Am J Cardiovasc Drugs 2002; 2 (2): 77-89

THERAPY IN PRACTICE 1175-3277/02/002-0077/$25.00/0

© Adis International Limited. All rights reserved.

Antihypertensive Drugs
An Overview
C. Venkata S. Ram
Texas Blood Pressure Institute, Dallas Nephrology Associates, The University of Texas Southwestern Medical Center of Dallas,
Dallas, Texas, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
1. Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
1.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
1.2 Special Types of Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2. Adrenergic Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2.1 β-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
2.2 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
3. α1-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
3.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
3.2 Other Effects Of α1-Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4. Combined α- and β-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
5. Central α-Adrenoceptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
5.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
6. Peripheral Adrenergic Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
7. ACE Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
7.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
8. Angiotensin Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
8.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
9. Calcium Channel Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
9.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
10.Direct Vasodilators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
10.1 Hydralazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
10.1.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
10.2 Minoxidil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
10.2.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
11.Drug Treatment of Hypertension: A General Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

Abstract For most patients with systemic hypertension, long-term drug treatment is indicated and is beneficial. There
is overwhelming evidence to suggest that antihypertensive drugs offer protection against complications of
hypertension. Whereas nondrug therapeutic options should be implemented in all patients, a vast majority will
require pharmacological treatment to achieve goal blood pressure levels. Fortunately, a number of drugs are
available to accomplish successful treatment of hypertensive disorders.
While it is conventional to initiate treatment with a single drug, a suitable combination of drugs is often
required to control the blood pressure effectively. Although diuretics and β-blockers are effective and well
tolerated, other classes of drugs are being increasingly used as the initial choice of therapy for hypertension.
Every class of antihypertensive drugs offer advantages and some disadvantage; the physician should weigh the
benefits and risks in selecting one drug over another. While the clinical parameters are followed in the manage-
ment of patients with hypertension, it is also necessary to monitor the patients’ biochemical profile periodically
in order to modify and adjust the therapy accordingly. A careful selection of drug therapy along with close
follow-up offers the best prospect to reduce the burden of morbidity and mortality in hypertension. This article
provides an overview of drugs in the management of patients with hypertension.
78 Ram

Systemic hypertension is an important indication for the use uretics are a gold standard against which the modern drugs such
of drugs in the US. Although a number of effective antihyperten- as ACE inhibitors, angiotensin receptor antagonists, or calcium
sive drugs are available, new agents continue to be introduced, channel antagonists, are often compared. Despite the ongoing de-
increasing the therapeutic options for the management of patients bate regarding their effect on long-term outcomes, it is generally
with hypertension. While many antihypertensive drugs are accepted that diuretics are effective antihypertensive drugs and
equally effective in the treatment of mild to moderate (stage I - II) that they offer protection against myocardial infarction, stroke
hypertension, specific preferences are often used in the manage- and heart failure. Diuretic therapy, of course, is less expensive
ment of hypertension reflecting the physicians’ judgment and na- compared with other drugs.
tional and international guidelines. Currently available antihyper- Differences in their chemical structures determines the site
tensive drugs, when complemented by lifestyle modifications, of action and duration of activity of various diuretics.[3] Thiazide
could potentially control the blood pressure in most patients.[1] diuretics act at the distal convoluted tubule where they inhibit
Antihypertensive drugs are most effective in combination with sodium and chloride reabsorption, thereby decreasing plasma and
dietary restriction of sodium and caloric intake, weight loss, in- extracellular fluid volume and cardiac output. Although plasma
creased physical fitness, and adherence to other lifestyle modifi- volume tends to return towards normal after long-term use of
cations. Despite the convincing efficacy and tolerability of anti- diuretics, peripheral vascular resistance remains depressed. The
hypertensive drugs, surveys ironically indicate that only a small fall in peripheral vascular resistance therefore explains the long-
number of patients achieve adequate blood pressure control.[2] term antihypertensive efficacy of diuretics. A reactive increase in
Most surveys indicate that blood pressure is well controlled in plasma renin activity (PRA) may blunt the antihypertensive effi-
only about 25% of patients with hypertension. Even though the cacy of diuretics in some situations. ACE inhibitors potentiate the
number of available drugs has increased, the number of patients efficacy of diuretics by blocking reactive hyper-reninemia. The
with hypertension achieving the goal blood pressure has actually chemical structures of indapamide, chlorthalidone and
decreased! The reasons for poor blood pressure control are mul- metolazone are related to thiazides and they produce distinctive
tiple, and beyond the scope of this review. Nevertheless, unsatis- renal and cardiovascular effects.
factory adherence to prescribed therapy is the main reason for the Thiazide diuretics are as effective as other first-line therapeu-
alarming number of patients with uncontrolled hypertension. tic choices in the treatment of hypertension.[4] African-American
Whereas patients are often faulted for neglecting to take care of patients and the elderly respond more favorably to diuretics than
their hypertension, physicians should also shoulder some respon- Caucasians and younger patients. Diuretics potentiate the antihy-
sibility for not prescribing medicines in proper dosage or for using pertensive effects of other antihypertensive drugs. Thiazide di-
irrational combinations. uretics can be administered once daily or even every other day in
Physicians should strongly and consistently counsel the pa- some circumstances (table I). The initial dosage of hydrochloro-
tients about the importance of antihypertensive drug therapy; thiazide can be 6.25 to 12.5 mg/day with some patients eventually
drug dosages must be properly titrated to achieve the goal blood requiring dosages of up to 25 to 50 mg/day. In patients with nor-
pressure levels and when necessary, combination therapy should mal renal function, low dosage thiazide therapy is often effective.
be optimally used. Unless the patient has severe hypertension or Thiazides become less efficacious in the presence of excessive
a hypertensive emergency or urgency, blood pressure should al- salt intake, in patients with renal insufficiency (creatinine clear-
ways be reduced gradually as this avoids adverse effects and pre- ance <30 ml/min or serum creatinine >1.5 mg/dl), and in patients
cipitous drops in blood pressure. Several classes of drugs – old taking nonsteroidal inflammatory drugs. Studies indicate that
and new – are widely available in the modern management of long-term therapy with thiazide diuretics may protect against os-
hypertension. teoporosis because of their hypercalcemic effect.[5]

1. Diuretics 1.1 Adverse Effects

Diuretics were introduced for the treatment of hypertension Hypokalemia is a common adverse effect of thiazide diuret-
nearly five decades ago; yet they remain an important current ics; the magnitude of potassium depletion is dose dependent; low
option in the treatment of hypertension. Although, their popular- dosages producing least hypokalemia. A high salt intake[6] and
ity as preferred antihypertensive drugs has decreased, diuretics other concomitant potassium-losing conditions may aggravate
are widely used to treat hypertension either as monotherapy or the problem. The degree and duration of hypokalemia govern the
more commonly in combination with other classes of drugs. Di- occurrence of potential dangers such as cardiac arrhythmias, mus-

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Antihypertensive Drugs 79

Table I. Diuretics fonamide sensitivity. The role for loop diuretics in uncomplicated
Drug Therapeutic Frequency of hypertension is rather limited. Loop diuretics can cause electro-
dose (mg) administration lyte and volume depletion, and therefore should be used with
(times/day) appropriate precautions and under proper supervision.
Thiazides
Chlorothiazide 125-500 1
Hydrochlorothiazide 12.5-50 1 2. Adrenergic Inhibitors
Polythiazide 1.0-4.0 1 Adrenergic inhibitors have been used in the treatment of hy-
Thiazide-related compounds pertension on the principle that an inappropriate level of sympa-
Chlorthalidone 12.5-50 1 thetic activity plays a pathogenetic role in hypertensive disorders.
Indapamide 1.25-2.5 1
Sympathetic neurohormones such as norepinephrine and epi-
Metolazone 2.5-10 1
nephrine exert a multitude of cardiovascular actions by activating
Loop Diuretics the adrenergic receptors. Therefore, blockade of these receptors
Bumetanide 0.5-5.0 1-2
by pharmacological means lowers the peripheral vascular resis-
Ethacrynic acid 25-100 1-2
tance or cardiac output or both, in addition to interrupting other
Furosemide 20-480 2-3
pressor mechanisms such as the renin-angiotensin system.
Torasemide 5-40 1-2

Potassium-sparing agents
Amiloride 5-10 1 2.1 β-Adrenoceptor Antagonists
Spironolactone 25-100 1
Triamterene 50-150 1
Since their introduction in the early 1970s, β-adrenoceptor
antagonists (β-blockers) have been extensively used to treat hy-
pertension and other cardiovascular disturbances. β-Blockers
have been shown to provide secondary cardioprotection after
cle weakness, polyuria, and insulin resistance.[7] Thiazide diuret-
myocardial infarction which is their main therapeutic advan-
ics may also cause hypomagnesemia, hypercalcemia, and
tage.[9] A number of β-blockers are available for clinical use (table
hyperuricemia. Long-term high dosage (>50 mg/day) thiazide
II); they are classified according to their pharmacological prop-
therapy may cause hyperlipidemia: plasma levels of total and low
erties - β1 selectivity (cardiac), lipid solubility and intrinsic sym-
density lipoprotein cholesterol may go up with no major alter-
pathomimetic activity (ISA). Some drugs, such as labetalol, pos-
ations in plasma levels of high density lipoprotein cholesterol or
sess both α- and β-blocking actions. Although β-blockers lower
triglycerides. Skin reactions, blood dyscrasias, acute cholecysti-
the cardiac output acutely, their long-term action in the manage-
tis, pancreatitis and vasculitis have been uncommonly reported
ment of hypertension, most likely is mediated by a fall in periph-
with thiazide use; excessive volume losses can of course, cause
eral vascular resistance. The bioavailability of lipid soluble β-
azotemia. The relationship between thiazide use and renal cell
blockers such as propranolol and metropolol is considerably less
carcinoma remains controversial.[8]
than that of lipophobic β-blockers such as atenolol. Both the car-

1.2 Special Types of Diuretics Table II. β-adrenoceptor antagonists

Loop diuretics act by blocking chloride reabsorption in the Drug Therapeutic Frequency of
dose (mg) administration
thick ascending loop of Henle and thus lead to marked natriuresis.
(times/day)
The loop diuretics are considered to be more potent than the thi- Acebutolol 20-1200 1
azides and have a rapid onset of action. However, in uncompli- Atenolol 25-100 2
cated hypertension, loop diuretics are no more effective than thi- Bisoprolol 2.5-20 1
azides. Their major therapeutic role is in patients with impaired Metoprolol 50-200 1-2
renal function (serum creatinine >1.5 mg/dl or creatinine clear- Nadolol 20-240 1
ance <30 ml/min), refractory edema, or congestive heart failure. Pindolol 10-60 1
Furosemide and bumetanide have to be administered at least Propranolol 40-240 2-3
twice daily because of their short duration of action, whereas Combined α- and β-blockers
torasemide can be given once daily. Ethacrynic acid is rarely used Carvedilol 12.5-50 1-2
because of ototoxicity but can be considered in patients with sul- Labetalol 200-1200 1-2

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
80 Ram

dio (β1) selective and nonselective β-blockers, however, are bolism.[13] In susceptible individuals, β-blockers (especially, the
equally effective in the treatment of hypertension. The cardio- nonselective ones) can aggravate bronchospasm. Hence consid-
selective β-blockers are less likely to provoke bronchospasm and erable caution is advisable when prescribing a β-blocker to pa-
peripheral vasoconstriction compared with nonselective β-block- tients with asthma and/or chronic obstructive pulmonary disease.
ers. It should be recognized, however, that no β-blocker is abso- β-Blockers do not alter calcium or electrolyte metabolism signif-
lutely cardioselective and all β-blockers are nonselective at high icantly. β-Blockers can cause some degree of fatigue, reduce ex-
dosages. It has been suggested that β1-selective blockers tend to ercise performance and may aggravate vasospastic symptoms.
exert less unfavorable effects on lipid, glucose and insulin meta- Although abrupt discontinuation of β-blocker therapy does cause
bolism. β-Blockers such as pindolol and acebutalol cause gentle rebound hypertension, it may result in angina pectoris in patients
stimulation of β-receptors (ISA or partial agonistic activity) and with coronary artery disease. Whenever possible, therefore, β-
hence are less likely to depress the cardial output or alter lipid blockers should be gradually tapered rather than abruptly
metabolism or bronchial reactivity. Most β-blockers also stopped.
demonstrate antianginal and anti-ischemic effects.[10] For cardiac
protection,[11] it is best to choose a β1-selective, non-ISA β-
blocker such as metoprolol.
3. α1-Adrenoceptor Antagonists
β-Blockers are used as monotherapy or in combination with
other drugs (particularly diuretics) in the treatment of hyperten-
α-Adrenoceptor antagonists (α1-blockers) are not widely
sion. It is generally believed that β-blockers are less effective in
used in the modern treatment of hypertension although their effi-
African-Americans[12] and in the elderly but this is not an absolute
cacy is well established. α1-blockers also improve insulin resis-
finding. While it is true that patients with high plasma renin ac-
tance, lipid metabolism and cause reversal of left ventricular hy-
tivity respond better to β-blockers than those who have low
pertrophy (LVH). Despite these advantages, the future scope of
plasma renin levels, therapy can be initiated without knowing the
α1-blockers in the treatment of hypertension is jeopardized by the
patients’ renin status and the dosage can be adjusted as necessary.
findings of the antihypertensive and lipid-lowering treatment to
Concomitant treatment with β-blockers is also useful in patients
prevent heart attack trial (ALLHAT).[14] In this major trial, the
requiring vasodilator therapy (e.g. hydralazine, minoxidil), as the
doxazosin arm was discontinued because of an increased inci-
latter drugs cause a reflex increase in the sympathetic activity,
dence of congestive heart failure. Prazosin is a rapidly active
which can then be blunted by coadministration of a β-blocker.
α1-blocker[15] with a short duration of action, while doxazosin
Patients with anxiety disorders, asymmetrical septal hypertrophy,
and terazosin have a gradual onset and sustained duration of ac-
hyperkinetic circulatory states and congestive heart failure may
tion (table III). The antihypertensive efficacy of α1-blockers
particularly benefit from β-blocker therapy.
equals that of β-blockers, diuretics, calcium channel antagonists
and ACE inhibitors. α1-blockers can be used as monotherapy or
in combination with diuretics, calcium channel antagonists or
2.2 Adverse Effects
β-blockers. The starting dosage should always be 1 mg/day and
Adverse effects from β-blockers can be largely attributed to titrated up gradually to achieve the desired fall in blood pressure;
their pharmacological effects (i.e. β-adrenoceptor blockade). long-acting α1-blockers such as doxazosin or terazosin can be
Therefore, they can cause adverse events such as insomnia, de- conveniently given once daily. Although tachyphylaxis to α1-
pression and nightmares in some patients but not in any predict- blockers has been reported in patients with heart failure, it does
able manner. β-Blockers can negatively affect carbohydrate me- not seem to occur in patients with hypertension. Loss of blood
tabolism in several ways; the counter-regulatory responses to pressure-lowering effect during α1-blocker therapy requires ad-
hypoglycemia are blunted by β-blockers with the potential danger dition of a diuretic.
of prolonging the degree and duration of insulin-mediated hypo-
glycemia. Although β-blockers can aggravate hyperglycemia in Table III. α1-Adrenoceptor antagonists
patients with diabetes mellitus, these drugs need not be avoided Drug Therapeutic Frequency of
if there is a good indication, i.e. coronary artery disease. β-Block- dose (mg) administration
ers can also induce insulin resistance. Some β-blockers can raise (times/day)
serum triglyceride levels while lowering the serum high-density Prazosin 1-20 2-3
lipoprotein-cholesterol levels. β-Blockers with ISA or cardio- Terazosin 1-20 1-2
selectivity are less likely to exert an adverse effect on lipid meta- Doxazosin 1-16 1

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
Antihypertensive Drugs 81

3.1 Adverse Effects been associated with serious hepatotoxicity and therefore, peri-
odic monitoring of liver function tests is recommended.[19]
Adverse effects such as headache, drowsiness and fatigue
have been reported with α1-blockers and are probably nonspe-
cific. First-dose hypotension mainly reported with prazosin can 5. Central α-Adrenoceptor Agonists
be avoided by giving the initial dose at bedtime and by adjusting
the dosage gradually and not rapidly. This phenomenon, however, The centrally acting drugs are one of the oldest classes of
is uncommon with the second generation α1-blockers such as antihypertensive drugs and they are still used in the management
doxazosin and terazosin. of hypertension (table IV). Methyldopa, the prototypical drug in
this class, was originally thought to have a peripheral action but
subsequent studies suggested a central action: stimulation of α-
3.2 Other Effects Of α1-Blockade
adrenoceptors in the vasomotor center which causes a reduction
α1-Blockers are useful in the medical management of ob- in sympathetic outflow with a resultant decrease in peripheral
structive uropathy because of benign prostatic hypertrophy. Al- vascular resistance and a modest decrease in the heart rate/cardiac
though the relief of obstructive symptoms is most likely from an output. Methyldopa is still one of the most well tolerated antihy-
improvement in the dynamics of urine flow, α1-blockers may also pertensive agents in patients who are pregnant. The second gen-
reduce the growth of the prostate gland. At present, α1-blockers eration α-adrenoceptor agonists such as clonidine are more spe-
are perhaps more frequently used in the management of benign cific for the (central) imidazoline receptor and cause fewer
prostatic hyperplasia (BPH) than in hypertension. α1-blockers adverse effects compared with methyldopa. Clonidine, guana-
have been repeatedly shown to improve the lipid profiles and benz, guanfacine and methyldopa have similar therapeutic effects
insulin resistance; these drugs enhance the activity of lipoprotein but clonidine is the most widely used drug in this class.
lipase and augment insulin sensitivity.[16] Despite this seemingly Clonidine can be administered orally or transdermally. Oral
favorable cardiovascular profile, the doxazosin arm of ALLHAT clonidine is given twice daily, but larger dosages should be pref-
was terminated because of increased risk of heart failure. Patients erably given at bedtime to reduce adverse effects; guananbenz
included in the ALLHAT trial were a high-risk group: with severe and guanfacine can be administered once daily. The dosage of
hypertension; diabetes mellitus; elderly; or African-Americans. central α-adrenoceptor agonists has to be adjusted upwards (or
One can argue that switching this high-risk population to downwards) gradually. These drugs work best in conjunction
monotherapy with an α1-blocker was unwise. Nevertheless, the with sodium restriction or with diuretics. Although, their use has
ALLHAT[17] findings would make the choice of α1-blocker un- decreased, central α-adrenoceptor agonists (especially clonidine)
attractive in preventive cardiology. are often used as a component of combination therapy in patients
with difficult-to-treat hypertension. The usual therapeutic dosage
4. Combined α- and β-Blockers of clonidine is <0.4 mg/day although the maximum dosage is 1.2
mg/day which increases the likelihood of possible adverse ef-
Labetalol and carvedilol are drugs which block both the β-
fects. Alternatively, clonidine can be used as a transdermal prep-
and α-adrenergic receptors; their dominant adrenergic inhibition,
aration; the dosage of transdermal clonidine is 0.1 to 0.3mg ap-
however, is at the β-receptor site whereas the α-blocker compo-
plied weekly.[20] The transdermal preparation may cause fewer
nent is an ancillary effect. The latter phenomenon adds to the
adverse effects but some patients experience local dermal reac-
vasodilatory actions of these compounds. Labetalol is indicated
tions. The centrally acting α-adrenoceptor agonists can be used
for the treatment of hypertension whereas in the US carvedilol is
to produce modest bradycardia or prevent reflex tachycardia in
indicated for the treatment of mild to severe heart failure. Labet-
situations where β-blockers are contraindicated. Clonidine has
alol is also available for intravenous use to treat hypertensive
also been used to block withdrawal manifestations in drug ad-
emergencies and hypertensive urgencies. Because of its mecha-
nism of action, intravenous labetalol is an attractive therapeutic
option in the short-term management of severe hypertension.[18] Table IV. Central α-adrenoceptor agonists
Drug Usual dosage Possible adverse effects
range (mg/day)
4.1 Adverse Effects
Clonidine 0.2-1.2 Withdrawal symptoms
Labetalol and carvedilol can cause the same adverse effects Guanabenz 8-32
that occur with pure β- or α- blockers. Orthostatic hypotension Guanfacine 1-3 Withdrawal symptoms
can occur with large initial doses of these drugs. Labetalol has Methyldopa 500-3000 Hepatic and ‘autoimmune’ disorders

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
82 Ram

dicts. Moxonidine, which represents an improvement over Table V. Peripheral adrenergic inhibitors
clonidine , is an excellent therapeutic choice among this class of Drug Usual dosage Possible adverse effects
drugs; it is well tolerated and offers an important option in the range (mg/day)
management of hypertension. However, moxonidine is not avail- Guanadrel 10-75 Postural hypotension, diarrhea
able in the US. Guanethidine 10-150 Postural hypotension, diarrhea
Reserpine 0.05-0.25 Nasal congestion, sedation,
depression, activation of peptic ulcer
5.1 Adverse Effects

The most common adverse effects of the centrally acting

drugs are sedation, dry mouth, and impotence, which can be min- bination with diuretics and/or hydralazine. Reserpine may cause
imized by using lower dosages or with transdermal preparation nasal stuffiness, increased gastric secretions (and peptic ulcer-
of clonidine. Abrupt discontinuation of (high dosages) of clonid- ation), diarrhea, and marked depression. At the present time, there
ine may result in severe rebound hypertension.[21,22] Hemolytic is no good reason to select reserpine over other well tolerated
anemia and hepatocellular dysfunction have been occasionally adrenergic inhibitors such as β-blockers, α-blockers, and central
reported with methyldopa. Central α-adrenoceptor agonists may α-adrenoceptor agonists.
exert adverse drug interactions with tricyclic antidepressants and Guanethidine shares similar mechanisms of action as reser-
phenothiazines. pine i.e. depletion of norepinephine stores. But unlike reserpine,
guanethidine has little or no effect on catecholamine stores in the
brain and adrenal glands. In the 1950s and 60s, guanethindine was
6. Peripheral Adrenergic Inhibitors widely used despite several adverse effects. It has a long duration
Since the sympathetic nervous system plays a role in the of action; the dosage is 25 to 50 mg/day. To avoid the develop-
pathogenesis of hypertension, sympathetic blocking compounds ment of ‘pseudotolerance’, guanethidine should be administered
were one of the first drugs to be developed for the treatment of along with a suitable dosage of a diuretic. Adverse effects asso-
hypertension (table V). In fact, before the advent of modern an- ciated with the use of guanethidine include such as postural hy-
tihypertensive drugs, sympathetic blockers were the mainstay in potension, diarrhea, retrograde ejaculation, erectile dysfunction
the management of hypertension. However, development of other and drug interactions with tricyclic antidepressants. Another pe-
classes of antihypertensive drugs with superior tolerability pro- ripheral sympathetic blocker, guanadrel, is similar to guanethi-
files led to the decline in the use of sympathetic blockers. Gan- dine in its action, therapeutic efficacy, and adverse effects. How-
glion blocking drugs, which act by interrupting the sympathetic ever, these drugs are rarely used these days because of the
outflow at the post-ganglionic site, are no longer available for availability of effective and better tolerated antihypertensive
clinical use (except for trimethaphan). Trimethaphan is still used, agents.
albeit infrequently, in the management of acute aortic dissection.
Given as an intravenous drip it lowers the blood pressure, heart
7. ACE Inhibitors
rate, and myocardial contractility. The fall in blood pressure,
however, is not substantial unless the postural sympathetic As the name implies, ACE inhibitors decrease the formation
hemodynamic reflexes are activated by raising the head end of of angiotensin II by inhibiting ACE activity. In addition, ACE
the bed. Prolonged use of trimethaphan causes intolerable adverse inhibitors also prevent the breakdown of bradykinin, thereby po-
effects (of ganglion blockade) such as paralytic ileus, urinary tentiating its vasodilatory and other actions. Although all ACE
retention, and mydriasis. The place of trimethaphan in the treat- inhibitors exert similar qualitative hemodynamic effects, there
ment of patients with aortic dissection is uncertain because of the are some distinct pharmacological differences that influence their
availability of more effective and better tolerated drugs such as tissue affinity and metabolic fate. Chemically, ACE inhibitors are
labetalol and other parenteral antihypertensive agents. also distinguished by the presence of sulfhydryl, carboxyl or
Rauwolfia alkaloids, exemplified by reserpine, are hardly phosphoryl groups. Not only is the circulating renin-angiotensin
used in the treatment of hypertension because of unacceptable system inhibited by ACE inhibitors but some of these drugs also
adverse effects. By causing depletion of norepinephrine stores, block the tissue renin-angiotensin mechanisms.[24] Most ACE in-
reserpine lowers the peripheral vascular resistance and, thereby, hibitors are predominantly excreted by the kidney. Fosinopril is
the blood pressure. Reserpine is an effective but poorly tolerated excreted both by the kidney and the liver (table VI).
drug. In dosages of 0.10 to 0.50 mg/day, reserpine causes a sig- ACE inhibitors relieve vasoconstriction primarily by inhib-
nificant fall in blood pressure[23] either as monotherapy or in com- iting the formation of angiotensin II.[25] However, additional

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
Antihypertensive Drugs 83

pathways, such as potentiation of bradykinin and nitric oxide gen- another is dictated by the drug’s duration of action and by the
eration, are also likely to be involved in the cardiovascular and consideration of data related to their effects on target organs. The
renal consequences of ACE inhibition. Angiotensin inhibition de- first ACE inhibitor, captopril, has the shortest duration of action;
creases aldosterone production, resulting in natriuresis and potas- enalapril has an intermediate duration of action requiring twice
sium retention. Plasma aldosterone levels may return to baseline daily administration; other ACE inhibitors have a longer duration
values during long term therapy with ACE inhibitors. ACE inhib- of action permitting once daily administration. Monotherapy with
itors may also suppress the activity of the sympathetic nervous ACE inhibitors is effective in 60 to 70% of patients with uncompli-
system, and decrease endothelin secretion. ACE inhibitors (either cated stage I-II hypertension. Caucasians, younger individuals and
directly or indirectly) improve endothelial function and augment those with high plasma renin activity show a better response with
vascular distensibility. ACE inhibitors produce significant rever- ACE inhibitors and older patients, African-Americans[27] and those
sal of cardiac and vascular hypertrophy and protect against ex- with low plasma renin activity respond less favorably to ACE inhib-
itors. When monotherapy is not sufficiently effective, a diuretic
perimental atherosclerosis.
should be added. ACE inhibitor plus a diuretic produce substantial
Whereas ACE inhibitors continue to be used widely in the
falls in the blood pressure.[28] In addition to this synergistic effect,
treatment of hypertension, they are also beneficial in the treat-
ACE inhibitors minimize or even reverse the hypokalemic effects of
ment of congestive heart failure and they offer renal protection.
diuretics. However, caution is advised when initiating ACE inhibitor
Their hemodynamic actions, as well as their direct effects on the
therapy in patients already on a diuretic or who are volume depleted
heart may mediate the cardiac benefits of ACE inhibitors.
because of the risk of hypotension; the same precaution is valid for
Renoprotection, in part, is because of the preferential dilation of patients with high plasma renin activity.
the efferent arterioles which in turn reduces the intraglomerular ACE inhibitors provide special benefits in patients with heart
pressure. This inhibition of glomerular hyperfiltration is thought failure and in those with renal dysfunction, particularly from dia-
to decrease glomerulosclerosis. ACE inhibitors are known to im- betic nephropathy.[28] Studies have also shown that ACE inhibi-
prove the insulin sensitivity. The renal and metabolic effects of tors are cardioprotective following acute myocardial infarction.
ACE inhibitors make them a superior choice for patients with Most patients with heart failure and diabetic renal disease are
diabetes mellitus. In the Heart Outcomes Prevention and Evalu- candidates for ACE inhibitor therapy.
ation (HOPE) study, ramipril reduced the morbidity and mortality
drastically in patients who were considered to be at high risk.[26]
It is interesting to recall that ACE inhibitors were introduced 7.1 Adverse Effects
to treat patients with hypertension ‘unresponsive’ to other agents.
At the present time, ACE inhibitors are used and recommended as The originally reported adverse effects induced by ACE in-
hibitors such as neutropenia or renal dysfunction are rather un-
initial monotherapy in patients with hypertension with co-morbid con-
usual in clinical practice because of refined patient selection and
ditions. At the optimal dosage, various ACE inhibitors exert similar
use of appropriate dosages. The relative incidence of adverse ef-
antihypertensive effects but with variable duration of action. ACE
fects from various ACE inhibitors is similar at equipotent dos-
inhibitors are generally well tolerated and the choice of one over
ages. An abrupt fall in blood pressure can occur when an ACE
inhibitor is given to volume depleted or patients with high plasma
Table VI. ACE Inhibitors renin activity. The likelihood of this ‘first dose’ phenomenon is
Drug Therapeutic Frequency of less likely with a low dosage or with a slow-acting ACE inhibitor.
dose (mg) administration Cough (dry, hacking, nonproductive) is the most common ad-
(times/day) verse effect of ACE inhibitors; bronchospasm is uncommon.
Benazepril 20-40 1 ACE inhibitor-induced cough is estimated to occur in 2 to 15%
Captopril 75-200 2-3
of recipients. Increased levels of bradykinin are assumed to be a
Enalapril 5-40 1-2
causative factor in the genesis of ACE inhibitor-induced cough;
Fosinopril 10-40 1
Lisinopril 10-40 1
a genetic polymorphism has also been suggested. ACE inhibitor-
Moexipril 7.5-30 1-2 induced cough is more frequently reported (or volunteered) by
Perindopril 4-16 1 certain segments of the population - women, Asians and African-
Quinapril 10-80 1 Americans.[29] Angioneurotic edema, an infrequent adverse effect
Ramipril 2.5-20 1 of ACE inhibitor therapy, is reported to occur in 0.1 to 0.2% of
Trandolapril 1-4 1 recipients.Taste disturbances and skin reactions have been mainly

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
84 Ram

reported with sulfhydryl-containing ACE inhibitors such as Table VII. Angiotensin receptor antagonists
captopril. Leukopenia is more likely to occur in patients who are Drug Therapeutic Frequency of
immunocompromised. dose (mg) administration
Serum potassium levels may rise with ACE inhibitor therapy (times/day)
Candesartan 8-32mg 1
particularly in the presence of diabetes mellitus or renal impair-
Eprosartan 400-800mg 1
ment. While an improvement in insulin sensitivity is a desirable
Irbesartan 150-300mg 1
effect of ACE inhibition, hypoglycemia has been rarely reported Losartan 50-100mg 1-2
in patients with diabetes mellitus.[30] Abrupt deterioration in renal Telmisartan 40-80mg 1
function has occurred when ACE inhibitors were given to the Valsartan 80-320mg 1
following subgroups of patients: severe renal damage, marked
volume depletion, bilateral renal artery stenoses, stenosis of sol-
itary kidney and severe cardiac decompensation. Hence, these All the currently available angiotensin receptor antagonists
drugs are to be avoided in these situations. However, a modest are effective in the treatment of hypertension as monotherapy as
short term increase in serum creatinine level (up to 30%) can well as in combination with diuretics. They differ in their duration
occur during the first several weeks of ACE inhibitor therapy in of action and receptor binding characteristics. Losartan is a rela-
some patients[31] but the drug should not be discontinued as long- tively short-acting drug and is best given twice daily. Other an-
term renal protection can be expected. Pregnancy is an absolute giotensin receptor antagonists have a long duration of action and
contra-indication for ACE inhibitor therapy because of fetal (and are effective when given once daily. Angiotensin receptor antag-
placental) toxicity. onists have additive antihypertensive effects when combined
with a diuretic and, therefore, many angiotensin receptor antag-
onists are available in a fixed dose combination with hydrochlo-
rothiazide. It is speculated that angiotensin receptor antagonists
8. Angiotensin Receptor Antagonists
and ACE inhibitors produce additive antihypertensive effects but
this aspect remains to be further studied. Like ACE inhibitors,
Orally effective angiotensin receptor antagonists represent
angiotensin receptor antagonists also decrease proteinuria in pa-
an important therapeutic advance in the interruption of renin-
tients with renal impairment.[35] However, long-term studies eval-
angiotensin cascade to lower the blood pressure.[32] Angiotensin
uating the renal protective and antiproteinuric studies of angio-
receptor antagonists such as saralasin were discovered more than
tensin receptor antagonists are currently lacking. Similarly there
25 years ago but were only suitable for intravenous use. At the
are no comparative data versus ACE inhibitors. It has been pro-
present time, a number of orally active angiotensin receptor an-
posed that angiotensin receptor antagonists cause less hyperkale-
tagonists are available for the treatment of hypertension[33] (table
mia than ACE inhibitors.[36]
VII). Several subtypes of angiotensin II receptors have been dis-
Like ACE inhibitors, angiotensin receptor antagonists also
covered but the drugs that selectively block the AT1 receptor sub-
cause regression of LVH. On the other hand, however, effective-
type are effective in the treatment of hypertension. Angiotensin
ness of angiotensin receptor antagonists in congestive heart fail-
receptor antagonists block the actions of angiotensin II on the
ure and post myocardial infarction continues to be questioned.
blood vessel, the heart, the adrenal cortex and possibly other tis-
sues. Consequences of angiotensin receptor antagonism are re-
versal of vasoconstriction, myocardial and vascular hypertrophy 8.1 Adverse Effects
and inhibition of aldosterone secretion - actions also seen with
ACE inhibitors. Angiotensin receptor antagonists displace angio- Angiotensin receptor antagonists have an excellent adverse
tensin II from its receptor sites; thus the circulating levels of effect profile which is their major advantage over ACE inhibitors.
angiotensin may actually rise in response to angiotensin receptor Study after study has demonstrated that adverse effects with an-
antagonists.[34] Because of angiotensin blockade, this reactive giotensin receptor antagonists are no greater than with a placebo
rise in plasma angiotensin II levels is not harmful. In contrast to in patients with hypertension. Unlike ACE inhibitors, angiotensin
ACE inhibitors, angiotensin receptor antagonists do not interfere receptor antagonists do not cause cough although surprisingly
with bradykinin metabolism. Since the antihypertensive effects some cases of angioneurotic edema have been reported. As with
of angiotensin receptor antagonists and ACE inhibitors are sim- ACE inhibitors, angiotensin receptor antagonists should be avoided
ilar, it is unclear whether the lack of bradykinin potentiation with in pregnancy. Treatment with an angiotensin receptor antagonist
angiotensin receptor antagonists is a disadvantage. should be introduced cautiously in patients who are volume de-

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
Antihypertensive Drugs 85

pleted or in those with high plasma renin activity. Similarly, an- (amlodipine, felodipine) provide 24-hour blood pressure control
giotensin receptor antagonists should be avoided in patients with with once daily administration. As the risks from short-acting calcium
bilateral renal artery stenoses or stenosis of a solitary kidney. channel antagonists (nifedipine capsules) became evident, their use
has declined significantly.
Calcium channel antagonists are effective as monotherapy or
9. Calcium Channel Antagonists
in combination with other antihypertensive drugs. Dihydro-
Calcium channel antagonists were originally developed to pyridines appear to be more effective than verapamil or diltiazem
treat angina pectoris or cardiac arrhythmias, but are now popular in the treatment of hypertension. β-blockers can be safely com-
antihypertensive drugs.[37] Calcium channel antagonists have bined with dihydropyridines but can produce additive bradycar-
earned widespread acceptance despite occasional reports of their dia and cardiodepression when combined with verapamil or
adverse effects.[38] From a pharmacological perspective, calcium diltiazem; long-acting preparations are available for all calcium
channel antagonists are classified into dihydropyridines (e.g. channel antagonists. Nifedipine capsules (oral/sublingual) have
amlodipine, nifedipine), benzothiazepines (diltiazem) and phenyl- been used mainly to lower the blood pressure acutely, but this
alkylamines (verapamil).[39] Alternatively, calcium channel antag- practice is eroding because of reports of several adverse events.
onists are also classified into (heart) rate accelerating drugs Amlodipine is a popular calcium channel antagonist used widely
(dihydropyridines) and rate limiting drugs (verapamil, diltia- in the treatment of hypertension.[42] It has been suggested that
zem)[40] (table VIII). The dihydropyridine calcium channel antag- advancing age predisposes to greater antihypertensive response
onists are powerful vasodilators whereas verapamil and diltiazem from calcium channel antagonists but this observation is likely
have moderate vasodilatory properties. Dihydropyridines pro- because of the higher levels of systolic blood pressure in the el-
mote cardiac contractility and increase AV conduction; on the derly. African-American patients clearly respond much better to
other hand, verapamil and diltiazem depress myocardial contractility calcium channel antagonists than to ACE inhibitors or to β-block-
and slow down the AV conduction. The vasodilatory effects of cal- ers.[43] Dietary sodium restriction or diuretic therapy diminishes the
cium channel antagonists are predominantly mediated by the antihypertensive effect of calcium channel antagonists whereas vol-
blockade of L-type calcium channels; binding of calcium channel ume expansion and a high sodium intake may augment their ef-
antagonists to the L-type calcium channel dictates their tissue effects ficacy; similarly salt-sensitive patients respond easily to calcium
and duration of action. channel antagonists. It is known that calcium channel antagonists
Nifedipine capsules that lead to a rapid hemodynamic effect tend to exert a moderate natriuretic effect; this effect is best ex-
exemplify short-acting dihydrophridines;[41] long-acting slow re- pressed on a high salt diet that would cause a greater fall in the blood
lease dihydropyridines are exemplified by amlodipine, felodip- pressure. Despite these observations, studies have shown a signifi-
ine, and the tablet formulation of nifedipine. Nifedipine capsules cantly superior effect on blood pressure when calcium channel an-
(orally or sublingually) produce a rapid fall in blood pressure and tagonists are combined with diuretics.
may cause tachycardia. The slow release formulations of dihydropy- The effect of calcium channel antagonists on renal func-
ridines have a gradual onset but a sustained duration of action and tion continues to be examined closely. The nondihydropyridine
do not activate the sympathetic nervous system to the same extent calcium channel antagonists may show an antiproteinuric ef-
as nifedipine capsules. Dihydropyridines with a slow onset of action
fect but dihydropyridines do not decrease protein excretion. In
the African-American Study of Kidney (AASK) disease,
Table VIII. Calcium channel antagonists amlodipine (in contrast to the ACE inhibitor ramipril) did not slow
Drug Therapeutic Frequency of the progression of renal disease. Short-acting calcium channel
dose (mg) administration antagonists have been shown to increase the mortality and mor-
(times/day) bidity in patients with coronary artery disease. In contrast, long-act-
Dihydropyridines ing calcium channel antagonists have been shown to be car-
Amlodipine 2.5-10 1
dioprotective. For example in the Systolic Hypertension in
Felodipine 2.5-10 1
Europe study, nitrendipine, a dihydropyridine calcium channel
Isradipine 2.5-10 1-2
Nicardipine 60-120 1-2 antagonist was shown to substantially reduce the risk of stroke and
Nifedipine 30-120 1-2 coronary events.[44] Slow release calcium channel antagonists have
Nisoldipine 20-140 1-2 also been shown to be useful in the medical management of cor-
Diltiazem 180-480 1-2 onary artery disease. Verapamil and diltiazem have been shown to
Verapamil 120-480 1-2 be cardioprotective in patients with non-Q-wave myocardial infarc-

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
86 Ram

tion. Although calcium channel antagonists have been shown to Table IX. Direct vasodilators
cause regression of LVH, they are not beneficial in the manage- Drug Usual dosage Possible adverse effects
ment of heart failure.[45] Another dihydropyridine calcium chan- range (mg/day)
nel antagonist, nimodipine, is approved for relief of vasospasm Hydralazine 50-300 Headaches, fluid retention,
tachycardia, Lupus syndrome
after subarachnoid hemorrhage.[46]
Minoxidil 5-100 Hirsutism, fluid retention,
tachycardia

9.1 Adverse Effects

As stated above, a short-acting calcium channel antagonists 10.1 Hydralazine

should be used with considerable caution, if at all. Nifedipine
capsules can cause unwanted reduction in blood pressure and Hydralazine, a typical direct arterial vasodilator, was intro-
reflex tachycardia which may provoke myocardial ischemia.[47] duced in the early 1950s for clinical use in hypertension. Al-
In comparison with β-blockers, short-acting calcium channel an- though hydralazine reduces blood pressure, the problems men-
tagonists have adverse outcomes in patients with coronary artery tioned above limited its use until β-adrenergic blockers were
disease.[48] Long-acting calcium channel antagonists have a better developed which together with diuretics prevented the adverse
record of tolerability.[49] Dihydropyridines can cause certain ad- effects of hydralazine. Therapy with hydralazine should routinely
verse effects such as headaches, flushing, and ankle edema. Ver- be combined with an antiadrenergic drug and a diuretic. The pre-
apamil can cause constipation and AV block; it should be avoided dominant mode of action of hydralazine is to induce direct relax-
in patients with cardiac conduction disturbances, and be used with ation of vascular smooth muscle in the resistance vessels. This
much caution in patients receiving β-blockers. Diltiazem causes leads to a fall in peripheral vascular resistance. The antihyperten-
similar problems, but to a lesser extent. Gingival hyperplasia has sive effect of hydralazine is accompanied by a reflex activation
been reported with dihydropyridines. Plasma levels of calcium of the autonomic reflexes with resultant increases in the heart
channel antagonists may increase when consumed with grapefruit rate and cardiac output. Hydralazine also stimulates the renin-
juice.[50,51] The risks of bleeding and cancer attributed to calcium angiotensin system, leading to aldosterone release, sodium reten-
channel antagonists have not been substantiated. tion, and expansion of plasma volume. Since the efficacy of
hydralazine is best sustained in combination with a β-blocker and
a diuretic, its use is restricted to patients who require multiple
10. Direct Vasodilators drug therapy. The drug can be given twice daily, despite the drugs
Hypertension is characterized by increased peripheral vascu- short half-life. The total daily dosage should be limited to 200 to
lar resistance, and drugs that directly relax resistance vessels 300mg because higher dosages clearly pose a risk of inducing a
would seem to be desirable in the management of high blood lupus-like syndrome (see section 10.1.1). In fast acetylators,
pressure (table IX). However, the efficacy of direct vasodilators, higher dosages may be used because the risk of this reaction is
such as hydralazine and minoxidil, is blunted and modified by low. When a β-blocker is contraindicated, other antiadrenergic
reflex responses to vasodilation. Certain important negative con- drugs, usually central α-adrenoceptor agonists, are appropriate
sequences of direct vasodilation limit the use of these drugs as alternatives.
monotherapy for hypertension. Direct arterial dilation triggers
baroreceptor-mediated sympathetic activation,[52] resulting in 10.1.1 Adverse Effects
tachycardia and increased cardiac output and myocardial oxygen Hydralazine causes numerous bothersome and sometimes se-
demand, making it dangerous to use these agents alone in patients rious adverse effects. In addition to the adverse effects described
with known or suspected coronary artery disease. Second, direct above, some patients develop nausea and vomiting and occasion-
vasodilators cause unpleasant adverse effects such as flushing, ally peripheral neuropathy. Fluid retention can cause not only
headache, and palpitations. Third, direct vasodilators cause sig- edema but also ‘pseudotolerance’ to hydralazine, an effect that
nificant fluid retention, which may decrease their therapeutic ef- can be overcome by diuretic therapy and/or dietary salt restric-
fectiveness. These disadvantages, however, can be overcome by tion. Hydralazine-induced lupus usually presents with arthralgias
combining vasodilators with antiadrenergic agents and diuretics. and may be accompanied by malaise, weight loss, skin rash, sple-
When used in this fashion, vasodilators are effective in the long- nomegaly, and pleural and pericardial effusions. Rarely, patients
term treatment of hypertension, especially in patients with resis- with hydralazine-induced lupus have associated glomerulone-
tant hypertension.[53] phritis. The syndrome occurs only in slow acetylators and is more

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
Antihypertensive Drugs 87

common in women. Hyrdralazine-induced lupus appears between edema formation, respectively, even if high dosages are neces-
6 and 24 months after initiation of therapy.[54] The risk is propor- sary. Rarely, a loop diuretic and a thiazide or metolazone need to
tional to the dosage; long-term therapy at dosages >200 mg/day be used in combination to treat otherwise refractory edema. In the
clearly enhances the risk. The syndrome is reversible following event of contraindications to the use of β-blockers, a centrally
discontinuation of treatment, and full recovery occurs within acting α-adrenoceptor agonist can be used.
weeks, somewhat longer in advanced cases. In contrast to sys- Some studies have shown that prolonged minoxidil therapy
temic lupus erythematosus, hydralazine-induced lupus is associ- stabilizes or improves the renal function in patients with hyper-
ated with antibodies directed against single-stranded DNA rather tension and renal failure, and sustained blood pressure control
than against the native double-stranded DNA. with minoxidil occasionally has resulted in the discontinuation of
Therapy with hydralazine can be initiated with 10 to 25mg dialysis. The improvement in renal function is primarily because
twice daily, which can be increased at weekly intervals to 200 to of aggressive and effective blood pressure control, rather than a
400 mg/day. Intramuscular or intravenous administration of hydral- specific renoprotective effect of minoxidil.
azine is used for hypertensive crises. The dose requirements to
achieve the therapeutic goal are unpredictable. The commonly used 10.2.1 Adverse Effects
dose is 10 to 20mg, which may be repeated as necessary. Although an In addition to fluid retention and symptoms because of the
effect on the blood pressure may be seen in a few minutes, maximum reflex activation of sympathetic tone, other specific adverse re-
decrease occurs between 15 and 75 minutes. Parenteral hydralaz- actions occur. ST segment depression and T-wave flattening or
ine therapy was successful and well tolerated in the management inversion are frequently seen in patients receiving minoxidil.
of severe hypertension in pregnancy. Whether this observation represents cardiac ischemia or is a man-
ifestation of LVH is unclear. Pericardial effusion[58] including
tamponade has also been reported in patients receiving minoxidil
10.2 Minoxidil therapy. The true incidence of this adverse effect is not known
because many patients receiving minoxidil are already predis-
Minoxidil is a more potent vasodilator than hydralazine but posed to develop fluid retention as a result of cardiac or renal
is similar in its actions.[55] Although it is extremely effective, its dysfunction. Rarely, pericarditis with effusion has been noted in
adverse effects have limited its routine use in clinical practice, some patients receiving minoxidil therapy, and clinical suspicion
and its use is recommended only in patients with hypertension may warrant echocardiographic confirmation of the diagnosis
who are refractory to all other drugs. Like hydralazine, minoxidil and discontinuation of minoxidil therapy. Elevated pulmonary
dilates the resistance vessels directly and lowers the peripheral artery pressures have been documented in patients receiving
vascular resistances. There is some evidence that minoxidil may long-term minoxidil therapy, an effect less likely to occur in pa-
act by opening potassium channels at the cellular level. The dom- tients receiving concurrent β-blockers. Hypertrichosis occurs in
inant action of minoxidil is on the arterial side of the circulatory nearly all patients treated with minoxidil. This is particularly ev-
system. Venodilation does not occur, and so postural hypotension ident on the face, which is a serious limitation to the use of this
is not observed. As a result of marked reduction in peripheral drug in women. The mechanism for minoxidil-induced hair
vascular resistance, minoxidil causes considerable activation of growth is not known. Hypertrichosis disappears within a few
the sympathetic nervous system and the renin-angiotensin sys- weeks after discontinuation of the drug but can also be treated
tem, with resultant reflex tachycardia and secondary hyperaldo- with depilatory agents.
steronism - consequences that blunt its antihypertensive actions. The usual starting dosage of minoxidil is 5 mg/day, and the
Minoxidil is frequently necessary in patients with marked renal maintenance dosage for most patients is 10 to 40 mg/day given
insufficiency, who are often refractory to all other drugs. Minox- once or twice daily in divided dosages. A few patients, particu-
idil therapy is effective regardless of the severity or etiology of larly those with renal failure, require dosages greater than 40 to
hypertension and the status of renal function. Unsatisfactory re- 50 mg/day to achieve a therapeutic effect.
sponse to minoxidil is extremely rare in the authors clinical ex-
perience.[56,57] Prior to the availability of minoxidil, bilateral ne-
phrectomy was the only other therapeutic option in patients with 11. Drug Treatment of Hypertension:
A General Approach
uncontrolled hypertension and renal damage. Minoxidil should
always be administered with a β-blocker and a potent diuretic, Systemic hypertension remains a leading indication for drug
usually a loop diuretic. The dosage of the β-blocker and the di- therapy. While non-drug therapies are useful and often necessary,
uretic should be adjusted as needed to prevent tachycardia and most patients require antihypertensive drugs for adequate blood

© Adis International Limited. All rights reserved. Am J Cardiovasc Drugs 2002; 2 (2)
88 Ram

pressure control. Drug selection should be individualized based 12. Jamerson K, Dequattro V. The impact of ethnicity on response to antihypertensive
therapy. Am J Med 1996; 101 Suppl. 3A: S22-32
upon clinical assessment of the patient and associated morbid
13. Lardinois CK, Neuman SL. The effects of antihypertensive agents on serum lipids
conditions and risk factors. Although the Joint National Commit- and lipoproteins. Arch Intern Med 1988; 148: 1280-8
tee recommends diuretics and β-blockers as initial therapy for 14. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
hypertension, other classes of drugs can also be selected based Group. Major cardiovascular events in hypertensive patients randomized to
doxazosin vs chlorthalidone. JAMA 2000; 283: 1967-75
upon concomitant conditions and risk factor assessment. Drug 15. Ram CVS, Anderson RJ, Hart GR, et al. Alpha-adrenergic blockade by Prazosin
selection, therefore has to be individualized with the clinicians’ in therapy of essential hypertension. Clin Pharmacol Ther 1981; 29 (6): 719-22
judgment playing a key role in the disease management. The 16. Rabkin SW. Mechanisms of action of adrenergic receptor blockers on lipids during
antihypertensive drug treatment. J Clin Pharmacol 1993; 33: 286-91
healthcare delivery system and formulary considerations may go
17. Messerli FH. Implications of discontinuation of doxazosin arm of ALLHAT. Lan-
against physicians’ preferences with regard to drug selection. For cet 2000; 355: 863-4
most patients, low dose drug therapy should be instituted and 18. Grubb BP, Sirio C, Zelis R. Intravenous labetalol in acute aortic dissection. JAMA
uptitrated to attain the target blood pressure level. For most pa- 1987; 258: 78-9
19. Clark JA, Zimmerman HJ, Tanner LA. Labetalol hepatotoxicity. Ann Intern Med
tients, combination therapy may be required to achieve and to 1990; 113: 210-3
maintain target blood pressure levels. Fixed-dose combination 20. Langley MS, Heel RC. Transdermal clonidine. Drugs 1988; 35: 123-42
preparations have a definite place in blood pressure control. Spe- 21. Ram CVS, Holland OB, Fairchild C, et al. Withdrawal syndrome following ces-
cific drug selections should also be based upon considerations sation of guanabenz therapy. J Clin Pharmacol 1979; 19: 148-50
22. Ram CVS, Engelman K. Abrupt discontinuation of clonidine therapy. JAMA
beyond blood pressure alone, e.g. presence of diabetic nephrop- 1979; 242 (19): 2104-5
athy, isolated systolic hypertension, etc. To assure patient com- 23. Bhatia BB. On the use of rauwolfia serpentina in high blood pressure. J Ind Med
pliance and participation, adverse effects and drug interactions Assoc 1942; 11: 262-5
24. Brown NJ, Vaughan DE. Angiotensin-converting enzyme inhibitors. Circulation
should be minimized and avoided. The goal of antihypertensive
1998; 97: 1411-20
drug therapy is to maintain target organ protection while control- 25. Ram CVS. Captopril. Arch Intern Med 1982; 142 (5): 914-6
ling blood pressure effectively. 26. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of an
angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in
high-risk patients. N Engl J Med 2000; 342: 145-53
Acknowledgements 27. Saunders E, Weir MR, Kong BW, et al. A comparison of the efficacy and safety
of a β -blocker, a calcium channel blocker, and a converting enzyme inhibitor
The authors acknowledge the excellent secretarial assistance provided by in hypertensive blacks. Arch Intern Med 1990; 150: 1707-13
Mrs Kathy Miller in the preparation of this manuscript. 28. Schrier RW, Estacio RO. Additional follow-up from the ABCD trial in patients
with type 2 diabetes and hypertension. [letter] N Engl J Med 2000; 343: 1969
29. Elliott WJ. Higher incidence of discontinuation of angiotensin converting enzyme
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