2.3 Lipid-Lowering & Antianginal Agents

Statins: HMG-CoA Reductase Inhibitors

Statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis. Reduced intrahepatic cholesterol upregulates LDL receptors, increasing LDL clearance from blood. Statins are grouped by intensity - the average LDL-C reduction they produce:

Adverse effects and monitoring. The muscle toxicity spectrum runs from common benign myalgia (muscle ache with normal CK) through myopathy (symptoms with elevated CK) to rare rhabdomyolysis (massive CK elevation, myoglobinuria, acute kidney injury). Check CK only when the patient reports muscle symptoms, not routinely. Statins can also raise transaminases: obtain baseline liver function tests and repeat only for symptoms of hepatotoxicity; discontinue if ALT exceeds three times the upper limit of normal. There is a small increased risk of new-onset diabetes, outweighed by cardiovascular benefit in indicated patients.

Dosing and interactions. Short-half-life statins (simvastatin, immediate-release fluvastatin) are taken in the evening when hepatic cholesterol synthesis peaks; atorvastatin and rosuvastatin have long half-lives and can be taken any time. The headline interaction is CYP3A4: simvastatin and lovastatin are CYP3A4 substrates, and co-administration with strong CYP3A4 inhibitors - clarithromycin, erythromycin, itraconazole, ketoconazole, HIV protease inhibitors - is contraindicated because plasma statin levels and rhabdomyolysis risk soar; large quantities of grapefruit juice do the same. Simvastatin also carries dose caps with moderate inhibitors (e.g., limit to 10 mg daily with diltiazem or verapamil, 20 mg with amlodipine or amiodarone). Pravastatin, rosuvastatin, fluvastatin, and pitavastatin are less CYP3A4-dependent and are safer choices with interacting drugs.

Non-Statin Lipid-Lowering Agents

• Ezetimibe inhibits the NPC1L1 transporter, blocking intestinal absorption of dietary and biliary cholesterol. As add-on therapy it lowers LDL-C a further ~18-25%, is very well tolerated, and improved outcomes when added to simvastatin (IMPROVE-IT).
• PCSK9 monoclonal antibodies (evolocumab, alirocumab) prevent PCSK9-mediated degradation of hepatic LDL receptors. Given subcutaneously every 2-4 weeks, they lower LDL-C by ~50-60% on top of statins (FOURIER, ODYSSEY OUTCOMES) and are used in familial hypercholesterolemia or high-risk patients not at goal. Main adverse effect: injection-site reactions.
• Fibrates (fenofibrate, gemfibrozil) are PPAR-alpha agonists that lower triglycerides and modestly raise HDL; their main role is severe hypertriglyceridemia to prevent pancreatitis. Gemfibrozil inhibits statin glucuronidation and the OATP1B1 transporter, raising statin concentrations - the gemfibrozil-statin combination carries a high myopathy/rhabdomyolysis risk and should be avoided; fenofibrate is the preferred fibrate if combination is required. Fibrates also increase biliary cholesterol saturation (gallstones), and fenofibrate can raise serum creatinine.
• Bile acid sequestrants (cholestyramine, colestipol, colesevelam) bind bile acids in the gut, forcing hepatic conversion of cholesterol to new bile acids. They cause constipation and bloating, can raise triglycerides (avoid in hypertriglyceridemia), and bind other drugs - separate other medications by giving them at least 1 hour before or 4 hours after the sequestrant.
• Icosapent ethyl is a purified eicosapentaenoic acid (EPA) ethyl ester. In REDUCE-IT it cut major cardiovascular events by ~25% in statin-treated patients with elevated triglycerides and high cardiovascular risk; adverse effects include a small increase in atrial fibrillation hospitalizations and bleeding.

Antianginal Agents

Nitrates

Nitroglycerin (glyceryl trinitrate) sublingual tablets or spray relieve acute angina within minutes; isosorbide mononitrate/dinitrate and transdermal patches provide prophylaxis. Nitrates are converted to nitric oxide, which raises cGMP in vascular smooth muscle. Venodilation predominates, reducing preload and myocardial oxygen demand; coronary vasodilation also improves supply. Adverse effects: headache, flushing, postural hypotension, and reflex tachycardia.

Two facts dominate exam questions:

1. Tolerance: continuous, uninterrupted nitrate exposure depletes sulfhydryl groups and blunts the response within 24 hours. Prevent it with a daily nitrate-free interval of 10-12 hours (remove the patch overnight, or dose oral nitrates asymmetrically).
2. PDE5 inhibitor contraindication: combining a nitrate with sildenafil (or vardenafil) within 24 hours, or tadalafil within 48 hours, can cause profound, potentially fatal hypotension. This is an absolute contraindication. Also use caution with right ventricular infarction, severe aortic stenosis, and pre-existing hypotension.

Beta-Blockers and Calcium Channel Blockers

Beta-blockers are first-line for chronic stable angina: they lower heart rate, contractility, and blood pressure, reducing myocardial oxygen demand, and they improve post-MI survival. Avoid them in vasospastic (Prinzmetal) angina, where unopposed alpha-mediated coronary constriction can worsen spasm - calcium channel blockers are the agents of choice there. Dihydropyridines (amlodipine) and non-dihydropyridines are both effective antianginals, but remember that non-DHPs are avoided in HFrEF and must not be combined with beta-blockers.

Ivabradine and Ranolazine

Ivabradine selectively inhibits the If ("funny") current in the sinoatrial node, producing pure heart-rate reduction with no effect on contractility or blood pressure. It is used in stable angina and HFrEF for patients in sinus rhythm with a resting heart rate of 70 bpm or more despite maximally tolerated beta-blockade, or when beta-blockers are contraindicated. Adverse effects: bradycardia, phosphenes (transient luminous visual phenomena), and atrial fibrillation.

Ranolazine inhibits the late inward sodium current, reducing intracellular calcium overload in ischemic myocytes - an anti-ischemic effect with no clinically meaningful effect on heart rate or blood pressure, making it a useful add-on for refractory angina. It prolongs the QT interval (avoid other QT-prolonging drugs) and is a CYP3A4 substrate, so strong CYP3A4 inhibitors and inducers are contraindicated.

Antiplatelet Agents for Secondary Prevention

Aspirin irreversibly acetylates platelet cyclooxygenase-1 (COX-1), abolishing thromboxane A2 production for the platelet's lifespan (~7-10 days). Low doses (75-100 mg daily) are the backbone of secondary prevention; the main risks are dyspepsia and gastrointestinal bleeding.

The P2Y12 ADP receptor antagonists differ in ways the exam tests heavily:

• Clopidogrel is an irreversible P2Y12 blocker and a prodrug requiring activation, mainly by CYP2C19. CYP2C19 poor metabolizers generate less active metabolite and have higher rates of stent thrombosis and cardiovascular events. CYP2C19 inhibitors such as omeprazole and esomeprazole similarly blunt activation - prefer pantoprazole if a proton pump inhibitor is needed. Clopidogrel is the usual choice in aspirin intolerance and in dual antiplatelet therapy (DAPT).
• Prasugrel is an irreversible thienopyridine with faster, more potent, and more consistent activation than clopidogrel. It is contraindicated in patients with prior stroke or TIA (intracranial hemorrhage in TRITON-TIMI 38) and is generally avoided in patients aged 75 or older or under 60 kg body weight; it causes more bleeding than clopidogrel.
• Ticagrelor is a reversible, direct-acting P2Y12 antagonist - no metabolic activation required - and is more potent than clopidogrel. Signature adverse effects are dyspnea (adenosine-mediated), bradycardia with ventricular pauses, and hyperuricemia. It is dosed twice daily, is a CYP3A4 substrate (avoid strong inhibitors and inducers), and the concomitant aspirin dose should be kept at 100 mg or less.

After an acute coronary syndrome or coronary stent, dual antiplatelet therapy - aspirin plus a P2Y12 inhibitor - is typically continued for about 12 months, with duration individualized to ischemic versus bleeding risk.