop diuretics.

Question 40

Bumetanide

Answer 40

Sulphanomide loop diuretic (aka high ceiling diuretic as it has the capactiy to cause a high rate of urine flow).

Question 41

Hydrochlorothiazide

Answer 41

Thiazide diuretic. Less powerful than loop diuretics, but can still cause loss of 10-15% of the filtered load. Some inhibition of CA, but its primary mode of action is blocking Na+/Cl- cotransport in the early distal tubules. It also has vasodilator effects, decreasing blood pressre. It is used to treat hypertension and heart failure. it carries similar side effects to the loop diuretics.

Question 42

Bendroflumethiazide

Answer 42

Thiazide diuretic. Less powerful than loop diuretics, but can still cause loss of 10-15% of the filtered load. Some inhibition of CA, but its primary mode of action is blocking Na+/Cl- cotransport in the early distal tubules. It also has vasodilator effects, decreasing blood pressre. It is used to treat hypertension and heart failure. it carries similar side effects to the loop diuretics.

Question 43

Amiloride

Answer 43

Potassium sparing diuretic that prevents Na+ re-absorption by blocking apical Na+ channels. Its diuretic effect is weak, but K+ loss is decreased.

Question 44

Triamterene

Answer 44

Potassium sparing diuretic that prevents Na+ re-absorption by blocking apical Na+ channels. Its diuretic effect is weak, but K+ loss is decreased.

Question 45

Spironolactone

Answer 45

Potassium sparing diuretic that acts as an aldosterone antagonist. it is metabolised to canrenone and it is actually the K+ salt, potassium canrenoate that works as a potassium sparing diuretic. Its effects are only significant when distal tubule cells are under the influence of aldosterone.