Student Notes: Angina & ACS PDF

2024/08/21 TREATMENT OF ANGINA PECTORIS & CORONARY SYNDROMES DR SARENTHA CHETTY BPHARM, MSC, PHD INTRODUCTION Ischemic heart disease (IHD) - one of the most common CVD - developed countries Angina pectoris- chest pain caused by accumu...

2024/08/21 TREATMENT OF ANGINA PECTORIS & CORONARY SYNDROMES DR SARENTHA CHETTY BPHARM, MSC, PHD INTRODUCTION Ischemic heart disease (IHD) - one of the most common CVD - developed countries Angina pectoris- chest pain caused by accumulation of metabolites from myocardial ischemia Most common cause of angina is atheromatous obstruction of the large coronary vessels (coronary artery disease, CAD) Inadequate blood flow in the presence of CAD results in effort angina or classic angina Diagnosis - history and stress testing, sometimes supplemented by coronary angiography  2024/08/21 Some patients have symptoms of angina in spite of normal epicardial coronary vessels called coronary microvascular dysfunction. Both types of angina -associated with diminished coronary fractional flow reserve Transient spasm of localized portions of vessels, usually associated with underlying atheromas, myocardial ischemia and pain → vasospastic or variant angina or Prinzmetal angina Variant angina, ↓oxygen delivery because of reversible coronary vasospasm, which also causes ischemia and pain. Primary cause of angina pectoris is an imbalance between oxygen requirement of the heart and the oxygen supplied Effort angina, when myocardial oxygen requirement increases (e.g. exercise) but the coronary blood flow does not ↑ proportionately Results in ischemia and accumulation of acidic metabolites →pain Coronary flow- frequently impaired due to endothelial dysfunction, and impaired vasodilation leading to ischemia In some individuals, the ischemia is not always accompanied by pain, resulting in “silent” or “ambulatory” ischemia  2024/08/21 Acute coronary syndrome (ACS) - when episodes of angina occur at rest and there is an increase in the severity, frequency, and duration of chest pain in patients with previously stable angina or an event occurs without prior history of angina Also includes myocardial infact (STEMI or NSTEMI) Unstable angina - caused by episodes ↑ coronary artery resistance or small clots occurring in the vicinity of an atherosclerotic plaque where there is reduced blood flow The course and the prognosis of unstable angina is variable, but is associated with a high risk of MI and death and is considered a medical emergency. VIDEOS Different types of Angina https://www.youtube.com/watch?v=-I-NN2PSAU8 Acute coronary symptoms https://www.youtube.com/watch?v=C0BUPHYQ1h4  2024/08/21 PATHOPHYSIOLOGY OF ANGINA: DETERMINANTS OF MYOCARDIAL OXYGEN DEMAND Effects of arterial BP and venous pressure – affects myocardial wall stress Myocardial oxygen requirement ↑s when ↑ heart rate, contractility, arterial pressure, or ventricular volume Normal heart - ↑demand for oxygen is met ↑coronary blood flow Coronary blood flow is directly related to the aortic diastolic pressure and the duration of diastole Coronary blood flow is inversely proportional to coronary vascular resistance. Resistance includes: metabolic products and autonomic activity Damage to the endothelium of coronary vessels affects ability to dilate and to increase coronary vascular resistance DETERMINANTS OF VASCULAR TONE Peripheral arteriolar and venous tone (vascular smooth muscle tension) affect myocardial wall stress Arteriolar tone controls peripheral vascular resistance and arterial BP In systole, intraventricular pressure must exceed aortic pressure to eject blood Venous tone determines the capacity of the venous circulation and the amount returned to the heart Venous tone - determines the right ventricular diastolic wall stress  2024/08/21 1. Increasing cGMP: cGMP facilitates the dephosphorylation of myosin light chains, preventing the interaction of myosin with actin. Nitric oxide (NO) is an effective activator of soluble guanylyl cyclase and acts mainly through increasing cGMP Molecular donors of nitric oxide include nitroprusside (used in hypertensive emergencies) and the organic nitrates used in angina Atherosclerotic disease may  endogenous endothelial NO synthesis, thus making the vascular smooth muscle more dependent upon exogenous sources of NO. 2. Decreasing intracellular Ca2+ : Calcium channel blockers cause vasodilation by reducing intracellular Ca2+ Beta blockers and calcium channel blockers also reduce Ca2+ influx in cardiac muscle fibers→ reducing rate, contractility, and oxygen demands 3. Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane: The membrane potential of excitable cells is stabilized near the resting potential by ↑ potassium permeability cGMP may increase permeability of Ca2+activated K+ channels Potassium channel openers e.g minoxidil sulfate ↑permeability of K+ channels  2024/08/21 BASIC PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA Organic nitrates, calcium channel blockers, β blockers ↓ myocardial oxygen requirement by  one/more of the major determinants of oxygen demand (heart size, heart rate, blood pressure, and contractility) Nitrates and calcium channel blockers may also cause a redistribution of coronary flow and ↑oxygen delivery to ischemic tissue Variant angina, these two drug groups also ↑ myocardial oxygen delivery by reversing coronary artery spasm The nitrates - acute anginal pain and prophylaxis Calcium channel blockers and β blockers are used for prophylaxis. NITRATES & NITRITES Nitroglycerin Sublingual tablet form May lose potency- highly volatile and adsorption to plastic surfaces Must be stored in a tightly closed glass containers Nitroglycerin is not sensitive to light. Different nitrates have identical mechanisms of action and similar toxicities, but development of tolerance may vary  2024/08/21 PHARMACOKINETICS Low bioavailability (10-20%) Liver nitrate reductase removes nitrate groups and inactivates the drug Sublingual route - avoids the first-pass effect and rapid therapeutic blood level Nitroglycerin and isosorbide dinitrate - total dose administered by this route must be limited to avoid excessive effect Other routes of administration -nitroglycerine: transdermal and buccal absorption from slow-release preparations All nitrates Unchanged organic nitrate compounds have half-lives (2–8 min) Partially de-nitrated metabolites - much longer half-lives (up to 3 hours) Isosorbide mononitrate and isosorbide dinitrate – oral 5-mononitrate metabolite is an active metabolite of isosorbide dinitrate Bioavailability - 100% Renal excretion, primarily as glucuronide derivatives of the denitrated metabolites  2024/08/21 PHARMACODYNAMICS A. Mechanism of Action in Smooth Muscle Nitroglycerin activation: De-nitration by glutathione S-transferase Aldehyde dehydrogenase isoform 2 (ALDH2) & possibly isoform 3 (ALDH3) - activation and release of NO from nitroglycerin Different enzymes may be involved in the de-nitration of isosorbide dinitrate and mononitrate Free nitrite ion (NO2-) is released and converted to nitric oxide (NO) NO (complexed with cysteine) combines with the heme group of soluble guanylyl cyclase, activating that enzyme and ↑ cGMP → smooth muscle relaxation Prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarization may also be involved. B. Organ System Effects 1. Vascular smooth muscle Veins & arteries relax in response to nitroglycerin Veins - ↑venous capacitance and  ventricular preload Pulmonary vascular pressures and heart size are significantly reduced Cardiac output is reduced Because ↑venous capacitance - orthostatic hypotension and syncope Dilation of coronary arteries may improve oxygen delivery in the presence of atheromas or collateral vessels Temporal artery pulsations and a throbbing headache common effects of nitroglycerin and amyl nitrite In heart failure, preload is often abnormally high; the nitrates and other vasodilators, by reducing preload, may have a beneficial effect on cardiac output  2024/08/21 Redistribution of coronary flow from normal to ischemic regions Nitroglycerin also exerts a weak negative inotropic effect on the heart via nitric oxide Compensatory responses to  arterial pressure are tachycardia and ↑cardiac contractility Retention of salt and water may also be significant, especially with intermediate and long-acting nitrates Compensatory responses contribute to the development of nitrate tolerance 2. Other smooth muscle organs Nitrites readily release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase The resulting increase in cGMP causes dephosphorylation of myosin light chains and relaxation which enhances erection 3. Action on platelets Nitric oxide from nitroglycerin stimulates guanylyl cyclase in platelets ↑cGMP causes a decrease in platelet aggregation Intravenous nitroglycerin may be of value in acute coronary syndrome, in part through its action on platelets 4. Other effects Nitrite ion (not nitrate ion) reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (by oxidation of ferrous to ferric iron). Methemoglobin - low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death Fortunately, plasma concentration of nitrite from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults  2024/08/21 Cyanide poisoning results from complexing and inactivation of cytochrome iron by the CN− ion Methemoglobin iron has a very high affinity for CN−; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure regenerates active cytochrome The cyanomethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3) →formation of thiocyanate ion (SCN−), a less toxic ion that is readily excreted. Methemoglobinemia- if excessive, can be treated by I/V methylene blue Antidote for cyanide poisoning Inhaled amyl nitrite plus intravenous sodium nitrite, followed by intravenous sodium thiocyanate and, if needed, methylene blue) is now being replaced by hydroxocobalamin, a form of vitamin B12, which also has a very high affinity for cyanide ion and combines with it to generate cyanocobalamin and free cytochrome.  2024/08/21 NITRATES: TOXICITY & TOLERANCE A. Acute Adverse Effects Major acute toxicities of organic nitrates: orthostatic hypotension, tachycardia, and throbbing headaches Nitrates are contraindicated in elevated intracranial pressure Rarely, transdermal nitroglycerin patches have ignited when external defibrillator electroshock was applied to the chest of patients in ventricular fibrillation. B. TOLERANCE Continuous exposure to nitrates, isolated smooth muscle may develop complete tolerance (tachyphylaxis) Progressively more tolerant when long-acting preparations (oral, transdermal) or continuous IV infusions are used for continuously > a few hours Mechanisms by which tolerance develops are not completely understood  2024/08/21 Mechanism of Tolerance developement: ↓ in tissue sulfhydryl groups, eg cysteine Can be partially prevented or reversed with a sulfhydryl regenerating agent ↑generation of free radicals during nitrate therapy → tolerance Some evidence suggests that diminished availability of calcitonin gene related peptide (CGRP, a potent vasodilator) is also associated with nitrate tolerance Continuous exposure to high levels of nitrates can occur in the chemical (explosives) industry When contamination of the workplace with volatile organic nitrate compounds is severe, workers find that upon starting their work week (Monday), they suffer headache and transient dizziness (Monday disease) After a day or so, these symptoms disappear - development of tolerance Over the weekend, no exposure, tolerance disappears, so symptoms recur each Monday  2024/08/21 C. CARCINOGENICITY OF NITRATE AND NITRITE DERIVATIVES Nitrosamines structure R2–N–NO formed from the combination of nitrates and nitrites with amines Some nitrosamines are powerful carcinogens in animals through conversion to reactive derivatives. Although there is no direct proof that these agents cause cancer in humans There is a strong epidemiologic correlation between the incidence of esophageal and gastric carcinoma and the nitrate content of food in certain cultures Nitrosamines are also found in tobacco and in cigarette smoke There is no evidence that the small doses of nitrates used in the treatment of angina result in significant body levels of nitrosamines.  2024/08/21 NITRATE EFFECTS IN ANGINA A. Nitrate Effects in Angina of Effort ↓ venous return to the heart →reduction of intra-cardiac volume ↓Arterial pressure ↓intraventricular pressure and left ventricular volume associated with ↓wall tension (Laplace relation) and ↓ myocardial oxygen requirement Rare instances, a paradoxical ↑myocardial oxygen demand may occur as a result of excessive reflex tachycardia and increased contractility The reduction in oxygen demand is the major mechanism for the relief of effort angina. B. Variant Angina Benefits patients by relaxing the smooth muscle of the coronary arteries and relieving coronary artery spasm. C. Nitrate Effects in Acute Coronary Syndromes Useful in the treatment of the acute coronary syndrome of unstable angina, but the precise mechanism for beneficial effects is not clear. Nitrates may exert their beneficial effects both by dilating the epicardial coronary arteries and by simultaneously reducing myocardial oxygen demand. As previously noted, nitroglycerin also decreases platelet aggregation, and this effect may be important in acute coronary syndrome.  2024/08/21 CLINICAL USE OF NITRATES Rapid onset of action (1–3 minutes)- sublingual nitroglycerin →immediate treatment Short duration of action (not exceeding 20–30 minutes)- not suitable for maintenance therapy IV nitroglycerin -rapid onset (mins) restricted to severe, recurrent rest angina Slowly absorbed preparations of nitroglycerin provide blood concentrations for long periods but may lead to tolerance. Transdermal administration may provide blood levels of nitroglycerin ≥ 24 hrs, the beneficial effects do not persist >8–10 hr A nitrate free period -at least 8 hours between doses of long acting and slow release forms should be observed to prevent tolerance. OTHER NITROVASODILATORS Nicorandil Nicotinamide nitrate ester with vasodilating properties in coronary arteries Tx of angina Activates Na+/Ca2+ exchanger and ↓ intracellular Ca2+ overload Activation of cardiac KATP channels Reduces both preload and afterload Molsidomine - prodrug that is converted to a nitric oxide releasing metabolite Efficacy comparable to that of the organic nitrates and no tolerance.  2024/08/21 CALCIUM CHANNEL BLOCKING DRUGS Calcium influx needed for the contraction of smooth and cardiac muscle Oral, IV High first-pass effect, high plasma protein binding, and extensive metabolism Inhibit L-type voltage-sensitive calcium channels in arterial smooth muscle → relaxation and vasodilatation Preload is not significantly affected Calcium channels in myocardium and heart conducting tissues - by reducing calcium influx during the plateau phase of the action potential  negative inotropic effect Dihydropyridines (e.g. nifedipine, amlodipine) Relatively little effect on the heart At clinical doses, vasodilatation causes a reflex increase in sympathetic tone that causes a mild tachycardia and counteracts the mild negative inotropic effect Amlodipine - has a long duration of action, produces less tachycardia than nifedipine.  2024/08/21 Verapamil, to a lesser extent, diltiazem depresses the sinus node, causing a mild resting bradycardia Verapamil binds preferentially to open channels Conduction in the atrioventricular node is slowed and, and it effectively slows the ventricular rate in atrial muscle The negative inotropic effects of verapamil and diltiazem are partially offset by the reflex increase in adrenergic tone and the decrease in afterload Diltiazem has actions intermediate between those of verapamil and nifedipine and is popular in the treatment of angina because it does not cause tachycardia TOXICITY Excessive inhibition of calcium influx can cause serious cardiac depression, including bradycardia, atrioventricular block, cardiac arrest, and heart failure. Quick release nifedipine - ↑ risk of myocardial infarction in patients with HT Dihydropyridines, compared with ACE inhibitors reported to increase the risk of adverse cardiac events in patients with HT with or without diabetes Patients receiving β-blocking drugs are more sensitive to the cardiodepressant effects of calcium channel blockers Minor toxicities (troublesome but not usually requiring discontinuance of therapy) include flushing, dizziness, nausea, constipation, and peripheral edema. Constipation is particularly common with verapamil Drug –food interaction – verapamil and grapefruit  2024/08/21 MECHANISMS OF CLINICAL EFFECTS ↓ myocardial contractile force, which ↓ myocardial oxygen requirements Blocks calcium channel in arterial smooth muscle ↓arterial and intraventricular pressure Some (eg, verapamil, diltiazem) also possess a non-specific anti-adrenergic effect, which may contribute to peripheral vasodilation Left ventricular wall stress declines, which ↓ myocardial oxygen requirements Verapamil and Diltiazem ↓heart rate causing further ↓ myocardial oxygen demand Calcium channel blocking agents also relieve and prevent focal coronary artery spasm in variant angina and is most effective prophylactic treatment for this form of angina pectoris. Verapamil and diltiazem ↓ atrioventricular nodal conduction - management of supraventricular re-entry tachycardia and in decreasing ventricular rate in atrial fibrillation or flutter. Non-specific sympathetic antagonism is most marked with diltiazem and much less with verapamil Nifedipine does not appear to have this effect, probably because reflex tachycardia in response to hypotension occurs most frequently with nifedipine and much less so with diltiazem and verapamil These differences in pharmacologic effects should be considered in selecting calcium channel blocking agents for the management of angina.  2024/08/21 CLINICAL USES OF CALCIUM CHANNEL BLOCKING DRUGS Angina, hypertension, supraventricular tachyarrhythmias Moderate efficacy in hypertrophic cardiomyopathy, migraine, and Raynaud phenomenon Nifedipine safer than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with β blockers may produce atrioventricular block and depression of ventricular function In the presence of overt heart failure, all calcium channel blockers can cause further worsening of failure due to the negative inotropic effect Amlodipine, does not ↑ mortality in patients with heart failure due to non- ischemic left ventricular systolic dysfunction, therefore - can be used safely in these patients. In patients with relatively low BP, dihydropyridines can cause further deleterious lowering of pressure In patients receiving digitalis, verapamil should be used with caution, because it may increase digoxin blood levels through a pharmacokinetic interaction In patients with unstable angina, immediate release short-acting calcium channel blockers can ↑ the risk of adverse cardiac events and therefore are contraindicated However, in patients with non–Qwave myocardial infarction, diltiazem can decrease the frequency of post infarction angina and may be used.  2024/08/21 BETA-BLOCKING DRUGS Is the prophylactic treatment of choice in chronic effort angina ↓ heart rate, BP, and contractility—which ↓myocardial oxygen demand at rest and during exercise Improved exercise tolerance Beta blockers may also be valuable in treating silent or ambulatory ischemia. Because this condition causes no pain, it is usually detected by electrocardiographic signs of ischemia The total amount of “ischemic time” per day is reduced by long- term therapy with a β blocker. Beta-blocking agents ↓ mortality of patients with HF or recent MI and improve survival and prevent stroke in patients with HT. Patients with stable angina have better outcome and symptomatic improvement with β-blockers compared with calcium channel blockers.  2024/08/21 UNDESIRABLE EFFECTS OF BETA-ΒLOCKING ↑ in end diastolic volume and an ↑ in ejection time, both of which tend to increase myocardial oxygen requirement These deleterious effects of β-blocking agents can be balanced by the concomitant use of nitrates Contraindications: asthma, other bronchospastic conditions, severe bradycardia, atrioventricular blockade, bradycardia tachycardia syndrome, and severe unstable left ventricular failure Fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, worsening of claudication, and erectile dysfunction. VIDEO: PHARMACOLOGY OF DRUGS USED IN ANGINA https://www.youtube.com/watch?v=aOofXg1nB0Q  2024/08/21 NEWER ANTIANGINAL DRUGS Ranolazine Reduces a late sodium current (INa) that facilitates calcium entry via the sodium/calcium exchanger ↓intracellular calcium concentration ↓ diastolic tension, cardiac contractility, and work Effective in stable angina Prolongs the QT interval in patients with coronary artery disease (but shortens it in patients with long QT syndrome, LQT3) May inhibit the metabolism of digoxin and simvastatin.  2024/08/21 Trimetazidine*: Metabolic modulators known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium In ischemic myocardium the metabolism shifts to oxidation of fatty acids which ↑ oxygen requirement Partial inhibition of the enzyme required for fatty acid oxidation (longchain 3-ketoacyl-thiolase, LC3KAT) appears to improve the metabolic status of ischemic tissue. Inhibits LC3KAT - efficacy in stable angina Ivabradine Relatively selective sodium channel blockers ↓ cardiac rate by inhibiting the hyperpolarization activated sodium channel in the sinoatrial node Appears to reduce angina attacks with efficacy similar to calcium channel blockers and β-blockers The lack of effect on gastrointestinal and bronchial smooth muscle is an advantage of ivabradine Used in angina and heart failure  2024/08/21 Rho kinases (ROCK) - enzymes - inhibit vascular relaxation Excessive activity of these enzymes - implicated in coronary spasm, pulmonary HT Fasudil - inhibitor of smooth muscle Rho kinase and ↓ coronary vasospasm in experimental animals In clinical trials - patients with CAD, has improved performance in stress tests Investigational in angina Allopurinol - inhibits xanthine oxidase This enzyme contributes to oxidative stress and endothelial dysfunction. Studies suggest that high dose allopurinol (eg, 600 mg/d) prolongs exercise time in patients with atherosclerotic angina The mechanism is uncertain, but the drug appears to improve endothelium dependent vasodilation. Allopurinol is not currently approved for use in angina. CLINICAL PHARMACOLOGY  2024/08/21 CLINICAL PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA Treatment includes both medical and surgical methods. Refractory angina and acute coronary syndromes are best treated with physical revascularization, ie, percutaneous coronary intervention (PCI), with insertion of stents, or coronary artery bypass grafting (CABG) The standard of care for acute coronary syndrome (ACS) is urgent stenting Prevention of ACS and treatment of chronic angina - pharmacologic therapy. Most common cause of angina is atherosclerotic disease of the coronaries Modification of risk factors: hypertension, hyperlipidemia, obesity, smoking, clinical depression Tobacco smoking: Smoking is prothrombotic and atherogenic It ↓coronary blood flow, heart rate and BP which heart oxygen demands Carboxyhaemoglobin - ↓oxygen carrying capacity of the blood Some patients improve remarkably on giving up smoking. Antiplatelet drugs (aspirin, ADP receptor blockers) and lipid lowering agents, especially statins may be required. Statins - shown to reduce the incidence and severity of ischemia in patients during exercise testing and the incidence of cardiac events (including infarction and death) in clinical trials.  2024/08/21 ACE inhibitors also ↓ the risk of adverse cardiac events in patients at high risk for coronary artery disease Unstable angina and non-ST segment elevation myocardial infarction, aggressive therapy consisting of coronary stenting, anti- lipid drugs, heparin, and antiplatelet agents is recommended. In established angina and other manifestations of myocardial ischemia Treatment based on reduction of myocardial oxygen demand and increase of coronary blood flow to the potentially ischemic myocardium to restore the balance between myocardial oxygen supply and demand Angina of Effort β blockers, nitrates, and calcium channel blockers increase time to onset of angina and ST depression during treadmill tests in patients with angina of effort Although exercise tolerance increases, there is usually no change in the angina threshold, ie, the heart rate x blood pressure product at which symptoms occur Maintenance therapy of chronic stable angina β blockers, calcium channel blocking agents, or long-acting nitrates In hypertensive patients, monotherapy with either slow release or long- acting calcium channel blockers or β blockers In normotensive patients, long acting nitrates may be suitable  2024/08/21 β blocker with a calcium channel blocker (eg, propranolol with nifedipine) or two different calcium channel blockers (eg, nifedipine and verapamil) has been shown to be more effective than individual drugs used alone If a dihydropyridine is used, a longer acting agent should be chosen (amlodipine or felodipine) If response to a single drug is inadequate, a drug from a different class should be added to maximize the beneficial reduction of cardiac work while minimizing undesirable effects Some patients may require therapy with all three drug groups Addition of an ACE inhibitor may improve control of angina attacks Ranolazine or ivabradine (off-label), Combined with β blockers, may be effective in some patients refractory to traditional drugs. Most experts recommend coronary angiography and revascularization (if not contraindicated) in patients with stable chronic angina refractory to three drug combinations  2024/08/21 Vasospastic Angina Nitrates and the calcium channel blockers, but not β blockers, are effective drugs Approximately 70% of patients treated with nitrates plus calcium channel blockers, angina attacks are completely abolished Prevention of coronary artery spasm (with or without fixed atherosclerotic coronary artery lesions) is the principal mechanism for this beneficial response All presently available calcium channel blockers appear to be equally effective Surgical revascularization and angioplasty not indicated in patients with variant angina. Unstable Angina & Acute Coronary Syndromes Unstable angina with recurrent ischemic episodes at rest, recurrent platelet- rich thrombus formation is the principal mechanism Aggressive antiplatelet therapy with a combination of aspirin and clopidogrel If percutaneous coronary intervention with stenting is required, glycoprotein IIb/IIIa inhibitors such as abciximab should be added In addition, therapy with nitroglycerin and β-blockers should be considered Calcium channel blockers should be added in refractory cases for relief of myocardial ischemia Primary lipid-lowering and ACE inhibitor therapy should also be initiated.  2024/08/21 TREATMENT OF PERIPHERAL ARTERY DISEASE & INTERMITTENT CLAUDICATION Atherosclerosis can result in ischemia of peripheral arteries If blood flow is limited, pain (claudication) occurs in skeletal muscles, especially in the legs, during exercise and disappears with rest Peripheral artery disease (PAD) - associated with ↑ mortality, can severely limit exercise tolerance, and may ↑risk of chronic ischemic ulcers, susceptibility to infection, and the need for amputation. Intermittent claudication results from obstruction of blood flow by atheromas in large and medium arteries Insertion of stents in the obstructed vessels is usually indicated and can save a limb Supervised exercise therapy is of benefit in reducing claudication and increasing painfree walking distance. Medical treatment directed at reversal or control of atherosclerosis, requires control of hyperlipidemia, hypertension and obesity; cessation of smoking; and control of diabetes Physical therapy and exercise training are of proven benefit Antiplatelet drugs such as aspirin or clopidogrel are often used to prevent clotting in the region of plaques and have documented benefit in reducing the risk of myocardial infarction, stroke, and vascular death even though they have little or no effect on claudication Percutaneous angioplasty with stenting may be effective in patients with medically intractable signs and symptoms of lower limb ischemia.  2024/08/21 DRUG TREATMENT Cilostazol: phosphodiesterase type 3 (PDE3) inhibitor Selective antiplatelet and vasodilating effects ↑ exercise tolerance in patients with severe claudication and approved for PAD Naftidrofuryl: 5HT2 antagonist Pentoxifylline, a xanthine derivative, is widely promoted for use in this condition but is not recommended. It is thought to act by reducing the viscosity of blood and perhaps increasing the deformability of red blood cells, allowing blood to flow more easily through partially obstructed areas.  2024/08/21 CASE STUDY A 67 year old woman presents in the emergency department of a small rural hospital with a history of chest pain and shortness of breath while watching television. While nasal oxygen is administered and an ECG is recorded, blood is drawn for high sensitivity troponin measurement. Her husband provides the history that she has a history of exercise induced angina pectoris and has taken nitroglycerin for relief in the past. Two doses of nitroglycerin have not relieved her pain on this occasion. She smokes and has a history of hyperlipidemia with elevated “bad cholesterol” (low density lipoprotein [LDL]) and hypertension. Her father survived a “heart attack” at age 55, and an uncle died of some cardiac disease at age 60. On physical examination, the patient’s blood pressure is 145/90 mm Hg, and her heart rate is 100 bpm. The ECG shows no ST elevation, but ST depression is present in several leads. Assuming that a diagnosis of acute coronary syndrome (ACS) is correct, what treatment should be implemented? REFERENCES NEAL, M.J. - MEDICAL PHARMACOLOGY AT A GLANCE. Katzung – Basic and Clinical Pharmacology Goodman and Gilman - The Pharmacological Basis of Therapeutics  2024/08/21 REFERENCES Katzung Pharmacology at a Glance