Pharmacology chapters
Antianginal and antiarrhythmic drugs
How nitrates, beta blockers, calcium channel blockers and newer agents relieve angina, nitrate tolerance and interactions, and the Vaughan Williams classes of antiarrhythmic drugs with their key members (lidocaine, flecainide, amiodarone, adenosine, verapamil, digoxin) and adverse effects; plus antiplatelets, anticoagulants and statins used in coronary disease.
- Nitrates (glyceryl trinitrate, isosorbide mononitrate) release nitric oxide → cGMP → smooth muscle relaxation, mainly venodilation (less preload, less oxygen demand) plus coronary dilation; sublingual GTN avoids first-pass; adverse effects headache, flushing, postural hypotension, reflex tachycardia; tolerance is prevented by a nitrate-free interval; never combine with sildenafil (severe hypotension).
- Vaughan Williams classes: I sodium channel blockers (Ia quinidine, procainamide; Ib lidocaine for ventricular arrhythmias; Ic flecainide, avoided in structural heart disease), II β blockers, III potassium channel blockers (amiodarone, sotalol: prolong QT), IV calcium channel blockers (verapamil, diltiazem); plus adenosine (first-line drug for terminating SVT; very short-acting, avoid in asthma), digoxin, atropine and magnesium (torsades de pointes).
- Amiodarone adverse effects: pulmonary fibrosis, hypo- or hyperthyroidism, liver toxicity, corneal deposits, photosensitivity and blue-grey skin, peripheral neuropathy, many interactions (raises warfarin and digoxin levels).
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Angina: the aim of treatment
Angina occurs when myocardial oxygen demand exceeds supply. Demand rises with heart rate, contractility and wall tension (preload and afterload). Drugs either reduce demand or increase supply.
Antianginal drugs
Nitrates
Glyceryl trinitrate (GTN) (sublingual spray or tablet, IV, patch), isosorbide dinitrate and isosorbide mononitrate (oral, long-acting).
Mechanism: release nitric oxide (NO) → activates guanylyl cyclase → cGMP ↑ → smooth muscle relaxation.
- Venodilation (main effect at usual doses) → less venous return → less preload → less wall tension and oxygen demand.
- Arterial and coronary dilation at higher doses; relieves coronary spasm (Prinzmetal angina).
Pharmacokinetics: GTN has high first-pass metabolism, so it is given sublingually (acts within 1–3 minutes, lasts about 30 minutes), transdermally or IV. Isosorbide mononitrate has no first-pass loss.
Uses: acute angina relief and prevention, unstable angina, acute heart failure and pulmonary oedema, hypertensive emergencies (IV), oesophageal spasm, anal fissure (topical).
Adverse effects: throbbing headache (commonest), flushing, postural hypotension, dizziness, reflex tachycardia; methaemoglobinaemia (large doses).
Tolerance: continuous use quickly reduces effect. Prevented by a nitrate-free period of several hours each day (for example, asymmetric dosing of isosorbide mononitrate, or removing patches at night).
Nitrates + phosphodiesterase-5 inhibitors (sildenafil, tadalafil) → both raise cGMP → severe hypotension. Contraindicated together.
Monday disease: workers exposed to nitrates develop tolerance during the week, lose it at the weekend, and get headaches on Mondays.
Other antianginal drugs
| Drug | Mechanism | Notes |
|---|---|---|
| β blockers (atenolol, bisoprolol, metoprolol) | ↓ heart rate and contractility → less demand; longer diastole → better coronary filling | First-line for stable angina; reduce mortality after MI; avoid in Prinzmetal angina |
| Calcium channel blockers | Vasodilation (amlodipine); ↓ rate (verapamil, diltiazem) | First-line alternative; drug of choice for Prinzmetal (vasospastic) angina |
| Nicorandil | Potassium channel opener + nitrate action | Add-on; oral and anal ulceration |
| Ivabradine | Inhibits the If ("funny") pacemaker current of the sinoatrial node, lowering heart rate | For people in sinus rhythm who cannot take β blockers; visual phosphenes |
| Ranolazine | Inhibits late sodium current | Add-on; prolongs QT |
Prevention of events in coronary disease: aspirin, statin, ACE inhibitor (selected patients), β blocker after MI, stopping smoking.
Antiarrhythmic drugs: Vaughan Williams classification
| Class | Mechanism | Drugs | Key points |
|---|---|---|---|
| Ia | Block Na⁺ channels (moderate); prolong action potential | Quinidine, procainamide, disopyramide | Prolong QT (torsades); quinidine: cinchonism (tinnitus, headache), diarrhoea; procainamide: drug-induced lupus; disopyramide: anticholinergic |
| Ib | Block Na⁺ channels (weak, fast on-off); shorten action potential; act on ischaemic tissue | Lidocaine (lignocaine), mexiletine, phenytoin | Ventricular arrhythmias (especially after MI); IV only (first-pass); CNS toxicity (confusion, seizures) |
| Ic | Block Na⁺ channels (strong); no effect on action potential duration | Flecainide, propafenone | SVT and AF in structurally normal hearts ("pill in the pocket"); increased deaths after MI (proarrhythmic) – avoid in structural heart disease |
| II | β blockers: ↓ SA and AV node activity | Propranolol, metoprolol, esmolol, atenolol | Rate control in AF, SVT, reduce sudden death after MI |
| III | Block K⁺ channels → prolong repolarisation (action potential and QT) | Amiodarone, sotalol (also β blocker), dronedarone, dofetilide | Amiodarone: broad spectrum (AF, VT, cardiac arrest); sotalol: torsades risk |
| IV | Block Ca²⁺ channels → slow SA and AV node | Verapamil, diltiazem | SVT, rate control in AF; avoid in VT and with β blockers; avoid in WPW with AF |
| Others | (various) | Adenosine, digoxin, atropine, magnesium sulphate | See below |
Class I = Na⁺, II = β blockers, III = K⁺, IV = Ca²⁺ ("Some Block Potassium Channels": Sodium, Beta, Potassium, Calcium).
Amiodarone
Class III but with actions of all four classes; very long half-life (weeks), large Vd; contains iodine.
Adverse effects:
- Lungs: pulmonary fibrosis, pneumonitis.
- Thyroid: hypothyroidism or hyperthyroidism (iodine load).
- Liver: raised enzymes, hepatitis.
- Eyes: corneal microdeposits (common, usually harmless), optic neuropathy.
- Skin: photosensitivity, blue-grey discolouration.
- Heart: bradycardia, QT prolongation (torsades is uncommon).
- Nerves: peripheral neuropathy.
- Interactions: inhibits CYP enzymes and P-glycoprotein → raises warfarin and digoxin levels.
Check thyroid, liver function and chest X-ray before starting and during treatment.
Other agents
- Adenosine: acts on A1 receptors → K⁺ channels open, AV node briefly blocked. First-line drug to terminate SVT (after vagal manoeuvres); given as a rapid IV bolus because its half-life is under 10 seconds. Adverse effects: transient chest tightness, flushing, breathlessness, a brief pause. Avoid in asthma (bronchospasm); effect increased by dipyridamole, reduced by theophylline and caffeine.
- Digoxin: slows AV conduction; rate control in AF, especially with heart failure.
- Atropine: symptomatic bradycardia.
- Magnesium sulphate: torsades de pointes; also digoxin-induced arrhythmias.
Drugs that prolong QT (torsades de pointes risk)
Class Ia and III antiarrhythmics (sotalol, quinidine, amiodarone), macrolides (erythromycin, clarithromycin), fluoroquinolones, antipsychotics (haloperidol), tricyclics, methadone, ondansetron, domperidone, antimalarials (quinine, chloroquine), and low potassium or magnesium.
Antithrombotic and lipid-lowering drugs in coronary disease
| Drug | Mechanism | Key points |
|---|---|---|
| Aspirin | Irreversibly inhibits platelet COX-1 → less thromboxane A2 | Low dose (75–150 mg) for secondary prevention; gut bleeding, peptic ulcer; Reye syndrome in children |
| Clopidogrel, prasugrel, ticagrelor | Block P2Y12 (ADP) receptor on platelets | Dual antiplatelet therapy after acute coronary syndrome and stents; clopidogrel is a prodrug (CYP2C19) |
| Unfractionated heparin | Activates antithrombin III → inhibits thrombin (IIa) and Xa | IV; monitor APTT; reversed by protamine; heparin-induced thrombocytopenia, osteoporosis (long use); safe in pregnancy |
| Low-molecular-weight heparin (enoxaparin) | Antithrombin III → mainly factor Xa | Subcutaneous; no routine monitoring; accumulates in renal failure; partly reversed by protamine |
| Warfarin | Vitamin K antagonist → less factors II, VII, IX, X (and proteins C, S) | Oral; monitor INR; many interactions (CYP2C9); teratogenic; reverse with vitamin K and prothrombin complex concentrate (or fresh frozen plasma) |
| Direct oral anticoagulants (apixaban, rivaroxaban, dabigatran) | Xa inhibitors; dabigatran inhibits thrombin | Fixed doses, no INR; specific reversal agents exist |
| Thrombolytics (streptokinase, alteplase) | Convert plasminogen to plasmin → dissolve fibrin | STEMI when primary PCI is not available in time, ischaemic stroke (alteplase); bleeding; streptokinase is antigenic (allergy, not repeated) |
| Statins (atorvastatin, simvastatin, rosuvastatin) | Inhibit HMG-CoA reductase (rate-limiting step of cholesterol synthesis) → more LDL receptors → lower LDL | Reduce cardiovascular events; myopathy and rarely rhabdomyolysis (higher with fibrates, macrolides, azoles), raised liver enzymes; avoid in pregnancy; taken at night for short-acting statins |
INR = (patient PT ÷ mean normal PT)^ISI
ISI = international sensitivity index of the reagent
Patient PT = 30 s, normal PT = 12 s, ISI = 1.0
INR = (30 ÷ 12)^1 = 2.5 → within the usual target 2–3 for AF or DVT
Same sample with reagent ISI = 1.2:
INR = 2.5^1.2 ≈ 3.0
Expect: nitrate mechanism (NO, cGMP, venodilation), sublingual GTN and first-pass, nitrate adverse effects, tolerance and nitrate-free interval, sildenafil interaction, drugs for Prinzmetal angina, Vaughan Williams classes with examples, lidocaine and flecainide uses and dangers, amiodarone adverse effects, adenosine for SVT, magnesium for torsades, QT-prolonging drugs, aspirin and clopidogrel mechanisms, heparin vs warfarin (monitoring and reversal), and statin mechanism and myopathy.
Quick revision
- Nitrates: NO → cGMP; venodilation; headache; nitrate-free interval; never with sildenafil.
- Stable angina: β blocker or CCB; Prinzmetal: CCB, nitrate.
- Class I Na⁺ (Ia quinidine, Ib lidocaine, Ic flecainide), II β blockers, III K⁺ (amiodarone, sotalol), IV Ca²⁺ (verapamil).
- Amiodarone: lungs, thyroid, liver, cornea, skin; ↑ warfarin and digoxin.
- SVT: adenosine (avoid in asthma). Torsades: magnesium.
- Heparin: APTT, protamine. Warfarin: INR, vitamin K.
- Statins: HMG-CoA reductase; myopathy.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
How do nitrates relieve angina?
They release nitric oxide, which raises cGMP and relaxes vascular smooth muscle; the main effect is venodilation, which lowers preload and the heart's oxygen demand.
How is nitrate tolerance prevented?
By leaving a nitrate-free period of several hours each day.
What is the first drug used to terminate supraventricular tachycardia?
Adenosine, given as a rapid intravenous bolus after vagal manoeuvres have failed.
What are the adverse effects of amiodarone?
Pulmonary fibrosis, thyroid disorders, liver damage, corneal deposits, photosensitivity and blue-grey skin, neuropathy, and interactions with warfarin and digoxin.