Anti-Anginal Drugs PDF

ANTI-ANGINAL DRUGS DR. AZLINI BINTI ISMAIL 1 DENS 2201: CARDIOVASCULAR & RESPIRATORY SYSTEMS SPECIFIC LEARNING OBJECTIVES 1. Explain the different classes of antianginal drugs with their specific mechanisms of a...

ANTI-ANGINAL DRUGS DR. AZLINI BINTI ISMAIL 1 DENS 2201: CARDIOVASCULAR & RESPIRATORY SYSTEMS SPECIFIC LEARNING OBJECTIVES 1. Explain the different classes of antianginal drugs with their specific mechanisms of action. 2. Recognise any interactions, contraindications, and side effects of these drugs. 2 OVERVIEW 3  OVERVIEW ▪ Angina pectoris- sudden, severe, pressing chest radiating to the neck, jaw, back and arms. ▪ Atherosclerotic disease of coronary arteries, also known as coronary artery disease (CAD) or ischemic heart disease. ▪ Atherosclerotic lesions in coronary arteries can obstruct blood flow, leading to an imbalance in myocardial O2 supply & demand. 4  OVERVIEW ▪ Besides obstruction due to atherosclerotic lesions, this imbalance may result during exertion & also from a spasm of vascular smooth muscle. *Vascular spasm: A sudden & brief contraction/constriction of muscle cells inside the walls of a blood vessel. 5 OVERVIEW ▪ Transient episodes of myocardial ischemia - occur from 15 seconds to 15 minutes - do not usually result in cellular death. ▪ Chronic ischemia – lead to deterioration of cardiac function → heart failure, arrhythmia & sudden death. ▪ Most common cause of mortality around the world. 6 SIGNS & SYMPTOMS ▪ Typical angina pectoris - sudden, severe, crushing chest pain that may radiate to the neck, jaw, back & arms. ▪ Patients may also present with dyspnea. ▪ Atypical symptoms includes indigestion, nausea, vomiting, or diaphoresis*. * sweating, especially to an unusual degree as a symptom of disease or a side effect of a drug. 7 TYPES OF ANGINA 1. Stable (effort-induced, classic, These results from or typical) angina increased myocardial 2. Rest (prinzmetal, variant, or demand vasospastic) angina & decreased myocardial 3. Unstable angina perfusion (supply) 8 TYPES OF ANGINA 1. Stable (effort-induced, classic or typical) angina ▪ Most common, typical & stable. ▪A short-lasting burning, heavy, or squeezing feeling in chest. ▪ Atypical symptoms*: Extreme fatigue, nausea, or diaphoresis. ▪ Others may not present with any symptoms (silent angina). *more commonly found in women, diabetic patients & elderly. 9  TYPES OF ANGINA 1. Stable (effort-induced, classic or typical) angina (cont’d) ▪ Caused by reduction of coronary perfusion due to fixed obstruction of coronary artery produced by atherosclerosis. ▪ Blood supply to heart cannot increase → heart becomes vulnerable to ischemia whenever there is increased demand or any other cause of increased cardiac workload. ▪ E.g. during physical activity, emotional stress or excitement 10 TYPES OF ANGINA 1. Stable (effort-induced, classic or typical) angina (cont’d) ▪ Promptly relieved by rest or nitroglycerin. ▪ When the pattern of chest pains & amount of effort needed to trigger the chest pains do not change over Sublingual time, angina is named “stable nitroglycerin angina.” 11 TYPES OF ANGINA 2. Rest (Prinzmetal, variant, vasospastic) angina ▪ Uncommon pattern, occurs at rest. ▪ Symptoms caused by a decreased blood flow to heart muscle due to spasm of coronary artery. ▪ May have significant coronary atherosclerosis* but angina attacks are unrelated to physical activity, HR, or BP. ▪ Generally responds promptly to coronary vasodilators, such as nitroglycerin & calcium channel blockers (CCBs). 12  TYPES OF ANGINA 3. Unstable angina ▪ Unstable angina is classified between stable angina & myocardial infarction. ▪ In unstable angina, chest pain occurs with increased frequency, duration & intensity (worsening). ▪ Any episode of rest angina longer than 20 minutes, any new-onset angina, any increasing (crescendo) angina, or even sudden development of shortness of breath is suggestive of unstable angina. ▪ Symptoms of angina are not relieved by rest or nitroglycerin. 13 TYPES OF ANGINA 3. Unstable angina (cont’d) ▪ Unstable angina is considered as a form of acute coronary syndrome* which requires hospital admission, more aggressive therapy to prevent progression to MI & death. *Acute coronary syndrome: An emergency, commonly results from rupture of atherosclerotic plaque & partial or complete thrombosis of a coronary artery. This process ends in intraluminal thrombosis & vascular occlusion. 14  ACUTE CORONARY SYNDROME ▪ If thrombus occludes most of blood vessel & if occlusion is untreated, necrosis of cardiac muscle may ensue. ▪ Myocardial infarction (necrosis) is typified by increases in serum levels of biomarkers such as troponins & creatine kinase- MB*. *Levels of troponin & creatine kinase is elevated during heart attacks, signaling that the heart muscle is damaged. 15  THERAPEUTIC MANAGEMENT 1. Lifestyle modifications (smoking cessation, physical activity, weight management) 2. Management of modifiable risk factors (hypertension, diabetes, dyslipidemia) to reduce CV morbidity & mortality. 3. Use of variety of anti- anginal medications 16 ANTI-ANGINAL DRUGS 1. β-blockers Used either alone or in combination 2. Calcium channel Commonly used to manage blockers patients with stable angina ▪ Dihydropyridines They help to balance cardiac O2 supply & demand ▪ Nondihydropyridines equation by affecting; 3. Nitrates ✓ BP ✓ Venous return ✓ HR ✓ Heart contractility 17 1) β-BLOCKERS ▪ Atenolol (selective β1-antagonist) ▪ Bisoprolol (selective β1-antagonist) ▪ Metoprolol (selective β1- antagonist) ▪ Propranolol (non-selective β- antagonist) 18  1) β-BLOCKERS ▪ MOA: They block β1 receptors (primarily on heart) → resulting in decreased HR, contractility, CO & BP → thereby decreasing O2 demands of myocardium ▪ β-blockers; ▪ reduce myocardial O2 demand during exertion & at rest. ▪ reduce frequency & severity of angina attacks. Can increase exercise ▪ can increase exercise duration & duration tolerance in patients with effort- induced angina. 19 1) β-BLOCKERS ▪ Recommended as initial anti-anginal therapy in all patients unless contra-indicated (e.g. β-blockers are ineffective & may actually worsen symptoms of vasospastic angina). ▪ β-blockers reduce death risk & myocardial infarction (MI) in patients who have had a prior MI & also reduce mortality in patients with HPT & HFrEF. Note: β-blockers with intrinsic Should avoid sympathomimetic activity (ISA) such as pindolol (partial β-agonist) should be avoided in patients with angina & those who have had a MI. 20 1) β-BLOCKERS ▪ Propranolol (prototype) is not cardio-selective, thus, other more selective β-blockers, such as metoprolol & atenolol, are preferred. (However, all β-blockers are non-selective at high dose). Note: β-blockers are contraindicated in patients with asthma, chronic obstructive pulmonary disease, diabetes & severe bradycardia. ▪ It is important not to discontinue β-blocker therapy abruptly. Dose should be gradually reduced over 2 to 3 weeks to avoid rebound angina, MI & 21 HPT 2) CALCIUM CHANNEL BLOCKERS ▪ Dihydropyridines ▪ Nifedipine ▪ Amlodipine ▪ Felodipine ▪ Non-dihydropyridines ▪ Verapamil ▪ Diltiazem 22 2) CALCIUM CHANNEL BLOCKER MOA: ▪ CCBs are arteriolar vasodilators. ▪ They inhibit entrance of calcium into cardiac & smooth muscle cells of coronary & systemic arterial beds → cause a SERCA: sarco/endoplasmic decrease in smooth muscle reticulum Ca2+-ATPase RyR: Ryanodine tone & vascular resistance receptor PLN: Phospholamban (peripheral & coronary LTCC: L-type Ca2+ arteriolar smooth muscle). channel 23 2) CALCIUM CHANNEL BLOCKER ▪ In treatment of effort-induced angina, CCBs decrease vascular resistance → decrease afterload → reduce myocardial O2 demand when aortic pressure is reduced. ▪ Efficient in vasospastic angina (unlike β-blockers) due to their ability to relax coronary arteries. 24 2) CALCIUM CHANNEL BLOCKER ▪ Amlodipine (dihydropyridine) - exerts greater effect on smooth muscle in peripheral vasculature (blood vessels). ▪ Verapamil (non-dihydropyridine) - mainly affects myocardial cells (heart -reducing force and rate of cardiac contraction). ▪ Diltiazem (non-dihydropyridine) - is intermediate in its actions. ▪ But, all of these CCBs lower BP. 25  2) CALCIUM CHANNEL BLOCKERS CCBS Dihydropyridine Non-Dihydropyridines -Nifedipine (1st generation, -Diphenylalkylamine prototype) (Verapamil) -Amlodipine& Felodipine -Benzothiazepine (2nd generation) (Diltiazem) 26 2) CALCIUM CHANNEL BLOCKER A. Dihydropyridines (Amlodipine): ▪ Oral ▪ Functions mainly as an arteriolar vasodilator - useful in treating rest angina caused by spontaneous coronary spasm. ▪ Minimal effect on cardiac conduction. *This drug may cause gingival hyperplasia 27 2) CALCIUM CHANNEL BLOCKER B. Nondihydropyridines (Verapamil) ▪ Affect calcium channel in heart. ▪ It slows AV conduction directly & decreases HR, contractility, BP & thus the O2 demand. ▪ It has greater negative inotropic effects than amlodipine, but it is a weaker vasodilator. Precaution: It is contraindicated in patients with pre-existing depressed cardiac function or atrioventricular (AV) conduction abnormalities. 28 *This may cause gingival hyperplasia 2) CALCIUM CHANNEL BLOCKER B. Nondihydropyridines (Diltiazem) ▪ Also affect calcium channel in heart. rest angina ▪ It also slows AV conduction, decreases rate of firing of sinus node pacemaker. ▪ It is also a coronary artery vasodilator. ▪ It can relieve coronary artery spasm, therefore, is particularly useful in patients with rest angina. *This may cause gingival 29 hyperplasia 2) CALCIUM CHANNEL BLOCKER B. Nondihydropyridines Precaution: Non-dihydropyridine CCBs can worsen HF due to their negative inotropic effect & their use should be avoided in this population. 30 3) NITRATES ▪ Nitroglycerin ▪ Isosorbide dinitrate ▪ Isosorbide mononitrate 31 3) NITRATES ▪ Vein dilators (mainly). ▪ Caused a reduction in myocardial oxygen demand, followed by relief of symptoms. ▪ Used for stable, rest & unstable angina. 32 3) NITRATES MOA: ▪ Nitrates are converted intracellularly to nitrite ions & then to nitric oxide (NO) → which activates guanylate cyclase → increases cyclic guanosine monophosphate (cGMP). ▪ Elevated cGMP then leads to dephosphorylation of the myosin light chain → resulting in vascular smooth muscle relaxation. 33  NTG: Nitroglycerin dephosphorylate GTP: Guanosine triphosphate cGMP: cyclic guanosine monophosphate LC: light chain 34 3) NITRATES MOA (cont’d) ▪ Nitrates such as nitroglycerin cause dilation of large veins, which reduces preload → reduces the work of heart mainly (perhaps their main MOA in treatment of angina). ▪ Nitrates also dilate coronary vasculature → providing an increased blood supply to heart muscle. 35 3) NITRATES Pharmacokinetics ▪ Nitrates differ in their onset of action & rate of elimination. ▪ Onset of action varies from 1 minute (nitroglycerin) to 30 minutes (isosorbide mononitrate). Time to peak effect and duration of action for some common organic nitrate preparations. 36 3) NITRATES Pharmacokinetics ▪ For prompt relief of angina attack caused by exercise or emotional stress, sublingual (or spray form) nitroglycerin is the drug of choice. ▪ Patients suffering from angina should have nitroglycerin on hand to treat acute angina attacks. ▪ Significant first-pass metabolism of nitroglycerin occurs in liver → thus, commonly administered via sublingual or transdermal route (patch or ointment) to avoid hepatic first-pass effect. 37 3) NITRATES Adverse effects Drug interaction ▪ Headache-most common. ▪ High doses - postural Phosphodiesterase type 5 hypotension, facial flushing & inhibitors such as sildenafil tachycardia. potentiate action of nitrates. Note: Long-acting nitrate -To preclude dangerous (extended-release formulation) hypotension that may occur, is used to prevent rebound this combination is tachycardia. contraindicated. Do not combine 38 3) NITRATES Tolerance ▪ Tolerance develops rapidly as blood vessels become desensitized to vasodilation. -Should overcome by providing daily “nitrate- free interval” to restore sensitivity to drug. -Usually, interval of 10 to 12 hrs at night because demand on heart is decreased at that Transdermal patch time. -E.g. Nitroglycerin patches are worn for 12 hrs & then removed for 12 hrs. -However, rest angina worsens early in morning, perhaps due to circadian catecholamine surges → therefore, nitrate-free interval in these patients should occur in late afternoon. E.g.: For stable angina: 10 pm to 10 am (nitrate-free), 10 am to 10 pm (with nitrate patch) For rest-angina: 4 pm to 4am (nitrate free), 4am to 4pm (with nitrate patch) 39 Treatment of angina in patients with concomitant diseases 40  Treatment algorithm for patients with stable angina *Ranolazine inhibits persistent or late inward sodium current (INa) in heart muscle in a variety of voltage-gated sodium channels. Inhibiting that current leads to reductions in intracellular calcium levels. This in turn leads to reduced tension in the heart wall, leading to reduced oxygen requirements for the muscle. 41 REFERENCES 1. Harvey, R. A., Clark, M. A., Finkel, R., Rey, J. A., & Whalen, K. (2012). Lippincott’s illustrated reviews: Pharmacology. Philadelphia: Wolters Kluwer. 2. Katzung, B. G., & Trevor, A. J. (2016). Basic & clinical pharmacology. New York: McGraw-Hill Medical. 42