Anti-Ischemic Drugs L46 PDF

1 46 Therapeutic control of ischemic heart diseases ILOs By the end of this lecture, students will be able to 1. Interpret how different drugs act to decrease anginal pains by agents that can increase myocardial O2 supply versus those that can decrease myocardial O2 demand. 2. Identify how each drug...

1 46 Therapeutic control of ischemic heart diseases ILOs By the end of this lecture, students will be able to 1. Interpret how different drugs act to decrease anginal pains by agents that can increase myocardial O2 supply versus those that can decrease myocardial O2 demand. 2. Identify how each drug will act to achieve its target in the face of a probable hazard. 3. Justify drugs available to improve prognosis. 4. Correlate the selection of drugs used in treatment of myocardial infarction to the varying degree of occlusion. Strategies for the treatment of ischemic heart disease (IHD) can be targeted at either increasing the coronary blood flow (by coronary vasodilation) or decreasing the work done by the heart. The latter can be achieved by reducing the force of cardiac muscle contraction either by reducing preload on the heart or by reducing cardiac contractility. Other changes in workload of the heart can be achieved by reducing heart rate or arterial blood pressure (decreased afterload). Drugs that are used to treat IHD are called antianginal drugs as they treat different types of angina, including stable angina. They are classified according to their goal of use into the following: I. Agents that improve ischemic symptoms. Four major classes are used either monotherapy or in combination: 1. Organic nitrates Vasodilators: Drugs that increase coronary flow & oxygen supply 2. Calcium channel blockers 3. Potassium channel openers 4. Beta-adrenoceptor blockers: negative inotropes that reduce cardiac work and hence oxygen demand. II. Agents that improve prognosis to achieve the main goal of prophylactic therapy halting the progression of the disease, thus preventing acute insults, and improving survival. These drugs include: 1. Antithrombotic drugs, as antiplatelet: aspirin and clopidogrel prevent development of thrombosis. 2. Statins halt progression of atherosclerosis. 3. ACEIs or ARBs dampen the renin-angiotensin-aldosterone-system (RAAS) damaging effects especially in presence of hypertension. 4. Beta-adrenoceptor blockers limit cardiac oxygen demand and prevent dysrhythmias. 1. Organic Nitrates They are exogenous sources of the natural vasodilator nitric oxide. The most widely used drug in this category is nitroglycerine, also known as glyceryl trinitrate (GTN), which is a rapid-onset drug that is used to terminate an acute attack. There is an increasing number of other drugs including isosorbide mononitrate and isosorbide dinitrate (short-/long-acting drugs) that are used for short- or long-term ischemic control. - Mechanism of Action: Organic nitrates act mainly on venous capacitance vessels more than on arterioles. They are considered nitric oxide (NO) donors as inside the body they are de-nitrated to nitrite ions by glutathione-S-transferase in endothelial cells. These nitrite ions mimic the action of the endogenous NO, which will activate guanylate cyclase (GC) and increase cGMP in vascular smooth muscle. Excess cGMP will activate PKG, reducing Ca+2 intracellularly and thus inhibiting myosin light chain kinase (MLCK) that will lead to vascular smooth muscle relaxation. OMNIA NAYEL 2 - Pharmacological action: They provide the following anti-anginal actions: 1. Relaxing venous smooth muscle leads to a reduced preload on the heart and consequently ventricular filling pressure and cardiac work. 2. Vasodilation on the arterial side of the circulation leads to a reduction in blood pressure and reduced afterload on the heart and hence cardiac work is reduced too. 3. The vasodilating effect of nitrates on coronary blood vessels are often minimal. Vessels may already be maximally dilated under the influence of local metabolites, which have accumulated in the hypoxic cardiac tissue. 4. Additionally, nitrates may help to improve blood flow through collateral vessels in myocardium and can also relieve coronary artery spasm when that is a cause of angina. 5. Some members (Long-acting nitrates) can inhibit platelet aggregation by increasing synthesis of endothelial prostacyclin (PGI2). - Route of administration: As many nitrate drugs undergo extensive first-pass metabolism in the liver they are not suitable for intestinal absorption. Sublingual (under the tongue), buccal (between upper lip and gum), or transdermal (through the skin from an adhesive patch) routes, are commonly used sites of administration to ensure the direct systemic arrival of the drugs. However, oral sustained release formulations of all forms of organic nitrates are also used. 2. Calcium Channel Blockers Calcium channel blockers such as nifedipine sustained release (SR) and amlodipine (dihydropyridines), and verapamil and diltiazem (non-dihydropyridines) reduce the flux of Ca+2 ions into smooth muscle and cardiac muscle but not skeletal muscle. - Mechanism of Action: The main site of action of calcium channel blockers is on voltage-gated L-type (long-acting) slow Ca+2 channels in most excitable tissues. In VSMCs, they decrease the entry of extracellular Ca+2 mainly in arteries leading to vasodilatation. Voltage-gated Ttype (transient) rapid channels are also blocked in pacemaker tissue of the sinoatrial (SAN) and atrioventricular (AVN) nodes altering their frequency of opening in response to depolarization. - Pharmacological action: Beneficial effects of CCBs in the relief of angina include 1. Systemic arteriolar vasodilatation (reduced arterial blood pressure and thus reduced afterload) and also coronary artery dilatation (in case of vasospasm). 2. In cardiomyocytes, the decrease in Ca+2 entry reduces heart rate (-ve chronotropism), cardiac contractility (-ve inotropism), as well as cardiac conduction (-ve dromotropic effect), thus reducing cardiac workload. It should be stressed that the different drugs in this broad category have a wide spectrum of activity and they are not identical. For example, verapamil and diltiazem both reduce heart rate and contractility but the dihydropyridine drugs nifedipine and amlodipine do not. Amlodipine and nifedipine have marked effects on VSMCs leading to arteriolar vasodilatation to the contrary of non-dihydropyridines that have a little vasodilating effect. N.B.: Never use short-acting nifedipine, which leads to sudden drop in BP precipitating a reflex tachycardia that can cause myocardial hypoperfusion up to death. However, amlodipine is a longacting CCB that does not lead to tachycardia and does not affect myocardial perfusion. OMNIA NAYEL 3 3. Potassium Channel Openers Potassium channel opening drugs such as nicorandil open ATP-sensitive K+ channels and hence lead to smooth muscle hyperpolarization. This inhibits the opening of L-type voltage-gated Ca+2 channels and so produces vasodilatation in both systemic and, where possible, coronary blood vessels. They are also weak NO donner being chemically related to nitrates, thus they partially induce venular dilation. Though, they exert a dual action, yet they are weaker than others antiischemic drugs, thus they are preserved for second – line therapy as add-on drug. 4. Beta-adrenoceptor Blockers Beta-blockers are considered the first choice on prolonged use as they reduce the incidence of sudden death. - Pharmacological action: Beta-adrenoceptor blockers (beta-blockers) reduce the force of cardiac contraction (reduce contractility) and heart rate, thus decreasing cardiac output (CO). Also, they inhibit the renin angiotensin system, which together with decreasing CO, will lower blood pressure (reducing afterload). These effects reduce myocardial oxygen demand as they decrease cardiac workload and limit exercise performance. The reduction in heart rate with the consequent lengthening of diastole, the phase of the cardiac cycle when most of the coronary perfusion occurs, will lead to increase in coronaries filling time, myocardial perfusion, and thus myocardial oxygen supply. Some β–adrenoceptor blockers, such as atenolol, bisoprolol, metoprolol and nebivolol, are referred to as ‘cardio-selective’ as they are relatively selective for the β1-subtype of adrenergic receptors, the main type found in the heart. The first β-adrenoceptor blocker developed, propranolol, is non-selective and has approximately equivalent actions on β1 and β2 receptors. This drug is still used in other indications but is contraindicated in asthmatics as the β2 blockade may lead to bronchospasm. N.B.: Beta-blockers are not direct vasodilators, on the contrary non-selective members block beta2 receptors in VSMCs and thus induce vasoconstriction. Anti-ischemic drugs combination The combination of anti-ischemic drugs is frequently used in different stages of angina pectoris least adopting the following cautions: 1. Organic nitrates can be either combined with non-dihydropyridine group or with beta-blockers to limit the reduction in BP and reflex tachycardia. 2. Dihydropyridines can be combined with beta-blockers to protect against occurrence of tachycardia. They can be given in IHD if heart failure supervenes as they do not inhibit cardiac contractility. 3. Non-dihydropyridines cannot be combined with beta-blockers to avoid conduction defect (bradycardia and heart block). They are preferably used when hypotension exists as they do not cause vasodilatation. OMNIA NAYEL 4 4. pFOX inhibitors (metabolic acting drugs (non-hemodynamic): They are partial FFA oxidation inhibitors that can be combined with anti-ischemic drugs. They shift cardiomyocyte metabolism to the utilization of CHO [low O2 demand] rather than FFA [high O2 demand] to spare O2 to the ischemic myocardium. By preventing beta-oxidation of FFA via inhibiting enzyme responsible for transfer of FFA across the mitochondrial membranes. Treatment of Acute Insults (AMI) Acute myocardial infarction (AMI) results when there is complete interruption of blood flow to an area of myocardium. Whenever suspected, patients should be transferred immediately to nearby specialized hospitals as time to hospital is very critical for the prognosis of the cases. The following should be performed to rescue the patients: 1. Before & during transfer: i. Nitroglycerine sublingual up to 3 doses at 5 min. intervals. ii. Analgesics (morphine) for severe pain. iii. Chewable aspirin 160-300 mg + loading dose clopidogrel reduce morbidity and mortality. iv. Ensure better oxygenation and if needed I.V. fluids and CPR are implemented. 2. In ER, ICU or CCU: - Symptomatic treatment to relief the severe chest pain by IV infusion of GTN and IV morphine. - Open the occluded vessels can be done either by IV thrombolytic drugs as fibrin-specific agents (Alteplase) or by primary percutaneous coronary intervention (PCI, is a nonsurgical, invasive procedure with a goal to relieve the narrowing or occlusion of the coronary artery and improve blood supply to the ischemic tissue) based on the therapeutic window. - Improve survival by giving the following drugs: o Early beta-blockers limit dysrhythmias. o Early statins stabilize the existing plaque. o ACE Inhibitors reduce post-MI fibrosis and thus decrease the progression to HF. OMNIA NAYEL