CORONARY ARTERY DISEASE: CORONARY ARTERY DISEASE BY ZEENATH BANU M.PHARMACY 1 st YEAR ATHEROGENESIS: ATHEROGENESIS Atheroma is a focal disease of the intima of large and medium-sized arteries. Lesions evolve over decades, during most of which time they are clinically silent, the occurrence of symptoms signalling advanced disease . Presymptomatic lesions are often difficult to detect non-invasively, although ultrasound is useful in accessible arteries and associated changes such as reduced aortic compliance and arterial calcification can be detected by measuring, respectively, aortic pulse wave velocity and coronary artery calcification. EPIDEMIOLOGY: EPIDEMIOLOGY Raised low-density lipoprotein cholesterol. Reduced high-density lipoprotein cholesterol. Hypertension. Diabetes mellitus. Cigarette smoking. Obesity. Physical inactivity. Raised C-reactive protein. Raised coagulation factors (e.g. factor VII, fibrinogen ). Raised lipoprotein ATHEROGENESIS STAGES: ATHEROGENESIS STAGES Endothelial dysfunction, with altered prostaglandins, NO biosynthesis , predisposes to atherosclerosis . Injury of dysfunctional endothelium encourages monocyte attachment and migration of monocytes from the lumen into the intima. Endothelial cells and monocytes/macrophages generate free radicals that oxidise LDL resulting in lipid peroxidation. The oxidise LDL is taken up by macrophages via 'scavenger' receptors. Such macrophages are called foam cells. PowerPoint Presentation: Sub endothelial collections of foam cells and T lymphocytes form fatty streaks . Activated platelets, macrophages and endothelial cells release cytokines and growth factors, causing proliferation of smooth muscle and deposition of connective tissue components. This inflammatory fibroproliferative response leads to a dense fibrous cap overlying a lipid-rich core, the whole structure comprising the atheromatous plaque. Plaque can rupture, forming a substrate for thrombosis . The presence of large numbers of macrophages predisposes to plaque rupture, whereas vascular smooth muscle and matrix proteins stabilise the plaque. PowerPoint Presentation: Stages of atherosclerosis LIPOPROTEIN TRANSPORT: LIPOPROTEIN TRANSPORT Lipids and cholesterol are transported in the bloodstream as complexes of lipid and protein known as lipoproteins. These consist of a central core of hydrophobic lipid encased in a hydrophilic coat of polar phospholipid, free cholesterol and apoprotein. There are four main classes of lipoprotein HDL particles (contain apoA1 and apoA2), diameter 7-20 nm LDL particles (contain apoB-100), diameter 20-30 nm very-low-density lipoprotein (VLDL) particles (contain apoB-100), diameter 30-80 nm chylomicrons (contain apoB-48), diameter 100-1000 nm. PowerPoint Presentation: Cholesterol transport in the tissues, with sites of action of the main d rugs affecting lipoprotein metabolism PowerPoint Presentation: Endogenous pathway Very-low-density lipoproteins (VLDLs), which transport cholesterol and newly synthesised triglycerides to the tissues, where triglycerides are removed as before, leaving: Intermediate-density and low-density lipoprotein (LDL) particles with a large component of cholesterol; some LDL cholesterol is taken up by the tissues and some by the liver, by endocytosis via specific LDL receptors. High-density lipoprotein (HDL) particles adsorb cholesterol derived from cell breakdown in tissues (including arteries) and transfer it to VLDL and LDL particles via cholesterol ester transport protein (CETP). PowerPoint Presentation: Exogenous pathway Chylomicrons transport triglycerides and cholesterol from the gastrointestinal tract to the tissues, where triglyceride is split by lipoprotein lipase, releasing free fatty acids and glycerol. These are taken up in muscle and adipose tissue. Chylomicron remnants are taken up in the liver, where cholesterol is stored, secreted in bile, oxidised to bile acids or can enter endogenous pathway. DYSLIPIDAEMIA: DYSLIPIDAEMIA Dyslipidaemia may be primary or secondary. The primary forms are due to a combination of diet and genetics (often but not always polygenic). They are classified according to which lipoprotein particle is abnormal into six phenotypes (the Frederickson classification ). Secondary forms of dyslipidaemia are a consequence of other conditions, such as diabetes mellitus, alcoholism, nephrotic syndrome, chronic renal failure etc. The higher the LDL cholesterol and the lower the HDL cholesterol, the higher the risk of ischaemic heart disease. PREVENTION OF ATHEROMATOUS DISEASE: PREVENTION OF ATHEROMATOUS DISEASE Angiotensin-converting enzyme inhibitors improve endothelial function and prolong life in patients with atheromatous disease. Measures to increase HDL: moderate alcohol consumption increases HDL, and epidemiological evidence favors moderate alcohol consumption in older people. Regular exercise also increases circulating HDL. Antioxidants (e.g. vitamin C and vitamin E) improve endothelial function in patients with increased oxidant stress, and because of epidemiological evidence that a diet rich in antioxidants is associated with reduced risk of coronary artery disease. ISCHAEMIC HEART DISEASE: ISCHAEMIC HEART DISEASE Ischaemic heart disease(IHD) is defined as acute or chronic form of cardiac disability arising from imbalances between the myocardial supply and demand for oxygenated blood. Since, narrowing or obstruction of the coronary arterial system is the most common cause of myocardial anoxia, the alternate term coronary artery disease(CAD) is used synonymously with IHD. Its risk increases with age, smoking, hypercholesterolaemia, diabetes, and hypertension. SIGNS AND SYMPTOMS : SIGNS AND SYMPTOMS Ischaemic heart disease may be present with any of the following problems: Angina pectoris Acute chest pain: acute coronary syndrome, unstable angina or myocardial infarction.(" heart attack", severe chest pain unrelieved by rest associated with evidence of acute heart damage) Heart failure (difficulty in breathing or swelling of the extremities due to weakness of the heart muscle. Heart burn. ANGINA : ANGINA Angina occurs when the oxygen supply to the myocardium is insufficient for its needs. The pain has a characteristic distribution in the chest, arm and neck, and is brought on by exertion, cold or excitement. TYPES OF ANGINA : TYPES OF ANGINA STABLE ANGINA Predictable Occurs on exercise, emotion or eating. Caused by increase demand of the heart and by a fixed narrowing of coronary vessels, almost always by atheroma. Coronary obstruction is fixed Blood flow fails to increase during increased demand despite the local factors mediated vasodilation and so ischemic pain. So , the diastolic pressure increases and this causes a endocrinal crunch and thus causing Ischaematic pain in this region. PowerPoint Presentation: Thus, a form of acutely developing and rapidly reversible left ventricular failure results which is relieved by taking rest and reducing the myocardial workload. UNSTABLE ANGINA: UNSTABLE ANGINA This is characterized by pain that occurs with less and less exertion, culminating in pain at rest. The pathology is similar to that involved in myocardial infarction, namely platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel. PowerPoint Presentation: VARIANT ANGINA Uncommon Occurs at rest generally during sleep Caused by Large Coronary artery spasm Therapy is with Coronary artery vasodilators.(e.g. organic nitrates, calcium antagonists). DRUGS USED IN ANGINA AND THEIR SITE OF ACTIONS: DRUGS USED IN ANGINA AND THEIR SITE OF ACTIONS PowerPoint Presentation: ORGANIC NITRATES It is used in the treatment of angina pectoris are simple nitric and nitrous acid esters of glycerol. They differ in their volatility, e.g. isosorbide dinitrate and isosorbide mononitrate are solids at room temperature, nitroglycerin is only moderately volatile, and amyl nitrite is extremely volatile . These compounds cause a rapid reduction in myocardial oxygen demand, followed by rapid relief of symptoms . They are effective in stable and unstable angina as well as in variant angina pectoris. PowerPoint Presentation: Mechanism of action Nitrates decrease coronary vasoconstriction or spasm and increase perfusion of the myocardium by relaxing coronary arteries . In addition, they relax veins, decreasing preload and myocardial oxygen consumption . Organic nitrates, such as nitroglycerin, which is also known as glyceryl trinitrate , are thought to relax vascular smooth muscle by their intracellular conversion to nitrite ions, and then to nitric oxide, which in turn activates guanylate cyclase and increases the cells' cyclic guanosine monophosphate (GMP ). Elevated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation. PowerPoint Presentation: Effects of nitrates and nitrites on smooth muscle PowerPoint Presentation: Pharmacokinetics The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate . Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take the drug either sublingually or via a transdermal patch, thereby avoiding this route of elimination . Isosorbide mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown. Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity. PowerPoint Presentation: Time to peak effect and duration of action for some common organic nitrate preparations PowerPoint Presentation: Adverse effects The most common adverse effect of nitroglycerin, as well as of the other nitrates, is headache . High doses of organic nitrates can also cause postural hypotension, facial flushing, and tachycardia. Sildenafil potentiates the action of the nitrates . To preclude the dangerous hypotension that may occur, this combination is contraindicated. 2. β BLOCKERS: 2. β BLOCKERS The β b lockers decrease the oxygen demands of the myocardium by lowering both the rate and the force of contraction of the heart. They suppress the activation of the heart by blocking β receptors , and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure. With β blockers , the demand for oxygen by the myocardium is reduced both during exertion and at rest. Propranolol is the prototype for this class of compounds, but it is not cardio selective. Thus , other β blockers , such as metoprolol or atenolol, are preferred. Agents with intrinsic sympathomimetic activity (for example, pindolol ) are less effective and should be avoided in angina. 3. CALCIUM-CHANNEL BLOCKERS: 3. CALCIUM-CHANNEL BLOCKERS Calcium channels Three types of Ca 2+ channel (a ) Voltage sensitive channel : Activated when membrane potential drops to around -40 m V or lower. (b) Receptor operated channel : Activated by Adr and other agonists-independent of membrane depolarization (NA contracts even depolarized aortic smooth me bypromoting influx of Ca 2+ through this channel and releasing Ca 2+ from sarcoplasmic reticulum). (c) Leak channel : Small amounts of Ca 2+ leak into resting cell and are pumped out by Ca 2+ PowerPoint Presentation: Only the voltage sensitive L-type channels are blocked by the CCBs. The three groups of CCBs viz. phenylalkylamines (verapamil), benzothiazepine (diltiazem ) and dihydropyridines ( nifedipine) bind to their own specific binding sites on the α 1, subunit; all restricting Ca 2+ entry, though characteristics of channel blockade differ. Further , different drugs may have differing affinities for various site specific isoforms of the L-channels. This may account for the differences in action exhibited by various CCBs. The vascular smooth muscle has a more depolarized mernbrane (RMP about -40 mV) than heart . This may contribute to vascular selectivity of certain CCBs. Pharmacokinetic characteristics of calcium channel blockers : Pharmacokinetic characteristics of calcium channel blockers Clinical uses of calcium channel blockers: Clinical uses of calcium channel blockers Arrhythmias (verapamil ): To slow ventricular rate in rapid atrial fibrillation. To prevent recurrence of supraventricular tachycardia (SVT ). Hypertension : Usually a dihydropyridine drug (e.g. amlodipine or slow-release nifedipine). To prevent angina (e.g. dihydropyridine or diltiazem) MYOCARDIAL INFARCTION : MYOCARDIAL INFARCTION Myocardial infarction occurs when a coronary artery has been blocked by thrombus. This may be fatal and is a common cause of death, usually as a result of mechanical failure of the ventricle or from arrhythmia. Cardiac myocytes rely on aerobic metabolism. If the supply of oxygen remains below a critical value, a sequence of events leading to cell death (by necrosis or apoptosis) detected clinically by an elevation of circulating troponin. PowerPoint Presentation: Effects of myocardial ischaemia : This leads to cell death by one of two pathways: Necrosis or apoptosis PowerPoint Presentation: The main therapeutic drugs include drugs to improve cardiac function by maintaining oxygenation and reducing cardiac work as well as treating pain and preventing further thrombosis. They are used in combination, and include: Combinations of thrombolytic, antiplatelet and antithrombotic (a heparin preparation) drugs to open the blocked artery and prevent reocclusion. Oxygen if there is arterial hypoxia. Opioids (given with an antiemetic) to prevent pain organic nitrate. β- adrenoceptor antagonists. Angiotensin-converting enzyme inhibitors (ACEIs). PowerPoint Presentation: β-Adrenoceptor antagonists reduce cardiac work and thereby the metabolic needs of the heart, and are used as soon as the patient is stable. ACEIs and ARBs also reduce cardiac work and improve survival as does opening the coronary artery (with angioplasty or thrombolytic drug) and antiplatelet treatment . REFERENCES: REFERENCES Rang & Dale's, Pharmacology 7 th edition. Lippincott's Illustrated Reviews: Pharmacology, 4 th edition . KD Tripathi, Essentials Of Medical Pharmacology, 6 th edition.