CLINICAL PHARMACOLOGY OF ANTIANGINAL AND HYPOCHOLESTEROL DRUGS. CLINICAL PHARMACOLOGY OF ANTIARRHYTHMIC DRUGS AND AGENTS IMPROVING MYOCARDIUM METABOLISM. DRUG THERAPY IN VASCULAR TONE DISORDERS
Clinical pharmacology of antianginal drugs
Ischemic heart disease is the most common cardiovascular disease in developed countries, and angina pectoris is the most common condition involving tissue ischemia in which vasodilator drugs are used. The name denotes chest pain caused by accumulation of metabolites resulting from myocardial ischemia. The organic nitrates, eg, nitroglycerin, are the mainstay of therapy for the immediate relief of angina. Another group of vasodilators, the calcium channel blockers, is also important, especially for prophylaxis, and beta-blockers, which are not vasodilators, are also useful in prophylaxis. Several newer groups of drugs are under investigation, including drugs that alter myocardial metabolism and selective cardiac rate inhibitors.
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.
Nitroglycerin 2 % (NITRO-BID Ointment) (20-, 60-mg tubes) is indicated for the treatment and prevention of angina pectoris due to coronary artery disease. Controlled clinical trials have demonstrated that this form of nitroglycerin is effective in improving exercise tolerance in patients with exertional angina pectoris. Clinical trials have shown significant improvement in exercise time until chest pain for up to six hours after single aplication of various doses of nitroglycerin ointment (mean doses ranged from 5 to 36 mg) to a 36-inch2 (150×150 mm) area of trunk.
When applying the ointment, place the dose-determining applicator supplied with the package printed-side down and squeeze the necessary amount of ointment from the tube onto the applicator. Then place the applicator with the ointment-side down onto the desired area of skin, usually the chest or back.. A suggested started dose for NITRO-BID is 7,5 mg applied to a 1×3 inch area every 8 hours. If angina pectoris occurs while the ointment is in place, the dose should be increased, for example, to
Isosorbide dinitrate is an orally active nitrate. The drug is not readily metabolized by the liver or smooth muscle and has lower potency thaitroglycerin in relaxing vascular smooth muscle.
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.
The beneficial and deleterious effects of nitrate-induced vasodilation are summarized in Table 2.
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.
Atenolol
BRAND NAME: Tenormin
DRUG CLASS AND MECHANISM: Atenolol is a beta-adrenergic blocking agent that blocks the effects of adrenergic drugs, for example, adrenaline or epinephrine, oerves of the sympathetic nervous system. One of the important functions of beta-adrenergic stimulation is to stimulate the heart to beat more rapidly. By blocking the stimulation of these nerves, atenolol reduces the heart rate and is useful in treating abnormally rapid heart rhythms. Atenolol also reduces the force of contraction of heart muscle and lowers blood pressure. By reducing the heart rate, the force of muscle contraction, and the blood pressure against which the heart must pump, atenolol reduces the work of heart muscle and the need of the muscle for oxygen. Since angina occurs when oxygen demand of the heart muscle exceeds the supply, atenolol is helpful in treating angina. Atenolol was approved by the FDA in August 1981.
Metoprolol
BRAND NAMES: Lopressor, Toprol XL
DRUG CLASS AND MECHANISM: Metoprolol is a beta-adrenergic blocking agent that is used for treating high blood pressure, heart pain, abnormal rhythms of the heart, and some neurologic conditions. Examples of beta-adrenergic blockers include propanolol (Inderal), atenolol (Tenormin), and timolol (Blocadren). Metoprolol blocks the action of the sympathetic nervous system, a portion of the involuntary nervous system, by blocking beta receptors on sympathetic nerves. Since the sympathetic nervous system is responsible for increasing the rate with which the heart beats, by blocking the action of these nerves metoprolol reduces the heart rate and is useful in treating abnormally rapid heart rhythms.
Metoprolol also reduces the force of contraction of heart muscle and thereby lowers blood pressure. By reducing the heart rate and the force of muscle contraction, metoprolol reduces the need for oxygen by heart muscle. Since heart pain (angina pectoris) occurs when oxygen demand of the heart muscle exceeds the supply of oxygen, metoprolol, by reducing the demand for oxygen, is helpful in treating heart pain. The FDA approved metoprolol in August 1978.
PREPARATIONS: Tablets: 25, 50, and 100 mg. Tablets (extended release): 25, 50, 100, and 200 mg. Injection: 1 mg/ml
PRESCRIBED FOR: Metoprolol is prescribed for patients with high blood pressure (hypertension). It is also used to treat chest pain (angina pectoris) related to coronary artery disease. Metoprolol is also useful in slowing and regulating certain types of abnormally rapid heart rates (tachycardias). Other uses for metoprolol include the prevention of migraine headache and the treatment of certain types of tremors (familial or hereditary essential tremors).
DOSING: Metoprolol should be taken before meals or at bedtime. The dose for treating hypertension is 100-450 mg daily in single or divided doses. Angina is treated with 100-400 mg daily in two divided doses. Acute myocardial infarction is treated with three 5 mg injections administered 2 minutes apart followed by treatment with 50 mg oral metoprolol every 6 hours for 48 hours. After 48 hours, patients should receive 100 mg orally twice daily for at least 3 months.
DRUG INTERACTIONS: Calcium channel blockers and digoxin (Lanoxin) can lower of blood pressure and heart rate to dangerous levels when administered together with metoprolol.
Metoprolol can mask the early warning symptoms of low blood sugar (hypoglycemia) and should be used with caution in patients receiving treatment for diabetes.
PREGNANCY: Safe use of metoprolol during pregnancy has not been established.
NURSING MOTHERS: Small quantities of metoprolol are excreted in breast milk and may potentially cause adverse effects in the infant.
SIDE EFFECTS: Metoprolol is generally well tolerated. Side effects include abdominal cramps, diarrhea, constipation, fatigue, insomnia, nausea, depression, dreaming, memory loss, fever, impotence, lightheadedness, slow heart rate, low blood pressure, cold extremities, sore throat, and shortness of breath or wheezing. Metoprolol can aggravate breathing difficulties in patients with asthma, chronic bronchitis, or emphysema.
CLINICAL PHARMACOLOGY
CORGARD (nadolol) is a nonselective beta-adrenergic receptor blocking agent. Clinical pharmacology studies have demonstrated beta-blocking activity by showing (1) reduction in heart rate and cardiac output at rest and on exercise, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
CORGARD (nadolol) specifically competes with beta-adrenergic receptor agonists for available beta receptor sites; it inhibits both the beta1 receptors located chiefly in cardiac muscle and the beta2 receptors located chiefly in the bronchial and vascular musculature, inhibiting the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation proportionately. CORGARD has no intrinsic sympathomimetic activity and, unlike some other beta-adrenergic blocking agents, nadolol has little direct myocardial depressant activity and does not have an anesthetic-like membrane stabilizing action. Animal and human studies show that CORGARD slows the sinus rate and depresses AV conduction. In dogs, only minimal amounts of nadolol were detected in the brain relative to amounts in blood and other organs and tissues. CORGARD has low lipophilicity as determined by octanol/water partition coefficient, a characteristic of certain beta-blocking agents that has been correlated with the limited extent to which these agents cross the blood-brain barrier, their low concentration in the brain, and low incidence of CNS-related side effects.
In controlled clinical studies, CORGARD (nadolol) at doses of 40 to 320 mg/day has been shown to decrease both standing and supine blood pressure, the effect persisting for approximately 24 hours after dosing.
The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents has not been established; however, factors that may be involved include (1) competitive antagonism of catecholamines at peripheral (non-CNS) adrenergic neuron sites (especially cardiac) leading to decreased cardiac output, (2) a central effect leading to reduced tonic-sympathetic nerve outflow to the periphery, and (3) suppression of renin secretion by blockade of the beta-adrenergic receptors responsible for renin release from the kidneys.
While cardiac output and arterial pressure are reduced by nadolol therapy, renal hemodynamics are stable, with preservation of renal blood flow and glomerular filtration rate.
By blocking catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, CORGARD (nadolol) generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, nadolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.
Although beta-adrenergic receptor blockade is useful in treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
Absorption of nadolol after oral dosing is variable, averaging about 30 percent. Peak serum concentrations of nadolol usually occur in three to four hours after oral administration and the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol absorption. Approximately 30 percent of the nadolol present in serum is reversibly bound to plasma protein.
Unlike many other beta-adrenergic blocking agents, nadolol is not metabolized by the liver and is excreted unchanged, principally by the kidneys.
The half-life of therapeutic doses of nadolol is about 20 to 24 hours, permitting once-daily dosage. Because nadolol is excreted predominantly in the urine, its half-life increases in renal failure. Steady-state serum concentrations of nadolol are attained in six to nine days with once daily dosage in persons with normal renal function. Because of variable absorption and different individual responsiveness, the proper dosage must be determined by titration.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.
INDICATIONS AND USAGE
Angina Pectoris
Nadolol is indicated for the long-term management of patients with angina pectoris.
Hypertension
Nadolol is indicated in the management of hypertension; it may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.
CONTRAINDICATIONS
Nadolol is contraindicated in bronchial asthma, sinus bradycardia and greater than first-degree conduction block, cardiogenic shock, and overt cardiac failure
WARNINGS
Cardiac Failure
Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, they can be used with caution in patients with a history of failure who are well compensated, usually with digitalis and diuretics. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.
IN PATIENTS WITHOUT A HISTORY OF HEART FAILURE, continued use of beta-blockers can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of heart failure, the patient should be digitalized and/or treated with diuretics, and the response observed closely, or nadolol should be discontinued (gradually, if possible).
Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal
Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered nadolol, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of one to two weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, nadolol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue nadolol therapy abruptly even in patients treated only for hypertension.
Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema)
PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS. Nadolol should be administered with caution since it may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 receptors.
Major Surgery
Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of general anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output, it has generally been suggested that such therapy should be withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, beta-blockers should be withdrawn well before surgery takes place. In the event of emergency surgery, the anesthesiologist should be informed that the patient is on beta-blocker therapy. The effects of nadolol can be reversed by administration of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or levarterenol. Difficulty in restarting and maintaining the heart beat has also been reported with beta-adrenergic receptor blocking agents.
Diabetes and Hypoglycemia
Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia and blood pressure changes) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic drugs.
Thyrotoxicosis
Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-adrenergic blockade which might precipitate a thyroid storm.
PRECAUTIONS
Impaired Renal Function
Nadolol should be used with caution in patients with impaired renal function. (See
Drug Interactions
When administered concurrently, the following drugs may interact with beta-adrenergic receptor blocking agents:
Anesthetics, general: Exaggeration of the hypotension induced by general anesthetics
Antidiabetic drugs (oral agents and insulin): Hypoglycemia or hyperglycemia; adjust dosage of antidiabetic drug accordingly Catecholamine-depleting drugs (e.g.,reserpine): Additive effect; monitor closely for evidence of hypotension and/or excessive bradycardia (e.g., vertigo, syncope, postural hypotension).
Response to Treatment for Anaphylactic Reaction
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In chronic oral toxicologic studies (one to two years) in mice, rats, and dogs, nadolol did not produce any significant toxic effects. In two- year oral carcinogenic studies in rats and mice, nadolol did not produce any neoplastic, preneoplastic, or non-neoplastic pathologic lesions. In fertility and general reproductive performance studies in rats, nadolol caused no adverse effects.
Pregnancy Category
In animal reproduction studies with nadolol, evidence of embryo- and fetotoxicity was found in rabbits, but not in rats or hamsters, at doses 5 to 10 times greater (on a mg/kg basis) than the maximum indicated human dose. No teratogenic potential was observed in any of these species.
There are no adequate and well-controlled studies in pregnant women. Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms.
Nursing Mothers
Nadolol is excreted in human milk. Because of the potential for adverse effects iursing infants, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of CORGARD (nadolol) to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Most adverse effects have been mild and transient and have rarely required withdrawal of therapy.
Cardiovascular: Bradycardia with heart rates of less than 60 beats per minute occurs commonly, and heart rates below 40 beats per minute and/or symptomatic bradycardia were seen in about 2 of 100 patients. Symptoms of peripheral vascular insufficiency, usually of the Raynaud type, have occurred in approximately 2 of 100 patients. Cardiac failure, hypotension, and rhythm/conduction disturbances have each occurred in about 1 of 100 patients. Single instances of first degree and third degree heart block have been reported; intensification of AV block is a known effect of beta-blockers
Central Nervous System: Dizziness or fatigue has been reported in approximately 2 of 100 patients; paresthesias, sedation, and change in behavior have each been reported in approximately 6 of 1000 patients.
Respiratory: Bronchospasm has been reported in approximately 1 of 1000 patients
Gastrointestinal: Nausea, diarrhea, abdominal discomfort, constipation, vomiting, indigestion, anorexia, bloating, and flatulence have been reported in 1 to 5 of 1000 patients.
Miscellaneous: Each of the following has been reported in 1 to 5 of 1000 patients: rash; pruritus; headache; dry mouth, eyes, or skin; impotence or decreased libido; facial swelling; weight gain; slurred speech; cough; nasal stuffiness; sweating; tinnitus; blurred vision. Reversible alopecia has been reported infrequently.
The following adverse reactions have been reported in patients taking nadolol and/or other beta-adrenergic blocking agents, but no causal relationship to nadolol has been established.
Central Nervous System: Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability with slightly clouded sensorium, and decreased performance oeuropsychometrics.
Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis; elevated liver enzymes.
Hematologic: Agranulocytosis; thrombocytopenic or nonthrombocytopenic purpura.
Allergic: Fever combined with aching and sore throat; laryngospasm; respiratory distress.
Miscellaneous: Pemphigoid rash; hypertensive reaction in patients with pheochromocytoma; sleep disturbances; Peyronie’s disease.
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with nadolol.
OVERDOSAGE
Nadolol can be removed from the general circulation by hemodialysis.
In addition to gastric lavage, the following measures should be employed, as appropriate. In determining the duration of corrective therapy, note must be taken of the long duration of the effect of nadolol.
Excessive Bradycardia
Administer atropine (0.25 to 1.0 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.
Cardiac Failure
Administer a digitalis glycoside and diuretic. It has been reported that glucagon may also be useful in this situation.
Hypotension
Administer vasopressors, e.g., epinephrine or levarterenol. (There is evidence that epinephrine may be the drug of choice.)
Bronchospasm
Administer a beta2-stimulating agent and/or a theophylline derivative.
DOSAGE AND ADMINISTRATION
DOSAGE MUST BE INDIVIDUALIZED. NADOLOL MAY BE ADMINISTERED WITHOUT REGARD TO MEALS.
Angina Pectoris
The usual initial dose is 40 mg CORGARD (nadolol) once daily. Dosage may be gradually increased in 40 to 80 mg increments at 3 to 7 day intervals until optimum clinical response is obtained or there is pronounced slowing of the heart rate. The usual maintenance dose is 40 or 80 mg administered once daily. Doses up to 160 or 240 mg administered once daily may be needed.
The usefulness and safety in angina pectoris of dosages exceeding 240 mg per day have not been established. If treatment is to be discontinued, reduce the dosage gradually over a period of one to two weeks.
Hypertension
The usual initial dose is 40 mg CORGARD (nadolol) once daily, whether it is used alone or in addition to diuretic therapy. Dosage may be gradually increased in 40 to 80 mg increments until optimum blood pressure reduction is achieved. The usual maintenance dose is 40 or 80 mg administered once daily. Doses up to 240 or 320 mg administered once daily may be needed.
Dosage Adjustment in Renal Failure
Absorbed nadolol is excreted principally by the kidneys and, although nonrenal elimination does occur, dosage adjustments are necessary in patients with renal impairment. The following dose intervals are recommended:
|
Creatinine |
Dosage |
|
> 50 |
24 |
|
31 – 50 |
24 – 36 |
|
10 – 30 |
24 – 48 |
|
< 10 |
40 – 60 |
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 United States vary in their chemical structures and effects on body tissues. Seven of these are chemically dihydropyridines, of which nifedipine is the prototype. Bepridil, diltiazem, and verapamil differ chemically from the dihydropyridines and each other. Nifedipine and related drugs act mainly on vascular smooth muscle to produce vasodilation, whereas verapamil and diltiazem have greater effects on the cardiac conduction system.
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.
CARDIAC DYSRHYTHMIAS
Cardiac arrhythmias are a common problem in clinical practice, occurring in up to 25% of patients treated with digitalis, 50% of anesthetized patients, and over 80% of patients with acute myocardial infarction. Arrhythmias may require treatment because rhythms that are too rapid, too slow, or asynchronous can reduce cardiac output. Some arrhythmias can precipitate more serious or even lethal rhythm disturbances; for example, early premature ventricular depolarizations can precipitate ventricular fibrillation. In such patients, antiarrhythmic drugs may be precipitate ventricular fibrillation. In such patients, antiarrhythmic drugs may be lifesaving. On the other hand, the hazards of antiarrhythmic drugs—and in particular the fact that they can precipitate lethal arrhythmias in some patients—has led to a reevaluation of their relative risks and benefits. In general, treatment of asymptomatic or minimally symptomatic arrhythmias should be avoided for this reason.
Cardiac dysrhythmias can originate in any part of the conduction system or from atrial or ventricular muscle. They result from disturbances in electrical impulse formation (automaticity), conduction (conductivity), or both. The characteristic of automaticity allows myocardial cells other than the SA node to depolarize and initiate the electrical impulse that culminates in atrial and ventricular contraction. This may occur when the SA node fails to initiate an impulse or does so too slowly. When the electrical impulse arises anywhere other than the SA node, it is an abnormal or ectopic focus. If the ectopic focus depolarizes at a rate faster than the SA node, the ectopic focus becomes the dominant pacemaker. Ectopic pacemakers may arise in the atria, AV node, Purkinje fibers, or ventricular muscle. They may be activated by hypoxia, ischemia, or hypokalemia. Ectopic foci indicate myocardial irritability (increased responsiveness to stimuli) and potentially serious impairment of cardiac function.
A common mechanism by which abnormal conduction causes dysrhythmias is called reentry excitation. During normal conduction, the electrical impulse moves freely down the conduction system until it reaches recently excited tissue that is refractory to stimulation. This causes the impulse to be extinguished. The SA node then recovers, fires spontaneously, and the conduction process starts over again. Reentry excitation means that an impulse continues to reenter an area of the heart rather than becoming extinguished. For this to occur, the impulse must encounter an obstacle in the normal conducting pathway. The obstacle is usually an area of damage, such as myocardial infarction. The damaged area allows conduction in only one direction and causes a circular movement of the impulse.
Dysrhythmias may be mild or severe, acute or chronic, episodic or relatively continuous. They are clinically significant if they interfere with cardiac function (ie, the heart’s abil-ity to pump sufficient blood to body tissues). The normal heartcan maintain an adequate cardiac output with ventricular rates ranging from 40 to 180 beats per minute. The diseased heart, however, may not be able to maintain an adequate cardiac output with heart rates below 60 or above 120. Dysrhythmias are usually categorized by rate, location, or patterns of conduction.
BRADYCARDIAS AND HEART BLOCK
Bradycardias may be due to failure of impulse formation (sinus bradycardia) or failure of impulse conduction from the atria to the ventricles (atrioventricular block).
Bradycardia
Sinus bradycardia
Sinus bradycardia is due to extrinsic factors influencing a relatively normal sinus node or due to intrinsic sinus node disease. The mechanism can be acute and reversible or chronic and degenerative. Common causes of sinus bradycardia
include:
Extrinsic causes
■ hypothermia, hypothyroidism, cholestatic jaundice and raised intracranial pressure
■ drug therapy with beta-blockers, digitalis and other antiarrhythmic drugs
■ neurally mediated syndromes.
Intrinsic causes
■ acute ischaemia and infarction of the sinus node (as a complication of acute myocardial infarction)
■ chronic degenerative changes such as fibrosis of the atrium and sinus node (sick sinus syndrome).
Sick sinus syndrome or sinoatrial disease is usually caused by idiopathic fibrosis of the sinus node. Other causes of fibrosis such as ischaemic heart disease, cardiomyopathy or myocarditis can also cause the syndrome. Patients develop episodes of sinus bradycardia or sinus arrest and commonly, owing to diffuse atrial disease, experience paroxysmal atrial tachyarrhythmias (tachy-bradysyndrome).
Neurally mediated syndromes
Neurally mediated syndromes are due to a reflex (called Bezold–Jarisch) that may result in both bradycardia (sinus bradycardia, sinus arrest and AV block) and reflex peripheral vasodilatation. These syndromes usually present as syncope or pre-syncope (dizzy spells).
Carotid sinus syndrome occurs in the elderly and mainly results in bradycardia. Syncope occurs.
Neurocardiogenic (vasovagal) syncope (syndrome) usually presents in young adults but may present for the first time in elderly patients. It results from a variety of situations (physical and emotional) that affect the autonomic nervous system. The efferent output may be predominantly bradycardic, predominantly vasodilatory or mixed.
Postural orthostatic tachycardia syndrome (POTS) is a sudden and significant increase in heart rate associated with normal or mildly reduced blood pressure produced by standing.
The underlying mechanism is a failure of the peripheral vasculature to appropriately constrict in response to orthostatic stress, which is compensated by an excessive increase in heart rate.
Many medications, such as antihypertensives, tricyclic antidepressants and neuroleptics can be the cause of syncope, particularly in the elderly. Careful dose titration and avoidance of combining two agents with potential to cause syncope help to prevent iatrogenic syncope.
Treatment
The management of sinus bradycardia is first to identify and if possible remove any extrinsic causes. Temporary pacing may be employed in patients with reversible causes until a normal sinus rate is restored and in patients with chronic degenerative conditions until a permanent pacemaker is implanted.
Chronic symptomatic sick sinus syndrome requires permanent pacing (DDD), with additional antiarrhythmic drugs (or ablation therapy) to manage any tachycardia element. Thromboembolism is common in tachy-brady syndrome and patients should be anticoagulated unless there is a contraindication. Patients with carotid sinus hypersensitivity (asystole > 3 s), especially if symptoms are reproduced by carotid sinus massage, and in whom life-threatening causes of syncope have been excluded, benefit from pacemaker implantation. Treatment options in vasovagal attacks include avoidance, if possible, of situations known to cause syncope in a particular patient. Increased salt intake, compression of the lower legs with hose and drugs such as beta-blockers, alpha-agonists or myocardial negative inotropes (such as disopyramide) may be helpful. In selected patients with ‘malignant’ neurocardiogenic syncope (syncope associated with injuries) permanent pacemaker therapy is helpful. These patients benefit from dual chamber pacemakers with a feature called ‘rate drop response’ which, once activated, paces the heart at a fast rate for a set period of time in order to prevent syncope.
Heart block
Heart block or conduction block may occur at any level in the conducting system. Block in either the AV node or the His bundle results in AV block, whereas block lower in the conduction system produces bundle branch block.
Atrioventricular block
There are three forms:
First-degree AV block
This is simple prolongation of the PR interval to more than 0.22 s. Every atrial depolarization is followed by conduction to the ventricles but with delay (Fig.).
An ECG showing first-degree atrioventricular block with a prolonged PR interval. In this trace coincidental ST depression is also present.
Three varieties of seconddegree atrioventricular (AV) block. (a) Wenckebach (Mobitz type I) AV block. The PR interval gradually prolongs until the P wave does not conduct to the ventricles (arrows). (b) Mobitz type II AV block. The P waves that do not conduct to the ventricles (arrows) are not preceded by gradual PR interval prolongation. (c) Two P waves to each QRS complex. The PR interval prior to the dropped P wave is always the same. It is not possible to define this type of AV block as type I or type II Mobitz block and it is, therefore, a third variety of second-degree AV block (arrows show P waves).
Two examples of complete heart block. (a) Congenital complete heart block. The QRS complex is narrow (0.08 s) and the QRS rate is relatively rapid (52 b.p.m.). (b) Acquired complete heart block. The QRS complex is broad (0.13 s) and the QRS rate is relatively slow (38 b.p.m.).
Second-degree AV block
This occurs when some P waves conduct and others do not.
There are several forms (Fig.):
■ Mobitz I block (Wenckebach block phenomenon) is progressive PR interval prolongation until a P wave fails to conduct. The PR interval before the blocked P wave is much longer than the PR interval after the blocked P wave.
■ Mobitz II block occurs when a dropped QRS complex is not preceded by progressive PR interval prolongation. Usually the QRS complex is wide (> 0.12 s). Usually the QRS complex is wide (> 0.12 s).
■ 2 : 1 or 3 : 1 (advanced) block occurs when every second or third P wave conducts to the ventricles. This form of second-degree block is neither Mobitz I nor II. Wenckebach AV block in general is due to block in the AV node, whereas Mobitz II block signifies block at an infranodal level such as the His bundle. The risk of progression to complete heart block is greater and the reliability of the resultant escape rhythm is less with Mobitz II block. Therefore pacing is usually indicated in Mobitz II block, whereas patients with Wenckebach AV block are usually monitored. Acute myocardial infarction may produce second-degree heart block. In inferior myocardial infarction, close monitoring and transcutaneous temporary back-up pacing are all that is required. In anterior myocardial infarction, second-degree heart block is associated with a high risk of progression to complete heart block, and temporary pacing followed by permanent pacemaker implantation is usually indicated. 2 : 1 Heart block may either be due to block in the AV node or at an infra-nodal level. Management depends on the clinical setting in which it occurs.
Third-degree (complete) AV block
Complete heart block occurs when all atrial activity fails to conduct to the ventricles (Fig.). In patients with complete heart block the aetiology needs to be established. In this situation life is maintained by a spontaneous escape rhythm.
Narrow complex escape rhythm (< 0.12 s QRS complex) implies that it originates in the His bundle and therefore that the region of block lies more proximally in the AV node. The escape rhythm occurs with an adequate rate (50–60 b.p.m.) and is relatively reliable.
Treatment depends on the aetiology. Recent-onset narrow-complex AV block due to transient causes may respond to intravenous atropine, but temporary pacing facilities should be available for the management of these patients. Chronic narrow-complex AV block requires permanent pacing (dual chamber) if it is symptomatic or associated with heart disease. Pacing is also advocated for isolated,
congenital AV block, even if asymptomatic. Broad complex escape rhythm (> 0.12 s) implies that the escape rhythm originates below the His bundle and therefore that the region of block lies more distally in the His–Purkinje system.
The resulting rhythm is slow (15–40 b.p.m.) and relatively unreliable. Dizziness and blackouts (Stokes–Adams attacks) often occur. In the elderly, it is usually caused by degenerative fibrosis and calcification of the distal conduction system (Lev’s disease). In younger individuals, a proximal progressive cardiac conduction disease due to the inflammatory process is known as Lenegre’s syndrome. Sodium channel abnormalities have been identified in both syndromes. Broad-complex AV block may also be caused by ischaemic heart disease, myocarditis or cardiomyopathy. Permanent pacemaker implantation is indicated, as pacing considerably reduces the mortality. Because ventricular arrhythmias are not uncommon, an implantable cardioverter–defibrillator (ICD) may be indicated in those with severe left ventricular dysfunction (> 0.30 s).
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. Class IA agents slow the rate of rise of the action potential, thus slowing conduction, and prolong the action potential and increase the ventricular effective refractory period. They have an intermediate speed of association with activated/inactivated sodium channels, and an intermediate rate of dissociation from resting channels. Class IB drugs have little effect on the rate of depolarization, but rather they decrease the duration of the action potential by shortening repolarization. They rapidly interact with sodium channels. Class IC agents markedly depress the rate of rise of the membrane action potential, and therfore they cause marked conduction slowing but have little effect on the duration of the membrane action potential or the ventricular effective refractory period. They bind slowly to sodium channels.
Quinidine (200, 300 mg) is the prototype Class IA drug. At high doses, it can actually precipitate arrhythmias, which can lead to fatal ventricular fibrillation. Because of quinidine’s toxic potential, calcium antagonists, such as verapamil, are increasingly replacing this drug in clinical use. Quinidine is used in the treatment of a wide variety of arrhythmias, including atrial, AV junctional, and ventricular tachyarrhythmias. Quinidine is used to maintain sinus rhythm after direct current cardioversion of atrial flutter or fibrillation and to prevent frequent ventricular tachycardia. A potential adverse effect of quinidine (or any antiarrhythmic drug) is exacerbation of the arrhythmia. Quinidine may cause SA and AV block or asystole. At toxic levels, the drug may induce ventricular tachycardia. Cardiotoxic effects are exacerbated by hyperkalemia. Quinidine can increase the steady state concentration of digoxine by displacement of digoxin from tissue binding sites. Nauses, vomiting and diarrhea are commonly observed. Large doses may induce the symptoms of conchonism, for ex., blurred vision, tinnitus, headache, disorientation, and psychosis. The drug has a mild α-adrenergic blocking action as well as an atropine-like effect.
Procainamide (500 mg) – this Class IA drug, a derivative of the local anesthetic procaine, shows actions similar to those of quinidine. Adverse effects: With chronic use procainamide causes a high incidence of side effects, including a reversible lupus erythematosus-like syndrome that develops in 25 to 30 % of patients. Toxic concentrations of procainamide may cause asystole or induction of ventricular arrhythmias. Central nervous system side effects include depression, hallucination and psychosis. With this drug, gastrointestinal intolreance is less frequent than with quinidine.
Disopyramide (caps. 100, 150 mg) produces a negative inotropic effect that is greater than the weak effect exerted by quinidine and procainamide, and unlike the latter drugs, disopyramide causes peripheral vasoconstriction. The drug may produce a clinically important decrease in myocardial contractility in patients with preexisting impairment of left ventricular function. Disopyramide is used for treatment of ventricular arrhythmias as an alternative to procainamide or quinidine. Adverse effects: Disopyramide shows effects of anticholinergic activity, for ex., dry mouth, urinary retention, blurred vision, and constipation.
Lidocaine (amp. 1 % 10, 20 ml [10 mg/ml]; 2 % 2, 10 ml[20 mg/ml]) is a Class IB drug. The IB agents rapidly associate and dissociate from sodium channels. Class IB drugs are particularly useful in treating ventricular arrhythmias. Lidocaine is the drug of choice for emergency treatment of cardiac arrhythmias. Unlike quinidine, which suppresses arrhythmias caused by increased normal automaticity, lidocaine suppresses arrhythmias caused by abnormal automaticity. Lidocaine, like quinidine, abolishes ventricular reentry. Lidocaine is useful in treating ventricular arrhythmias arising during myocardial ischemia, such as that experienced during a myocardial infarction. The drug does not markedly slow conduction and thus has little effect on atrial or AV junction arrhythmias. Lidocaine is given intravenously because of extensive first-pass transformation by the liver, which precludes oral administration. Lidocaine has fairly wode toxic-to-therapeutic ratio; it shows little impairment of left ventricular function, and has no negative inotropic effect. The CNS effects include drowsiness, slurred speech, paresthesia, agitation, confusion, and convulsions; cardiac arrhythmias may also occur.
Mexiletine (caps. 150, 200, 250 mg) and tocainide (tab. 400 mg) are Class IB drugs with actions similar to those of lidocaine. These agents can be administered orally. Tocainide has pulmonary toxicity, which may lead to pulmonary fibrosis.
Flecainide (tab. 50, 100, 150 mg) is a Class IC drug. These drugs are approved only for refractory ventricular arrhythmias. It is particularly useful in suppressing premature ventricular contraction. Flecainide has a negative inotropic effect and can aggravate congestive heart failure. Flecainide is absorbed orally and has a half-life of 16 to 20 hours. Flecainide can cause dizziness, blured vision, headache, and nausea. Like other Class IC drugs, flecainide can aggravate preexisting arrhythmias or induce life-threatening ventricular tachycardia that is resistant to treatment.
Propafenone (tab. 150, 300 mg) is Class IC drug shows actions similar to those of flecainide.
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.
Propranolol (tab. 10, 20, 40, 60, 80 mg) (a nonselective b-antagonist) reduces the incidence of sudden arrhythmic death after myocardial infarction (the most common cause of death in this group of patients). Propranolol diminishes cardiac output, having both negative inotropic and chronotropic effects. It directly depresses sino-auricular and atrioventricular activity. The b-blockers are effective in attenuating supraventricular cardiac arrhythmias but are generally not effective against ventricular arrhythmias. Propranolol has a serious and potentially lethal side effect when administered to an asthmatic. An immediate contraction of the bronchiolar smooth muscle prevents air from entering the lungs. Therefore, propranolol must never be used in treating any individual with obstructive pulmonary disease. Treatment with the b-blockers must never be stopped quickly because of the risk of precipitating cardiac arrhythmias, which may be severe. The b-blockers must be tapered off gradually for 1 week. Long-term treatment with a b-antagonists leads to up-regulation of the b-receptor. Some men do complain of impaired sexual activity. Fasting hypoglycemia may occur. Drugs that interfere with the metabolism of propranolol, such as cimetidine, furosemide, and chlorpromazine. May potentiate its antihypertensive effects.
Drugs that preferentially block the b1 receptors have been developed to eliminate the unwanted bronchoconstrictor effect (b2) of propranolol seen among asthmatic patients. Cardioselective b-blockers, such as metoprolol (tab. 50, 100 mg, amp. 5 ml), esmolol (amp. 10 ml (
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.
Ibutilide is indicated for management of recent onset of AF or atrial flutter, in which the goal is conversion to NSR. The drug enhances the efficacy of cardioversion. Ibutilide is structurally similar to sotalol but lacks clinically significant beta-blocking activity. Ibutilide is widely distributed and has an elimination half-life of about 6 hours. Most of a dose is metabolized, and the metabolites are excreted in urine and feces. Adverse effects include supraventricular and ventricular dysrhythmias (particularly torsades de pointes) and hypotension. Ibutilide should be administered in a setting with personnel and equipment available for emergency use.
Dofetilide is indicated for the maintenance of normal sinus rhythm in symptomatic clients who are in AF of more than one-week duration. Adverse effects increase with decreasing creatinine clearance levels so renal function must be assessed and initial dosage is dependent on creatinine clearance levels. High dosages in clients with renal dysfunction result in drug accumulation and prodysrhythmia (torsades de pointes). The drug has an elimination half-life of approximately 8 hours with the kidneys being the major route of elimination. The drug should initially be administered in a setting with personnel and equipment available for emergency use.
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 United States because of its potential for causing undesirable cardiac events. It may be used to treat life-threatening ventricular dysrhythmias (eg, sustained ventricular tachycardia) that have not responded to safer drugs.
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.
CLINICAL PHARMACOLOGY OF 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
|
CONCOMITANT DISEASE |
DRUGS COMMONLY USED IN TREATING HYPERTENSION |
|||
|
Angina pectoris |
|
|
|
|
|
Commonly used drugs |
|
b-Blockers |
|
Ca++ Channel blockers |
|
Alternative drugs |
diuretics |
|
ACE inhibitors |
|
|
Diabetes (insulin-dependent) |
|
|
|
|
|
Commonly used drugs |
|
|
ACE inhibitors |
Ca++ Channel blockers
|
|
Alternative drugs |
|
|
|
|
|
Hyperlipidemia |
|
|
|
|
|
Commonly used drugs |
|
|
ACE inhibitors |
Ca++ Channel blockers
|
|
Alternative drugs |
|
|
|
|
|
Congestive heart failure |
|
|
|
|
|
Commonly used drugs |
diuretics |
|
ACE inhibitors |
|
|
Alternative drugs |
|
|
|
Avoid verapamil |
|
Previous myocardial infarction |
|
|
|
|
|
Commonly used drugs |
|
b-Blockers |
ACE inhibitors |
|
|
Alternative drugs |
diuretics |
|
|
Ca++ Channel blockers |
|
Chronic renal disease |
|
|
|
|
|
Commonly used drugs |
diuretics |
|
|
Ca++ Channel blockers |
|
Alternative drugs |
|
b-Blockers |
ACE inhibitors |
|
|
Asthma, chronic pulmonary disease |
|
|
|
|
|
Commonly used drugs |
diuretics |
|
|
Ca++ Channel blockers |
|
Alternative drugs |
|
|
ACE inhibitors |
|
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). Loop diretics may be required in these patients.
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 maintain normal 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.
References
|
1. Bhatt AB, Stone PH: Current strategies for the prevention of angina in patients with stable coronary artery disease. Curr Opin Cardiol 2006;21:492. [PMID: 16900014] |
|
2. Borer JS: Clinical effect of ‘pure’ heart rate slowing with a prototype If inhibitor: placebo-controlled experience with ivabradine. Adv Cardiol 2006;43:54. [PMID: 16936472] |
|
3. Braunwald E et al: ACC/AHA Guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—2002. Circulation 2002;106:1893. [PMID: 12356647] |
|
4. Carmichael P, Lieben J: Sudden death in explosives workers. Arch Environ Health 1963;7:50. |
|
5. Chaitman BR: Efficacy and safety of a metabolic modulator drug in chronic stable angina: Review of evidence from clinical trials. J Cardiovasc Pharmacol Ther 2004;9(Suppl 1):S47. |
|
6. Chaitman BR et al: Effects of ranolazine, with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with sever chronic angina. A randomized controlled trial. JAMA 2004;291:309. [PMID: 14734593] |
|
7. DeWitt CR, Waksman JC: Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity. Toxicol Rev 2004;23:223. [PMID: 15898828] |
|
8. Galie N et al: Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148. [PMID: 16291984] |
|
9. Gibbons RJ et al: ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 2003;41:159. [PMID: 12570960] |
|
10. Ignarro LJ et al: Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside, and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;218:739. [PMID: 6115052] |
|
11. Lacinova L: Voltage-dependent calcium channels. Gen Physiol Biophys 2005;24(Suppl 1):1. |
|
12. Peng J, Li Y-J: New insights into nitroglycerin effects and tolerance: Role of calcitonin gene-related peptide. Eur J Pharmacol 2008;586:9. [PMID: 18367169] |
|
13. Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2008;51:591. [PMID: 18037193] |
|
14. Saint DA: The cardiac persistent sodium current: An appealing therapeutic target? Br J Pharmacol 2008;153:1133. [PMID: 18071303] |
|
15. Triggle DJ: Calcium channel antagonists: clinical uses—past, present and future. Biochem Pharmacol 2007;74:1. [PMID: 17276408] |
