Step 1 · Cardiovascular

Antiarrhythmics & Antianginals

Name: Antiarrhythmics & Antianginals
Creator: Veli Bakalov, MD

The Vaughan-Williams classes, the drugs for chest pain, and the lipids that cause it

Cardiovascular·Pharmacology·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Vaughan-Williams: I = Na+ block (phase 0), II = β-blockers, III = K+ block (phase 3, ↑ QT), IV = nodal Ca2+ block; II and IV act mainly on the AV node.
Class IA (quinidine, procainamide, disopyramide) prolongs QRS and QT: torsades, cinchonism with quinidine, drug-induced lupus with procainamide.
Class IB (lidocaine, mexiletine) targets ischemic, depolarized tissue: post-MI ventricular and digoxin-induced arrhythmias; toxicity is CNS (tremor, seizures).
Class IC (flecainide, propafenone) strongly widens QRS; fine in structurally normal hearts but contraindicated in structural or ischemic disease (CAST).
Amiodarone (40% iodine, half-life ~58 days) causes pulmonary fibrosis, hepatotoxicity, thyroid dysfunction, corneal deposits, and blue-gray skin: monitor PFTs, LFTs, TFTs.
Adenosine (half-life under 15 s) transiently blocks the AV node to terminate SVT; theophylline and caffeine blunt it; magnesium is first-line for torsades.
Nitrates raise NO/cGMP and venodilate to cut preload and O2 demand; never combine with PDE5 inhibitors; ranolazine blocks the late Na+ current without changing HR or BP.
Statins (HMG-CoA reductase) lower LDL most and cause myopathy (worse with fibrates); PCSK9 inhibitors and ezetimibe (NPC1L1) add LDL lowering.
Fibrates (PPAR-α) lower triglycerides most and cause gallstones; niacin raises HDL most, with flushing blunted by aspirin.

The Vaughan-Williams classification

Four classes, four targets. Class I drugs block Na+ channels (phase 0), class II are β-blockers, class III block K+ channels (phase 3 repolarization), and class IV block Ca2+ channels in nodal cells. Classes II and IV act mainly at the SA and AV nodes; classes I and III act mainly on atrial and ventricular myocytes.

Antiarrhythmic classes

Class	Drugs	Action and ECG effect	Signature toxicities
IA	Quinidine, procainamide, disopyramide	Moderate Na+ plus K+ block; ↑ QRS and QT	Torsades; cinchonism (quinidine); lupus (procainamide); heart failure (disopyramide)
IB	Lidocaine, mexiletine	Weak Na+ block; shortens action potential; favors ischemic tissue	CNS: tremor, seizures
IC	Flecainide, propafenone	Strong Na+ block; markedly ↑ QRS, QT unchanged	Proarrhythmia in structural or ischemic disease (CAST)
II	Metoprolol, esmolol	↓ cAMP and Ca2+ current; slows SA and AV nodes; ↑ PR	Bradycardia, AV block, bronchospasm, masked hypoglycemia
III	Amiodarone, sotalol, dofetilide, ibutilide	K+ block; prolongs repolarization and QT	Torsades; amiodarone organ toxicity
IV	Verapamil, diltiazem	Nodal Ca2+ block; ↑ PR	AV block, constipation, worsened heart failure

Class I: sodium channel blockers

Use dependence. Class I drugs slow phase 0 and bind preferentially to channels in rapidly firing, depolarized tissue, so they act most on fast rhythms and ischemic myocardium. Na+-blocking strength runs IC > IA > IB; the subclasses differ in their effect on action-potential duration and QT.

IA. Quinidine, procainamide, and disopyramide (mnemonic: Double Quarter Pounder) moderately block Na+ and also block K+, widening the QRS and prolonging QT, with a risk of torsades. Quinidine causes cinchonism (tinnitus, headache); procainamide causes drug-induced lupus with anti-histone antibodies; disopyramide depresses contractility and can precipitate heart failure.

IB. Lidocaine and mexiletine weakly block Na+ and shorten the action potential. Their preference for ischemic, depolarized tissue suits them to post-MI ventricular arrhythmias and digoxin-induced arrhythmias. Lidocaine toxicity is mainly neurologic: tremor and seizures.

IC. Flecainide and propafenone block Na+ strongly, markedly widening the QRS with no effect on QT. They are used for SVT and atrial fibrillation in structurally normal hearts.

Class IC drugs are contraindicated in structural or ischemic heart disease: in the CAST trial, flecainide and encainide increased mortality after MI.

Classes II, III, and IV

Class II. β-blockers such as metoprolol and esmolol lower cAMP and Ca2+ currents, flattening nodal phase 4 and slowing AV conduction (longer PR). They are used for rate control and after MI; esmolol's very short action suits IV titration. β-blocker overdose is treated with glucagon.

Class III. Amiodarone, sotalol, dofetilide, and ibutilide block K+ channels, prolonging repolarization, the effective refractory period, and QT, with a risk of torsades. Sotalol also blocks β-receptors.

Amiodarone. Has class I, II, and IV activity as well. It is lipophilic, about 40% iodine by weight, and accumulates in tissues, producing pulmonary fibrosis, hepatotoxicity, hypo- or hyperthyroidism, corneal deposits, blue-gray skin, and photosensitivity; monitor PFTs, LFTs, and TFTs. Torsades is uncommon despite QT prolongation, and CYP inhibition raises warfarin and digoxin levels.

~58 daysamiodarone half-life — why toxicity lingers

40%iodine content of amiodarone by weight

<15 sadenosine half-life

Class IV. Verapamil and diltiazem block L-type Ca2+ channels in the SA and AV nodes, slowing conduction for rate control in atrial fibrillation and for SVT.

Adenosine, magnesium, and digoxin

Adenosine. Acting on A1 receptors, it increases K+ efflux (hyperpolarizing nodal cells) and reduces Ca2+ current, transiently blocking AV nodal conduction to terminate paroxysmal SVT. Effects are brief: flushing, chest pressure, a sense of impending doom, bronchospasm, and transient asystole. Theophylline and caffeine, adenosine receptor antagonists, blunt its effect.

Magnesium. IV magnesium is first-line for torsades de pointes and for digoxin-toxic arrhythmias.

Digoxin. Besides positive inotropy, it raises vagal tone to slow AV nodal conduction, providing rate control in atrial fibrillation.

Antianginal drugs

Nitric oxide releasedcGMP rises and vascular smooth muscle relaxes.
VenodilationBlood pools in capacitance veins, reducing preload.
Lower wall stressA smaller ventricle needs less oxygen.

Nitrates. Nitroglycerin and isosorbide dilate veins more than arteries, cutting preload and myocardial O2 demand. Side effects: reflex tachycardia, headache, flushing, and tolerance, which a daily nitrate-free interval prevents.

Nitrates plus PDE5 inhibitors such as sildenafil cause life-threatening hypotension.

Ranolazine. Inhibits the late inward Na+ current, reducing Na+-driven Ca2+ overload and diastolic wall tension. It treats refractory angina without changing heart rate or blood pressure.

β-blockers and calcium channel blockers. β-blockers lower heart rate and contractility and blunt nitrate-induced reflex tachycardia, so the pair works better than either alone. In vasospastic (Prinzmetal) angina, calcium channel blockers and nitrates are preferred.

Lipid-lowering drugs

Lipid drugs by dominant effect

Drug	Mechanism	Main effect	Adverse effects
Statins	Inhibit HMG-CoA reductase, the rate-limiting step of cholesterol synthesis; hepatocytes up-regulate LDL receptors	↓ LDL most	Hepatotoxicity (↑ LFTs), myopathy and rhabdomyolysis, worse with fibrates
Ezetimibe	Blocks intestinal cholesterol uptake via NPC1L1	↓ LDL	Few; diarrhea
PCSK9 inhibitors	Evolocumab, alirocumab prevent LDL-receptor degradation	Large ↓ LDL	Injection-site reactions
Fibrates	Gemfibrozil, fenofibrate activate PPAR-α, boosting lipoprotein lipase	↓ Triglycerides most	Myopathy (especially with statins), cholesterol gallstones
Bile acid resins	Bind bile acids, diverting hepatic cholesterol into bile acid synthesis	↓ LDL	GI upset, poor absorption of fat-soluble vitamins and other drugs
Niacin	Reduces hepatic VLDL production and adipose lipolysis	↑ HDL most; ↓ triglycerides	Flushing (blunted by aspirin), hyperglycemia, hyperuricemia