CLINICAL PHARMACY IN CARDIOLOGY (III)
Clinical Pharmacy in cardiology. Symptoms and syndromes in major cardiovascular system diseases. Clinical pharmacology of drugs used for the treatment of atherosclerosis, coronary heart disease, hypertension, chronic heart failure.
HYPERTENSION
Hypertension is persistently high blood pressure that results from abnormalities in regulatory mechanisms. It is usually defined as a systolic pressure above 140 mm Hg or a diastolic pressure above 90 mm Hg on multiple blood pressure measurements.
Primary or essential hypertension (that for which no cause can be found) makes up 90% to 95% of known cases. Secondary hypertension may result from renal, endocrine, or central nervous system disorders and from drugs that stimulate the SNS or cause retention of sodium and water. Primary hypertension can be controlled with appropriate therapy; secondary hypertension can sometimes be cured by surgical therapy.
Etiology of Hypertension
A specific cause of hypertension can be established in only 10–15% of patients. Patients in whom no specific cause of hypertension can be found are said to have essential or primaryhypertension. Patients with a specific etiology are said to have secondaryhypertension. It is important to consider specific causes in each case, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing’s disease, and primary aldosteronism.
In most cases, elevated blood pressure is associated with an overall increase in resistance to flow of blood through arterioles, whereas cardiac output is usually normal. Meticulous investigation of autonomic nervous system function, baroreceptor reflexes, the renin-angiotensin-aldosterone system, and the kidney has failed to identify a single abnormality as the cause of increased peripheral vascular resistance in essential hypertension. It appears, therefore, that elevated blood pressure is usually caused by a combination of several (multifactorial) abnormalities. Epidemiologic evidence points to genetic factors, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as contributing to the development of hypertension. Increase in blood pressure with aging does not occur in populations with low daily sodium intake. Patients with labile hypertension appear more likely thaormal controls to have blood pressure elevations after salt loading.
The heritability of essential hypertension is estimated to be about 30%. Mutations in several genes have been linked to various rare causes of hypertension. Functional variations of the genes for angiotensinogen, angiotensin-converting enzyme (ACE), the 2 adrenoceptor, and adducin (a cytoskeletal protein) appear to contribute to some cases of essential hypertension.
Diagnosis
The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure (Table 1). The diagnosis serves primarily as a prediction of consequences for the patient; it seldom includes a statement about the cause of hypertension.
Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. Even mild hypertension (blood pressure 140/90 mm Hg) increases the risk of eventual end-organ damage. Starting at 115/75 mm Hg, cardiovascular disease risk doubles with each increment of 20/10 mm Hg throughout the blood pressure range. Both systolic hypertension and diastolic hypertension are associated with end-organ damage; so-called isolated systolic hypertension is not benign. The risks—and therefore the urgency of instituting therapy—increase in proportion to the magnitude of blood pressure elevation. The risk of end-organ damage at any level of blood pressure or age is greater in African Americans and relatively less in premenopausal women than in men. Other positive risk factors include smoking; metabolic syndrome, including obesity, dyslipidemia, and diabetes; manifestations of end-organ damage at the time of diagnosis; and a family history of cardiovascular disease.
It should be noted that the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. In fact, hypertension is usually asymptomatic until overt end-organ damage is imminent or has already occurred.
The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, published in 1997, classified blood pressures in adults (in mm of Hg), as follows:
• Normal = systolic 130 or below; diastolic 85 or below
• High normal = systolic 130 to 139; diastolic 85 to 89
• Stage 1 hypertension (mild) = systolic 140 to 159; diastolic
90 to 99
• Stage 2 hypertension (moderate) = systolic 160 to 179;
diastolic 100 to 109
• Stage 3 hypertension (severe) = systolic 180 to 209; diastolic
110 to 119
• Stage 4 hypertension (very severe) = systolic 210 or above; diastolic 120 or above
A systolic pressure of 140 or above with a diastolic pressure below 90 is called isolated systolic hypertension and is more common in the elderly.
Hypertension profoundly alters cardiovascular function by increasing the workload of the heart and causing thickening and sclerosis of arterial walls. As a result of increased cardiac workload, the myocardium hypertrophies as a compensatory mechanism and heart failure eventually occurs. As a result of endothelial dysfunction and arterial changes (vascular remodeling), the arterial lumen is narrowed, blood supply to tissues is decreased, and risks of thrombosis are increased. In addition, necrotic areas may develop in arteries, and these may rupture with sustained high blood pressure. The areas of most serious damage are the heart, brain, kidneys, and eyes. These are often called target organs.
Initially and perhaps for years, primary hypertension may produce no symptoms. If symptoms occur, they are usually vague and nonspecific. Hypertension may go undetected, undetected, or it may be incidentally discovered when blood pressure measurements are taken as part of a routine physical examination, screening test, or assessment of other disorders. Eventually, symptoms reflect target organ damage.
Hypertension is often discovered after a person experiences angina pectoris, myocardial infarction, heart failure, stroke, or renal disease. Hypertensive emergencies are episodes of severely elevated blood pressure that may be an extension of malignant (rapidly progressive) hypertension or caused by cerebral hemorrhage, dissecting aortic aneurysm, renal disease, pheochromocytoma, or eclampsia. These require immediate management, usually intravenous (IV) antihypertensive drugs, to lower blood pressure. Symptoms include severe headache, nausea, vomiting, visual disturbances, neurologic disturbances, disorientation, and decreased level of consciousness (drowsiness, stupor, coma). Hypertensive urgencies are episodes of less severe hypertension and are often managed with oral drugs. The goal of management is to lower blood pressure within 24 hours. In most instances, it is better to lower blood pressure gradually and to avoid wide fluctuations in blood pressure.
Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any of four drugs depending on the individual patient: a diuretic, a b-blocker, an ACE inhibitor, or a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is added. A b-blocker is usually added if the initial drug was a diuretic, or a diuretic is added if the first drug was a b-blocker. A vasodilator can be added as a third step for those patients who still fail to respond.
Certain subsets of the hypertensive population respond better to one class of drug than another. For example, black patients respond well to diuretics and calcium channel blockers, but therapy with b-blockers or ACE inhibitors is often less effective. Similarly, calcium channel blockers, ACE inhibitors, and diuretics are favored for treatment of hypertension in the elderly, whereas b-blockers and a-antagonists are less well tolerated. Furthermore, hypertension may coexist with other diseases that can be aggravated by some of the antihypertensive drugs.
ANTIHYPERTENSIVE DRUGS
Drugs used in the management of primary hypertension belong to several different groups, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), also called angiotensin II receptor antagonists (AIIRAs), antiadrenergics, calcium channel blockers, diuretics, and direct vasodilators. In general, these drugs act to decrease blood pressure by decreasing cardiac output or peripheral vascular resistance.
I. DIURETICS
Bumetanide, furosemide, hydrochlorthiazide, spironolactone, triamterene
II. b-BLOCKERS
Atenolol, labetalol, metoprolol, propranolol, timolol
III. ACE INHIBITORS
Captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril
IV. ANGIOTENSIN II ANTAGONIST
Losartan
V. Ca++CHANNEL BLOCKERS
Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil
VI. a-BLOCKERS
Doxazosin, prazosin, terazosin
VII. OTHER
Clonidine, diazoxide, hydralazine, a-methyldopa, minoxidil, sodium nitroprusside
Treatment of hypertension in patients with concomitant diseases
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CONCOMITANT DISEASE |
DRUGS COMMONLY USED IN TREATING HYPERTENSION |
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Angina pectoris |
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Commonly used drugs |
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b-Blockers |
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Ca++ Channel blockers |
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Alternative drugs |
diuretics |
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ACE inhibitors |
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Diabetes (insulin-dependent) |
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Commonly used drugs |
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ACE inhibitors |
Ca++ Channel blockers
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Alternative drugs |
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Hyperlipidemia |
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Commonly used drugs |
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ACE inhibitors |
Ca++ Channel blockers
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Alternative drugs |
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Congestive heart failure |
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Commonly used drugs |
diuretics |
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ACE inhibitors |
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Alternative drugs |
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Avoid verapamil |
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Previous myocardial infarction |
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Commonly used drugs |
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b-Blockers |
ACE inhibitors |
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Alternative drugs |
diuretics |
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Ca++ Channel blockers |
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Chronic renal disease |
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Commonly used drugs |
diuretics |
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Ca++ Channel blockers |
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Alternative drugs |
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b-Blockers |
ACE inhibitors |
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Asthma, chronic pulmonary disease |
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Commonly used drugs |
diuretics |
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Ca++ Channel blockers |
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Alternative drugs |
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ACE inhibitors |
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DIURETICS and/or b-Blockers are currently recommended as the first-line drug therapy for hypertension. Low-dose diuretic therapy is safe and effective in preventing stroke, myocardial infarction, congestive heart failure and total mortality. Recent data suggest that diuretics are superior to b-Blockers in older adults.
Antihypertensive effects of diuretics are usually attributed to sodium and water depletion. In fact, diuretics usually produce the same effects as severe dietary sodium restriction. In many cases of hypertension, diuretic therapy alone may lower blood pressure. When diuretic therapy is begun, blood volume and cardiac output decrease. With long-term administration of a diuretic, cardiac output returns to normal, but there is a persistent decrease in peripheral vascular resistance. This has been attributed to a persistent small reduction in extracellular water and plasma volume, decreased receptor sensitivity to vasopressor substances such as angiotensin, direct arteriolar vasodilation, and arteriolar vasodilation secondary to electrolyte depletion in the vessel wall.
In moderate or severe hypertension that does not respond to a diuretic alone, the diuretic may be continued and another antihypertensive drug added, or monotherapy with a different type of antihypertensive drug may be tried.
Thiazide diuretics. All oral diuretics are effective in the treatment of hypertension, but the thiazides have the most widespread use. Thiazides, such as hydochlorothiazide, lower blood pressure , initially by increasing sodium and water excretion. This causes a decrease in extracellular volume , resulting in a decrease in cardiac output and renal blood flow. With long term treatment, plasma volume approaches a normal value, but peripheral resistance decreases. Spironolactone, a potassium-sparing diuretic, is often used with thiazides.
Thiazide diuretics are usefull in combination therapy with a variety of other antihypertensive agents including b-blockers and ACE inhibitors. Thiazides are particularly useful in the treatment of black or elderly patients, and in those with chronic renal disease. Thiazides are not effective in patients with inadequate kidney function (creatinine clearance less than 50 mls/min).
Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 % of patients, and hyperglycemia in 10 % of patients. Serum potassium levels should be monitored closely on patients who are predisposed to cardiac arrhythmias (with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart failure) (to prevent development of fatigue, cramps, and arrhythmias) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides. Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia.
The loop diuretics act promptly, even in patients who have poor renal function or who have not responded to thiazides or other diuretics.
b-ADRENOCEPTOR BLOCKING AGENTS – reduce blood pressure primarily by decreasing cardiac output. They may also decrease sympathetic outflow from the CNS and inhibit the release of renin from the kidneys. The prototype b-blocker is propranolol, which acts at both b1 and b2 receptors. Newer agents, such as atenolol, metoprolol, bisoprolol, are selective for b1 receptors. These agents are commonly used in disease states such as asthma, in which propranolol is contraindicated.
The b-blockers are more effective for treating hypertension in white young patients. They are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, glaucoma, and migraine headache.
The b-blockers are orally active. The b-blockers may take several weeks to develop their full effects.
Adverse effects. The b-blockers may cause CNS side effects such as fatigue, lethargy, insomnia, hypotension, and hallucinations; they may decrease libido and cause impotence; drug-induced sexual dysfunction can severly reduce patient compliance. The b-blockers may disturb lipid metabolism, decreasing high-density lipoproteins and increasing plasma triacylglycerol.
Drug withdrawal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation on b-receptors. Patients should be taped off of b-blocker therapy in order to avoid precipitation of arrhythmias. The b-blockers should be avoided in treating patients with asthma, congestive heart failure, and peripheral vascular disease.
Renin, angiotensin, and aldosterone play important roles in at least some people with essential hypertension. Approximately 20% of patients with essential hypertension have inappropriately low and 20% have inappropriately high plasma renin activity. Blood pressure of patients with high-renin hypertension responds well to drugs that interfere with the system, supporting a role for excess renin and angiotensin in this population.
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.
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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.
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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.
GANGLION-BLOCKING AGENTS
Historically, drugs that block activation of postganglionic autonomic neurons by acetylcholine were among the first agents used in the treatment of hypertension. Most such drugs are no longer available clinically because of intolerable toxicities related to their primary action.
Ganglion blockers competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. In addition, these drugs may directly block the nicotinic acetylcholine channel, in the same fashion as neuromuscular nicotinic blockers.
The adverse effects of ganglion blockers are direct extensions of their pharmacologic effects. These effects include both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc). These severe toxicities are the major reason for the abandonment of ganglion blockers for the therapy of hypertension.
ADRENERGIC NEURON–BLOCKING AGENTS
These drugs lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons.
In high enough doses, guanethidine can produce profound sympathoplegia. The resulting high maximal efficacy of this agent made it the mainstay of outpatient therapy of severe hypertension for many years. For the same reason, guanethidine can produce all of the toxicities expected from “pharmacologic sympathectomy,” including marked postural hypotension, diarrhea, and impaired ejaculation. Because of these adverse effects, guanethidine is now rarely used.
Guanethidine is too polar to enter the central nervous system. As a result, this drug has none of the central effects seen with many of the other antihypertensive agents described in this chapter.
Guanadrel is a guanethidine-like drug that is available in the USA. Bethanidine and debrisoquin, antihypertensive agents not available for clinical use in the USA, are similar.
Guanethidine inhibits the release of norepinephrine from sympathetic nerve endings (see Figure 6–4). This effect is probably responsible for most of the sympathoplegia that occurs in patients. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug’s action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine. Because it replaces norepinephrine, the drug causes a gradual depletion of norepinephrine stores in the nerve ending.
Because neuronal uptake is necessary for the hypotensive activity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal (see Chapter 6) block its effects. These include cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine.
Because of guanethidine’s long half-life (5 days), the onset of sympathoplegia is gradual (maximal effect in 1–2 weeks), and sympathoplegia persists for a comparable period after cessation of therapy. The dose should not ordinarily be increased at intervals shorter than 2 weeks.
Therapeutic use of guanethidine is often associated with symptomatic postural hypotension and hypotension following exercise, particularly when the drug is given in high doses. Guanethidine-induced sympathoplegia in men may be associated with delayed or retrograde ejaculation (into the bladder). Guanethidine commonly causes diarrhea, which results from increased gastrointestinal motility due to parasympathetic predominance in controlling the activity of intestinal smooth muscle.
Interactions with other drugs may complicate guanethidine therapy. Sympathomimetic agents, at doses available in over-the-counter cold preparations, can produce hypertension in patients taking guanethidine. Similarly, guanethidine can produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma. When tricyclic antidepressants are administered to patients taking guanethidine, the drug’s antihypertensive effect is attenuated, and severe hypertension may follow.
Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina, was one of the first effective drugs used on a large scale in the treatment of hypertension. At present, it is rarely used owing to its adverse effects.
Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with the vesicular membrane-associated transporter (VMAT). This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal medulla are also depleted of catecholamines, although to a lesser extent than are the vesicles of neurons. Reserpine’s effects on adrenergic vesicles appear irreversible; trace amounts of the drug remain bound to vesicular membranes for many days.
Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms.
At lower doses used for treatment of mild hypertension, reserpine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance.
At the low doses usually administered, reserpine produces little postural hypotension. Most of the unwanted effects of reserpine result from actions on the brain or gastrointestinal tract.
High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0.25 mg/d). Much less frequently, ordinary low doses of reserpine produce extrapyramidal effects resembling Parkinson’s disease, probably as a result of dopamine depletion in the corpus striatum. Although these central effects are uncommon, it should be stressed that they may occur at any time, even after months of uneventful treatment. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears.
Reserpine rather often produces mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. The drug should not be given to patients with a history of peptic ulcer.
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1Creatinine clearance ≥ 30 mL/min. Many of these drugs do require dosage adjustment if creatinine clearance falls below 30 mL/min. 2The active metabolite of benazepril has a half-life of 10 hours. 3The active metabolite of losartan has a half-life of 3–4 hours. |
PRINCIPLES OF THERAPY
Therapeutic Regimens
Once the diagnosis of hypertension is established, a therapeutic regimen must be designed and implemented. The goal of management for most clients is to achieve and maintaiormal blood pressure range (below 140/90 mm Hg). If this goal cannot be achieved, lowering blood pressure to any extent is still considered beneficial in decreasing the incidence of coronary artery disease and stroke.
The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommends a management algorithm in which initial interventions are lifestyle modifications (ie, reduction of weight and sodium intake, regular physical activity, moderate alcohol intake, and no smoking). If these modifications do not produce goal blood pressure or substantial progress toward goal blood pressure within 3 to 6 months, antihypertensive drug therapy should be initiated and the lifestyle modifications should be continued. Although the Committee recommends monotherapy (use of one antihypertensive drug) with a diuretic or a beta blocker because research studies demonstrate reduced morbidity and mortality with these agents, a drug from another classification (eg, ACE inhibitors, ARBs, calcium channel blockers, alpha1-adrenergic blockers) may also be used effectively. Studies also indicate decreased cardiovascular morbidity and mortality with ACE inhibitors.
If the initial drug (and dose) does not produce the desired blood pressure, options for further management include increasing the drug dose, substituting another drug, or adding a second drug from a different group. If the response is still inadequate, a second or third drug may be added, including a diuretic if not previously prescribed. When current management is ineffective, reassess the client’s compliance with lifestyle modifications and drug therapy. In addition, review other factors that may decrease the therapeutic response,such as over-the-counter appetite suppressants, dietary or herbal supplements, or nasal decongestants, which raise blood pressure.
The World Health Organization and the International Society of Hypertension guidelines for management of hypertension include considering age, ethnicity, and concomitant cardiovascular disorders when choosing an antihypertensive drug; starting with a single drug, in the lowest available dose; changing to a drug from a different group, rather than increasing dosage of the first drug or adding a second drug, if the initial drug is ineffective or not well tolerated; and using long-acting drugs (ie, a single dose effective for 24 hours). The guidelines also note that many clients require two or more drugs to achieve adequate blood pressure control. When this is the case, fixed-dose combinations or long-acting agents may be preferred, as they decrease the number of drugs and doses that are required and may increase compliance.
OUTPATIENT THERAPY OF HYPERTENSION
The initial step in treating hypertension may be nonpharmacologic. As discussed previously, sodium restriction may be effective treatment for many patients with mild hypertension. The average American diet contains about 200 mEq of sodium per day. A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day, which can be achieved by not salting food during or after cooking and by avoiding processed foods that contain large amounts of sodium. Eating a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat, and moderation of alcohol intake (no more than two drinks per day) also lower blood pressure.
Weight reduction even without sodium restriction has been shown to normalize blood pressure in up to 75% of overweight patients with mild to moderate hypertension. Regular exercise has been shown in some but not all studies to lower blood pressure in hypertensive patients.
For pharmacologic management of mild hypertension, blood pressure can be normalized in many patients with a single drug. However, most patients with hypertension require two or more antihypertensive medications (see Resistant Hypertension & Polypharmacy below). Thiazide diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers have all been shown to reduce complications of hypertension and may be used for initial drug therapy. There has been concern that diuretics, by adversely affecting the serum lipid profile or impairing glucose tolerance, may add to the risk of coronary disease, thereby offsetting the benefit of blood pressure reduction. However, a recent large clinical trial comparing different classes of antihypertensive mediations for initial therapy found that chlorthalidone (a thiazide diuretic) was as effective as other agents in reducing coronary heart disease death and nonfatal myocardial infarction, and was superior to amlodipine in preventing heart failure and superior to lisinopril in preventing stroke.
The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. For example, drugs that inhibit the renin-angiotensin system are particularly useful in patients with diabetes or evidence of chronic kidney disease with proteinuria. Beta blockers or calcium channel blockers are useful in patients who also have angina; diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers or hydralazine combined with nitrates in patients who also have heart failure; and beta1 blockers in men who have benign prostatic hyperplasia. Race may also affect drug selection: African Americans respond better on average to diuretics and calcium channel blockers than to beta-blockers and ACE inhibitors. Ethnic Chinese patients are more sensitive to the effects of beta-blockers and may require lower doses.
If a single drug does not adequately control blood pressure, drugs with different sites of action can be combined to effectively lower blood pressure while minimizing toxicity (“stepped care”). If a diuretic is not used initially, it is often selected as the second drug. If three drugs are required, combining a diuretic, a sympathoplegic agent or an ACE inhibitor, and a direct vasodilator (eg, hydralazine or a calcium channel blocker) is often effective. In the USA, fixed-dose drug combinations containing a beta-blocker, an ACE inhibitor, or an angiotensin receptor blocker plus a thiazide, and a calcium channel blocker plus an ACE inhibitor are available. Fixed-dose combinations have the drawback of not allowing for titration of individual drug doses but have the advantage of allowing fewer pills to be taken, potentially enhancing compliance.
Assessment of blood pressure during office visits should include measurement of recumbent, sitting, and standing pressures. An attempt should be made to normalize blood pressure in the posture or activity level that is customary for the patient. The recent large Hypertension Optimal Treatment study suggests that the optimal blood pressure end point is 138/83 mm Hg. Lowering blood pressure below this level produces no further benefit. In diabetic patients, however, there is a continued reduction of event rates with progressively lower blood pressures. Systolic hypertension (> 140 mm Hg in the presence of normal diastolic blood pressure) is a strong cardiovascular risk factor in people older than 50 years of age and should be treated.
In addition to noncompliance with medication, causes of failure to respond to drug therapy include excessive sodium intake and inadequate diuretic therapy with excessive blood volume, and drugs such as tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, over-the-counter sympathomimetics, abuse of stimulants (amphetamine or cocaine), or excessive doses of caffeine and oral contraceptives that can interfere with actions of some antihypertensive drugs or directly raise blood pressure.
Resistant Hypertension & Polypharmacy
Monotherapy of hypertension (treatment with a single drug) is desirable because compliance is likely to be better and cost is lower, and because in some cases adverse effects are fewer. However, most patients with hypertension require two or more drugs, preferably acting by different mechanisms (polypharmacy). According to some estimates, up to 40% of patients may respond inadequately even to two agents and are considered to have “resistant hypertension.” Some of these patients have treatable secondary hypertension that has been missed but most do not and three or more drugs are required.
One rationale for polypharmacy in hypertension is that most drugs evoke compensatory regulatory mechanisms for maintaining blood pressure, which may markedly limit their effect. For example, vasodilators such as hydralazine cause a significant decrease in peripheral vascular resistance, but evoke a strong compensatory tachycardia and salt and water retention that is capable of almost completely reversing their effect. The addition of a blocker prevents the tachycardia; addition of a diuretic (eg, hydrochlorothiazide) prevents the salt and water retention. In effect, all three drugs increase the sensitivity of the cardiovascular system to each other’s actions.
A second reason is that some drugs have only modest maximum efficacy but reduction of long-term morbidity mandates their use. Many studies of angiotensin-converting enzyme (ACE) inhibitors report a maximal lowering of blood pressure of less than 10 mm Hg. In patients with stage 2 hypertension (pressure > 160/100 mm Hg), this is inadequate to prevent all the sequelae of hypertension, but ACE inhibitors have important long-term benefits in preventing or reducing renal disease in diabetic persons, and reduction of heart failure.
Finally, the toxicity of some effective drugs prevents their use at maximally effective dosage. The widespread indiscriminate use of beta-blockers has been criticized because several large clinical trials indicate that some members of the group, eg, metoprolol and carvedilol, have a greater benefit than others, eg, atenolol. However, all beta-blockers appear to have similar benefits in reducing mortality after myocardial infarction, so these drugs are particularly indicated in patients with an infarct and hypertension.
In practice, when hypertension does not respond adequately to a regimen of one drug, a second drug from a different class with a different mechanism of action and different pattern of toxicity is added. If the response is still inadequate and compliance is known to be good, a third drug should be added. If three drugs (usually including a diuretic) are inadequate, dietary sodium restriction and an additional drug may be necessary.
Drug Selection
Because many effective antihypertensive drugs are available, choices depend primarily on client characteristics and responses.
Some general guidelines include:
1. Angiotensin-converting enzyme inhibitors may be effective alone in white hypertensive clients or in combination with a diuretic in African-American hypertensive clients. They are also recommended for hypertensive adults with diabetes mellitus and kidney damage. Based on research studies that indicate reduced morbidity and mortality from cardiovascular diseases, these drugs are increasingly being prescribed as a component of a multidrug regimen.
2. Angiotensin II receptor blockers have therapeutic effects similar to those of ACE inhibitors, with fewer adverse effects. They may be used in most clients with
hypertension.
3. Antiadrenergics may be effective in any hypertensive population. Alpha agonists and antagonists are most often used in multidrug regimens for stages 2, 3, or 4 hypertension, because they may cause postural hypotension and syncope. Clonidine is available in a skin patch that is applied once a week and reportedly reduces adverse effects and increases compliance. An additional advantage of transdermal clonidine is that clients who cannot take oral medications can use it. A disadvantage of this system is a delayed onset of effect (2 to 3 days), so other antihypertensive medications must also be given during the first 2 to 3 days of clonidine transdermal therapy. Other disadvantages include cost, a 20% incidence of local skin rash or irritation, and a 2- to 3-day delay in “offset” of action when transdermal therapy is discontinued.
Beta blockers are the drugs of first choice for clients younger than 50 years of age with high-renin hypertension, tachycardia, angina pectoris, myocardial infarction, or left ventricular hypertrophy. Most beta blockers are approved for use in hypertension and are probably equally effective. However, the cardioselective drugs are preferred for hypertensive clients who also have asthma, peripheral vascular disease, or diabetes mellitus.
4. Calcium channel blockers may be used for monotherapy or in combination with other drugs. They may be especially useful for hypertensive clients who also have angina pectoris or other cardiovascular disorders. Note that sustained-release forms of nifedipine, diltiazem, and verapamil and other long-acting drugs (eg, amlodipine, felodipine) are recommended.
5. Diuretics are preferred for initial therapy in older clients and African-American hypertensive clients. They should be included in any multidrug regimen for these and other populations. Thiazide and related diuretics are equally effective. Hydrochlorothiazide is commonly used.
6. Vasodilators are used in combination with a beta blocker and a diuretic to prevent hypotension-induced compensatory mechanisms (stimulation of the SNS and fluid retention) that raise blood pressure.
7. Combination products usually combine two drugs with different mechanisms of action (eg, a thiazide or related diuretic plus a beta blocker or other antiadrenergic, an ACE inhibitor, an ARB, or a calcium channel blocker). Most are available in various formulations. Potential advantages of fixed-dose combination products include comparable or improved effectiveness, smaller doses of individual components, fewer adverse effects, improved compliance, and possibly decreased costs.
Dosage Factors
1. Dosage of antihypertensive drugs must be titrated according to individual response. Dosage should be started at minimal levels and increased if necessary. Lower doses decrease the incidence and severity of adverse effects.
2. For many clients, it may be more beneficial to change drugs or add another drug rather than increase dosage. Two or three drugs in small doses may be more effective and cause fewer adverse effects than a single drug in large doses. When two or more drugs are given, the dose of each drug may need to be reduced.
Duration of Therapy
Clients who maintain control of their blood pressure for 1 year or so may be candidates for reduced dosages or reduced numbers of drugs. Any such adjustments must be gradual and carefully supervised by a health care provider. Expected benefits include fewer adverse effects and greater compliance.
Sodium Restriction
Therapeutic regimens for hypertension include sodium restriction. Severe restrictions usually are not acceptable to clients; however, moderate restrictions (4 to 6 g of salt a day) are beneficial and more easily implemented. Avoiding heavily salted foods (eg, cured meats, sandwich meats, pretzels, and potato chips) and not adding salt to food at the table can achieve this.
Research and clinical observations indicate the following:
1. Sodium restriction alone reduces blood pressure.
2. Sodium restriction potentiates the antihypertensive actions of diuretics and other antihypertensive drugs.
Conversely, excessive sodium intake decreases the antihypertensive actions of all antihypertensive drugs. Clients with unrestricted salt intake who are taking thiazides may lose excessive potassium and become hypokalemic.
3. Sodium restriction may decrease dosage requirements of antihypertensive drugs, thereby decreasing the incidence and severity of adverse effects.
HYPERTENSIVE EMERGENCY – is a life-threatening situation in which the diastolic blood pressure is either over 150 mm Hg (with systolic blood pressure greater than 210 mm Hg) in an otherwise healthy person, or 130 mm Hg in an individual with preexisting complications, such as encephalopathy, cerebral hemorrhage, left ventricular failure, or aortic stenosis. The therapeutic goal is to rapidly reduce blood pressure.
Nitroprusside is administered intravenously, and causes prompt vasodilation, with reflex tachycardia. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. It can reduce cardiac preload. Nitroprusside is metabolized rapidly and requires continuous infusion to maintain its hypotensive action. Nitroprusside is poisonous if given orally because of its hydrolysis to cyanide.
Diazoxide is a direct-acting arteriolar vasodilator. It has vascular effects like those of hydralazine. Foe patients with coronary insufficiency, diazoxide is administered intravenously with a b-blocker, which diminishes reflex activation of the heart. Diazoxide is useful in the treatment of hypertensive emergencies, hypertensive encephalopathy, and eclampsia. Excessive hypotension is the most serious toxicity.
Labetalol is the both an a– and b-blocker that has been successfully used on hypertensive emergencies. Labetalol does not cause the reflex tachycardia that may be associated with diazoxide. Labetalol carries the contraindications of a nonselective b-blocker.
|
Drug |
Dose |
Onset |
Side effects |
|
Sodium nitroprussid |
0,5-10 mcg/kg/min (dropply) |
immediately |
nausea, vomiting, fibrillation of muscles, sweating |
|
Nitroglyceri-num |
5-10 mcg/kg (dropply) |
2-5 min |
tachicardia, flushing, headache, vomiting, |
|
Diazoxidum |
50-100 mg (quickly) 300 mg (during 10 min) |
2-4 min |
nausea, vomiting,, hypotension, tachicardia, flushing, redness of skin, chest pain |
|
Apressinum |
10-20 mg |
10 min |
flushing, redness of skin, headache, vomiting |
|
Furosemidum |
20-60-100 mg during 10-15 sec |
2-3 min |
hypotension, fatigue |
|
Clophelinum |
0,5-1 ml 0,01 % solution (in 15-20 ml 0,9 % solution NaCI slowly) |
15-20 min |
somnolence |
|
Anaprilinum |
5 ml 0,1 % solution (in 20 ml 0,9 % NaCI solution slowly) |
20-30 min |
bradicardia |
|
Magnesium sulfas |
5-10-20 ml 25 % solution (i. v. very slowly or dropply) |
15-20 min |
redness of skin |
|
Labetololum |
20-80 mg (slowly – 10 min) or 2 mg/kg (dropply); the whole dose – 50-300 mg |
5-10 min |
nausea, vomiting,, hypotension, dizzeness |
ANTIHYPOTENSIVE DRUGS
Shock is a clinical syndrome characterized by decreased blood supply to body tissues. Clinical symptoms depend on the degree of impaired perfusion of vital organs (eg, brain, heart, and kidneys). Common signs and symptoms include oliguria, heart failure, mental confusion, cool extremities, and coma. Most, but not all, people in shock are hypotensive.
In a previously hypertensive person, shock may be present if a drop in blood pressure of greater than 50 mm Hg has occurred, even if current blood pressure readings are “normal.” An additional consequence of inadequate blood flow to tissues is that cells change from aerobic (oxygen-based) to anaerobic metabolism. Lactic acid produced by anaerobic metabolism leads to generalized metabolic acidosis and eventually to organ failure and death if blood flow is not promptly restored.
Types of Shock
There are three general categories of shock that are based on the circulatory mechanisms involved. These mechanisms are intravascular volume, the ability of the heart to pump, and vascular tone.
Hypovolemic shock involves a loss of intravascular fluid volume that may be due to actual blood loss or relative loss from fluid shifts within the body.
Cardiogenic shock, also called pump failure, occurs when the myocardium has lost its ability to contract efficiently and maintain an adequate cardiac output.
Distributive or vasogenic shock is characterized by severe, generalized vasodilation, which results in severe hypotension and impairment of blood flow. Distributive shock is further divided into anaphylactic, neurogenic, and septic shock:
• Anaphylactic shock results from a hypersensitivity (allergic) reaction to drugs or other substances.
• Neurogenic shock results from inadequate sympathetic nervous system (SNS) stimulation. The SNS normally maintains sufficient vascular tone (ie, a small amount of vasoconstriction) to support adequate blood circulation. Neurogenic shock may occur with depression of the vasomotor center in the brain or decreased sympathetic outflow to blood vessels.
• Septic shock can result from almost any organism that gains access to the bloodstream but is most often associated with gram-negative and gram-positive bacterial infections and fungi. It is important to know the etiology of shock because management varies among the types.
ANTISHOCK DRUGS
Drugs used in the management of shock are primarily the adrenergic drugs. In this chapter, the drugs are discussed only in relation to their use in hypotension and shock. In these conditions, drugs with alpha-adrenergic activity (eg, norepinephrine, phenylephrine) are used to increase peripheral vascular resistance and raise blood pressure. Drugs with beta-adrenergic activity (eg, dobutamine, isoproterenol) are used to increase myocardial contractility and heart rate, which in turn raises blood pressure. Some drugs have both alpha- and beta-adrenergic activity (eg, dopamine, epinephrine). In many cases, a combination of drugs is used, depending on the type of shock and the client’s response to treatment. In an emergency, the drugs may be used to maintain adequate perfusion of vital organs until sufficient fluid volume is replaced and circulation is restored.
Adrenergic drugs with beta activity may be relatively contraindicated in shock states precipitated or complicated by cardiac dysrhythmias. Beta-stimulating drugs also should be used cautiously in cardiogenic shock after myocardial infarction because increased contractility and heart rate will increase myocardial oxygen consumption and extend the area of infarction. Individual drugs are described in the following section.
INDIVIDUAL DRUGS
Dopamine is a naturally occurring catecholamine that functions as a neurotransmitter. Dopamine exerts its actions by stimulating alpha, beta, or dopaminergic receptors, depending on the dose being used. In addition, dopamine acts indirectly by releasing norepinephrine from sympathetic nerve endings and the adrenal glands. Peripheral dopamine receptors are located in splanchnic and renal vascular beds. At low doses (0.5 to 10 mcg/kg/min), dopamine selectively stimulatesdopaminergic receptors that may increase renal blood flow and glomerular filtration rate (GFR). It has long been accepted that stimulation of dopamine receptors by low doses of exogenous dopamine produces vasodilation in the renal circulation and increases urine output. More recent studies indicate that low-dose dopamine enhances renal function only when cardiac function is improved. At doses greater than 3 mcg/kg/min, dopamine binds to beta and alpha receptors and the selectivity of dopaminergic receptors is lost beyond 10 mcg/kg/min. At doses that stimulate beta receptors (3 to 20 mcg/kg/min), there is an increase in heart rate, myocardial contractility, and blood pressure. At the highest doses (20 to 50 mcg/kg/min), beta activity remains, but increasing alpha stimulation (vasoconstriction) may overcome its actions.
Dopamine is useful in hypovolemic and cardiogenic shock. Adequate fluid therapy is necessary for the maximal pressor effect of dopamine. Acidosis decreases the effectiveness of dopamine.
Dobutamine is a synthetic catecholamine developed to provide less vascular activity than dopamine. It acts mainly on beta1 receptors in the heart to increase the force of myocardial contraction with a minimal increase in heart rate. Dobutamine also may increase blood pressure with large doses. It is less likely to cause tachycardia, dysrhythmias, and increased myocardial oxygen demand than dopamine and isoproterenol. It is most useful in cases of shock that require increased cardiac output without the need for blood pressure support. It is recommended for short-term use only. It may be used with dopamine to augment the beta1 activity that is sometimes overridden by alpha effects when dopamine is used alone at doses greater than 10 mcg/kg/min.
Dobutamine has a short plasma half-life and therefore must be administered by continuous IV infusion. A loading dose is not required because the drug has a rapid onset of action and reaches steady state within approximately 10 minutes after the infusion is begun. It is rapidly metabolized to inactive metabolites.
Epinephrine is a naturally occurring catecholamine produced by the adrenal glands. At low doses, epinephrine stimulates beta receptors, which increases cardiac output by increasing the rate and force of myocardial contractility. It also causes bronchodilation. Larger doses act on alpha receptors to increase blood pressure.
Epinephrine is the drug of choice for management of anaphylactic shock because of its rapid onset of action and antiallergic effects. It prevents the release of histamine and other mediators that cause symptoms of anaphylaxis, thereby reversing vasodilation and bronchoconstriction. In early management of anaphylaxis, it may be given subcutaneously to produce therapeutic effects within 5 to 10 minutes, with peak activity in approximately 20 minutes.
Epinephrine is also used to manage other kinds of shock and is usually given by continuous IV infusion. However, bolus doses may be given in emergencies, such as cardiac arrest. It may produce excessive cardiac stimulation, ventricular dysrhythmias, and reduced renal blood flow. Epinephrine has an elimination half-life of about 2 minutes and is rapidly inactivated to metabolites, which are then excreted by the kidneys.
Isoproterenol is a synthetic catecholamine that acts exclusively on beta receptors to increase heart rate, myocardial contractility, and systolic blood pressure. However, it also stimulates vascular beta2 receptors, which causes vasodilation, and may decrease diastolic blood pressure. For this reason, isoproterenol has limited usefulness as a pressor agent. It also may increase myocardial oxygen consumption and decrease coronary artery blood flow, which in turn causes myocardial ischemia. Cardiac dysrhythmias may result from excessive beta stimulation. Because of these limitations, use of isoproterenol is limited to shock associated with slow heart rates and myocardial depression.
Metaraminol is used mainly for hypotension associated with spinal anesthesia. It acts indirectly by releasing norepinephrine from sympathetic nerve endings. Thus, its vasoconstrictive actions are similar to those of norepinephrine, except that metaraminol is less potent and has a longer duration of action.
Milrinone is used to manage cardiogenic shock in combination with other inotropic agents or vasopressors. It increases cardiac output and decreases systemic vascular resistance without significantly increasing heart rate or myocardial oxygen consumption. The increased cardiac output improves renal blood flow, which then leads to increased urine output, decreased circulating blood volume, and decreased cardiac workload.
Norepinephrine (Levophed) is a pharmaceutical preparation of the naturally occurring catecholamine norepinephrine. It stimulates alpha-adrenergic receptors and thus increases blood pressure primarily by vasoconstriction. It also stimulates beta1 receptors and therefore increases heart rate, force of myocardial contraction, and coronary artery blood flow. It is useful in cardiogenic and septic shock, but reduced renal blood flow limits its prolonged use. Norepinephrine is used mainly with clients who are unresponsive to dopamine or dobutamine. As with all drugs used to manage shock, blood pressure should be monitored frequently during infusion.
Phenylephrine (Neo-Synephrine) is an adrenergic drug that stimulates alpha-adrenergic receptors. As a result, it constricts arterioles and raises systolic and diastolic blood pressures. Phenylephrine resembles epinephrine but has fewer cardiac effects and a longer duration of action. Reduction of renal and mesenteric blood flow limit prolonged use.
Choice of Drug
The choice of drug depends primarily on the pathophysiology involved. For cardiogenic shock and decreased cardiac output, dopamine or dobutamine is given. With severe heart failure characterized by decreased cardiac output and high peripheral vascular resistance, vasodilator drugs (eg, nitroprusside, nitroglycerin) may be given along with the cardiotonic drug. The combination increases cardiac output and decreases cardiac workload by decreasing preload and afterload. However, vasodilators should not be used alone because of the risk of severe hypotension and further compromising tissue perfusion.
Milrinone may be given when other drugs fail. For distributive shock characterized by severe vasodilation and decreased peripheral vascular resistance, a vasoconstrictor or vasopressor drug, such as norepinephrine, is the drug of first choice. Drug dosage must be carefully titrated to avoid excessive vasoconstriction and hypertension, which causes impairment rather than improvement in tissue perfusion.
Guidelines for Management of Hypotension and Shock
• Vasopressor drugs are less effective in the presence of inadequate blood volume, electrolyte abnormalities, and acidosis. These conditions also must be treated if present. In addition, normalizing the blood pH and body temperature facilitates the release of oxygen from hemoglobin to the cells.
• Minimal effective doses of adrenergic drugs are recommended because of their extreme vasoconstrictive effects that can produce lactic acidosis at the cell level and create metabolic acidosis. Because catecholamine drugs have short half-lives, varying the flow rate of IV infusions can easily control dosage. Dosage and flow rate usually are titrated to maintain a low-normal blood pressure. Such titration depends on frequent and accurate blood pressure measurements.
• Septic shock due to bacterial infection requires appropriate antibiotic therapy in addition to other management measures. If an abscess is the source of infection, it must be surgically drained.
• Hypovolemic shock is most effectively managed by IV fluids that replace the type of fluid lost; that is, blood loss should be replaced with whole blood; gastrointestinal losses should be replaced with solutions containing electrolytes (eg, Ringer’s lactate or sodium chloride solutions with added potassium chloride).
· Cardiogenic shock may be complicated by pulmonary congestion, for which diuretic drugs are indicated and IV fluids are contraindicated (except to maintain a patent IV line).
· Anaphylactic shock is often managed by nonadrenergic drugs as well as epinephrine. For example, the histamine-induced cardiovascular symptoms (eg, vasodilation and increased capillary permeability) are thought to be mediated through both types of histamine receptors. Thus, management may include a histamine- 1 receptor blocker (eg, diphenhydramine 1 mg/ kg IV) and a histamine2 receptor blocker (eg, cimetidine 4 mg/kg IV), given over at least 5 minutes. In addition, IV corticosteroids are often given, such as methylprednisolone (20 to 100 mg) or hydrocortisone (100 to 500 mg). Doses may need to be repeated every 2 to 4 hours. Corticosteroids increase tissue responsiveness to adrenergic drugs in approximately 2 hours but do not produce anti-inflammatory effects for several hours.
Use in Children
Little information is available about adrenergic drugs for the management of hypotension and shock in children. Children who lose up to one fourth of their circulating blood volume may produce minimal changes in arterial blood pressure and a relatively low heart rate. In general, management is the same as for adults, with drug dosages adjusted for weight.
Use in Older Adults
Older adults often have disorders such as atherosclerosis, peripheral vascular disease, and diabetes mellitus and may not demonstrate common symptoms of volume depletion (eg, thirst, skin turgor changes). Also, when adrenergic drugs are given, their vasoconstricting effects may decrease blood flow and increase risks of tissue ischemia and thrombosis.
Careful monitoring of vital signs, skin color and temperature, urine output, and mental status is essential.
Use in Renal Impairment
Although adrenergic drugs may be lifesaving, they can reduce renal blood flow and cause renal failure because of their vasoconstrictive effects. Renal impairment may occur in clients with previously normal renal function and may be worsened in clients whose renal function is already impaired.
Low-dose dopamine is commonly used to increase renal perfusion in oliguric clients, but the effectiveness of this practice is being questioned. In men with benign prostatic hypertrophy, oliguric renal failure may need to be differentiated from post-renal failure (urinary retention) because some adrenergic drugs (eg, epinephrine, norepinephrine, phenylephrine) cause urinary retention.
Most adrenergic drugs are metabolized in the liver and the metabolites are excreted in the urine. However, little accumulation of the drugs or metabolites is likely because the drugs have short half-lives.
Use in Hepatic Impairment
Catecholamine drugs are metabolized by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). MAO is widely distributed in most body tissues, whereas COMT is located mainly in the liver. Thus, the drugs are eliminated mainly by liver metabolism and must be used cautiously in clients with impaired liver function. Clients should be monitored closely and drug dosage should be adjusted as symptoms warrant. However, the half-life of most adrenergic drugs is very brief, and this decreases the chances of drug accumulation in hepatically impaired clients.
Use in Critical Illness
The adrenergic catecholamines (eg, dopamine, dobutamine, epinephrine, norepinephrine) are widely used in clients witha low cardiac output that persists despite adequate fluid replacement and correction of electrolyte imbalance. By improving circulation, the drugs also help to prevent tissue injury from ischemia (eg, renal failure).
Although the drugs may be used initially in almost any setting, most clients with hypotension and shock are managed in critical care units. Dobutamine and dopamine are usually the cardiotonic agents of choice in critically ill clients. Dopamine varies in clearance rate in adult and pediatric clients. However, this variance may result from the use of non–steadystate plasma concentrations in calculating the clearance rate. When a dopamine IV infusion is started, it may take 1 to 2 hours to achieve a steady-state plasma level. Relatively large doses of dopamine are given for cardiotonic and vasoconstrictive effects.
Epinephrine and norepinephrine are also widely used in critically ill clients. Recommended infusion rates in critically ill clients vary from 0.01 to 0.15 mcg/kg/min for epinephrine and from 0.06 to 0.15 mcg/kg/min for norepinephrine. All clients receiving drugs for management of hypotension and shock should be closely monitored regarding drug dosage,vital signs, relevant laboratory test results, and other indicators of clinical status. Continuous invasive hemodynamic monitoring with an arterial catheter and a pulmonary artery catheter may be indicated to titrate drug dosage and monitor the response to drug therapy. Close monitoring of the critically ill is essential as these clients often have multiple organ impairments and are clinically unstable.
SUMMARY: DRUGS USED IN HYPERTENSION
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References
|
1. ACE Inhibitors in Diabetic Nephropathy Trialist Group: Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001;134:370. |
|
2. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes of high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blockers vs diuretic: The antihypertensive and lipid-lowering treatment to prevent heart attack trial. JAMA 2002;288:2981. |
|
3. Appel LJ et al: Effects of comprehensive lifestyle modification on blood pressure control: Main results of the PREMIER clinical trial. JAMA 2003;289:2083. [PMID: 12709466] |
|
4. August P: Initial treatment of hypertension. N Engl J Med 2003;348:610. [PMID: 12584370] |
|
5. Aronson S et al: The ECLIPSE trials: Comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension in cardiac surgery patients. Anesth Alang 2008;107:1110. [PMID: 18806012] |
|
6. Bangalore S et al: Beta-blockers for primary prevention of heart failure in patients with hypertension: Insights from a meta-analysis. J Am Coll Cardiol 2008;52:1062. [PMID: 18848139] |
|
7. Calhoun DA et al: Resistant hypertension: Diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation 2008;117:e510. |
|
8. Chobanian AV et al: The Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003;289:2560. [PMID: 12748199] |
|
9. Garg J, Messerli AW, Bakris GL: Evaluation and treatment of patients with systemic hypertension. Circulation 2002;105:2458. [PMID: 12034648] |
|
10. Heran BS et al: Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension. Cochrane Database Syst Rev 2008;(4):CD003823. |
|
11. Kaplan NM: Management of hypertension in patients with type 2 diabetes mellitus: Guidelines based on current evidence. Ann Intern Med 2001;135:1079. [PMID: 11747387] |
|
12. Khan NA et al: The 2008 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2—therapy. Can J Cardiol 2008;24:465. [PMID: 18548143] |
|
13. Jamerson K et al: Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417. [PMID: 19052124] |
|
14. Mark PE and Varon J: Hypertensive Crisis. Challenges and Management. Chest 2007;131:1949. |
|
15. Moser M, Setaro JF: Resistant or difficult-to-control hypertension. N Engl J Med 2006;355:385. [PMID: 16870917] |
|
16. Psaty BM et al: Health outcomes associated with various antihypertensive therapies used as first-line agents: A network meta-analysis. JAMA 2003;289:2534. [PMID: 12759325] |
|
17. Ram CV: Angiotensin receptor blockers: Current status and future prospects. Am J Med 2008;121:656. [PMID: 18691475] |
|
18. Verdecchia P et al: Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension 2005;46:386. [PMID: 16009786] |
|
19. Vermes E et al: Enalapril reduces the incidence of diabetes in patients with chronic heart failure: Insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003;107:1291. [PMID: 12628950] |
|
20. Vollmer WM et al: Effects of diet and sodium intake on blood pressure: Subgroup analysis of the DASH-Sodium trial. Ann Intern Med 2001;135:1019. [PMID: 11747380] |
|
21. Wang TJ, Ramachandran SV: Epidemiology of uncontrolled hypertension in the United States. Circulation 2005;112:1651. [PMID: 16157784] |
|
22. Wing LMH et al: A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583. [PMID: 12584366] |
|
23. Wright JT Jr et al: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. Results from AASK Trial. JAMA 2002;288:2421. [PMID: 12435255] |
