Vasodilator agents

===Lecture Details===
Robert Widdop; Week 12 MED1022; Pharmacology
===Lecture Content===
Angina has pain, crushing, sub-sternal, may radiate. Lasts a few minutes, causes CAD, coronary vasospasm due to insufficient O2 supply to heart (myocardial O2 demand is more than supply). Urgent medical attention is required for worsening angina, chest pain lasting more than a few minutes. There is chronic, stable angina (exercise, CAD), unstable angina (thrombi formation), variant angina (spasm of coronary artery). Precipitated by cold, stress, large meals. ST depression during angina indicates MI as might occur on exercise testing. Treatment is by modification of risk factors (smoking, obesity, hypertension, hyperlipidaemia, diabetes), surgery/angioplasty/stents, drug treatment. Drugs for angina increase coronary perfusion to increase oxygen supply, decrease metabolic demand, combination of both. Determinants of myocardial oxygen requirement are heart rate, contractility, ventricular volume, arterial pressure; venodilation causes decreased CO, decreased oxygen consumption; atrial dilation causes decreased peripheral resistance, decreased oxygen consumption. Coronary dilatation causes increased oxygen supply.
Nitrates result in release of nitric oxide in vascular smooth muscle with consequent vasodilation, particularly in veins. They have no effect on cardiac or skeletal muscle. NOS changes L-arginine to L-citrulline which creates NO, guanylate cyclase increases cGMP and decreases Ca causing relaxation. Nitrovasodilators can donate NO from their structure. Venous dilation decreases venous pressure and preload with consequent fall in cardiac oxygen consumption. Coronary dilatation eg variant angina. Decreased blood pressure is associated with reflex tachycardia which increases oxygen consumption. Nitrates have hepatic first pass metabolism, nitroglycerin is inactive orally so given sublingually or transdermally. Glyceryl nitrate (nitroglycerin) can be sublingual (lasts 30 minutes, transdermal 24 hours), isosorbide dinitrate (sublingual <2hr, oral <6hr). Used for acute angina attack, immediate prophylaxis. Adverse effects can be hypotension, tachycardia, headache, flushing. Tolerance develops after continual exposure, nitrate-free period reduces tolerance. Viagra potentiates NO donors, decreases BP, contraindicated with nitrates. Nitrates can be used prophylactically.
Calcum antagonists block L type Ca channels, reduces Ca entry into vascular/cardiac cells causing a reduction in intracellular Ca. Verapamil has greatest effects, diltiazem second, nifedipine/amlodipine last (causes increase in HR). They cause vasodilation, reduced cardiac contractility and reduced AV conduction. Indications are angina, hypertension, tachyarrhythmias. In angina there is decreased TPR and cardiac work, reduced cardiac oxygen demand. Coronary vasodilation can help variant angina (due to vessel spasm). Adverse effects are cardiac depression, bradycardia, flushing, edema, dizziness, headache, constipation, nausea. Contraindications are heart failure and beta blockers.
Beta blockers (propanolol non-selective, atenolol selective) are used in angina, hypertension, arrythmias, clinically stable heart failure. Angina has decreased oxygen demand, decreased heart rate which increases coronary artery perfusion during diastole, increased oxygen supply to the heart. Adverse effects of beta blockers can be respiratory (bronchoconstriction), CV (decreased contractility, bradycardia, exercise intolerance), brain (depression, sedation, sleep problems). Beware of beta blockers in variant angina. Unstable angina can use aspirin, dipyrimadole (increased adenosine).
===Readings===