Cardiovascular Pharmacology

Question 1

Mechanism of action of catecholamines

Answer 1

B-agonists

Question 2

Describe the Vaughan-Williams classification of antiarrhythmics and how they relate to the action potential.

Answer 2

1. Na+ channel blockers (e.g. procainamide, lidocaine, flecainide); acts at phase 0 (inward Na+ channels) of the action potential
2. Beta-blockers: acts at phase 4 (K+ rectifier channels) of the action potential
3. K+ channel inhibitor (e.g. amiodarone); acts at phase 3 (K+ outward channels) of the action potential
4. Ca2+ blockers/CCBs (e.g. verapamil, diltiazem); acts at phase 2 (Ca2+ inward channels) of the action potential

Question 3

Name the side effects and contraindications of ACEis and ARBs.

Answer 3

• cough (due to increased bradykinin) in ACEis
• angioedema, hyperkalaemia, first-dose hypotension
• C/I: pregnancy/breastfeeding, renovascular disease, idiopathic angioedema, high-dose furosemide (hypotension)

Question 4

Describe the selective nature of beta-blocker drugs.

Answer 4

• selectivity of action on different beta-adrenergic receptors (B1 in the heart, B2 in the lungs)
• cardioselective (B1): remember A-N, e.g. atenolol, bisoprolol, esmolol, metoprolol
• non-selective (B1 + B2): remember O-Z, e.g. labetalol, nadolol, propranolol, sotalol, timolol; carvedilol is the main important exception in this class

Question 5

Describe the main adverse effects of beta-blockers.

Answer 5

• cardiac: bradycardia, heart block
• pulmonary: bronchospasm, particularly in asthma
• metabolic: deranged glucose control
• other: headache, constipation

Question 6

Describe how CCB drugs are classified.

Answer 6

• CCBs are classified as either non-dihydropyridines (rate-limiting) or dihydropyridines (non-rate-limiting)
• Rate-limiting: indicated in arrhythmia, and include verapamil and diltiazem; s/e are related to the myocardium (e.g. heart failure, hypotension, bradycardia, peripheral oedema, constipation)
• Non-rate-limiting: indicated in hypertension, and end in ‘-dipine’ (e.g. amlodipine, lercandipine, nifedipine); s/e are related to vasodilatation (e.g. flushing, headache, peripheral oedema)

Question 7

Describe the broad classification of diuretic drugs.

Answer 7

• loop diuretics (e.g. furosemide, bumetanide) - Na/K/Cl cotransporter in the thick ascending limb
• thiazide diuretics (e.g. bendroflumethiazide, hydrochlorothiazide) - Na/Cl transporter in the distal convoluted tubule (DCT)
• thiazide-like diuretics (e.g. chlortalidone, indapamide)
• mineralocorticoid receptor antagonists (MRAs) (e.g. spironolactone, epleronone) - affects aldosterone receptors in the DCT
• K+-sparing (e.g. amiloride, triamterene) - epithelial Na+ channels in the collecting duct

Question 8

Describe the electrolyte disturbances observed with different diuretic types.

Answer 8

• loop: reduced Na+, K+ Mg2+, Ca2+
• thiazide and thiazide-like: reduced Na+, K+, elevated Ca2+
• MRAs and K+-sparing: hyperkalaemia (particularly when used in combination with ACEis)

Question 9

Name the salient adverse effects observed with diuretic use (excluding electrolyte imbalance).

Answer 9

• loop: nephrotoxicity, ototoxicity, impaired glucose tolerance, gout (less so than thiazides)
• thiazides: dehydration, postural hypotension, impaired glucose tolerance, impotence, gout (more so than loops) and agranulocytosis, pancreatitis (rare)
• MRAs: breast tenderness, gynaecomastia

Question 10

?Mechanism of action of glycosides

Answer 10

Affects ion channels

Question 11

Mechanism of action of anti-muscarinics

Answer 11

Blocks ACh reaching cardiac receptors

Question 12

?Mechanism of action of PDE inhibitors

Answer 12

Increase intracellular cAMP

Question 13

Mechanism of action of nitric oxide (NO)

Answer 13

Increases action of guanylyl cyclase, increasing [cGMP]i

Question 14

?When would a renin inhibitor be used? Name the main one.

Answer 14

Aliskiren, for essential hypertension

Question 15

?Which two drugs reduce afterload and vasodilate but their mechanism is uncertain?

Answer 15

Hydralazine, propofol

Question 16

?Why should hydralazine be taken with care?

Answer 16

Can cause an autoimmunity resembling lupus

Question 17

Which class of drug potentiates nitric oxide and cGMP?

Answer 17

Nitrates (i.e. GTN)

Question 18

?What is the purpose of digoxin?

Answer 18

Improves symptoms, no effect on mortality

Question 19

Mechanism of ivabradine

Answer 19

Blocks the pacemaker If current

Question 20

Mechanism of statins

Answer 20

• statins block HMG-CoA-reductase
• increase HDL, lowers LDL (by increasing LDL receptor expression in the liver)

Question 21

What are the side effects of statins?

Answer 21

• common: headache, dizziness, nausea, fatigue, digestive system problems, muscle pain
• uncommon: hair loss, hepatitis, pancreatitis, loss of libido, erectile dysfunction
• rare: myopathy, peripheral neuropathy, rhabomyolysis

Question 22

Describe the dosing of atorvastatin in relation to prevention of cardiovascular disease.

Answer 22

• familial hypercholesterolaemia: 10mg OD initially
• primary prevention: 20mg OD initially
• secondary prevention: 80mg OD
• maximum dose is 80mg

Question 23

Describe the main drug interactions of statins.

Answer 23

• antibiotics (macrolides) and antifungals (azoles) are contraindicated; statin therapy needs to be stopped throughout treatment (these are potent CYP3A4 inhibitors)
• amiodarone, CCBs (diltiazem, verapamil), and ciclosporin require monitoring and reduction of statin dose
• warfarin: requires monitoring of INR throughout treatment, especially when dose of warfarin is changed

Question 24

?Which types of drug prevent breakdown of BNP?

Answer 24

Neprilysin inhibitors

Question 25

Describe the broad classification of anticoagulation agents.

Answer 25

there are 3 main classes: vitamin K antagonists (VKAs), DOACs, and heparins. they work at different points in the coagulation cascade. * VKA: warfarin. affects factors X, IX, VII, II (remember 1972) and proteins C and S * DOAC agents: divided into factor Xa (direct, indirect) and factor IIa (thrombin) inhibitors * heparins: divided into unfractionated (UFH) and low molecular weight (LMWH)

Question 26

Name the main anticoagulant drugs and their classes.

Answer 26

* VKAs: warfarin * direct Xa DOACs: api**xa**ban, rivaro**xa**ban, edo**xa**ban * indirect Xa DOAC: fondaparinux * direct IIa DOACs: dabigatran, argatroban, bivalirudin * heparin: UFH * LMWH: dalte**parin** (Fragmin), enoxa**parin**

Question 27

Describe the pharmacological differences between UFH and LMWHs.

Answer 27

* LMWHs (-***parins***) activate antithrombin III, which in turn inhibits factor Xa. it has a slower onset of action than UFH (2-6hr) * UFH: as well as activating antithrombin III (for factor Xa), UFH also has a site for IIa (thus, blocks both Xa and IIa)

Question 28

Describe the use of anticoagulation in renal disease.

Answer 28

* heparins are preferred over DOACs; UFH is also preferred over LWMH as it has a faster onset of action, a lesser association with bleeding, and is easier to reverse * if the DOACs are to be used, they require dose adjustment (as most are heavily renally excreted) * warfarin is safe to use in renal disease alongside INR monitoring

Question 29

Describe heparin-induced thrombocytopaenia (HIT).

Answer 29

* an immune mediated process, where antibodies form against complexes of platelet factor 4 (PF4) and heparin * classic presentation is a >50% reduction of platelets in the context of recently starting heparin therapy * if anticoagulation is still required (as in most cases), this should be given as a direct IIa inhibitor (e.g. argatroban, bivalirudin)

Question 30

Describe the main worrying side effects of warfarin therapy.

Answer 30

* bleeding (e.g. bruising, prolonged bleeding from cuts, gums, GI/GU); treated with vitamin K * skin necrosis: painful, localised skin lesions, due to thrombosis of venules and capillaries within SC fat; can notably occur with normal INR range; warfarin should be stopped * calciphylaxis: vascular calcification with cutaneous necrosis

Question 31

Describe the salient drug interactions of warfarin (e.g. enhancers and reducers).

Answer 31

* P450 inhibitors reduce warfarin clearance and increase INR. May be remembered as **ASS-ZOLES**: **A**ntibiotics (ciprofloxacin, erythromycin), **S**SRIs, **S**odium valproate, **-zoles** (antifungals, omeprazole) * P450 inducers increase warfarin clearance and lower INR. May be remembered as **SCARS**: **S**moking, **C**hronic alcohol intake, **A**ntiepileptics (excluding sodium valproate), **R**ifampicin, and **S**t. John's wort

Question 32

Define INR.

Answer 32

* international normalised ratio * derived from the prothrombin time (PT), which is collected as a ratio of the patient's PT to a control PT standardised by the WHO * e.g., INR = patient PT/control PT * PT (time, s) is measured in the plasma to form a clot in the presence of sufficient concentration of calcium and tissue thromboplastin by activating coagulation via the extrinsic pathway

Question 33

Describe the different target INR values.

Answer 33

* 2.5: 'standard' INR target * 3.0: target prior to cardioversion (4 weeks) * 3.0: aortic valve metal prosthesis * 3.5: mitral valve metal prosthesis * 3.5: recurrent VTE in people already recieving anticoagulation and with an INR >2

Question 34

Describe the management of a raised INR (including major bleeding).

Answer 34

* assess for signs of minor bleeding if major bleeding (e.g. variceal haemorrhage, intracranial haemorrhage) is absent **no signs of bleeding** * INR 5-8: withhold 1-2 doses, reduce subsequent dose * INR >8: stop warfarin, PO vitamin K 1-5mg, repeat vitamin K if necessary after 24hr, restart warfarin when INR <5 **minor bleeding** * INR 5-8: stop warfarin, IV vitamin K 1-3mg, restart warfarin when INR <5 * INR >8: stop warfarin, IV vitamin K 1-3mg, repeat vitamin K if necessary after 24hr, restart when INR <5 **major bleeding** * stop warfarin, IV vitamin K 5mg, give prothrombin complex (FFP if not available)