DRUGS USED IN THE MANAGEMENT OF ANGINA PECTORIS PRESENTED BY: LEILA SINGH & RENUKA TEWARI COURSE: MED 2209 LECTURERS: DR. PARKINSON & DR. HARRIS OUTLINE Introduction Pathogenesis Drugs Used Nitrates, And Nitrites Beta-blocking Drugs Calcium Channel-blocking Drugs Miscellaneous Summary table INTRODUCTION Angina pectoris: chest pain due to the accumulation of metabolites from myocardial ischemia Common cause: CAD Types: -Stable/effort/classical -Variant/vasospastic/prinzmetal -Unstable STABLE ANGINA occurs when doing strenous activities like exercising; goes away with rest VARIANT ANGINA secondary to epicardial coronary artery spasm UNSTABLE ANGINA more severe or frequent, lasts longer, or occurs while resting. Dangerous and a warning sign of a heart attack. Seek urgent medical care. You may need hospitalization. PATHOGENESIS Oxygen demand Oxygen supply Ischemia Pain DIAGNOSIS Clinical presentation History ECG Stress test TREATMENT OF CAD First-line therapy of CAD depends on modification of risk factors such as smoking, hypertension, hyperlipidemia, obesity, In addition, antiplatelet drugs are very important along with statins. DRUGS USED IN THE MANAGEMENT OF ANGINA PECTORIS NITRATES & NITRITES CALCIUM CHANNELBLOCKING DRUGS BETA-BLOCKING DRUGS MISCELLANEOUS NITRATES AND NITRITES NITRATES & NITRITES Simple nitric and nitrous acid esters of polyalcohols Vasodilators Nitroglycerin may be considered the prototype of the group (sublingual) Inactivated in the liver; oral BA/F is low NITROGLYCERIN (GTN) -SUBLINGUAL TABLET • 0.3 to 0.6 mg sublingually or in the buccal pouch every 5 minutes as needed, up to 3 doses in 15 minutes PROPHYLAXIS: 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack • If pain persists after maximum dose, prompt medical attention is recommended -Administer while sitting down (dizziness is possible) -Store in opaque, glass containers Short duration of action (20 to 30 minutes): unsuitable for maintenance therapy. NITRATES & NITRITES Isordil (Isosorbide Mononitrate) is used long term along with GTN (short term) There are also Amyl nitrites that are: Highly volatile Short acting, unpleasant odor not used anymore Excretion by kidney NITRATES & NITRITES Pharmacodynamics Mechanism of Action in Smooth Muscle Nitric oxide released from the drugs combines with the heme group of the soluble guanylyl cyclase. This enzyme is activated causing an increase in cGMP. cGMP is an important step towards muscle relaxation. NITRATES & NITRITES NITRATES & NITRITES Pharmacodynamics Organ System effects GTN relaxes all types of smooth muscles Has no direct effect on striated muscles NITRATES & NITRITES Pharmacodynamics Organ System effects Vascular smooth muscle – all parts of the vascular system are relaxed/dilated, from the large arteries to the large veins Arterioles and precapillary sphincters are dilated the least because of their reflex responses and because different vessels release different amounts of NO from the drug. NITRATES & NITRITES Pharmacodynamics Organ System effects Vascular smooth muscle – Marked venous relaxation w venous capacitance and ventricular preload (useful in heart failure treatment) In patients w/o heart failure, there is reduced CO NITRATES & NITRITES Pharmacodynamics Organ System effects Vascular smooth muscle – • venous capacitance can orthostatic hypotension and syncope Side effects of GTN and amyl nitrates: temporal artery pulsation, throbbing headaches NITRATES & NITRITES Pharmacodynamics Organ System effects Vascular smooth muscle – Indirect effects of GTN: reflex tachycardia and increased cardiac contractility (baroreceptors and hormonal mechanisms) Salt and water retention may be prominent with intermediate and long-acting nitrates. NITRATES & NITRITES Pharmacodynamics Organ System effects Action on platelets – NO stimulates guanylyl cyclase in platelets which increases cGMP levels which causes decreased platelet aggregation. IV nitroglycerin may be of use in unstable angina pectoris because of its action on platelets (prevents progression to acute MI). NITRATES & NITRITES Side effects: orthostatic hypotension, tachycardia and throbbing headaches Nitrite ions and hemoglobin methemoglobin tissue hypoxia • External defibrillator electroshock can ignite transdermal GTN patchesburns • Contraindicated in elevated intracranial pressure. NITRATES & NITRITES Tolerance and toxicity: Carcinogenicity When nitrates or nitrites combine with amines, we get nitrosamines. Some nitrosamines are extremely carcinogenic in animals. No direct proof that they cause cancer in humans NITRATES & NITRITES Mechanisms of clinical effect Nitrate effects in angina of effort– Decreased venous return to the heart and decreased intracardiac volume reduces preload. Decreased arterial pressure reduces afterload. Decreased left ventricular pressure helps to decrease wall tension in the heart and myocardial oxygen demand. NITRATES & NITRITES Mechanisms of clinical effect Nitrate effects in variant angina– Nitrates dilate the coronary arteries and relieve coronary artery spasm. Nitrate effects in unstable angina– Nitrates dilate the coronary arteries, reduce oxygen demand of the heart and decreases platelet aggregation. BETA-BLOCKING DRUGS BETA-BLOCKING DRUGS Cause: Decreased HR, BP and contractility decrease myocardial O2 requirements at rest and during exercise Lower HR Increased Diastolic perfusion time Increased coronary perfusion BETA-BLOCKING DRUGS Examples: For stable angina only PROPANALOL: Decreases 02 requirement of heart muscle reduces chest pain on exertion Useful in chronic management BETA-BLOCKING DRUGS NADOLOL: Long duration of action Long term management BETA-BLOCKING DRUGS SIDE EFFECTS: increase in end-diastolic volume increase in ejection time both of which tend to increase myocardial oxygen requirement USE NITRATES CONCOMITANTLY TO BALANCE THE EFFECTS BETA-BLOCKING DRUGS USE IS CONTRAINDICATED IN: asthma and other bronchospastic conditions, severe bradycardia bradycardia-tachycardia syndrome severe unstable left ventricular failure. CALCIUM CHANNEL -BLOCKING DRUGS CALCIUM CHANNEL-BLOCKING DRUGS There are 5 major classes of Ca++ channel blockers are known with diverse chemical structures: Dihydropyridines: nifedipine, nimodipine, amlodipine Benzothiazepines: Diltiazem Phenylalkylamines: Verapamil CALCIUM CHANNEL BLOCKING DRUGS Diarylaminopropylamine ethers: Bepridil Benzimidazole-substituted tetralines: Mibefradil CALCIUM CHANNEL BLOCKING DRUGS The calcium channel blockers are orally active agents Arteriolar vasodilators Reduce smooth muscle tone and vascular resistance High first pass effect Strong plasma protein binding Verapamil and diltiazem are also used by the intravenous route DIHYDROPYRIDINE CLASS The drugs all end in the suffix ‘pine’ Most selective smooth muscle class Decrease SVR and arterial pressure Mostly used in the treatment of hypertension Reflex tachycardia Increased contractility PHENYLALKYLAMINE CLASS Decreases O2 demand of the heart Reverses coronary vasospasm Can cause bradycardia Used mainly in the treatment of arrhythmias and angina Should not be given with β blockers BENZOTHIAZEPINE CLASS Cardio-depressant and vasodilator effects Decreases arterial pressure Can cause bradycardia Used in the treatment of angina, arrhythmias and hypertension CALCIUM CHANNEL BLOCKING DRUGS Pharmacodynamic Mechanism of action Calcium channel blockers block voltage-gated L-type calcium channels reduce intracellular calcium concentration Resulting in long lasting relaxation of smooth muscle Reduces cardiac muscle contractility throughout the heart and decreases in sinus node pacemaker rate and atrioventricular node conduction velocity. CALCIUM CHANNEL BLOCKING DRUGS Pharmacodynamics Organ system effects Smooth muscleAre relaxed by calcium channel blockers Vascular smooth muscle is most sensitive, but similar relaxation can be shown for bronchiolar, gastrointestinal, and uterine smooth muscle. Cardiac muscleReduce/block calcium- dependent action potential Decrease contractility CALCIUM CHANNEL BLOCKING DRUGS can reduce the oxygen requirement angina patients. Skeletal muscleSkeletal muscle is unaffected by the calcium channel blockers because it uses intracellular pools of calcium to support excitation-contraction coupling CALCIUM CHANNEL BLOCKING DRUGS Tolerance and toxicity The calcium channel blockers cause: constipation, pretibial edema, nausea, flushing, and dizziness More serious adverse effects include heart failure, AV blockade, and sinus node depression; these are most common with verapamil and least common with the dihydropyridines. CALCIUM CHANNEL BLOCKING DRUGS Grapefruit juice should be avoided as it can increase the effect of verapamil. Verapamil should be used with caution in patients taking digoxin, because verapamil increases digoxin levels Fluconazole stops nifedipine from being metabolized as usual, increasing its concentration risk of side effects CALCIUM CHANNEL BLOCKING DRUGS Use is contraindicated in: Hypersensitivity to CCBs Acute coronary syndrome Severe stenotic heart valve defects Pre-existing cardiac conduction disorder CALCIUM CHANNEL BLOCKING DRUGS Clinical uses Used in the treatment of: Hypertension Supraventricular tachyarrhythmias Moderate efficacy in a variety of other conditions, including hypertrophic cardiomyopathy, phenomenon. migraine, and Raynaud’s In patients with a history of atrial tachycardia, flutter, and fibrillation, verapamil and diltiazem provide a distinct advantage because of their antiarrhythmic effects MISCELLANEOUS DRUGS Ranolazine appears to act by reducing a late sodium current (INa) that facilitates calcium entry via the sodium-calcium exchanger Metabolic modulators (eg, trimetazidine) are known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium. Bradycardic drugs, relatively selective If sodium channel blockers (eg, ivabradine), reduce cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the sinoatrial node. MISCELLANEOUS DRUGS Fasudil is a potent inhibitor of smooth muscle Rho kinase and has been shown to reduces coronary vasospasm in experimental animals. SUMMARY SUMMARY SUMMARY SUMMARY REFERENCES Trevor,A., Katzung,B., Kruidering-Hall,B., Maters,S. 2013. Katzung and Trevor’s Pharmacology Examination and Board Review 10th edition. www.heart.org. (2019). Angina Pectoris (Stable Angina). [online] Available at: https://www.heart.org/en/health-topics/heart-attack/angina-chest-pain/angina-pectoris-stableangina [Accessed 22 Feb. 2019]. Drugs.com. (2019). Nitroglycerin Dosage Guide with Precautions - Drugs.com. [online] Available at: https://www.drugs.com/dosage/nitroglycerin.html [Accessed 2 Mar. 2019] Texas Heart Institute [Internet]. 2019.Calcium Channel Blockers [cited 22 February 2019]. Available from: https://www.texasheart.org/heart-health/heart-informationcenter/topics/calcium-channel-blockers/ Chart, P. (2019). Causal Analysis Essay Outline 40989993745 Pathophysiology of #473153993745 – Pathophysiology of Angina Pectoris in Flow Chart (+33 Similar files) | OfficialConsumerReport.com. [online] OfficialConsumerReport.com. Available at: https://officialconsumerreport.com/pathophysiology-of-angina-pectoris-in-flow-chart/causalanalysis-essay-outline-40989993745-pathophysiology-of/ [Accessed 24 Feb. 2019].
