Therapeutic Approaches for Angina

Therapeutic approaches for angina • Aims: relieving symptoms and improving survival (preventing infarction) Stable angina • Reduce cardiac workload e.g. organic nitrates, beta-blockers, Ca channel blockers • Thrombosis prophylaxis e.g. antiplatelet drugs such as aspirin • Treat atheromatous disease e.g. by lowering cholesterol using statins Unstable angina • Admission to hospital for bed rest with continuous telemetry monitoring • IV access should be obtained and supplemental O2 started • Standard therapy as for stable angina • Use of heparin or other anticoagulant/antiplatelet agents Classes of drugs used to treat stable angina • Vasodilators (dilate arteries and veins) o Calcium‐channel blockers o Nitrodilators • Cardioinhibitory drugs (reduce workload i.e. heart rate and contractility and thus O2 demand) o Beta‐blockers o Calcium‐channel blockers • Anti‐thrombotic drugs (prevent thrombus formation) o Anticoagulants o Anti‐platelet drugs Organic nitrates • Organic nitrates release nitric oxide → NO donors • Mechanism: o Organic nitrates → NO → activation of guanylate cyclase → cGMP → Ca2+ → vasodilatation → ▪ Effect on preload: by dilating peripheral veins ▪ Effect on afterload: by preferably dilating larger muscular arteries ▪  coronary collateral circulation and relief coronary spasm Molecular action of nitrates in smooth muscle Clinical uses of organic nitrates • Stable/unstable angina • Acute heart failure • Chronic heart failure • Examples: o Glyceral trinitrate (nitroglycerin) ▪ Rapidly inactivate by first hepatic pass metabolism ▪ Sublingually (tablets or spray) for acute episodes of angina ▪ 30mins effective duration o Isosorbide mono and dinitrate ▪ Longer acting (t1/2: 4 hrs) ▪ Oral drugs for prevention of angina • Adverse effects o Throbbing headache o Postural hypotension o o o Dizziness/light-headedness Facial flushing Tachycardia Nitrate tolerance • Despite clear benefits when given acutely the organic nitrates rapidly lose their hemodynamic and clinical effectiveness when used as sustained therapy • Occurs more common when o Use of longer lasting organic nitrates e.g. isosorbide mononitrate o Frequent use of glyceryl trinitrate (e.g. IV) ‐AR antagonists (beta‐blockers) • Mechanism of action: 1‐ antagonists →  heart rate and contractility →  oxygen consumption and allows time for more filling • Clinical uses: o Prophylaxis of anginal pain, often together with nitrates o Treating unstable angina o  risk of death following MI • Adverse effects: dizziness, headache, fatigue, bradycardia, cold peripheries, hypotension, nightmares and depression Calcium channel blockers/antagonists • Mechanism of action: Ca antagonists →  opening L-type VoC channels → o Cardiac effects: reduced cardiac contractility and rate o Dilatation of arteries/arterioles including coronary arteries • Clinical uses o Cardioselective: verapamil > diltiazem > nifedipine o Angina (especially variant angina) o Anti-arrhythmia (e.g. supraventricular tachycardia) o Hypertension • Adverse effects o Hypotension o Headache o Facial flushing o Constipation (verapamil) o Cardiac failure/heart block (verapamil) K+ channel activator – nicorandil • Nicorandil is an anti-angina medication that has the dual properties of a nitrate and a opener of mitochondrial ATP sensitive potassium channels o Mechanism of cardioprotection by KATP channels remains controversial ▪ One hypothesis: activate KATP channels →  K+ efflux → hyperpolarization → change of membrane potential → switch-off voltage-operated calcium channels →relaxation of vascular SM o NO donor →  NO • Clinical use: 2nd line treatment for those who remain symptomatic despite optimal treatment with other drugs • Adverse effects: headache, flushing, dizziness Anti-platelet drug – aspirin • Useful for prevention of thrombus formation in angina • Mechanism of action: inhibit COX-1 irreversibly →  synthesis of thromboxane A2 (TXA2) → change ratio of TXA2/ PGI2 → inhibit platelet aggregation • Clinical use: o Thromboprophylaxis → low doses selectively block TXA2 o Clinical trials show significant reductions of vascular deaths associated with MI • Adverse effects: o Gastric bleeding o Allergic reaction o Tinnitus and deafness o Mental confusion, convulsion o Renal failure