Antihypertensives
I. Overview
Hypertension is defined as either a sustained systolic blood pressure (SBP) of greater than 140 mm Hg or a sustained diastolic blood pressure (DBP) of greater than 90 mm Hg. chronic hypertension - aeither systolic or diastolic - can lead to cerebrovascular accidents (strokes), congestive heart failure, myocardial infarction, and renal damage. The categories are normal , prehypertension (SBP/DBP, 120,13980,89), stage 1 hypertension (SBP/DBP, 140159/90,m 99), and stage 2 hypertension (SBP/DBP 160,100).
II. Etiology of Hypertension
Although hypertension may occur secondary to other disease processes, more than 90 percent of patients have essential hypertension, a disorder of unknown origin affecting the blood pressure regulating mechanism.
III. Mechanisms for Controlling Blood Pressure
Arterial blood pressure is directly proportional to the product of the cardiac output and the peripheral vascular resistance . Cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms: the baroreflexes, which are mediated by the sympathetic nervous system, and the renin-angiotensin-aldosterone system
IV. Treatment Strategies
The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. B-blocker is usually added if the initial drug was a diuretic, or a diuretic is usually 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. However, angiotensin “converting enzyme inhibitors, angiotensin “AT1 receptor blockers, and calcium-channel blockers can also be used to initiate therapy.
V. Diuretics
A .Thiazide diuretics
1-Actions: Thiazide diuretics, such as hydrochlorothiazide lower blood pressure initially by increasing sodium and water excretion.With long-term treatment, plasma volume approaches a normal value, but peripheral resistance decreases.
2-Therapeutic uses: Thiazide diuretics are particularly useful in the treatment of black or elderly patients. They are not effective in
patients with inadequate kidney function (creatinine clearance, /<50 mL/min).
3-Pharmacokinetics: All thiazides are ligands for the organic acid secretory system of the nephron, and as such, they may compete with uric acid for elimination.
4-Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 percent of patients and hyperglycemia in 10 percent of patients. Hypomagnesemia may also occur.
B. Loop diuretics
The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics. Loop diuretics cause decreased renal vascular resistance and increased renal blood flow. \[Note:Loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease it[.
C. Potassium-sparing diuretics.
Amiloride and triamterene (inhibitors of epithelial sodium transport at the late distal and collecting ducts) as well as spironolactone and eplerenone none (aldosterone-receptor antagonists) reduce potassium loss in the urine.
VI. B-Adrenoceptor Blocking Agents
A. Actions
The B-blockers reduce blood pressure primarily by decreasing cardiac output They may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin from the kidneys.
B. Therapeutic uses
1-Subsets of the hypertensive population: The B-blockers are more effective for treating hypertension in white than in black patients and in young compared to elderly patients. \[Note: Conditions that discourage the use of B-blockers (for example, severe chronic obstructive lung disease, chronic congestive heart failure, or severe symptomatic occlusive peripheral vascular disease)
2-Hypertensive patients with concomitant diseases :The B-blockers are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, and migraine headache.
C. Pharmacokinetics
The B-blockers are orally active. Propranolol undergoes extensive and highly variable first-pass metabolism.
D. Adverse effects
1-Common effects: The B-blockers may cause bradycardia and CNS side effects such as fatigue, lethargy , insomnia, and hallucinations; these drugs can also cause hypotension The B-blockers may decrease libido and cause impotence.
2-Alterations in serum lipid patterns: The <00FF>²-blockers may disturb lipid metabolism, decreasing high-density lipoprotein cholesterol and increasing plasma triacylglycerol.
3-Drug withdrawal: Abrupt withdrawal may induce angina, myocardial infarction, or even sudden death in patients with ischemic heart disease. Therefore, the dose of these drugs must be tapered over 2 to 3 weeks in patients with hypertension and ischemic heart disease.
VII. ACE Inhibitors
The ACE inhibitors, such as enalapril or lisinopril are recommended when the preferred first-line agents (diuretics or B-blockers) are contraindicated or ineffective..
A. Actions
The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexively increasing cardiac output, rate, or contractility. These drugs block the ACE that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II The converting enzyme is also responsible for the breakdown of radykinin. ACE inhibitors decrease angiotensin II and increase bradykinin levels. 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 decrease the secretion of aldosterone, resulting in decreased sodium and water retention.
B. Therapeutic uses
ACE inhibitors are most effective in hypertensive patients who are white and young . ACE inhibitors slow the progression of diabetic nephropathy and decrease albuminuria. ACE inhibitors are also effective in the management of patients with chronic heart failure. ACE inhibitors are a standard in the care of a patient following a myocardial infarction.
C. Adverse effects
Common side effects include dry cough, rash, fever, altered taste, hypotension and hyperkalemia . Angioedema is a rare but potentially life-threatening reaction Because of the risk of angioedema and first-dose syncope, ACE inhibitors may be first administered in the physician's office with close observation. Reversible renal failure can occur in patients with severe bilateral renal artery stenosis. ACE inhibitors are fetotoxic and should not be used by women who are pregnant
.
VIII. Angiotensin II- Receptor Antagonists
The angiotensin II–receptor blockers (ARBs) are alternatives to the ACE inhibitors. These drugs block the AT1 receptors. Losartan is the prototypic ARB; currently, there are six additional ARBs. Their pharmacologic effects are similar to those of ACE inhibitors in that they produce arteriolar and venous dilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention. ARBs do not increase bradykinin levels. ARBs decrease the nephrotoxicity of diabetes, making them an attractive therapy in hypertensive diabetics. Their adverse effects are similar to those of ACE inhibitors , although the risks of cough and angioedema are significantly decreased. ARBs are also fetotoxic
IX. Renin Inhibitors
Aliskiren directly inhibits renin and, thus, acts earlier in the renin-angiotensin-aldosterone system. Aliskiren can cause diarrhea, especially at the higher doses. Aliskiren can also cause cough and angioedema but probably less often than ACE inhibitors. The drug is contraindicated during pregnancy. Hyperkalemia was significantly more common in patients who received both valsartan and aliskiren.
X. Calcium-Channel Blockers
They are effective in treating hypertension in patients with angina or diabetes. cardiac stimulation.
A. Classes of calcium-channel blockers
1- Diphenylalkylamines: Verapamil is the least selective of any calcium-channel blocker and has significant effects on both cardiac and vascular smooth muscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and migraine headache.
2- Benzothiazepines: Like verapamil, diltiazem affects both cardiac and vascular smooth muscle cells; however, it has a less pronounced negative inotropic effect on the heart compared to that of verapamil. Diltiazem has a favorable side-effect profile.
3- Dihydropyridines: The first-generation nifedipine and five second-generation agents for treating cardiovascular disease: amlodipine,felodipine isradipine nicardipine, and nisoldipine All dihydropyridineshave a much greater affinity for vascular calcium channels than for calcium channels in the heart. They are therefore particularly attractive in treating hypertension. Some of the newer agents, such as amlodipine and nicardipine, have the advantage that they show little interaction with other cardiovascular drugs, such as digoxin or warfarin.
B. Actions
Calcium enters muscle cells through special voltage-sensitive calcium channels. This triggers release of calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level of calcium. Calcium-channel antagonists block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles.
C. Therapeutic uses
Calcium-channel blockers have an intrinsic natriuretic effect. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease .
D. Pharmacokinetics
Most of these agents have short half-lives (3-8 hours) following an oral dose. Sustained-release preparations are available. Amlodipine has a very long half-life and does not required a sustained-release formulation.
E. Adverse effects
Constipation occurs in 10 percent of patients treated with verapamil . Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure are more frequent with dihydropyridines. Verapamil should be avoided in patients with congestive heart failure or with atrioventricular block due to its negative inotropic (force of cardiac muscle contraction) and dromotropic (velocity of conduction) effects.
XI. a-Adrenoceptor Blocking Agents
Prazosin , doxazosin , and terazosin produce a competitive block of a1-adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing relaxation of both arterial and venous smooth muscle. 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. Reflex tachycardia and first-dose syncope are almost universal adverse effects. Because of the side-effect profile, development of tolerance, and the advent of safer antihypertensives, a1-blockers are seldom used in the treatment of hypertension.
Tamsulosin , an a 1 a1-blocker with greater selectivity for prostate muscle, has been used in the treatment of prostate hyperplasia.
XII. a-B- Adrenoceptor Blocking Agents
Labetalol and carvedilol block both a1 - and b 1 - and B2 - receptors. Carvedilol, although an effective antihypertensive, is mainly used in the treatment of heart failure. Carvedilol has been shown to reduce mortality associated with heart failure.
XIII. Centrally Acting Adrenergic Drugs
A. Clonidine
This a2 -agonist diminishes central adrenergic outflow. Clonidine is used primarily for the treatment of hypertension that has not responded adequately to treatment with two or more drugs. Clonidine, is useful in the treatment of hypertension complicated by renal disease. Because it may cause sodium and water retention, clonidine may be administered in combination with a diuretic. Adverse effects are generally mild, but the drug can produce sedation and drying of the nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine . The drug should therefore be withdrawn slowly .
B. Methyldopa
This Alpha-2 -agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS. This leads to reduced total peripheral resistance and a decreased blood pressure. methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common side effects of methyldopa are sedation and drowsiness. It has been used in hypertensive pregnant patients.
XIV. Vasodilators
A. Hydralazine
This drug causes direct vasodilation, acting primarily on arteries and arterioles. This results in a decreased peripheral resistance, which in turn prompts a reflex elevation in heart rate and cardiac output. Hydralazine is used to treat moderately severe hypertension. It is almost always administered in combination with a I²-blocker, such as propranolol (to balance the reflex tachycardia), and a diuretic (to decrease sodium retention). Hydralazine monotherapy is an accepted method of controlling blood pressure in pregnancy-induced hypertension. Adverse effects of Hydralazine therapy include headache, tachycardia, 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.
B. Minoxidil
This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). Minoxidil is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs. Reflex tachycardia and fluid retention may be severe and require the concomitant use of a loop diuretic and a I²-blocker. Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart failure.[Note: Minoxidil treatment also causes hypertrichosis (the growth of body hair). This drug is now used topically to treat male pattern baldness.]
XV. Hypertensive Emergency
Hypertensive emergency is a rare but life-threatening situation in which the DBP is either >150 mm Hg (with SBP >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.
A. Sodium nitroprusside
Nitroprusside is administered intravenously and causes prompt vasodilation with reflex tachycardia. It is capable of reducing blood pressure in all patients regardless of the cause of hypertension. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. Nitroprusside is metabolized rapidly (half-life of minutes) and requires continuous infusion to maintain its hypotensive action.
Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production. Although cyanide toxicity is rare, it can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys. Nitroprusside is light sensitive, and when in solution, it should be protected from light.
B. Labetalol
Labetalol is both an a- and B-blocker and is given as an intravenous bolus or infusion in a nonselective I²-blocker.
C. Fenoldopam
Fenoldopam is a peripheral dopamine-1 receptor agonist that is given as an intravenous infusion. Unlike other parenteral antihypertensive agents, fenoldopam maintains or increases renal perfusion while it lowers blood pressure. Fenoldopam can be safely used in all hypertensive emergencies and may be particularly beneficial in patients with renal insufficiency. The drug is contraindicated in patients with glaucoma.
D. Nicardipine
Nicardipine , a calcium-channel blocker, can be given as an intravenous infusion. The initial dose is 5 mg/h and can be increased to a maximum of 15 mg/h. The major limitation of
Nicardipine in treating hypertensive emergency is its long half-time (approximately 8 hours), which precludes rapid titration.
I. Overview
Hypertension is defined as either a sustained systolic blood pressure (SBP) of greater than 140 mm Hg or a sustained diastolic blood pressure (DBP) of greater than 90 mm Hg. chronic hypertension - aeither systolic or diastolic - can lead to cerebrovascular accidents (strokes), congestive heart failure, myocardial infarction, and renal damage. The categories are normal , prehypertension (SBP/DBP, 120,13980,89), stage 1 hypertension (SBP/DBP, 140159/90,m 99), and stage 2 hypertension (SBP/DBP 160,100).
II. Etiology of Hypertension
Although hypertension may occur secondary to other disease processes, more than 90 percent of patients have essential hypertension, a disorder of unknown origin affecting the blood pressure regulating mechanism.
III. Mechanisms for Controlling Blood Pressure
Arterial blood pressure is directly proportional to the product of the cardiac output and the peripheral vascular resistance . Cardiac output and peripheral resistance are controlled mainly by two overlapping control mechanisms: the baroreflexes, which are mediated by the sympathetic nervous system, and the renin-angiotensin-aldosterone system
IV. Treatment Strategies
The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality. B-blocker is usually added if the initial drug was a diuretic, or a diuretic is usually 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. However, angiotensin “converting enzyme inhibitors, angiotensin “AT1 receptor blockers, and calcium-channel blockers can also be used to initiate therapy.
V. Diuretics
A .Thiazide diuretics
1-Actions: Thiazide diuretics, such as hydrochlorothiazide lower blood pressure initially by increasing sodium and water excretion.With long-term treatment, plasma volume approaches a normal value, but peripheral resistance decreases.
2-Therapeutic uses: Thiazide diuretics are particularly useful in the treatment of black or elderly patients. They are not effective in
patients with inadequate kidney function (creatinine clearance, /<50 mL/min).
3-Pharmacokinetics: All thiazides are ligands for the organic acid secretory system of the nephron, and as such, they may compete with uric acid for elimination.
4-Adverse effects: Thiazide diuretics induce hypokalemia and hyperuricemia in 70 percent of patients and hyperglycemia in 10 percent of patients. Hypomagnesemia may also occur.
B. Loop diuretics
The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics. Loop diuretics cause decreased renal vascular resistance and increased renal blood flow. \[Note:Loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease it[.
C. Potassium-sparing diuretics.
Amiloride and triamterene (inhibitors of epithelial sodium transport at the late distal and collecting ducts) as well as spironolactone and eplerenone none (aldosterone-receptor antagonists) reduce potassium loss in the urine.
VI. B-Adrenoceptor Blocking Agents
A. Actions
The B-blockers reduce blood pressure primarily by decreasing cardiac output They may also decrease sympathetic outflow from the central nervous system (CNS) and inhibit the release of renin from the kidneys.
B. Therapeutic uses
1-Subsets of the hypertensive population: The B-blockers are more effective for treating hypertension in white than in black patients and in young compared to elderly patients. \[Note: Conditions that discourage the use of B-blockers (for example, severe chronic obstructive lung disease, chronic congestive heart failure, or severe symptomatic occlusive peripheral vascular disease)
2-Hypertensive patients with concomitant diseases :The B-blockers are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyarrhythmia, previous myocardial infarction, angina pectoris, and migraine headache.
C. Pharmacokinetics
The B-blockers are orally active. Propranolol undergoes extensive and highly variable first-pass metabolism.
D. Adverse effects
1-Common effects: The B-blockers may cause bradycardia and CNS side effects such as fatigue, lethargy , insomnia, and hallucinations; these drugs can also cause hypotension The B-blockers may decrease libido and cause impotence.
2-Alterations in serum lipid patterns: The <00FF>²-blockers may disturb lipid metabolism, decreasing high-density lipoprotein cholesterol and increasing plasma triacylglycerol.
3-Drug withdrawal: Abrupt withdrawal may induce angina, myocardial infarction, or even sudden death in patients with ischemic heart disease. Therefore, the dose of these drugs must be tapered over 2 to 3 weeks in patients with hypertension and ischemic heart disease.
VII. ACE Inhibitors
The ACE inhibitors, such as enalapril or lisinopril are recommended when the preferred first-line agents (diuretics or B-blockers) are contraindicated or ineffective..
A. Actions
The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without reflexively increasing cardiac output, rate, or contractility. These drugs block the ACE that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II The converting enzyme is also responsible for the breakdown of radykinin. ACE inhibitors decrease angiotensin II and increase bradykinin levels. 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 decrease the secretion of aldosterone, resulting in decreased sodium and water retention.
B. Therapeutic uses
ACE inhibitors are most effective in hypertensive patients who are white and young . ACE inhibitors slow the progression of diabetic nephropathy and decrease albuminuria. ACE inhibitors are also effective in the management of patients with chronic heart failure. ACE inhibitors are a standard in the care of a patient following a myocardial infarction.
C. Adverse effects
Common side effects include dry cough, rash, fever, altered taste, hypotension and hyperkalemia . Angioedema is a rare but potentially life-threatening reaction Because of the risk of angioedema and first-dose syncope, ACE inhibitors may be first administered in the physician's office with close observation. Reversible renal failure can occur in patients with severe bilateral renal artery stenosis. ACE inhibitors are fetotoxic and should not be used by women who are pregnant
.
VIII. Angiotensin II- Receptor Antagonists
The angiotensin II–receptor blockers (ARBs) are alternatives to the ACE inhibitors. These drugs block the AT1 receptors. Losartan is the prototypic ARB; currently, there are six additional ARBs. Their pharmacologic effects are similar to those of ACE inhibitors in that they produce arteriolar and venous dilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention. ARBs do not increase bradykinin levels. ARBs decrease the nephrotoxicity of diabetes, making them an attractive therapy in hypertensive diabetics. Their adverse effects are similar to those of ACE inhibitors , although the risks of cough and angioedema are significantly decreased. ARBs are also fetotoxic
IX. Renin Inhibitors
Aliskiren directly inhibits renin and, thus, acts earlier in the renin-angiotensin-aldosterone system. Aliskiren can cause diarrhea, especially at the higher doses. Aliskiren can also cause cough and angioedema but probably less often than ACE inhibitors. The drug is contraindicated during pregnancy. Hyperkalemia was significantly more common in patients who received both valsartan and aliskiren.
X. Calcium-Channel Blockers
They are effective in treating hypertension in patients with angina or diabetes. cardiac stimulation.
A. Classes of calcium-channel blockers
1- Diphenylalkylamines: Verapamil is the least selective of any calcium-channel blocker and has significant effects on both cardiac and vascular smooth muscle cells. It is used to treat angina, supraventricular tachyarrhythmias, and migraine headache.
2- Benzothiazepines: Like verapamil, diltiazem affects both cardiac and vascular smooth muscle cells; however, it has a less pronounced negative inotropic effect on the heart compared to that of verapamil. Diltiazem has a favorable side-effect profile.
3- Dihydropyridines: The first-generation nifedipine and five second-generation agents for treating cardiovascular disease: amlodipine,felodipine isradipine nicardipine, and nisoldipine All dihydropyridineshave a much greater affinity for vascular calcium channels than for calcium channels in the heart. They are therefore particularly attractive in treating hypertension. Some of the newer agents, such as amlodipine and nicardipine, have the advantage that they show little interaction with other cardiovascular drugs, such as digoxin or warfarin.
B. Actions
Calcium enters muscle cells through special voltage-sensitive calcium channels. This triggers release of calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level of calcium. Calcium-channel antagonists block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly arterioles.
C. Therapeutic uses
Calcium-channel blockers have an intrinsic natriuretic effect. These agents are useful in the treatment of hypertensive patients who also have asthma, diabetes, angina, and/or peripheral vascular disease .
D. Pharmacokinetics
Most of these agents have short half-lives (3-8 hours) following an oral dose. Sustained-release preparations are available. Amlodipine has a very long half-life and does not required a sustained-release formulation.
E. Adverse effects
Constipation occurs in 10 percent of patients treated with verapamil . Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure are more frequent with dihydropyridines. Verapamil should be avoided in patients with congestive heart failure or with atrioventricular block due to its negative inotropic (force of cardiac muscle contraction) and dromotropic (velocity of conduction) effects.
XI. a-Adrenoceptor Blocking Agents
Prazosin , doxazosin , and terazosin produce a competitive block of a1-adrenoceptors. They decrease peripheral vascular resistance and lower arterial blood pressure by causing relaxation of both arterial and venous smooth muscle. 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. Reflex tachycardia and first-dose syncope are almost universal adverse effects. Because of the side-effect profile, development of tolerance, and the advent of safer antihypertensives, a1-blockers are seldom used in the treatment of hypertension.
Tamsulosin , an a 1 a1-blocker with greater selectivity for prostate muscle, has been used in the treatment of prostate hyperplasia.
XII. a-B- Adrenoceptor Blocking Agents
Labetalol and carvedilol block both a1 - and b 1 - and B2 - receptors. Carvedilol, although an effective antihypertensive, is mainly used in the treatment of heart failure. Carvedilol has been shown to reduce mortality associated with heart failure.
XIII. Centrally Acting Adrenergic Drugs
A. Clonidine
This a2 -agonist diminishes central adrenergic outflow. Clonidine is used primarily for the treatment of hypertension that has not responded adequately to treatment with two or more drugs. Clonidine, is useful in the treatment of hypertension complicated by renal disease. Because it may cause sodium and water retention, clonidine may be administered in combination with a diuretic. Adverse effects are generally mild, but the drug can produce sedation and drying of the nasal mucosa. Rebound hypertension occurs following abrupt withdrawal of clonidine . The drug should therefore be withdrawn slowly .
B. Methyldopa
This Alpha-2 -agonist is converted to methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS. This leads to reduced total peripheral resistance and a decreased blood pressure. methyldopa is especially valuable in treating hypertensive patients with renal insufficiency. The most common side effects of methyldopa are sedation and drowsiness. It has been used in hypertensive pregnant patients.
XIV. Vasodilators
A. Hydralazine
This drug causes direct vasodilation, acting primarily on arteries and arterioles. This results in a decreased peripheral resistance, which in turn prompts a reflex elevation in heart rate and cardiac output. Hydralazine is used to treat moderately severe hypertension. It is almost always administered in combination with a I²-blocker, such as propranolol (to balance the reflex tachycardia), and a diuretic (to decrease sodium retention). Hydralazine monotherapy is an accepted method of controlling blood pressure in pregnancy-induced hypertension. Adverse effects of Hydralazine therapy include headache, tachycardia, 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.
B. Minoxidil
This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). Minoxidil is administered orally for treatment of severe to malignant hypertension that is refractory to other drugs. Reflex tachycardia and fluid retention may be severe and require the concomitant use of a loop diuretic and a I²-blocker. Minoxidil causes serious sodium and water retention, leading to volume overload, edema, and congestive heart failure.[Note: Minoxidil treatment also causes hypertrichosis (the growth of body hair). This drug is now used topically to treat male pattern baldness.]
XV. Hypertensive Emergency
Hypertensive emergency is a rare but life-threatening situation in which the DBP is either >150 mm Hg (with SBP >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.
A. Sodium nitroprusside
Nitroprusside is administered intravenously and causes prompt vasodilation with reflex tachycardia. It is capable of reducing blood pressure in all patients regardless of the cause of hypertension. The drug has little effect outside the vascular system, acting equally on arterial and venous smooth muscle. Nitroprusside is metabolized rapidly (half-life of minutes) and requires continuous infusion to maintain its hypotensive action.
Sodium nitroprusside exerts few adverse effects except for those of hypotension caused by overdose. Nitroprusside metabolism results in cyanide ion production. Although cyanide toxicity is rare, it can be effectively treated with an infusion of sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the kidneys. Nitroprusside is light sensitive, and when in solution, it should be protected from light.
B. Labetalol
Labetalol is both an a- and B-blocker and is given as an intravenous bolus or infusion in a nonselective I²-blocker.
C. Fenoldopam
Fenoldopam is a peripheral dopamine-1 receptor agonist that is given as an intravenous infusion. Unlike other parenteral antihypertensive agents, fenoldopam maintains or increases renal perfusion while it lowers blood pressure. Fenoldopam can be safely used in all hypertensive emergencies and may be particularly beneficial in patients with renal insufficiency. The drug is contraindicated in patients with glaucoma.
D. Nicardipine
Nicardipine , a calcium-channel blocker, can be given as an intravenous infusion. The initial dose is 5 mg/h and can be increased to a maximum of 15 mg/h. The major limitation of
Nicardipine in treating hypertensive emergency is its long half-time (approximately 8 hours), which precludes rapid titration.
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