CLINICAL PHARMACOLOGY OF ANTIANGINAL DRUGS. CLINICAL PHARMACOLOGY OF ANTIHYPERTENSIVE MEDICATIONS. CLINICAL PHARMACOLOGY OF CARDIAC GLYCOSIDES
Antianginal drugs
Angina pectoris is a clinical syndrome characterized by episodes of chest pain. It occurs when there is a deficit in myocardial oxygen supply (myocardial ischemia) in relation to myocardial oxygen demand. It is most often caused by atherosclerotic plaque in the coronary arteries but may also be caused by coronary vasospasm. The development and progression of atherosclerotic plaque is called coronary artery disease (CAD). Atherosclerotic plaque narrows the lumen, decreases elasticity, and impairs dilation of coronary arteries. The result is impaired blood flow to the myocardium, especially with exercise or other factors that increase the cardiac workload and need for oxygen. The continuum of CAD progresses from angina to myocardial infarction. There are three main types of angina: classic angina, variant angina, and unstable angina. The Canadian Cardiovascular Society classifies clients with angina according to the amount of physical activity they can tolerate before anginal pain occurs. These categories can assist in clinical assessment and evaluation of therapy.
Classic anginal pain is usually described as substernal chest pain of a constricting, squeezing, or suffocating nature. It may radiate to the jaw, neck, or shoulder, down the left or both arms, or to the back. The discomfort is sometimes mistaken for arthritis, or for indigestion, as the pain may be associated with nausea, vomiting, dizziness, diaphoresis, shortness of breath, or fear of impending doom. The discomfort is usually brief, typically lasting 5 minutes or less until the balance
of oxygen supply and demand is restored.
For clients at any stage of CAD development, irrespective of symptoms of myocardial ischemia, optimal management involves lifestyle changes and medications, if necessary, to control or reverse risk factors for disease progression. Risk factors are frequently additive iature and are classified as nonmodifiable and modifiable. Nonmodifiable risk factors include age, race, gender, and family history. The risk factors that can be altered include smoking, hypertension, hyperlipidemia, obesity, sedentary lifestyle, stress, and the use of drugs that increase cardiac workload (eg, adrenergics, corticosteroids).
Thus, efforts are needed to assist clients in reducing blood pressure, weight, and serum cholesterol levels, when indicated, and developing an exercise program. For clients with diabetes mellitus, glucose and blood pressure control can reduce the microvascular changes associated with the condition. In addition, clients should avoid circumstances known to precipitate acute attacks, and those who smoke should stop. Smoking is harmful to clients because:
• Nicotine increases catecholamines which, in turn, increase heart rate and blood pressure.
• Carboxyhemoglobin, formed from the inhalation of carbon monoxide in smoke, decreases delivery of blood and oxygen to the heart, decreases myocardial contractility, and increases the risks of life-threatening cardiac dysrhythmias
(eg, ventricular fibrillation) during ischemic episodes.
• Both nicotine and carbon monoxide increase platelet adhesiveness and aggregation, thereby promoting thrombosis.
• Smoking increases the risks for myocardial infarction, sudden cardiac death, cerebrovascular disease (eg, stroke), peripheral vascular disease (eg, arterial insufficiency), and hypertension. It also reduces high-density lipoprotein, the “good” cholesterol.
Additional nonpharmacologic management strategies include surgical revascularization (eg, coronary artery bypass graft) and interventional procedures that reduce blockages (eg, percutaneous transluminal coronary angioplasty [PTCA], intracoronary stents, laser therapy, and rotoblators). However, most clients still require antianginal and other cardiovascular medications to manage their disease.
ANTIANGINAL DRUGS
Drugs used for myocardial ischemia are the organic nitrates, the beta-adrenergic blocking agents, and the calcium channel blocking agents. These drugs relieve anginal pain by reducing myocardial oxygen demand or increasing blood supply to the myocardium. Nitrates and beta blockers are described in the following sections and dosage ranges are listed in Drugs at a Glance: Nitrates and Beta Blockers. Calcium channel blockers are described in a following section; indications for use and dosage ranges are listed in Drugs at a Glance: Calcium Channel Blockers.
Organic nitrates (and nitrates) are simple nitric and nitrous acid esters of alcohols. These compounds cause a rapid reduction in myocardial oxygen demand followed by rapid relief of symptoms. They are effective in stable and anstable
angina, as well as Prinzmetal’s or variant angina pectoris.
Nitrates, b-blockers, and calcium channel-blockers are equally effective for relief of anginal symptoms. However, for prompt relief of an ongoing attack of angina precipitated by exercise or emotional stress, sublingual (or spray form) nitroglycerin (NITROSTAT) is the drug of choice.
Mechanisms of action: The organic nitrates, such as nitroglycerin, are thought to relax vascular smooth muscle by their intracellular conversion to nitrite ions and then to nitric oxide (NO), what leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation.
At therapeutic doses, nitroglycerin has two major effects. First, it causes dilation of the large veins, resulting in pooling blood in the veins. This diminishes preload (venous return to the heart), and reduces the work of the heart. Second, nitroglycerin dilates the coronary vasculature, providing increased blood supply to the heart muscle. Nitroglycerin causes a decrease in myocardial oxygen consumption because of decreased cardiac work.
Pharmacokinetics. The time to onset of action varies from one minute for nitroglycerin to more than one hour for isosorbide mononitrate. Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to give the drug either sublingually or via a transdermal patch.
Adverse effects. The most common adverse effect of nitroglycerin, as well as the other nitrates, is headache. 30 to 60 % of patients receiving intermittent nitrate therapy with long-acting agents develop headaches. High doses of organic nitrates can also cause postural hypotension, facial flushing, and tachycardia.
Tolerance to the actions of nitrates develops rapidly. It can be overcome by provision of a daily “nitrate-free interval” to restore sensitivity to the drug. This interval is typically 6 to 8, 10-12 hours, usually at night because there is decreased demand on the heart at that time. Nitroglycerin patches are worn for 12 hours and removed for 12 hours. However, Prinzmetal’s or variant angina worsens early in the morning, perhaps due to circardian catecholamine surges. These patients nitrate-free interval should be late afternoon.
Nitroglycerin Extended release Buccal Tablets (contain 1, 2, 2.5, 3, 5 mg of nitroglycerin). When a buccal tablet is placed under the lipp or in the buccal pouch, it adheres to the mucosa. As the tablets gradually dissolves, it releases nitroglycerin to the systemic circulation. Buccal nitroglycerin can be tried as a means of aborting an acute anginal attack.
Nitroglycerin tablets (NITROSTAT) – is a stabilized sublingual formulation, which contains 0,15, 0,3, 0,4, 0,6 mg of nitroglycerin. Nitroglycerin is rapidly absorbed following sublingual administration. Its onset is approximately one to three minutes. Significant pharmacologic effects are present for 30 to 60 minutes following administration by the above route. Nitroglycerin is indicated for the prophylaxis, treatment and management of patients with angina pectoris. One tablet should be dissolved under the tongue or in the buccal pouch at the first sign of an acute anginal attack. The dose may be repeated approximately every five minutes until relief is obtained. If the pain persists after a total of 3-tablets in a 15-minute period, drug combination should be recommended.
Nitroglycerin (NITRO-BID) 2,5, 6,5, 9 mg capsules. Capsules must be swollowed. Administer the smallest effective dose two or three times daily at 8 to 12 hours intervals. Contraindications: acute or recent myocardial infarction, severe anemia, closed-angled glaucoma, postural hypotension, increased intracranial pressure, and idiosyncrasy to the drug.
Nitroglycerin injection – for intravenous use only. Must be diluted in dextrose 5 % injection, or sodium chloride (0,9 %) injection. Nitroglycerin should not be mixed with other drugs. The concentration of the infusion solution should not exceed 400 mg/ml of nitroglycerin.
Indication and usage:
1. Control of blood pressure in perioperative hypertension: hypertension associated with surgical procedures, especially cardiovascular procedures, such as hypertension seen during intratracheal intubation, anesthesia, skin incision, sternotomy, cardiac bypass.
2. Congestive heart failure associated with acute myocardial infarction.
3. Treatment of angina pectoris.
4. Production of controlled hypotension during surgical procedures.
Isosorbide dinitrate (Isordil, Sorbitrate) is used to reduce the frequency and severity of acute anginal episodes. When given sublingually or in chewable tablets, it acts in about 2 minutes, and its effects last 2 to 3 hours. When higher doses are given orally, more drug escapes metabolism in the liver and produces systemic effects in approximately 30 minutes. Therapeutic effects last about 4 hours after oral administration. The effective oral dose is usually determined by increasing the dose until headache occurs, indicating the maximum tolerable dose. Sustained-release capsules also are available.
Isosorbide mononitrate (Ismo, Imdur) is the metabolite and active component of isosorbide dinitrate. It is well absorbed after oral administration and almost 100% bioavailable. Unlike other oral nitrates, this drug is not subject to first-pass hepatic metabolism. Onset of action occurs within 1 hour, peak effects occur between 1 and 4 hours, and the elimination half-life is approximately 5 hours. It is used only for prophylaxis of angina; it does not act rapidly enough to relieve acute attacks.
Sympathetic stimulation of beta1 receptors in the heart increases heart rate and force of myocardial contraction, both of which increase myocardial oxygen demand and may precipitate acute anginal attacks. Beta-blocking drugs prevent or inhibit sympathetic stimulation. Thus, the drugs reduce heart rate and myocardial contractility, particularly when sympathetic output is increased during exercise. A slower heart rate may improve coronary blood flow to the ischemic area. Beta blockers also reduce blood pressure, which in turn decreases myocardial workload and oxygen demand. In angina pectoris, beta-adrenergic blocking agents are used in long-term management to decrease the frequency and severity of anginal attacks, decrease the need for sublingual nitroglycerin, and increase exercise tolerance. When a beta blocker is being discontinued after prolonged use, it should be tapered in dosage and gradually discontinued or rebound angina can occur.
These drugs should not be given to clients with known or suspected coronary artery spasms because they may intensify the frequency and severity of vasospasm. This probably results from unopposed stimulation of alpha-adrenergic receptors, which causes vasoconstriction, when beta-adrenergic receptors are blocked by the drugs. Clients who continue to smoke may have reduced efficacy with the use of beta blockers. Clients with asthma should be observed for bronchospasm from blockage of beta2 receptors in the lung. Beta blockers should be used with caution in clients with diabetes mellitus because they can conceal signs of hypoglycemia except for sweating).
The b-adrenergic blockers agents supress the activation of the heart by blocking b1 receptors. They also reduce the work of the heart by decreasing cardiac output and causing a slight decrease in blood pressure. Propranolol is the prototype of this class of compounds, but other b-blockers, such as metoprolol and atenolol are equally effective. Propranolol decreases the oxygen requirement of heart muscle and therefore is effective in reducing the chest pain on exertion that is common in angina. Propranolol is therefore useful in the chronic management of stable angina (not for acute treatment). Tolerance to moderate exercise is increased and this is noticeable by improvement in the electrocardiogram. Agents with intrinsic sympathomymetic activity (for example, pindolol and acebutolol) are less effective and should be avoided. The b–blockers reduce the frequency and severity oh angina attacks. These agents are particularly useful in the treatment of patients with myocardial infarction. The b-blockers can be used with nitrates to increase exercise duration and tolerance. They are, however, contraindicated in patients with diabetes, peripheral vascular disease, or chronic pulmonary disease.
Propranolol is well absorbed after oral administration. It is then metabolized extensively in the liver; a relatively small proportion of an oral dose (approximately 30%) reaches the systemic circulation. For this reason, oral doses of propranolol are much higher than IV doses. Onset of action is 30 minutes after oral administration and 1 to 2 minutes after IV injection. Because of variations in the degree of hepatic metabolism, clients vary widely in the dosages required to maintain a therapeutic response.
Atenolol, metoprolol, and nadolol have the same actions, uses, and adverse effects as propranolol, but they have long half-lives and can be given once daily. They are excreted by the kidneys, and dosage must be reduced in clients with renal
impairment.
Calcium Channel Blocking Agents
Calcium channel blockers act on contractile and conductive tissues of the heart and on vascular smooth muscle. For these cells to functioormally, the concentration of intracellular calcium must be increased. This is usually accomplished by movement of extracellular calcium ions into the cell (through calcium channels in the cell membrane) and release of bound calcium from the sarcoplasmic reticulum in the cell. Thus, calcium plays an important role in maintaining vasomotor tone, myocardial contractility, and conduction. Calcium channel blocking agents prevent the movement of extracellular calcium into the cell. As a result, coronary and peripheral arteries are dilated, myocardial contractility is decreased, and the conduction system is depressed in relation to impulse formation (automaticity) and conduction velocity.
In angina pectoris, the drugs improve the blood supply to the myocardium by dilating coronary arteries and decrease the workload of the heart by dilating peripheral arteries. In variant angina, calcium channe l blockers reduce coronary artery vasospasm. In atrial fibrillation or flutter and other supraventricular tachydysrhythmias, diltiazem and verapamil slow the rate of ventricular response. In hypertension, the drugs lower blood pressure primarily by dilating peripheral arteries.
Calcium channel blockers are well absorbed after oral administration but undergo extensive first-pass metabolism in the liver. Most of the drugs are more than 90% protein bound and reach peak plasma levels within 1 to 2 hours (6 hours or longer for sustained-release forms). Most also have short elimination half-lives (<5 hours), so doses must be given three or four times daily unless sustained-release formulations are used. Amlodipine (30 to 50 hours), bepridil (24 hours), and felodipine (11 to 16 hours) have long elimination half-lives and therefore can be given once daily. The drugs are metabolized in the liver, and dosage should be reduced in clients with severe liver disease. Dosage reductions are not required with renal disease. The calcium channel blockers approved for use in the
The drugs also vary in clinical indications for use; most are used for angina or hypertension, and only diltiazem and verapamil are used to manage supraventricular tachydysrhythmias. In clients with CAD, the drugs are effective as monotherapy but are commonly prescribed in combination with beta blockers. In addition, nimodipine is approved for use only in subarachnoid hemorrhage, in which it decreases spasm in cerebral blood vessels and limits the extent of brain damage. In animal studies, nimodipine exerted greater effects on cerebral arteries than on other arteries, probably because it is highly lipid soluble and penetrates the blood–brain barrier. Contraindications include second- or third-degree heart block, cardiogenic shock, and severe bradycardia, heart failure, or hypotension. The drugs should be used cautiously with milder bradycardia, heart failure, or hypotension and with renal or hepatic impairment.
The calcium channel blockers inhibit the entrance of calcium into cardiac and smooth muscle cells of the coronary and systemic arterial beds. All calcium channel blockers are therefore vasodilators that cause a decrease in smooth muscle tone and vascular resistance. At clinical doses, these agents affect primarily the resistance of vascular smooth muscle and the myocardium. [Note: Verapamil mainly affects the myocardium, whereas nifedipine exertrs a greater effect on smooth muscle in the peripheral vasculature. Diltiazem is intermediate inits actions].
Nifedipine (adalat) – 10, 20 mg capsules – functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac conduction or heart rate. Nifedipine is administered orally and has a short life (about 4 hours) requiring multiple dosing. The vasodilation effect of nifedipine is useful in the treatment of variant angina caused by spontaneous coronary spasm.
Therapy should be initiated with 19 mg capsule. The starting dose is one 10 mg calsule, swallowed whole, 3 times/day. The usual effective dose range is 10 20 mg three times daily. Doses of 20-30 mg three or four times daily may be effective in patients with evidence of coronary artery spasm. More than 180 mg per day is not recommended. Nifedipine titration should proceed over a 7-14 day period. A single dose should rarely exceed 30 mg.
Nifedipine can cause flushing, headeache, hypotension, and peripheral edema as side effects of its vasodilation activity. The drug may cause reflex tachycardia if peripheral vasodilation is marked resulting in a substantial decrease in blood pressure.
Verapamil slows cardiac conduction directly and thus decreases heart rate and oxygen demand. Verapamil causes greater negative inotropic effects than does nifedipine, but it is a weaker vasodilator. Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV condunction abnormalities. It is also causes constipation. Verapamil should be used with caution in digitalized patients, since it increases digoxin levels.
Diltiazem has cardiovascular effects thah are similar to those of verapamil. It reducws the heart rate, although to a lesser extent than verapamil, and also decreases blood pressure. In addition, diltiazem can relieve coronary artery spasm and is therefore particularly useful in patients with variant angina. The incidence of adverse side effects is low.
Adjunctive Antianginal Drugs
In addition to antianginal drugs, several other drugs may be used to control risk factors and prevent progression of myocardial ischemia to myocardial infarction and sudden cardiac death. These may include:
• Aspirin. This drug has become the standard of care because of its antiplatelet (ie, antithrombotic) effects. Recommended doses vary from 81 mg daily to 325 mg daily or every other day; apparently all doses are beneficial in reducing the possibility of myocardial reinfarction, stroke, and death. Clopidogrel, 75 mg/day,
is an acceptable alternative for individuals with aspirin allergy.
• Antilipemics. These drugs may be needed by clients who are unable to lower serum cholesterol levels sufficiently with a low-fat diet. Lovastatin or a related “statin” is often used. The goal is usually to reduce the serum cholesterol level below 200 mg/dL and lowdensity lipoprotein cholesterol to below 130 mg/dL.
• Antihypertensives. These drugs may be needed for clients with hypertension. Because beta blockers and calcium channel blockers are used to manage hypertension as well as angina, one of these drugs may be effective for both disorders.
PRINCIPLES OF THERAPY
Goals of Therapy
The goals of drug therapy are to relieve acute anginal pain; reduce the number and severity of acute anginal attacks; improve exercise tolerance and quality of life; delay progression of CAD; prevent myocardial infarction; and prevent sudden cardiac death.
Choice of Drug and Dosage Form
For relief of acute angina and prophylaxis before events that cause acute angina, nitroglycerin (sublingual tablets or translingual spray) is usually the primary drug of choice. Sublingual or chewable tablets of isosorbide dinitrate also may be used. For long-term prevention or management of recurrent angina, oral or topical nitrates, beta-adrenergic blocking agents, or calcium channel blocking agents are used.
Combination drug therapy with a nitrate and one of the other drugs is common and effective. Clients taking one or more long-acting antianginal drugs should carry a short-acting drug as well, to be used for acute attacks.
Titration of Dosage
Dosage of all antianginal drugs should be individualized to achieve optimal benefit and minimal adverse effects. This is usually accomplished by starting with relatively small doses and increasing them at appropriate intervals as necessary. Doses may vary widely among individuals.
Tolerance to Long-Acting Nitrates
Clients who take long-acting dosage forms of nitrates on a regular schedule develop tolerance to the vasodilating (antianginal) effects of the drug. The clients more likely to develop tolerance are those on high-dose, uninterrupted therapy. Although tolerance decreases the adverse effects of hypotension, dizziness, and headache, therapeutic effects also may be decreased. As a result, episodes of chest pain may occur more often or be more severe than expected. In addition, shortacting nitrates may be less effective in relieving acute pain. Opinions seem divided about the best way to prevent or manage nitrate tolerance. Some authorities recommend using short-acting nitrates wheeeded and avoiding the long-acting forms. Others recommend using the long-acting forms for 12 to 16 hours daily during active periods and omitting them during inactive periods or sleep.
Thus, a dose of an oral nitrate or topical ointment would be given every 6 hours for three doses daily, allowing a rest period of 6 hours without a dose. Transdermal discs should be removed at bedtime. If anginal symptoms occur during sleeping hours, short-acting nitrates may be beneficial in relieving the symptoms. All nitrates should be administered at the lowest effective dosage.
Use in Children
The safety and effectiveness of antianginal drugs have not been established for children. Nitroglycerin has been given IV for heart failure and intraoperative control of blood pressure, with the initial dose adjusted for weight and later doses titrated to response.
Use in Older Adults
Antianginal drugs are often used because cardiovascular disease and myocardial ischemia are common problems in older adults. Adverse drug effects, such as hypotension and syncope, are likely to occur, and they may be more severe than in younger adults. Blood pressure and ability to ambulate safely should be closely monitored, especially when drug therapy is started or dosages are increased. Ambulatory clients also should be monitored for their ability to take the drugs correctly.
With calcium channel blockers, older adults may have higher plasma concentrations of verapamil, diltiazem, nifedipine, and amlodipine. This is attributed to decreased hepatic metabolism of the drugs, probably because of decreased hepatic blood flow. In addition, older adults may experience more hypotension with verapamil, nifedipine, and felodipine than younger clients. Blood pressure should be monitored with these drugs.
Use in Renal Impairment
Little information is available about the use of antianginal drugs in clients with impaired renal function. A few studies indicate that advanced renal failure may alter the pharmacokinetics of calcium channel blockers. Although the pharmacokinetics of diltiazem and verapamil are quite similar in clients with normal and impaired renal function, caution is still advised. With verapamil, about 70% of a dose is excreted as metabolites in urine.
Dosage reductions are considered unnecessary with verapamil and diltiazem but may be needed with nifedipine and several other dihydropyridine derivatives. With nifedipine, protein binding is decreased and the elimination half-life is prolonged with renal impairment. In a few clients, reversible elevations in blood urea nitrogen and serum creatinine have occurred. With nicardipine, plasma concentrations are higher in clients with renal impairment, and dosage should be reduced. Bepridil should be used with caution because its metabolites are excreted mainly in urine.
Use in Hepatic Impairment
Nitrates, beta blockers, and calcium channel blockers are metabolized in the liver, and all should be used with caution in clients with significant impairment of hepatic function from reduced blood flow or disease processes.
With oral nitrates, it is difficult to predict effects. On the one hand, first-pass metabolism is reduced, which increases bioavailability (amount of active drug) of a given dose. On the other hand, the nitrate reductase enzymes that normally deactivate the drug may increase if large doses are given. In this case, more enzymes are available and the drug is metabolized more rapidly, possibly reducing therapeutic effects of a given dose. Relatively large doses of oral nitrates are sometimes given to counteract the drug tolerance (reduced hemodynamic effects) associated with chronic use. In addition, metabolism of nitroglycerin and isosorbide dinitrate normally produces active metabolites. Thus, if metabolism is reduced by liver impairment, drug effects may be decreased and shorter in duration.
With calcium channel blockers, impairment of liver function has profound effects on the pharmacokinetics and pharmacodynamics of most of these drugs. Thus, the drugs should be used with caution, dosages should be substantially reduced, and clients should be closely monitored for drug effects (including periodic measurements of liver enzymes). These recommendations stem from the following effects:
• An impaired liver produces fewer drug-binding plasma proteins such as albumin. This means that a greater proportion of a given dose is unbound and therefore active.
• In clients with cirrhosis, bioavailability of oral drugs is greatly increased and metabolism (of both oral and parenteral drugs) is greatly decreased. Both of these effects increase plasma levels of drug from a given dose (essentially an overdose). The effects result from shunting of blood around the liver so that drug molecules circulating in the bloodstream do not come in contact with drug-metabolizing enzymes and therefore are not metabolized. For example, the bioavailability of verapamil, nifedipine, felodipine, and nisoldipine is approximately double and their clearance is approximately one third that of clients without cirrhosis.
• Although hepatotoxicity is uncommon, clinical symptoms of hepatitis, cholestasis, or jaundice and elevated liver enzymes (eg, alkaline phosphatase, creatine kinase [CK], lactate dehydrogenase [LDH], aspartate aminotransferase [AST], alanine aminotransferase [ALT]) have occurred, mainly with diltiazem, nifedipine, and verapamil. These changes resolve if the causative drug is stopped.
Use in Critical Illness
Antianginal drugs have multiple cardiovascular effects and may be used alone or in combination with other cardiovascular drugs in clients with critical illness. They are probably used most often to manage severe angina, severe hypertension, or serious cardiac dysrhythmias. For example, IV nitroglycerin may be used for angina and hypertension; an IV beta blocker or calcium channel blocker may be used to improve cardiovascular function with angina, hypertens ion, or supraventricular tachydysrhythmias. With any of these drugs, dosage must be carefully titrated and clients must be closely monitored for hypotension and other drug effects.
In addition, absorption of oral drugs or topical forms of nitroglycerin may be impaired in clients with extensive edema, heart failure, hypotension, or other conditions that impair blood flow to the gastrointestinal tract or skin.
HYPERTENSION
Hypertension is persistently high blood pressure that results from abnormalities in regulatory mechanisms. It is usually defined as a systolic pressure above
Primary or essential hypertension (that for which no cause can be found) makes up 90% to 95% of known cases. Secondary hypertension may result from renal, endocrine, or central nervous system disorders and from drugs that stimulate the SNS or cause retention of sodium and water. Primary hypertension can be controlled with appropriate therapy; secondary hypertension can sometimes be cured by surgical therapy.
The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, published in 1997, classified blood pressures in adults (in mm of Hg), as follows:
• Normal systolic 130 or below; diastolic 85 or below
• High normal systolic 130 to 139; diastolic 85 to 89
• Stage 1 hypertension (mild) systolic 140 to 159; diastolic
90 to 99
• Stage 2 hypertension (moderate) systolic 160 to 179;
diastolic 100 to 109
• Stage 3 hypertension (severe) systolic 180 to 209; diastolic
110 to 119
• Stage 4 hypertension (very severe) systolic 210 or above; diastolic 120 or above
A systolic pressure of 140 or above with a diastolic pressure below 90 is called isolated systolic hypertension and is more common in the elderly.
Hypertension profoundly alters cardiovascular function by increasing the workload of the heart and causing thickening and sclerosis of arterial walls. As a result of increased cardiac workload, the myocardium hypertrophies as a compensatory mechanism and heart failure eventually occurs. As a result of endothelial dysfunction and arterial changes (vascular remodeling), the arterial lumen is narrowed, blood supply to tissues is decreased, and risks of thrombosis are increased. In addition, necrotic areas may develop in arteries, and these may rupture with sustained high blood pressure. The areas of most serious damage are the heart, brain, kidneys, and eyes. These are often called target organs.
Initially and perhaps for years, primary hypertension may produce no symptoms. If symptoms occur, they are usually vague and nonspecific. Hypertension may go undetected, undetected, or it may be incidentally discovered when blood pressure measurements are taken as part of a routine physical examination, screening test, or assessment of other disorders. Eventually, symptoms reflect target organ damage.
Hypertension is often discovered after a person experiences angina pectoris, myocardial infarction, heart failure, stroke, or renal disease. Hypertensive emergencies are episodes of severely elevated blood pressure that may be an extension of malignant (rapidly progressive) hypertension or caused by cerebral hemorrhage, dissecting aortic aneurysm, renal disease, pheochromocytoma, or eclampsia. These require immediate management, usually intravenous (IV) antihypertensive drugs, to lower blood pressure. Symptoms include severe headache, nausea, vomiting, visual disturbances, neurologic disturbances, disorientation, and decreased level of consciousness (drowsiness, stupor, coma). Hypertensive urgencies are episodes of less severe hypertension and are often managed with oral drugs. The goal of management is to lower blood pressure within 24 hours. In most instances, it is better to lower blood pressure gradually and to avoid wide fluctuations in blood pressure.
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Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any of four drugs depending on the individual patient: a diuretic, a b-blocker, an ACE inhibitor, or a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is added. A b-blocker is usually added if the initial drug was a diuretic, or a diuretic is added if the first drug was a b-blocker. A vasodilator can be added as a third step for those patients who still fail to respond.
Certain subsets of the hypertensive population respond better to one class of drug than another. For example, black patients respond well to diuretics and calcium channel blockers, but therapy with b-blockers or ACE inhibitors is often less effective. Similarly, calcium channel blockers, ACE inhibitors, and diuretics are favored for treatment of hypertension in the elderly, whereas b-blockers and a-antagonists are less well tolerated. Furthermore, hypertension may coexist with other diseases that can be aggravated by some of the antihypertensive drugs.
ANTIHYPERTENSIVE DRUGS
Drugs used in the management of primary hypertension belong to several different groups, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), also called angiotensin II receptor antagonists (AIIRAs), antiadrenergics, calcium channel blockers, diuretics, and direct vasodilators. In general, these drugs act to decrease blood pressure by decreasing cardiac output or peripheral vascular resistance.
I. DIURETICS
Bumetanide, furosemide, hydrochlorthiazide, spironolactone, triamterene
II. b-BLOCKERS
Atenolol, labetalol, metoprolol, propranolol, timolol
III. ACE INHIBITORS
Captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril
IV. ANGIOTENSIN II ANTAGONIST
Losartan
V. Ca++CHANNEL BLOCKERS
Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil
VI. a-BLOCKERS
Doxazosin, prazosin, terazosin
VII. OTHER
Clonidine, diazoxide, hydralazine, a-methyldopa, minoxidil, sodium nitroprusside
Treatment of hypertension in patients with concomitant diseases
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CONCOMITANT DISEASE |
DRUGS COMMONLY USED IN TREATING HYPERTENSION |
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Angina pectoris |
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Commonly used drugs |
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b-Blockers |
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Ca++ Channel blockers |
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Alternative drugs |
diuretics |
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ACE inhibitors |
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Diabetes (insulin-dependent) |
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Commonly used drugs |
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ACE inhibitors |
Ca++ Channel blockers
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Alternative drugs |
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Hyperlipidemia |
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Commonly used drugs |
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ACE inhibitors |
Ca++ Channel blockers
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Alternative drugs |
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Congestive heart failure |
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Commonly used drugs |
diuretics |
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ACE inhibitors |
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Alternative drugs |
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Avoid verapamil |
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Previous myocardial infarction |
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Commonly used drugs |
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b-Blockers |
ACE inhibitors |
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Alternative drugs |
diuretics |
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Ca++ Channel blockers |
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Chronic renal disease |
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Commonly used drugs |
diuretics |
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Ca++ Channel blockers |
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Alternative drugs |
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b-Blockers |
ACE inhibitors |
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Asthma, chronic pulmonary disease |
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Commonly used drugs |
diuretics |
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Ca++ Channel blockers |
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Alternative drugs |
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ACE inhibitors |
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DIURETICS and/or b-Blockers are currently recommended as the first-line drug therapy for hypertension. Low-dose diuretic therapy is safe and effective in preventing stroke, myocardial infarction, congestive heart failure and total mortality. Recent data suggest that diuretics are superior to b-Blockers in older adults.
Antihypertensive effects of diuretics are usually attributed to sodium and water depletion. In fact, diuretics usually produce the same effects as severe dietary sodium restriction. In many cases of hypertension, diuretic therapy alone may lower blood pressure. When diuretic therapy is begun, blood volume and cardiac output decrease. With long-term administration of a diuretic, cardiac output returns to normal, but there is a persistent decrease in peripheral vascular resistance. This has been attributed to a persistent small reduction in extracellular water and plasma volume, decreased receptor sensitivity to vasopressor substances such as angiotensin, direct arteriolar vasodilation, and arteriolar vasodilation secondary to electrolyte depletion in the vessel wall.
In moderate or severe hypertension that does not respond to a diuretic alone, the diuretic may be continued and another antihypertensive drug added, or monotherapy with a different type of antihypertensive drug may be tried.
Thiazide diuretics. All oral diuretics are effective in the treatment of hypertension, but the thiazides have the most widespread use. Thiazides, such as hydochlorothiazide, lower blood pressure , initially by increasing sodium and water excretion. This causes a decrease in extracellular volume , resulting in a decrease in cardiac output and renal blood flow. With long term treatment, plasma volume approaches a normal value, but peripheral resistance decreases. Spironolactone, a potassium-sparing diuretic, is often used with thiazides.
Thiazide diuretics are usefull in combination therapy with a variety of other antihypertensive agents including b-blockers and ACE inhibitors. Thiazides are particularly useful in the treatment of black or elderly patients, and in those with chronic renal disease. Thiazides are not effective in patients with inadequate kidney function (creatinine clearance less than 50 mls/min).
Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 % of patients, and hyperglycemia in 10 % of patients. Serum potassium levels should be monitored closely on patients who are predisposed to cardiac arrhythmias (with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart failure) (to prevent development of fatigue, cramps, and arrhythmias) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides. Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia.
The loop diuretics act promptly, even in patients who have poor renal function or who have not responded to thiazides or other diuretics.
b-ADRENOCEPTOR BLOCKING AGENTS – reduce blood pressure primarily by decreasing cardiac output. They may also decrease sympathetic outflow from the CNS and inhibit the release of renin from the kidneys. The prototype b-blocker is propranolol, which acts at both b1 and b2 receptors. Newer agents, such as atenolol, metoprolol, bisoprolol, are selective for b1 receptors. These agents are commonly used in disease states such as asthma, in which propranolol is contraindicated.
The b-blockers are more effective for treating hypertension in white young patients. They are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, glaucoma, and migraine headache.
The b-blockers are orally active. The b-blockers may take several weeks to develop their full effects.
Adverse effects. The b-blockers may cause CNS side effects such as fatigue, lethargy, insomnia, hypotension, and hallucinations; they may decrease libido and cause impotence; drug-induced sexual dysfunction can severly reduce patient compliance. The b-blockers may disturb lipid metabolism, decreasing high-density lipoproteins and increasing plasma triacylglycerol.
Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation on b-receptors. Patients should be taped off of b-blocker therapy in order to avoid precipitation of arrhythmias. The b-blockers should be avoided in treating patients with asthma, congestive heart failure, and peripheral vascular disease.
ACE-INHIBITORS.
Angiotensin-converting enzyme (also called kininase) is mainly located in the endothelial lining of blood vessels, which is the site of production of most angiotensin II. This same enzyme also metabolizes bradykinin, an endogenous substance with strong vasodilating properties. ACE inhibitors block the enzyme that normally converts angiotensin I to the potent vasoconstrictor angiotensin II.
By blocking production of angiotensin II, the drugs decrease vasoconstriction (having a vasodilating effect) and decrease aldosterone production (reducing retention of sodium and water). In addition to inhibiting formation of angiotensin II, the drugs also inhibit the breakdown of bradykinin, prolonging its vasodilating effects. These effects and possibly others help to prevent or reverse the remodeling of heart muscle and blood vessel walls that impairs cardiovascular function and exacerbates cardiovascular disease processes. Because of their effectiveness
in hypertension and beneficial effects on the heart, blood vessels, and kidneys, these drugs are increasing in importance, number, and use. Widely used to treat heart failure and hypertension, the drugs may also decrease morbidity and mortality in other cardiovascular disorders. They improve post–myocardial infarction survival when added to standard therapy of aspirin, a beta blocker, and a thrombolytic.
ACE inhibitors may be used alone or in combination with other antihypertensive agents, such as thiazide diuretics. Although the drugs can cause or aggravate proteinuria and renal damage iondiabetic people, they decrease proteinuria and slow the development of nephropathy in diabetic clients.
Most ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, ramipril, and quinapril) also are used in the management of heart failure because they decrease peripheral vascular resistance, cardiac workload, and ventricular remodeling. Captopril and other ACE inhibitors are recommended as first-line agents for treating hypertension in diabetic clients, particularly those with type 1 diabetes and/or diabetic nephropathy, because they reduce proteinuria and slow progression of renal impairment.
ACE inhibitors are well absorbed with oral administration, produce effects within 1 hour that last approximately 24 hours, have prolonged serum half-lives with impaired renal function, and most are metabolized to active metabolites that are excreted in urine and feces. These drugs are well tolerated, with a low incidence of serious adverse effects (eg, neutropenia, agranulocytosis, proteinuria, glomerulonephritis, and angioedema). However, a persistent cough develops in approximately 10% to 20% of clients and may lead to stopping the drug. Also, acute hypotension may occur when an ACE inhibitor is started, especially in clients with fluid volume deficit. This reaction may be prevented by starting with a low dose, taken at bedtime, or by stopping diuretics and reducing dosage of other antihypertensive drugs temporarily. Hyperkalemia may develop in clients who have diabetes mellitus or renal impairment or who are taking nonsteroidal anti-inflammatory drugs, potassium supplements, or potassium-sparing diuretics.
These drugs are contraindicated during pregnancy because serious illnesses, including renal failure, have occurred ieonates whose mothers took an ACE inhibitor during the second and third trimesters.
The angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril, lisinopril) are recommended when the preferred first-line agents (diuretics or b-blockers) are contraindicated or ineffective. Despite their wide-spread use, it is not clear if antihypertensive therapy with ACE inhibitors increases the risk of other major diseases.
Actions. The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexly increasing cardiac output, rate, or contractility. These drugs block the angiotensin converting enzyme that cleaves angiotensin I to form the potent vasoconstrictor, angiotensin II. Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by diminished levels of angiotensin II and the potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels, ACE inhibitors also decreas the secretion of aldosterone, resulting in decreased sodium and water retention.
Like b-blockers, ACE inhibitors are most effective in hypertensive patients who are white and young. However, when used in combination with a diuretic, the effectiveness of ACE inhibitors is similar in white and black hypertensive patients. Unlike b-blockers, ACE inhibitors are effective in the management of patients with chronic congestive heart failure. ACE inhibitors are now a standard in the care of a patient following a myocardial infarction. Therapy is started 24 hours after the end of the infarction.
Adverse effects. Common side effects include dry cough, rashes, fever, altered taste, hypotension, and hyperkalemia. Potassium levels must be monitored, and potassium supplements or spironolactone are contraindicated. Because of the risk of angioedema and first dose syncope, ACE inhibitors are first administered in the physician’s office with close observation. Reversible renal failure can occur in patients with severe renal artery stenosis. ACE inhibitors are fetotoxic and should not be used in pregnant women.
ANGIOTENSIN II ANTAGONISTS.
Angiotensin II receptor blockers (ARBs) were developed to block the strong blood pressure–raising effects of angiotensin II. Instead of decreasing production of angiotensin II, as the ACE inhibitors do, these drugs compete with angiotensin II for tissue binding sites and prevent angiotensin II from combining with its receptors in body tissues. Although multiple types of receptors have been identified, the AT1 receptors located in brain, renal, myocardial, vascular, and adrenal tissue determine most of the effects of angiotensin II on cardiovascular and renal functions. ARBs block the angiotensin II AT1 receptors and decrease arterial blood pressure by decreasing systemic vascular resistance .
These drugs are similar to ACE inhibitors in their effects on blood pressure and hemodynamics and are as effective as ACE inhibitors in the management of hypertension and probably heart failure. They are less likely to cause hyperkalemia than ACE inhibitors, and the occurrence of a persistent cough is rare. Overall, the drugs are well tolerated, and the incidence of most adverse effects is similar to that of placebo.
Losartan, the first ARB, is readily absorbed and rapidly metabolized by the cytochrome P450 liver enzymes to an active metabolite. Both losartan and the metabolite are highly bound to plasma albumin, and losartan has a shorter duration of action than its metabolite. When losartan therapy is started, maximal effects on blood pressure usually occur within 3 to weeks. If losartan alone does not control blood pressure, a low dose of a diuretic may be added. A combination product of losartan and hydrochlorothiazide is available.
The nanopeptide losartan, a highly selective angiotensin II receptor blocker, has recently been approved for antihypertensive therapy. Its pharmacologic effects are similar to ACE inhibitors in that it produces vasodilation and blocks aldosterone secretion. Its adverse effects is improved over the ACE inhibitors, although it is fetotoxic.
CALCIUM CHANNEL BLOCKERS.
Most of the available drugs are approved for use in hypertension. Nifedipine, a short-acting calcium channel blocker, has been used to treat hypertensive emergencies or urgencies, often by puncturing the capsule and squeezing the contents under the tongue or having the client bite and swallow the capsule. Such use is no longer recommended, because this practice is associated with an increased risk of adverse cardiovascular events precipitated by rapid and severe decrease in blood pressure.
As a group, the calcium channel blockers are well absorbed from the gastrointestinal tract following oral administration and are highly bound to protein. The drugs are metabolized in the liver and excreted in urine.
Calcium channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective. Despite their wide-spread use, it is not clear what effects antihypertensive therapy with these drugs has on major disease. In hypertensive patients use of short-acting calcium channel blockers, especially in high doses, is associated with an increased risk of myocardial infarction.
The calcium channel blockers are divided into three chemical classes, each with different pharmacokinetic properties and clinical indications.
1. Diphenylalkylamines. Verapamil is the least selective of any calcium channel blocker, and has significant effects on both cardiac and smooth-muscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and migrane headache.
2. Benzothiazepines. Diltiazem affects both cardiac and vascular smooth-muscle cells; however, it has a less pronounced negative inotropic effect on the heart than does verapamil.
3. Dihydropyridines. This rapidly expanding class of calcium channel blockers includes the first-generation nifedipine, and new agents foe treating cardiovascular disease: amlodipine, felodipine, isradipine, nicardipine and nisoldipine. All the dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart. They are therefore particularly attractive in treating hypertension.
Calcium channel antagonists block the inward movement of calcium by binding to L-tipe calcium channels in the heart and in the smooth-muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles.
Calcium channel blockers have an intrinsic natriuretic ; therefore, they do not usually require the addition of a diuretic. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease.
Adverse effects. Although infrequent, side effects include constipation in 10 % of patients, dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure. Verapamil should be avoid in treating patients with congestive heart failure due to its negative inotropic effects.
a-ADRENERGIC BLOCKING AGENTS.
Prazosin, doxazosin and terazosin produce a competitive block of a1 adrenoreceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Postural hypotension may occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive effects.
CENTRALLY-ACTING ADRENERGIC DRUGS
Clonidine – a2-agonist – diminishes central adrenergic outflow. Clonidine does not decrease renal blood flow or glomerular filtration and therefore is useful in the treatment of hypertension complicated by renal disease. Because it causes sodium and water retention, clonidine is usually administered in combination witj diuretic. Adverse effects are generally mild, but the drug can produce sedation and drying of nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine. The drug therefore should be withdrawal slowly if the clinician wishes to change agents.
a-Methyldopa. This a2-agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS, leading to reduced total peripheral resistance and a decreased blood pressure. Because blood flow to the kidmey is not diminished by its use, a-methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common side effects of a-methyldopa are sedation and drowsiness.
VASODILATORS. The direct-acting smooth muscle relaxants, such as hydralazine and minoxidil, have traditionally not been used as primary drugs to treat hypertension. They act by producing relaxation of vascular smooth muscle, which decreases resistance and therefore decreases blood pressure. These agents produce reflex stimulation of the heart. They may prompt angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals.
Hydralazine. This drug causes direct vasodilation, acting primarily on arteries and arterioles. Hydralazine is used to treat moderately severe hypertension. It is almost always administered in combination with a b-blocker such as propranolol (to balance the reflex tachycardia) and a diuretic (to decrease sodium retention). Adverse effects of hydralazine therapy include headache, nausea, sweating, arrhythmia, and precipitation of angina. A lupus-like syndrome can occur with high dosage, but it is reversible on discontinuation of the drug.
Minoxidil. This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). It is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs. Reflex tachycardia may be severe and may require the concomitant use of a diuretic and a b-blocker. Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart failure.
PRINCIPLES OF THERAPY
Therapeutic Regimens
Once the diagnosis of hypertension is established, a therapeutic regimen must be designed and implemented. The goal of management for most clients is to achieve and maintaiormal blood pressure range (below 140/90 mm Hg). If this goal cannot be achieved, lowering blood pressure to any extent is still considered beneficial in decreasing the incidence of coronary artery disease and stroke.
The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends a management algorithm in which initial interventions are lifestyle modifications (ie, reduction of weight and sodium intake, regular physical activity, moderate alcohol intake, and no smoking). If these modifications do not produce goal blood pressure or substantial progress toward goal blood pressure within 3 to 6 months, antihypertensive drug therapy should be initiated and the lifestyle modifications should be continued. Although the Committee recommends monotherapy (use of one antihypertensive drug) with a diuretic or a beta blocker because research studies demonstrate reduced morbidity and mortality with these agents, a drug from another classification (eg, ACE inhibitors, ARBs, calcium channel blockers, alpha1-adrenergic blockers) may also be used effectively. Studies also indicate decreased cardiovascular morbidity and mortality with ACE inhibitors.
If the initial drug (and dose) does not produce the desired blood pressure, options for further management include increasing the drug dose, substituting another drug, or adding a second drug from a different group. If the response is still inadequate, a second or third drug may be added, including a diuretic if not previously prescribed. When current management is ineffective, reassess the client’s compliance with lifestyle modifications and drug therapy. In addition, review other factors that may decrease the therapeutic response,such as over-the-counter appetite suppressants, dietary or herbal supplements, or nasal decongestants, which raise blood pressure.
The World Health Organization and the International Society of Hypertension guidelines for management of hypertension include considering age, ethnicity, and concomitant cardiovascular disorders when choosing an antihypertensive drug; starting with a single drug, in the lowest available dose; changing to a drug from a different group, rather than increasing dosage of the first drug or adding a second drug, if the initial drug is ineffective or not well tolerated; and using long-acting drugs (ie, a single dose effective for 24 hours). The guidelines also note that many clients require two or more drugs to achieve adequate blood pressure control. When this is the case, fixed-dose combinations or long-acting agents may be preferred, as they decrease the number of drugs and doses that are required and may increase compliance.
Drug Selection
Because many effective antihypertensive drugs are available, choices depend primarily on client characteristics and responses.
Some general guidelines include:
1. Angiotensin-converting enzyme inhibitors may be effective alone in white hypertensive clients or in combination with a diuretic in African-American hypertensive clients. They are also recommended for hypertensive adults with diabetes mellitus and kidney damage. Based on research studies that indicate reduced morbidity and mortality from cardiovascular diseases, these drugs are increasingly being prescribed as a component of a multidrug regimen.
2. Angiotensin II receptor blockers have therapeutic effects similar to those of ACE inhibitors, with fewer adverse effects. They may be used in most clients with
hypertension.
3. Antiadrenergics may be effective in any hypertensive population. Alpha agonists and antagonists are most often used in multidrug regimens for stages 2, 3, or 4 hypertension, because they may cause postural hypotension and syncope. Clonidine is available in a skin patch that is applied once a week and reportedly reduces adverse effects and increases compliance. An additional advantage of transdermal clonidine is that clients who cannot take oral medications can use it. A disadvantage of this system is a delayed onset of effect (2 to 3 days), so other antihypertensive medications must also be given during the first 2 to 3 days of clonidine transdermal therapy. Other disadvantages include cost, a 20% incidence of local skin rash or irritation, and a 2- to 3-day delay in “offset” of action when transdermal therapy is discontinued.
Beta blockers are the drugs of first choice for clients younger than 50 years of age with high-renin hypertension, tachycardia, angina pectoris, myocardial infarction, or left ventricular hypertrophy. Most beta blockers are approved for use in hypertension and are probably equally effective. However, the cardioselective drugs are preferred for hypertensive clients who also have asthma, peripheral vascular disease, or diabetes mellitus.
4. Calcium channel blockers may be used for monotherapy or in combination with other drugs. They may be especially useful for hypertensive clients who also have angina pectoris or other cardiovascular disorders. Note that sustained-release forms of nifedipine, diltiazem, and verapamil and other long-acting drugs (eg, amlodipine, felodipine) are recommended.
5. Diuretics are preferred for initial therapy in older clients and African-American hypertensive clients. They should be included in any multidrug regimen for these and other populations. Thiazide and related diuretics are equally effective. Hydrochlorothiazide is commonly used.
6. Vasodilators are used in combination with a beta blocker and a diuretic to prevent hypotension-induced compensatory mechanisms (stimulation of the SNS and fluid retention) that raise blood pressure.
7. Combination products usually combine two drugs with different mechanisms of action (eg, a thiazide or related diuretic plus a beta blocker or other antiadrenergic, an ACE inhibitor, an ARB, or a calcium channel blocker). Most are available in various formulations. Potential advantages of fixed-dose combination products include comparable or improved effectiveness, smaller doses of individual components, fewer adverse effects, improved compliance, and possibly decreased costs.
Dosage Factors
1. Dosage of antihypertensive drugs must be titrated according to individual response. Dosage should be started at minimal levels and increased if necessary. Lower doses decrease the incidence and severity of adverse effects.
2. For many clients, it may be more beneficial to change drugs or add another drug rather than increase dosage. Two or three drugs in small doses may be more effective and cause fewer adverse effects than a single drug in large doses. When two or more drugs are given, the dose of each drug may need to be reduced.
Duration of Therapy
Clients who maintain control of their blood pressure for 1 year or so may be candidates for reduced dosages or reduced numbers of drugs. Any such adjustments must be gradual and carefully supervised by a health care provider. Expected benefits include fewer adverse effects and greater compliance.
Sodium Restriction
Therapeutic regimens for hypertension include sodium restriction. Severe restrictions usually are not acceptable to clients; however, moderate restrictions (4 to
Research and clinical observations indicate the following:
1. Sodium restriction alone reduces blood pressure.
2. Sodium restriction potentiates the antihypertensive actions of diuretics and other antihypertensive drugs.
Conversely, excessive sodium intake decreases the antihypertensive actions of all antihypertensive drugs. Clients with unrestricted salt intake who are taking thiazides may lose excessive potassium and become hypokalemic.
3. Sodium restriction may decrease dosage requirements of antihypertensive drugs, thereby decreasing the incidence and severity of adverse effects.
MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously)
|
Drug |
Dose |
Onset |
Side effects |
|
Sodium nitroprussid |
0,5-10 mcg/kg/min (dropply) |
immediately |
nausea, vomiting, fibrillation of muscles, sweating |
|
Nitroglyceri-num |
5-10 mcg/kg (dropply) |
2-5 min |
tachicardia, flushing, headache, vomiting, |
|
Diazoxidum |
50-100 mg (quickly) 300 mg (during 10 min) |
2-4 min |
nausea, vomiting,, hypotension, tachicardia, flushing, redness of skin, chest pain |
|
Apressinum |
10-20 mg |
10 min |
flushing, redness of skin, headache, vomiting |
|
Furosemidum |
20-60-100 mg during 10-15 sec |
2-3 min |
hypotension, fatigue |
|
Clophelinum |
0,5-1 ml 0,01 % solution (in 15-20 ml 0,9 % solution NaCI slowly) |
15-20 min |
somnolence |
|
Anaprilinum |
5 ml 0,1 % solution (in 20 ml 0,9 % NaCI solution slowly) |
20-30 min |
bradicardia |
|
Magnesium sulfas |
5-10-20 ml 25 % solution (i. v. very slowly or dropply) |
15-20 min |
redness of skin |
|
Labetololum |
20-80 mg (slowly – 10 min) or 2 mg/kg (dropply); the whole dose – 50-300 mg |
5-10 min |
nausea, vomiting,, hypotension, dizzeness |
HYPERTENSIVE EMERGENCY – is a life-threatening situation in which the diastolic blood pressure is either over
Nitroprusside is administered intravenously, and causes prompt vasodilation, with reflex tachycardia. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. It can reduce cardiac preload. Nitroprusside is metabolized rapidly and requires continuous infusion to maintain its hypotensive action. Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.
Diazoxide is a direct-acting arteriolar vasodilator. It has vascular effects like those of hydralazine. Foe patients with coronary insufficiency, diazoxide is administered intravenously with a b-blocker, which diminishes reflex activation of the heart. Diazoxide is useful in the treatment of hypertensive emergencies, hypertensive encephalopathy, and eclampsia. Excessive hypotension is the most serious toxicity.
Labetalol is the both an a– and b-blocker that has been successfully used on hypertensive emergencies. Labetalol does not cause the reflex tachycardia that may be associated with diazoxide. Labetalol carries the contraindications of a nonselective b-blocker.
SUMMARY: DRUGS USED IN HYPERTENSION
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CLINICAL PHARMACOLOGY OF ANTIHYPOTENSIVE DRUGS
Shock is a clinical syndrome characterized by decreased blood supply to body tissues. Clinical symptoms depend on the degree of impaired perfusion of vital organs (eg, brain, heart, and kidneys). Common signs and symptoms include oliguria, heart failure, mental confusion, cool extremities, and coma. Most, but not all, people in shock are hypotensive.
In a previously hypertensive person, shock may be present if a drop in blood pressure of greater than
Types of Shock
There are three general categories of shock that are based on the circulatory mechanisms involved. These mechanisms are intravascular volume, the ability of the heart to pump, and vascular tone.
Hypovolemic shock involves a loss of intravascular fluid volume that may be due to actual blood loss or relative loss from fluid shifts within the body.
Cardiogenic shock, also called pump failure, occurs when the myocardium has lost its ability to contract efficiently and maintain an adequate cardiac output.
Distributive or vasogenic shock is characterized by severe, generalized vasodilation, which results in severe hypotension and impairment of blood flow. Distributive shock is further divided into anaphylactic, neurogenic, and septic shock:
• Anaphylactic shock results from a hypersensitivity (allergic) reaction to drugs or other substances.
• Neurogenic shock results from inadequate sympathetic nervous system (SNS) stimulation. The SNS normally maintains sufficient vascular tone (ie, a small amount of vasoconstriction) to support adequate blood circulation. Neurogenic shock may occur with depression of the vasomotor center in the brain or decreased sympathetic outflow to blood vessels.
• Septic shock can result from almost any organism that gains access to the bloodstream but is most often associated with gram-negative and gram-positive bacterial infections and fungi. It is important to know the etiology of shock because management varies among the types.
ANTISHOCK DRUGS
Drugs used in the management of shock are primarily the adrenergic drugs. In this chapter, the drugs are discussed only in relation to their use in hypotension and shock. In these conditions, drugs with alpha-adrenergic activity (eg, norepinephrine, phenylephrine) are used to increase peripheral vascular resistance and raise blood pressure. Drugs with beta-adrenergic activity (eg, dobutamine, isoproterenol) are used to increase myocardial contractility and heart rate, which in turn raises blood pressure. Some drugs have both alpha- and beta-adrenergic activity (eg, dopamine, epinephrine). In many cases, a combination of drugs is used, depending on the type of shock and the client’s response to treatment. In an emergency, the drugs may be used to maintain adequate perfusion of vital organs until sufficient fluid volume is replaced and circulation is restored.
Adrenergic drugs with beta activity may be relatively contraindicated in shock states precipitated or complicated by cardiac dysrhythmias. Beta-stimulating drugs also should be used cautiously in cardiogenic shock after myocardial infarction because increased contractility and heart rate will increase myocardial oxygen consumption and extend the area of infarction. Individual drugs are described in the following section; indications for use and dosage ranges are listed in Drugs at a Glance: Drugs Used for Hypotension and Shock.
INDIVIDUAL DRUGS
Dopamine is a naturally occurring catecholamine that functions as a neurotransmitter. Dopamine exerts its actions by stimulating alpha, beta, or dopaminergic receptors, depending on the dose being used. In addition, dopamine acts indirectly by releasing norepinephrine from sympathetic nerve endings and the adrenal glands. Peripheral dopamine receptors are located in splanchnic and renal vascular beds. At low doses (0.5 to 10 mcg/kg/min), dopamine selectively stimulatesdopaminergic receptors that may increase renal blood flow and glomerular filtration rate (GFR). It has long been accepted that stimulation of dopamine receptors by low doses of exogenous dopamine produces vasodilation in the renal circulation and increases urine output. More recent studies indicate that low-dose dopamine enhances renal function only when cardiac function is improved. At doses greater than 3 mcg/kg/min, dopamine binds to beta and alpha receptors and the selectivity of dopaminergic receptors is lost beyond 10 mcg/kg/min. At doses that stimulate beta receptors (3 to 20 mcg/kg/min), there is an increase in heart rate, myocardial contractility, and blood pressure. At the highest doses (20 to 50 mcg/kg/min), beta activity remains, but increasing alpha stimulation (vasoconstriction) may overcome its actions.
Dopamine is useful in hypovolemic and cardiogenic shock. Adequate fluid therapy is necessary for the maximal pressor effect of dopamine. Acidosis decreases the effectiveness of dopamine.
Dobutamine is a synthetic catecholamine developed to provide less vascular activity than dopamine. It acts mainly on beta1 receptors in the heart to increase the force of myocardial contraction with a minimal increase in heart rate. Dobutamine also may increase blood pressure with large doses. It is less likely to cause tachycardia, dysrhythmias, and increased myocardial oxygen demand than dopamine and isoproterenol. It is most useful in cases of shock that require increased cardiac output without the need for blood pressure support. It is recommended for short-term use only. It may be used with dopamine to augment the beta1 activity that is sometimes overridden by alpha effects when dopamine is used alone at doses greater than 10 mcg/kg/min.
Dobutamine has a short plasma half-life and therefore must be administered by continuous IV infusion. A loading dose is not required because the drug has a rapid onset of action and reaches steady state within approximately 10 minutes after the infusion is begun. It is rapidly metabolized to inactive metabolites.
Epinephrine is a naturally occurring catecholamine produced by the adrenal glands. At low doses, epinephrine stimulates beta receptors, which increases cardiac output by increasing the rate and force of myocardial contractility. It also causes bronchodilation. Larger doses act on alpha receptors to increase blood pressure.
Epinephrine is the drug of choice for management of anaphylactic shock because of its rapid onset of action and antiallergic effects. It prevents the release of histamine and other mediators that cause symptoms of anaphylaxis, thereby reversing vasodilation and bronchoconstriction. In early management of anaphylaxis, it may be given subcutaneously to produce therapeutic effects within 5 to 10 minutes, with peak activity in approximately 20 minutes.
Epinephrine is also used to manage other kinds of shock and is usually given by continuous IV infusion. However, bolus doses may be given in emergencies, such as cardiac arrest. It may produce excessive cardiac stimulation, ventricular dysrhythmias, and reduced renal blood flow. Epinephrine has an elimination half-life of about 2 minutes and is rapidly inactivated to metabolites, which are then excreted by the kidneys.
Isoproterenol is a synthetic catecholamine that acts exclusively on beta receptors to increase heart rate, myocardial contractility, and systolic blood pressure. However, it also stimulates vascular beta2 receptors, which causes vasodilation, and may decrease diastolic blood pressure. For this reason, isoproterenol has limited usefulness as a pressor agent. It also may increase myocardial oxygen consumption and decrease coronary artery blood flow, which in turn causes myocardial ischemia. Cardiac dysrhythmias may result from excessive beta stimulation. Because of these limitations, use of isoproterenol is limited to shock associated with slow heart rates and myocardial depression.
Metaraminol is used mainly for hypotension associated with spinal anesthesia. It acts indirectly by releasing norepinephrine from sympathetic nerve endings. Thus, its vasoconstrictive actions are similar to those of norepinephrine, except that metaraminol is less potent and has a longer duration of action.
Milrinone is used to manage cardiogenic shock in combination with other inotropic agents or vasopressors. It increases cardiac output and decreases systemic vascular resistance without significantly increasing heart rate or myocardial oxygen consumption. The increased cardiac output improves renal blood flow, which then leads to increased urine output, decreased circulating blood volume, and decreased cardiac workload.
Norepinephrine (Levophed) is a pharmaceutical preparation of the naturally occurring catecholamine norepinephrine. It stimulates alpha-adrenergic receptors and thus increases blood pressure primarily by vasoconstriction. It also stimulates beta1 receptors and therefore increases heart rate, force of myocardial contraction, and coronary artery blood flow. It is useful in cardiogenic and septic shock, but reduced renal blood flow limits its prolonged use. Norepinephrine is used mainly with clients who are unresponsive to dopamine or dobutamine. As with all drugs used to manage shock, blood pressure should be monitored frequently during infusion.
Phenylephrine (Neo-Synephrine) is an adrenergic drug that stimulates alpha-adrenergic receptors. As a result, it constricts arterioles and raises systolic and diastolic blood pressures. Phenylephrine resembles epinephrine but has fewer cardiac effects and a longer duration of action. Reduction of renal and mesenteric blood flow limit prolonged use.
Choice of Drug
The choice of drug depends primarily on the pathophysiology involved. For cardiogenic shock and decreased cardiac output, dopamine or dobutamine is given. With severe heart failure characterized by decreased cardiac output and high peripheral vascular resistance, vasodilator drugs (eg, nitroprusside, nitroglycerin) may be given along with the cardiotonic drug. The combination increases cardiac output and decreases cardiac workload by decreasing preload and afterload. However, vasodilators should not be used alone because of the risk of severe hypotension and further compromising tissue perfusion.
Milrinone may be given when other drugs fail. For distributive shock characterized by severe vasodilation and decreased peripheral vascular resistance, a vasoconstrictor or vasopressor drug, such as norepinephrine, is the drug of first choice. Drug dosage must be carefully titrated to avoid excessive vasoconstriction and hypertension, which causes impairment rather than improvement in tissue perfusion.
Guidelines for Management of Hypotension and Shock
• Vasopressor drugs are less effective in the presence of inadequate blood volume, electrolyte abnormalities, and acidosis. These conditions also must be treated if present. In addition, normalizing the blood pH and body temperature facilitates the release of oxygen from hemoglobin to the cells.
• Minimal effective doses of adrenergic drugs are recommended because of their extreme vasoconstrictive effects that can produce lactic acidosis at the cell level and create metabolic acidosis. Because catecholamine drugs have short half-lives, varying the flow rate of IV infusions can easily control dosage. Dosage and flow rate usually are titrated to maintain a low-normal blood pressure. Such titration depends on frequent and accurate blood pressure measurements.
• Septic shock due to bacterial infection requires appropriate antibiotic therapy in addition to other management measures. If an abscess is the source of infection, it must be surgically drained.
• Hypovolemic shock is most effectively managed by IV fluids that replace the type of fluid lost; that is, blood loss should be replaced with whole blood; gastrointestinal losses should be replaced with solutions containing electrolytes (eg, Ringer’s lactate or sodium chloride solutions with added potassium chloride).
· Cardiogenic shock may be complicated by pulmonary congestion, for which diuretic drugs are indicated and IV fluids are contraindicated (except to maintain a patent IV line).
· Anaphylactic shock is often managed by nonadrenergic drugs as well as epinephrine. For example, the histamine-induced cardiovascular symptoms (eg, vasodilation and increased capillary permeability) are thought to be mediated through both types of histamine receptors. Thus, management may include a histamine- 1 receptor blocker (eg, diphenhydramine 1 mg/ kg IV) and a histamine2 receptor blocker (eg, cimetidine 4 mg/kg IV), given over at least 5 minutes. In addition, IV corticosteroids are often given, such as methylprednisolone (20 to 100 mg) or hydrocortisone (100 to 500 mg). Doses may need to be repeated every 2 to 4 hours. Corticosteroids increase tissue responsiveness to adrenergic drugs in approximately 2 hours but do not produce anti-inflammatory effects for several hours.
Use in Children
Little information is available about adrenergic drugs for the management of hypotension and shock in children. Children who lose up to one fourth of their circulating blood volume may produce minimal changes in arterial blood pressure and a relatively low heart rate. In general, management is the same as for adults, with drug dosages adjusted for weight.
Use in Older Adults
Older adults often have disorders such as atherosclerosis, peripheral vascular disease, and diabetes mellitus and may not demonstrate common symptoms of volume depletion (eg, thirst, skin turgor changes). Also, when adrenergic drugs are given, their vasoconstricting effects may decrease blood flow and increase risks of tissue ischemia and thrombosis.
Careful monitoring of vital signs, skin color and temperature, urine output, and mental status is essential.
Use in Renal Impairment
Although adrenergic drugs may be lifesaving, they can reduce renal blood flow and cause renal failure because of their vasoconstrictive effects. Renal impairment may occur in clients with previously normal renal function and may be worsened in clients whose renal function is already impaired.
Low-dose dopamine is commonly used to increase renal perfusion in oliguric clients, but the effectiveness of this practice is being questioned. In men with benign prostatic hypertrophy, oliguric renal failure may need to be differentiated from post-renal failure (urinary retention) because some adrenergic drugs (eg, epinephrine, norepinephrine, phenylephrine) cause urinary retention.
Most adrenergic drugs are metabolized in the liver and the metabolites are excreted in the urine. However, little accumulation of the drugs or metabolites is likely because the drugs have short half-lives.
Use in Hepatic Impairment
Catecholamine drugs are metabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). MAO is widely distributed in most body tissues, whereas COMT is located mainly in the liver. Thus, the drugs are eliminated mainly by liver metabolism and must be used cautiously in clients with impaired liver function. Clients should be monitored closely and drug dosage should be adjusted as symptoms warrant. However, the half-life of most adrenergic drugs is very brief, and this decreases the chances of drug accumulation in hepatically impaired clients.
Use in Critical Illness
The adrenergic catecholamines (eg, dopamine, dobutamine, epinephrine, norepinephrine) are widely used in clients witha low cardiac output that persists despite adequate fluid replacement and correction of electrolyte imbalance. By improving circulation, the drugs also help to prevent tissue injury from ischemia (eg, renal failure).
Although the drugs may be used initially in almost any setting, most clients with hypotension and shock are managed in critical care units. Dobutamine and dopamine are usually the cardiotonic agents of choice in critically ill clients. Dopamine varies in clearance rate in adult and pediatric clients. However, this variance may result from the use of non–steadystate plasma concentrations in calculating the clearance rate. When a dopamine IV infusion is started, it may take 1 to 2 hours to achieve a steady-state plasma level. Relatively large doses of dopamine are given for cardiotonic and vasoconstrictive effects.
Epinephrine and norepinephrine are also widely used in critically ill clients. Recommended infusion rates in critically ill clients vary from 0.01 to 0.15 mcg/kg/min for epinephrine and from 0.06 to 0.15 mcg/kg/min for norepinephrine. All clients receiving drugs for management of hypotension and shock should be closely monitored regarding drug dosage,vital signs, relevant laboratory test results, and other indicators of clinical status. Continuous invasive hemodynamic monitoring with an arterial catheter and a pulmonary artery catheter may be indicated to titrate drug dosage and monitor the response to drug therapy. Close monitoring of the critically ill is essential as these clients often have multiple organ impairments and are clinically unstable.
Antiarrhythmic agents
Antidysrhythmic agents are diverse drugs used for prevention and management of cardiac dysrhythmias. Dysrhythmias, also called arrhythmias, are abnormalities in heart rate or rhythm. They become significant when they interfere with cardiac function and ability to perfuse body tissues. To aid in understanding of dysrhythmias and antidysrhythmic drug therapy, the physiology of cardiac conduction and contractility is reviewed.
Effects of drugs on automaticity: Most of antiarrhythmic agents suppress automaticity (1) by decreasing the slope of diastolic depolarization and/or by raising the threshold of discharge to a less negative voltage. Such drugs cause the frequency of discharge to decrease, an effect that is more pronounced in cells with ectopic pacemaker activity than iormal cells.
Indications for Use
Antidysrhythmic drug therapy commonly is indicated in the following conditions:
1. To convert atrial fibrillation (AF) or flutter to normalsinus rhythm (NSR)
2. To maintain NSR after conversion from AF or flutter
3. When the ventricular rate is so fast or irregular that cardiac output is impaired. Decreased cardiac output leads to symptoms of decreased systemic, cerebral, and coronary circulation.
4. When dangerous dysrhythmias occur and may be fatal if not quickly terminated. For example, ventricular tachycardia may cause cardiac arrest.
Effects of drugs on conduction abnormalities: Antiarrhythmic agents prevent reentry by slowing conduction and/or increasing the refractory period to convent a unidirectional block into a bidirectional block.
As noted above, the antiarrhythmic drugs can modify impulse generation and conduction. More than a dozen such drugs that are patentially usefull in treating arrhythmias are currently available. However, only a limited number of these agents are clinically beneficial in the treatment of selected arrhythmias. For example, the acute termination of ventricular tachycardia by lidocaine or supraventricular tachycardia by adenosine or verapamil are examples in which antiarrhythmic therapy results in decreased morbidity. In contrast, many of the antiarrhythmic agents are now known to have lethal proarrhythmic actions, that is, to cause arrhythmias.
The antiarrhythmic drugs can be classified according to their predominant effects on the action potential. Although this classification is convenient, it is not entirely clear-cut, because many of the drugs have actions relating to more than one class or they have active metabolites with a different class of action.
Classification of antiarrhythmic drugs
|
CLASS |
Mechanism of Action |
Drug name |
|
IA |
Na+Channel blocker |
Disopyramide, procainamide, quinidine |
|
IB |
Na+Channel blocker |
Lidocaine, mexiletine, tocainide |
|
IC |
Na+Channel blocker |
Flecainide, propafenone |
|
II |
b Adrenoreceptor blocker |
Esmolol, metoprolol, pindolol, propranolol |
|
III |
K+Channel blocker |
Amiodarone, bretylium, sotalol |
|
IV |
Ca++ Channel blocker |
Diltiazem, verapamil |
|
Other antiarrhythmic drugs |
Adenosine, digoxin |
|
Class I drugs have been subdivided into three groups according to their effect on the duration of the action potential.
The Class II agents include the b-adrenergic antagonists. These drugs diminish Phase 4 depolarisation, thus depressing automaticity, prolonging AV conduction, and decreasing heart rate and contractility.
These agents exert antidysrhythmic effects by blocking sympathetic nervous system stimulation of beta receptors in the heart and decreasing risks of ventricular fibrillation. Blockage of receptors in the SA node and ectopic pacemakers decreases automaticity, and blockage of receptors in the AV node increases the refractory period. The drugs are effective for management of supraventricular dysrhythmias and those resulting from excessive sympathetic activity. Thus, they are most often used to slow the ventricular rate of contraction in supraventricular tachydysrhythmias (eg, AF, atrial flutter, paroxysmal supraventricular tachycardia [PSVT]).
As a class, beta blockers are being used more extensively because of their effectiveness and their ability to reduce mortality in a variety of clinical settings, including post–myocardial infarction and heart failure. Reduced mortality may result from the drugs’ ability to prevent ventricular fibrillation.Only four of the beta blockers marketed in the United States are approved by the Food and Drug Administration (FDA) for management of dysrhythmias.
Class II agents are useful in treating tachyarrhythmias caused by increased sympathetic activity. They are also used for atrial flutter and fibrillation, and for AV nodal reentrant tachycardia.
Class III agents block potassium channels and thus diminish the outward potassium current during repolarization of cardiac cells. They prolong the effective refractory period. All Class III drugs have the potential to induce arrhythmias.
Although the drugs share a common mechanism of action, they are very different drugs. As with beta blockers, clinical use of class III agents is increasing because they are associated with less ventricular fibrillation and decreased mortality compared with class I drugs.
Sotalol (tab. 80, 160 mg), although a class III antiarrhythmic agent, also has potent b-blocker activity. Sotalol blocks a rapid outward potassium current, known as the delayed rectifier. b-blockers are used for long-term therapy to decrease the rate of sudden death following an acute myocardial infarction. They have strong antifibrillary effects, particularly in the ischemic myocardium. Sotalol was more effective in preventing arrhythmia recurrence and in decreasing mortality than imipramine, mexiletine, procainamide, propafenone and quinidine in patients with sustained ventricular tachycardia. As with all drugs that prolong the QT interval, the syndrome of torside de pointes is a serious potential effect, typically seen in 3 to 4 % of patients.
Bretylium (amp. 10 ml – 500 mg) is reserved for the life-treatening ventricular arrhythmias, especially recurrent ventricular fibrillation or tachycardia. Bretylium initially increases release of catecholamines and therefore increases heart rate, blood pressure, and myocardial contractility. This is followed in a few minutes by a decrease in vascular resistance, blood pressure, and heart rate. It is used primarily in critical care settings for acute control of recurrent ventricular fibrillation, especially in clients with recent myocardial infarction. It is given by IV infusion, with a loading dose followed by a maintenance dose, or in repeated IV injections. Because it is excreted almost entirely by the kidney, drug half-life is prolonged with renal impairment and dosage must be reduced. Adverse effects include hypotension and dysrhythmias.
Amiodarone (tab. 200 mg) is effective in the treatment of severe refractory supraventricular avd ventricular tachyarrhythmia. Its dominant effect is prolongation of the action potential duration and the refractory period. Amiodarone has antianginal as well as antiarrhythmic activity. But its clinical usefulness is limited by its toxicity. Amiodarone is incompletely absorbed after oral administration. The drug is unusual in having a prolonged half-life of several weeks. Full clinical effects may not be achieved until 6 weeks after of treatment.
Although classified as a potassium channel blocker, amiodarone also has electrophysiologic characteristics of sodium channel blockers, beta blockers, and calcium channel blockers. Thus, it has vasodilating effects and decreases systemicvascular resistance; it prolongs conduction in all cardiac tissues and decreases heart rate; and it decreases contractility of the left ventricle. Intravenous and oral amiodarone differ in their electrophysiologic effects. When given IV, the major effect is slowing conduction through the AV node and prolonging the effective refractory period. Thus, it is given IV mainly for acute suppression of refractory, hemodynamically destabilizing ventricular tachycardia and ventricular fibrillation. It is given orally to treat recurrent ventricular tachycardia or ventricular
fibrillation and to maintain a NSR after conversion of AF and flutter. Low doses (100 to 200 mg/day) may preventrecurrence of AF with less toxicity than higher doses of amiodarone or usual doses of other agents, including quinidine.
Amiodarone shows a variety of toxic effects. After long-term use, more than one half of the patients receiving the drug show side effects sufficiently severe to prompt its discontinuation. Some of the more common effects include interstial pulmonary fibrosis, gastrointestinal tract intolerance, tremor, ataxia, dizziness, hyper- or hypothyroidism, liver toxicity, photosensitivity, neuropathy, muscle weakness, and blue skin discoloration caused by iodine accumulation in the skin. Recent clinical trials have shown that amiodarone did not reduce incidence of sudden death or prolong survival in patients with congestive heart failure. Adverse effects include hypothyroidism, hyperthyroidism, pulmonary fibrosis, myocardial depression, hypotension, bradycardia, hepatic dysfunction, central nervous system (CNS) disturbances (depression, insomnia, nightmares, hallucinations), peripheral neuropathy and muscle weakness, bluish discoloration of skin and corneal deposits that may cause photosensitivity, appearance of colored halos around lights, and reduced visual acuity. Most adverse effects areconsidered dose dependent and reversible.
The Class IV drugs are calcium channel blockers. They decrease the inward current carried by calcium and slowed conduction in tissues dependent on calcium currents, such as the AV node.
Verapamil and diltiazem. Verapamil (tab. 40, 80, 120, 240 mg) shows greater action on the heart than on vascular smooth muscle, whereas nifedipine, a calcium channel-blocker used to treat hypertension exerts a stronger effect on vascular smooth muscle than on the heart. Diltiazem (tab. 30, 60, 90, 120 mg) is intermediate in its actions. Verapamil and diltiazem bind only to open, depolarized channels, thus preventing repolarization until the drug dissociates from the channel. These drugs are therefore use-dependent, that is, they block most effectively when the heart beating rapidly, since in a normally paced heart, the calcium channels have time to repolarize, and the bound drug dissociates from the channel before the next conduction pulse.
Verapamil and diltiazem are more effective against atrial than ventricular dysrhythmias. They are useful in treating reentrant supraventricular tachycardia and reducing ventricular rate in atrial flutter and fibrillation. Verapamil and diltiazem are absorbed after oral administration. Verapamil is extensively metabolized by the liver; thus, care should be taken in administration of this drug to patients with hepatic dysfunction.
Verapamil and diltiazem have negative inotropic properties and therefore may be contraindicated in patients with preexisting depressed cardiac function. Both drugs can also cause a decrease in blood pressure caused by peripheral vasodilation.
Other antiarrhythmic drugs:
Digoxin (tab. 0.125, 0.25, 0.5 mg, amp. 1, 2 ml 0.025 %) shortens the refractory period in atrial and ventricular myocardial cells while prolonging the effective refractory period and diminishing conduction velocity in Purkinje fibers. Digoxin is used to control the ventricular response rate in atrial fibrillation and flutter. At toxic concentrations, digoxin causes ectopic ventricular beats that may result in ventricular tachycardia and fibrillation. [This arrhythmia is usually treated with lidocaine or phenytoin].
Adenosine is a naturally occurring nucleoside, but at high doses the drug decreases conduction velocity, prolongs the refractory period, and decreases automaticity in the AV node. Intravenous adenosine is the drug of choice for abolishing acute supraventricular tachycardia. It has low toxicity, but causes flushing, chest pain and hypotension. Adenosine has an extremely short duration of action (about 15 seconds).
Magnesium sulfate is given IV in the management of several dysrhythmias, including prevention of recurrent episodes of torsades de pointes and management of digitalis-induced dysrhythmias. Its antidysrhythmic effects may derive from imbalances of magnesium, potassium, and calcium. Hypomagnesemia increases myocardial irritability and is a risk factor for both atrial and ventricular dysrhythmias. Thus, serum magnesium levels should be monitored in clients at risk
and replacement therapy instituted when indicated. However, in some instances, the drug seems to have antidysrhythmic effects even when serum magnesium levels are normal.
Therapeutic indications for some commonly encountered arrhythmias
|
Type of arrhythmia |
Class I |
Class II |
Class III |
Class IV |
Other |
|
ATRIAL ARRHYTHMIAS |
|||||
|
Atrial flutter |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
Verapamil |
|
|
Alternative drugs |
Quinidine |
|
|
|
Digoxin |
|
Atrial fibrillation |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
|
Anticoagulant therapy |
|
Alternative drugs |
Quinidine |
|
Amiodarone |
|
|
|
SUPRAVENTRICULAR TACHYCARDIAS |
|||||
|
AV nodal reentry |
|
|
|
|
|
|
Commonly used drugs |
|
Propranolol |
|
Verapamil |
|
|
Alternative drugs |
|
|
|
|
Digoxin |
|
Acute supraventricular tachycardia |
|
|
|
|
|
|
Commonly used drugs |
|
|
|
|
Adenosine |
|
Alternative drugs |
|
|
|
Verapamil |
|
|
VENTRICULAR TACHYCARDIAS |
|||||
|
Acute ventricular tachycardia |
|
|
|
|
|
|
Commonly used drugs |
Lidocaine |
|
|
|
|
|
Alternative drugs |
|
|
Sotalol, amiodarone |
|
|
|
Ventricular fibrillation (not responding to electrical defibrillation) |
|
|
|
|
|
|
Commonly used drugs |
|
|
|
|
Epinephrine |
|
Alternative drugs |
Lidocaine |
|
Bretylium, amiodarone |
|
|
Pharmacologic Management of Dysrhythmias
Rational drug therapy for cardiac dysrhythmias requires accurate identification of the dysrhythmia, understanding of the basic mechanisms causing the dysrhythmia, observation of the hemodynamic and ECG effects of the dysrhythmia, knowledge of the pharmacologic actions of specific antidysrhythmic drugs, and the expectation that therapeutic effects will outweigh potential adverse effects. Even when these criteria are met, antidysrhythmic drug therapy is somewhat empiric. Although some dysrhythmias usually respond to particulardrugs, different drugs or combinations of drugs are often required.
General trends and guidelines for drug therapy of supraventricular and ventricular dysrhythmias are described in the following sections.
General Trends
1. There is a relative consensus of opinion among clinicians about appropriate management for acute, symptomatic dysrhythmias, in which the goals are to abolish the abnormal rhythm, restore NSR, and prevent recurrence of the dysrhythmia. There is less agreement about long-term use of the drugs, which is probably indicated only for clients who experience recurrent symptomatic episodes.
2. Class I agents do not prolong survival in any group of clients and their use is declining. For example, quinidine is no longer recommended to slow heart rate or prevent recurrence of AF. Some clinicians recommend restricting this class to clients without structural heart disease, who are less likely to experience increased
mortality than others.
3. Class II and class III drugs are being used increasingly, because of demonstrated benefits in relieving symptoms and decreasing mortality rates in clients with heart disease.
Supraventricular Tachydysrhythmias
1. Propranolol and other beta blockers are being increasingly used for tachydysrhythmias, especially in clients with myocardial infarction, heart failure, or exerciseinduced dysrhythmias. In addition to controlling dysrhythmias, the drugs decrease the mortality rate in these clients. Also, a beta blocker is the management of choice if a rapid heart rate is causing angina or other symptoms in a client with known coronary artery disease.
2. Atrial fibrillation is the most common dysrhythmia. Management may involve conversion to NSR by electrical or pharmacologic means or long-term drug therapy to slow the rate of ventricular response. Advantages of conversion to NSR include improvement of symptoms and decreased risks of heart failure or thromboembolic problems. If pharmacologic conversion is chosen, IV adenosine, dofetilide, ibutilide, verapamil, or diltiazem may be used. Once converted to NSR, clients usually require long-term drug therapy. Low-dose amiodarone seems to be emerging as the drug of choice for preventing recurrent AF after electrical or pharmacologic conversion. The low doses cause fewer adverse effects than the higher ones used for life-threatening ventricular dysrhythmias. When clients are not converted to NSR, drugs are given to slow the heart rate. This strategy is used for clients who:
a. Have chronic AF but are asymptomatic
b. Have had AF for longer than 1 year
c. Are elderly
d. Have not responded to multiple drugs
In addition to amiodarone, other drugs used to slow the heart rate include a beta blocker, digoxin, verapamil, or diltiazem. In most clients, a beta blocker, verapamil, or diltiazem may be preferred. In clients with heart failure, digoxin may be preferred. In addition, the class IC agents flecainide or propafenone may be
used to suppress paroxysmal atrial flutter and fibrillation in clients with minimal or no heart disease.
3. IV adenosine, ibutilide, verapamil, or diltiazem may be used to convert PSVT to a NSR. These drugs block conduction across the AV node.
Ventricular Dysrhythmias
1. Treatment of asymptomatic PVCs and nonsustained ventricular tachycardia (formerly standard practice with lidocaine in clients post–myocardial infarction) is not recommended.
3. Amiodarone, sotalol, or a beta blocker may be used to prevent recurrence of ventricular tachycardia or fibrillation in clients resuscitated from cardiac arrest.
4. Moricizine is infrequently used in the
Use in Children
Antidysrhythmic drugs are less ofteeeded in children than in adults, and their use has decreased with increased use of catheter ablative techniques. Catheter ablation uses radio waves to destroy dysrhythmia-producing foci in cardiac tissue
and reportedly causes fewer adverse effects and complications than long-term antidysrhythmic drug therapy.
Antidysrhythmic drug therapy is also less clear-cut in children. The only antidysrhythmic drug that is FDA approved for use in children is digoxin. However, pediatric cardiologists have used various drugs and developed guidelines for their use, especially dosages. As with adults, the drugs should be used only when clearly indicated, and children should be monitored closely because all of the drugs can cause adverse effects, including hypotension and new or worsened dysrhythmias.
Supraventricular tachydysrhythmias are the most common sustained dysrhythmias in children. IV adenosine, digoxin, procainamide, or propranolol can be used acutely to terminate supraventricular tachydysrhythmias. IV verapamil, which is often used in adults to terminate supraventricular tachydysrhythmias, is contraindicated in infants and small children. Although it can be used cautiously in older children, some clinicians recommend that IV verapamil be avoided in the pediatric population. Digoxin or a beta blocker may be used for longterm management of supraventricular tachydysrhythmias.
Propranolol is the beta blocker most commonly used in children. It is one of the few antidysrhythmic drugs available in a liquid solution. Propranolol has a shorter half-life (3 to 4 hours) in infants than in children older than 1 to 2 years of age and adults (6 hours). When given IV, antidysrhythmic effects are rapid, and clients require careful monitoring for bradycardia and hypotension. E molol is being used more frequently to treat tachydysrhythmias in children, especially those occurring after surgery.
Lidocaine may be used to treat ventricular dysrhythmias precipitated by cardiac surgery or digitalis toxicity. Class I or III drugs are usually started in a hospital setting, at lower dosage ranges, because of prodysrhythmic effects. Prodysrhythmia is more common in children with structural heart disease or significant dysrhythmias. In general, serum levels should be monitored with class IA and IC drugs and IV lidocaine. Flecainide is the class IC drug most commonly used in children. Class III drugs are used in pediatrics mainly to treat life-threatening refractory tachydysrhythmias. As in adults, most antidysrhythmic drugs and their metabolites are excreted through the kidneys and may accumulate in children with impaired renal function.
Digitalis
The cardiac glycosides are often called digitalis or digitalis glycosides because most of the drugs come from the digitalis (foxglove) plant. They are a group of chemically similar compounds that can increase the contractility of the heart muscle and are therefore widely used in treating heart failure. The cardiac glycosides influence the sodium and calcium ion flows in the cardiac muscle, thereby increasing contraction of the atrial and ventricular myocardium (positive inotropic action). The cardiac glycosides bind to and block the action of the sodium-potassium ATPase. They inhibit the extrusion of sodium from the cell, leading to an increase in sodium levels within the cell.
The digitalis glycosides show only a small difference between a therapeutically effective dose and doses that are toxic or even fatal. Therefore, the drugs have a low therapeutic index. The cardiac glycosides include digitoxin, and the most widely used agent, digoxin.
Administration of digitalis glycosides increases the force of cardiac contractility causing the cardiac output to more closely resemble that of the normal heart. An increased myocardial contraction leads to a decrease in end diastolic volume, thus increasing the efficiency of contraction. the resulting improve circulation leads to reduced sympathetic activity, which then reduces peripheral resistance. Together, these effects cause a reduction in heart rate. Vagal tone is also enhanced so the heart rate decreases and myocardial oxygen demand is diminished.
Therapeutic uses. Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after initiation of diuretic and vasodilation therapy. Digoxin is not indicated in patients with diastolic or right-sided heart failure. Dobutamine, another inotropic agent, can be given intravenously in the hospital, but at present no good oral inotropic agents exist other than digoxin. Patients with mild to moderate heart failure often respond to treatment with ACE inhibitors and diuretics and do not require digoxin.
1. Rapid digitalization. In previously undigitalized patients , a single initial digoxin dose of 0.4-0.6 mg usually produces a detectable effect in 0.5-2 hours that become maximal in 2 to 6 hours. Additional doses of 0.1 to 0.3 mg may be given cautiously at 6 to 8 hour intervals until clinical evidence of an adequate effect is noted.
2. Gradual digitalization. A patient in heart failure with an estimated lean body weight of 70 kg and creatinine clearance of 60 ml/min, should be given 0.2 mg of digoxin per day, usually taken as a 0.1 mg tablet after the morning and evening meals. Steady-state serum concentrarions should not be anticipated before 11 days.
Contraindications to Use
Digoxin is contraindicated in severe myocarditis, ventricular tachycardia, or ventricular fibrillation and must be used cautiously in clients with acute myocardial infarction, heart block, Adams-Stokes syndrome, Wolff-Parkinson-White syndrome (risk of fatal dysrhythmias), electrolyte imbalances (hypokalemia, hypomagnesemia, hypercalcemia), and renal impairment.
Adverse effects. Digitalis toxicity is one of the most commonly encountered adverse drug reactions. Side effects can often be managed by discontinuing cardiac glycoside therapy, determing serum potassium levels, and if indicated, by giving potassium supplements. In general, decreased serum levels of potassium predispose a patient to digoxin toxicity. Digoxin levels must be closely monitored in the presence of renal insufficiency and dosage adjustment may be necessary. Severe toxicity resulting in ventricular tachycardia may require administration of antiarrhythmic drugs, and the use of antibodies to digoxin, which bind and inactivate the drug. Types of adverse effects include:
1. Cardiac effects. The major effect is progressively more severe dysrhythmia, paroxysmal supraventricular tachycardia, atrial fibrillation, ventricular fibrillation, and complete heart block. The electrocardiogram is fundamental in determining the presence and nature of these cardiac dicturbances. Digoxin may also induce other changes in the ECG (e.g. PR prolongation, ST depression), which represent digoxin effect and may or may not be associated with digitalis toxicity.
2. Castrointestinal effects. Anorexia, nausea, and vomiting are commonly encountered adverse effects.
3. CNS effects. These include headache, fatigue, confusion, blurred vision, alteration of color perception , and haloes on dark objects.
Factors predisposing to digitalis toxicity. Electrolytic disturbances. Hypokalemia can precipitate serious arrhythmia. Reduction of serum potassium levels is the most frequently observed in patients receiving thiazide or loop diuretics, and can usually be prevented with potassium chloride. Hyperkalemia and hypomagnesemia also predispose to digitalis toxicity.
Drugs. Quinidine can cause digitalis intoxication both by displacing digitalis from plasma protein binding sites, and by competing with digitalis for renal excretion. Verapamil also displaces digitalis from plasma protein binding sites and can increase digoxin levels by 50 to 75 %; this may require a reduction in the dose of digoxin. Potassium-depleting diuretics, corticosteroids, and a variety of other drugs can also increase digitalis toxicity. Hypothyroidism, hypoxia, renal failure, and myocarditis are also predisposing factors to digitalis toxicity.
Treatment of digitalis intoxication. When `tachyarrhythmias result from digitalis intoxication, withdrawal of the drug and treatment with potassium, phenytoin, propranolol, or lidocaine are indicated. Potassium should be administered cautiously and by the oral route whenever possible if hypokalemia is present. It should be administered intravenously in 5 % dextrose. Potassium must not be employed in the presence of atrioventricular block or hyperkalemia, when phenytoin is most appropriate. Lidocaine is effective in the treatment of digitalis-induced ventricular tachyarrhythmias in the absence of preceding atrioventricular block.
b-Adrenergic agonists (dopamine, dobutamine, epinephrine, isoproterenol)
b-Adrenergic stimulation improve cardiac performance by positive inotropic effects and vasodilation. Dobutamine is the most commonly used inotropic agent other than digitalis. Dobutamine leads to an increase in intracellular cAMP, which results in the activation of protein kinase. Slow calcium channels are one important site of phosphorylation by protein kinase. When phosphorylated, the entry of calcium ion into the myocardial cells increases, thus enhancing contraction. Dobutamine must be given by intravenous infusion of 2.5 to 15 (mg/kg)/min, and is primarily used in the treatment of acute heart failure in a hospital setting. Adverse effecte include sinus tachycardia, tachyarrhythmias, and hypertension.
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