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25 Cards in this Set
- Front
- Back
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By regulation of smooth muscle tone, intramyocardial arterioles (resistance vessels
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maintain the balance between coronary blood flow and myocardial oxygen requirement.
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Drugs that may prevent or terminate angina may:
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either increase oxygen supply (coronary vasodilators) and/or
reduce oxygen demand (negative chronotropic drugs, vasodilators, and negative inotropic agents.) |
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Treatment of patients with significant coronary artery disease aims to achieve an "even" myocardial oxygen balance. Drugs are used to
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(a) reduce preload (nitrates), (b) reduce heart rate, myocardial work and oxygen consumption (beta-blockers), (c) maximize coronary vasodilation (calcium channel blockers).
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Coronary vascular bed has both alpha and beta-adrenoceptors
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Alpha receptor activation produces constriction, mainly in epicardial capacitance vessels where most of these receptors are found.
Coronary vessel vasodilation is mediated by beta receptors which are mainly localized in intramuscular arteries. Sympathetic activation produces more constriction than dilation and individuals with accentuated responses to alpha-receptor activation may be susceptible to vasospastic myocardial ischemia. In the epicardial vessels there are more alpha, in the intramyocardial vessels you have more beta. Epi and NE released, on the resistance vessels you cause vasodilation, in the capacitance vessels you will increase tone |
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Nitrates
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The drugs of first choice. Their main action is peripheral vasodilation, either venous (low doses), or both venous and arterial (higher doses). This vasodilation is mediated by production of nitric oxide (NO), and increased levels of intracellular guanosine 3',5'-monophosphate (cGMP) in vascular smooth muscle. The resulting pooling of blood in the capacitance vessels (veins) reduces venous return and decreases ventricular volume. This reduction in distension of the heart wall decreases oxygen demand and the pain of angina is relieved quickly. (preload)
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Nitrates
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At the same time nitrates improve myocardial oxygen supply by increasing the coronary blood flow to the endocardium. Cardiac output is usually unchanged or decreased slightly, and a reflex tachycardia occurs in normal subjects (filling less and your stroke volume goes down). However in patients with heart failure, who have a high systemic vascular resistance, cardiac output may increase and there is little change in the heart rate. (increase of vascular resistance)
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Glyceryl trinitrate (Nitroglycerin)
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a short-acting nitrate, with a duration of action of 30 minutes. It is more useful in preventing attacks of angina than in stopping them once they have begun. It may be given by a sublingual, transdermal or intravenous route. In the latter case, between 40-80% of the dose may be absorbed by the plastic giving set. Longer acting nitrates are more stable and may be effective for several hours, depending on the drug and formulation used. (eg. isosorbide dinitrate [Isordil], isosorbide mononitrate [Imdur]).
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Unwanted effects of nitrates
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include dilation of cranial vessels causing headaches, which can limit the dose used. More serious side effects are tachycardia and hypotension. These result respectively in increased myocardial oxygen demand and decreased coronary perfusion, both of which have an adverse effect on myocardial oxygen balance. Another well recognized problem is the development of tolerance to nitrates. Blood vessels become hypo- or non-reactive to the drugs, particularly when large doses, frequent dosing regimes and long acting formulations are used. To avoid this, nitrates are best used intermittently, allowing a few hours without treatment in each 24 hours period.
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The organic nitrates and nitrites are denitrated to produce nitric oxide (NO) which activates guanylyl cyclase.
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Activation of guanylyl cyclase results in increased concentrations of cyclic guanosine 3',5'-monophosphate (cyclic GMP) which results in vasodilation.
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cGMP mediated vasodilation occurs by
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decreasing calcium levels in the cell, thus decreasing calcium-calmodulin complex activation of myosin light chain kinase.
inhibition of myosin light chain kinase results in net dephosphorylation of myosin light chain and thus causes relaxation. cGMP also causes dephosphorylation of myosin light chain by activating other enzyme systems. Nitric oxide synthetase produces endogenous nitrates by action on L-arginine. |
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Nitrates:
Beneficial Effects |
Angina pectoris caused by temporary myocardial ischemia is responsive to treatment by organic nitrates. (primary benefit)
These agents act primarily by vasodilation (especially venodilation) which reduces myocardial preload and therefore myocardial oxygen demand. Nitrates also promote redistribution of blood flow to relative ischemic areas. Beneficial effects of low dose nitrates occurs primarily as a result of vasodilation. |
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Nitrate Toxicities
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Side effects are usually secondary to cardiovascular effects of nitrates, notable vasodilation. Adverse effects include:
headache (meningeal vascular dilatation)- decreasing dosage may help. dizziness, weakness due to postural hypotension. some incidence of drug rash, especially with pentaerythritol tetranitrate |
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Beta-adrenoceptor Antagonists: Beta-receptor blockers reduce myocardial oxygen demand by:
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reducing the increases in heart rate and contractility due to adrenergic activity. Therefore during exercise normal positive chronotropic and inotropic responses are blunted.
Propranolol, atenolol, and nadolol are examples of beta-receptor blockers used in management of chronic, classical angina |
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Beta blockers
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These are used to prevent angina as well as to treat hypertension, by blocking beta-1 receptors in the heart. In addition to this blocking action, some beta-blockers can actually stimulate the receptors at a low level. This so called intrinsic activity can be a disadvantage when treating angina. Drugs such as atenolol (Tenormin) and metoprolol (Lopressor) are the drugs of choice, because they are cardioselective, i.e. ‘only’ work on beta-1 receptors, and not the beta-2 receptors elsewhere in the body.
Most side effects of beta blockers are the consequence of their blocking action. Bronchoconstriction (mediated by beta-2 receptors) is normally of little importance. However in asthmatics it can be life-threatening, and beta blockers should not be used in these patients. Cold extremities, worsening of peripheral vascular disease, hypoglycemia and impotence are also caused by blockade of beta-2 receptors. Some patients with heart disease need a sympathetic "drive" to the heart to maintain adequate cardiac output, and blockade of beta-1 receptors in these patients can cause heart failure. (on the edge of CHF) |
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ß-Adrenoceptor Antagonists:
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Beneficial in reducing the frequency and severity of exertional angina attacks, but are not effective in variant angina and may even worsen that condition.
Propranolol (Inderal), timolol (Blocadren), metoprolol (Lopressor), atenolol (Tenormin) are effective antianginal drugs. Antianginal effects of beta-blockers are due to: Decreased heart rate Decreased contractility Decreased blood pressure during exercise (reduced afterload) Beta-adrenoceptor antagonists may be used in combination with nitrates and calcium channel blockers in select patients. Because they work through different mechanism. Harmful effects In patients with reduced left ventricular function and limited myocardial reserve, beta-receptor blockade may precipitate heart failure by blocking essential sympathetic |
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Calcium channel antagonists:
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Nifedipine, verapamil, diltiazem are examples of calcium channel blockers that may be effective in chronic treatment of angina.
They are coronary vasodilators that reduce arterial pressure and myocardial contractility. Therefore, they reduce myocardial oxygen requirements. Some agents, such as verapamil and diltiazem are more likely to affect cardiac conduction and contractility, while others have more prominent effects on vascular smooth muscle (nifedipine). Variant angina (Prinzmetal's angina) is often effectively managed by calcium channel blockers. These drugs act by blocking the calcium channels which open in response to depolarization of the cell membrane (voltage sensitive channels). Such channels occur in many different cells of the body, but the important pharmacological effects of these drugs are restricted to cardiac and smooth muscle. Calcium antagonists are divided into three sub-groups based on their chemical structure |
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Papaverine derivatives (phenylkalkylamines)
Verapamil (Calan) |
fairly selective for myocardium with little activity on vasculature
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Dihydropyridines
Nifedipine (Procardia), Amlodipine (Norvasc) |
Primary effect on vasculature decreased afterload
Most agents in this class are not used for angina due to reflex tachycardia (Nifedipine and Amlodipine are exceptions) |
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Benzothiazepines
Diltiazem (Cardizem) |
Effects on both vasculature and myocardium
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Calcium antagonists reduce afterload
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(by arterial vasodilation), dilate coronary arteries, and reduce cardiac work, thus improving myocardial oxygen balance. Verapamil and diltiazem also have an anti-arrhythmic effect, whereas the dihydropyridines predominantly affect vascular smooth muscle. Adverse effects of calcium antagonists include postural hypotension, flushing, peripheral edema and constipation. All calcium antagonists have a negative inotropic effect, especially verapamil, and should not be used in patients in cardiac failure.
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Calcium Channel Blockers
Variant Angina: |
Calcium Channel Blockers are effective in treating variant angina (Prinzmetal's angina).
Variant angina is caused by coronary vasospasm that reduces coronary flow. Calcium channel blockers exert their beneficial effects by direct coronary vasodilation (vasorelaxation), as opposed to peripheral hemodynamic effects. |
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Exertional Angina
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Calcium channel blockers are effective in managing exercise-induced angina probably by decreasing oxygen demand (decreased afterload and contractility) and/or increasing coronary blood flow.
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In patients with liver cirrhosis
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half lives and bioavailability may be increased and dosages may have to be reduced.
Most common side effects caused by calcium channel blockers administration are secondary to excessive vasodilatation including dizziness, hypotension, flushing, and nausea. Less commonly patients experience constipation, peripheral edema, coughing, pulmonary edema or wheezing. Relatively uncommon side effects include: rash, somnolence and liver function test changes. CCB |
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Calcium Channel Blocker Toxicity
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Worsening of myocardial ischemia may be observed with dihydropyridines (e.g. amlodipine (Norvasc), felodipine (Plendil), nicardipine (Cardene), nimodipine (Nimotop), nifedipine (Procardia, Adalat)) since they agents are more likely to produce excessive vasodilatation and reflex mediated tachycardia.
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Calcium Channel Blocker Toxicity
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Mechanisms which may be responsible for worsening ischemia include:
hypotension causing decreased coronary perfusion increasing coronary blood flow in non-ischemic regions at the expense of coronary flow in ischemic areas increase in myocardial oxygen demand due to tachycardia caused by reflex sympathetic stimulation. |
