Download Recommendations for nondrug therapy

Conf. dr. Laurenţiu Şorodoc MD, PhD
SYSTEMIC HYPERTENSION
THERAPY
Nondrug Therapy
LIFE STYLE MODIFICATIONS
Interest in the use of various nondrug therapies, better called life style modifications, for the
treatment of hypertension has risen markedly in the past few years, yet many practitioners either
do not use them or use them in a casual, perfunctory manner.
This hesitant attitude can be attributed both to the sparseness of firm evidence indicating that
these therapies succeed and to the difficulty many have faced in convincing patients to adhere to
them. This situation is likely to change:
Evidence for the effectiveness of these approaches in lowering blood pressure is growing,
techniques for improving adherence are being popularized, and patients seem increasingly willing
to adopt changes in life style.
Recommendations for nondrug therapy
Alcohol
Obesity
Saturated fat
Sodium/salt
Smoking
Exercise
Potassium
Other
Calcium
Magnesium
Stress management
Normotensive individuals
Hypertensive patients
2 drinks/day (8 oz. wine, 2 oz. 2 drinks/day (8 oz. wine, 2 oz.
liquor, 24 oz. beer)
liquor, 24 oz. beer); Abstinence if
BP still uncontrolled
Goal body weight = BMI 20–27 Reduce to acceptable BMI by diet
kg/m˛
and exercise
Total fat <30% total calories. Total fat <30% total calories.
Saturated fat <10% of total Saturated fat <10% of total
calories. Cholesterol <100 mg/ day calories. Cholesterol <100 mg/ day
Avoid high salt foods, minimize Avoid high salt foods, minimize
salt addition. Reduct intake to salt addition. Reduce intake to
<100 mmol (<2.3 g sodium, <6 g <100 mmol (<2.3 g sodium, <6 g
salt)/day
salt)/day
Stop smoking
Stop smoking
Regular exercise as beneficial for Regular, progressive exercise as
weight regulation and reducing beneficial for weight regulation
cardiovascular mortality
and
reducing
cardiovascular
mortality; avoid isometric exercise
Eat a potassium-rich diet (high in Eat a potassium-rich diet (high in
vegetables, fruits, low-fat dairy vegetables, fruits, low-fat dairy
products)
products,
especially
if
on
potassium-losing diuretics)
Data at present not sufficient to Data at present not sufficient to
recommend inclusion
recommend inclusion
Adapted form Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The Fifth Report of the Joint National
Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993:154–183; Laidlaw JC,
Chockalingam A. Canadian Consensus Conference on Nonpharmacological Approaches to the Management of High Blood Pressure:
Recommendations. J Cardiovasc Pharmacol 1990; 16:S48–S50; and Cressman MD. Management of hypercholesterolemia in the hypertensive
patient. Cleve Clin J Med 1989: 56:351–358.
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Conf. dr. Laurenţiu Şorodoc MD, PhD
Stepped Care
Over the past two decades, the concept of progressive, stepped care has evolved from a narrow
set of incremental options to a broader set of guidelines in JNC-V and VI:
Step 1: Prescribe lifestyle modifications, including weight reduction, moderated alcohol
intake, regular physical exercise, reduced sodium intake, and smoking cessation;
Step 2: If response is inadequate, continue the lifestyle modification and add monotherapy for mild to
moderate (Stage 1–2) hypertension with thiazide diuretics, ACE-inhibitors, calcium antagonists, a1blockers, a-b-blockers or b-blockers, unless there is a contra-indication.
Step 3: If response to initial treatment is inadequate, increase the drug dose or substitute
another antihypertensive drug or add a second agent from a different drug class;
Step 4: If response still inadequate, add a second or third agent of a different drug class
(including an appropriate diuretic, if not already administered).
This approach’s major advantages consist of simplicity of understanding and implementation,
emphasis on administration of complementary drug classes for synergism, and titration to
minimize toxicities.
DIETARY SODIUM RESTRICTION
Sodium restriction is useful for all persons, as a preventive measure in those who are
normotensive and, more certainly, as partial therapy in those who are hypertensive.
The easiest way to accomplish moderate sodium restriction is to substitute natural foods for
processed foods, because natural foods are low in sodium and high in potassium whereas most
processed foods have had sodium added and potassium removed.
Additional guidelines include the following:
1. Add no sodium chloride to food during cooking or at the table.
2. If a salty taste is desired, use a half sodium and half potassium chloride preparation
(such as Lite Salt) or a pure potassium chloride substitute.
3. Avoid or minimize the use of “fast foods,” many of which have high sodium content.
4. Recognize the sodium content of some antacids and proprietary medications.
5 Avoid drinking of mineral water.
Rigid degrees of sodium restriction are not only difficult for patients to achieve but may also
be counterproductive.
GENERAL GUIDELINES TO IMPROVE PATIENTS' ADHERENCE TO ANTIHYPERTENSIVE
THERAPY
1. Be aware of the problem of nonadherence and be alert to signs of patients' nonadherence.
2. Establish the goal of therapy: to reduce blood pressure to normotensive levels with minimal or no side
effects.
3. Educate the patient about the disease and its treatment.
a. Involve the patient in decision-making.
b. Encourage family support.
4. Maintain contact with the patient.
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Conf. dr. Laurenţiu Şorodoc MD, PhD
a. Encourage visits and calls to allied health personnel.
b. Allow the pharmacist to monitor therapy.
c. Give feedback to the patient via home blood pressure readings.
d. Make contact with patients who do not return.
5. Keep care inexpensive and simple.
a. Do the least work-up needed to rule out secondary causes.
b. Obtain follow-up laboratory data only yearly unless indicated more often.
c. Use home blood pressure readings.
d. Use nondrug, no-cost therapies.
e. Use the fewest daily doses of drugs needed.
f. If appropriate, use combination tablets.
g. Tailor medication to daily routines.
6. Prescribe according to pharmacological principles.
a. Add one drug at a time.
b. Start with small doses, aiming for 5 to 10 mm Hg reductions at each step.
c. Prevent volume overload with adequate diuretic and sodium restriction.
d. Take medication immediately on awakening or after 4 A.M. if patient awakens to void.
e. Ensure 24-hour effectiveness by home or ambulatory monitoring.
f. Continue to add effective and tolerated drugs, stepwise, in sufficient doses to achieve the goal of therapy.
g. Be willing to stop unsuccessful therapy and try a different approach.
h. Adjust therapy to ameliorate side effects that do not spontaneously disappear.
From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 188.
STARTING DOSAGES.
The need to start with a fairly small dose also reflects a greater responsiveness of some patients
to doses of medication that may be appropriate for the majority. All drugs exert increasing effect
with increasing doses.
DRUG COMBINATIONS.
Combinations of smaller doses of two drugs from different classes have been marketed to take
advantage of the differences in the dose-response curves for therapeutic and toxic (side) effects.
COMPLETE COVERAGE WITH ONCE DAILY DOSING.
A number of choices within each of the six major classes of antihypertensive drugs now
available provide full 24-hour efficacy. Therefore, single daily dosing should be feasible for
virtually all patients, thereby improving adherence to therapy.
THE INITIAL CHOICE.
The initial choice of antihypertensive therapy is perhaps the most important decision made
in the treatment process.
Two guidelines by expert committees have been published:
 The JNC-VI recommends diuretics or beta blockers as initial therapy for the relatively
small portion of patients with uncomplicated hypertension, and drugs from all of the six
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Conf. dr. Laurenţiu Şorodoc MD, PhD

major classes for patients with either a compelling indication or a comorbid condition that
has been shown to respond well to a particular therapy.
The 1999 WHO-ISH guidelines broaden the number of compelling indications but give
equal weight to all classes of drugs if there are no specific reasons to use one, stating that
“There is as yet no evidence that the main benefits of treating hypertension are due to any
particular drug property rather than to lowering of blood pressure per se.”
GUIDELINES FOR SELECTING DRUG TREATMENT
CLASS OF COMPELLING
DRUG
INDICATIONS
POSSIBLE
INDICATIONS
COMPELLING
CONTRAINDICATIONS
POSSIBLE
CONTRAINDICATIONS
Diuretics
Heart failure
Elderly patients
Systolic
hypertension
Diabetes
Gout
Dyslipidemia
Sexually active men
Beta
blockers
Angina
After myocardial
infarction
Tachyarrhythmias
Heart failure
Pregnancy
Diabetes
Asthma and COPD
Heart block*
Dyslipidemia
Athletes and physically
active patients
Peripheral vascular disease
ACE
inhibitors
Heart failure
Left ventricular
dysfunction
After myocardial
infarction
Diabetic
nephropathy
Calcium
antagonists
Angina
Elderly patients
Systolic
hypertension
Peripheral
vascular disease
Alpha
blockers
Prostatic
hypertrophy
Glucose
intolerance
Dyslipidemia
Angiotensin
II
antagonists
ACE inhibitor
cough
Heart failure
Pregnancy
Hyperkalemia
Bilateral renal artery
stenosis
Heart block†
Congestive heart failure‡
Orthostatic hypotension
Pregnancy
Bilateral renal artery
stenosis
Hyperkalemia
*Grade 2 or 3 atrioventricular block; †grade 2 or 3 atrioventricular block with verapamil or diltiazem; ‡verapamil or diltiazem. ACE = angiotensinconverting enzyme; COPD = chronic obstructive pulmonary disease.
DIURETICS
In two groups that constitute a rather large portion of the hypertensive population, the elderly
and blacks, diuretics may be particularly effective. One-half of a diuretic tablet per day is usually
all that is needed, minimizing cost and maximizing adherence to therapy. Even lower doses, i.e.,
6.25 mg of hydrochlorothiazide, may be adequate when combined with other drugs.
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The side effects of high-dose diuretic therapy are usually not overly bothersome, but the
hypokalemia, hypercholesterolemia, hyperinsulinemia, and worsening of glucose tolerance that
often accompany prolonged high-dose diuretic therapy gave rise to concerns about their long-term
benignity. However, lower doses are usually just as potent as higher doses in lowering the blood
pressure and less likely to induce metabolic mischief.
Diuretics useful in the treatment of hypertension may be divided into four major groups by
their primary site of action within the tubule, starting in the proximal portion and moving to the
collecting duct:
(1) agents acting on the proximal tubule, such as carbonic anhydrase inhibitors, which
have limited antihypertensive efficacy;
(2) loop diuretics;
(3) thiazides and related sulfonamide compounds;
(4) potassium-sparing agents.
A thiazide is the usual choice, often in combination with a potassium-sparing agent.
Loop diuretics should be reserved for those patients with renal insufficiency or resistant
hypertension.
SIDE EFFECTS.
A number of biochemical changes often accompany successful diuresis, including a decrease
in plasma potassium level and increases in glucose, insulin, and cholesterol levels
The mechanisms by which chronic diuretic therapy may lead to various complications. The mechanism for
hypercholesterolemia remains in question, although it is shown as arising via hypokalemia. Cl = Clearance;
PRA = plasma renin activity; GFR = glomerular filtration rate.
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Conf. dr. Laurenţiu Şorodoc MD, PhD
Site of action of diuretics. A common feature of all diuretics is their natriuretic action,
which leads to a decrease in total body sodium. The most potent diuretics (furosemide,
bumetanide, and ethacrynic acid) decrease sodium resorption in the thick ascending loop
of Henle. Urinary sodium excretion can be enhanced considerably with these agents by
increasing the dose. Loop diuretics remain effective even in patients with severely
impaired renal function. Thiazides, metolazone, and indapamide inhibit sodium
resorption in the early portion of the distal convoluted tubule. The dose-response curve
to these diuretics is rather flat. Furthermore, the natriuretic effect of thiazides and
indapamide is lost when the glomerular filtration rate (GFR) is reduced below
approximately 40 ml/min, whereas metolazone is still active down to a GFR of
approximately 20 ml/min. Loop diuretics, thiazides, and metolazone as well as
triamterene, amiloride, and spironolactone act in the late portion of the distal convoluted
tubule and the cortical collecting duct. Triamterene and amiloride have weak natriuretic
action.
1 = glomerulus; 2 = proximal convoluted tubule; 3 = loop of Henle; 4 = distal convoluted
tubule; 5 = collecting duct.
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Mechanisms of action of diuretics. Sixty percent of filtered sodium is resorbed in the proximal convoluted tubule
(obligatory resorption). The more distal segments of the nephron can modulate excretion of only a fraction of the
total filtered sodium. Diuretics that impair sodium resorption in the thick ascending loop of Henle (furosemide,
bumetanide, ethacrynic acid) interfere with the Na/K+/2Cl- cotransport system located at the apical membrane of the
renal tubule. These diuretics act at a site where a large quantity of sodium is normally resorbed. Thiazides,
metolazone, and indapamide inhibit the apical Na +/Cl- cotransport system. Only a small fraction of filtered sodium
normally is resorbed at this site of the nephron, which accounts for the limited natriuretic activity of the diuretics. In
the distal convoluted tubule and in the cortical collecting duct, sodium is transported at the apical level of the tubular
cell through a sodium channel. Sodium is then exchanged against a potassium ion at the basal membrane due to the
activity of Na+,K+ -ATPase. The activity of this enzyme is enhanced by aldosterone, the mineralocorticoid hormone
secreted by the adrenal glomerulosa. Spironolactone is a competitive antagonist of aldosterone and consequently
inhibits pump activity. Amiloride and triamterene block the apical sodium transport. The elimination of potassium is
reduced by diuretics acting in these most distal portions of the nephron because of decreased sodium-potassium
exchange. In contrast, loop diuretics and diuretics acting in the early distal convoluted tubule increase kaliuresis and
tend to cause hypokalemia. This is mainly because these agents enhance delivery of sodium downstream and
subsequently accentuate the sodium-potassium exchange. As a result, an increased quantity of sodium is available for
resorption in the late distal convoluted tubule and the cortical collecting duct. Potassium-sparing diuretics must be
avoided in patients with renal failure because they may cause life-threatening hyperkalemia. PF = peritubular
interstitial fluid; TL = tubular lumen.
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Conf. dr. Laurenţiu Şorodoc MD, PhD
DIURETICS AND POTASSIUM-SPARING AGENTS
DAILY DOSE
(mg)
AGENT
DURATION OF ACTION
(hr)
Thiazides
Bendroflumethiazide (Naturetin)
01.25–5.0
>18
Benzthiazide (Aquatag, Exna)
12.5–50
12–18
Chlorothiazide (Diuril)
125–500
6–12
Cyclothiazide (Anhydron)
0.125–1
18–24
(Esidrix, 6.25–50
12–18
Hydroflumethiazide (Saluron)
12.5–50
18–24
Methyclothiazide (Enduron)
2.5–5.0
>24
Polythiazide (Renese)
1–4
24–48
Trichlormethiazide (Metahydrin, Naqua)
1–4
>24
Chlorthalidone (Hygroton)
12.5–50
24–72
Indapamide (Lozol)
1.25–2.5
24
Metolazone (Mykrox, Zaroxolyn)
0.5–10
24
Quinethazone (Hydromox)
25–100
18–24
Bumetanide (Bumex)
0.5–5
4–6
Ethacrynic acid (Edecrin)
25–100
12
Furosemide (Lasix)
40–480
4–6
Torsemide (Demadex)
5–40
12
Amiloride (Midamor)
5–10
24
Spironolactone (Aldactone)
25–100
8–12
Triamterene (Dyrenium)
50–100
12
Hydrochlorothiazide
HydroDIURIL, Oretic)
Related Sulfonamide Compounds
Loop Diuretics
Potassium-Sparing Agents
From Kaplan NM: Clinical Hypertension. 7th ed. Baltimore, Williams & Wilkins, 1998, p 190.
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Conf. dr. Laurenţiu Şorodoc MD, PhD
Hypokalemia.
The degree of potassium wastage and hypokalemia is directly related to the dose of diuretic;
serum potassium level falls an average of 0.7 mmol/liter with 50 mg of hydrochlorothiazide 0.4
with 25, and little if any with 12.5.
Hypokalemia due to high doses of diuretic may precipitate potentially hazardous ventricular
ectopic activity and increase the risk of primary cardiac arrest, even in patients not known to
be susceptible because of concomitant digitalis therapy or myocardial irritability.
Most patients are unaware of mild diuretic-induced hypokalemia, although it may contribute to
leg cramps, polyuria, and muscle weakness, but subtle interference with antihypertensive
therapy may accompany even mild hypokalemia, and correction of hypokalemia may result in a
reduction in blood pressure.
Prevention of hypokalemia is preferable to correction of potassium deficiency. The following
maneuvers should help prevent diuretic-induced hypokalemia:







Use the smallest dose of diuretic needed.
Use a moderately long-acting (12- to 18-hour) diuretic, such as hydrocholorothiazide,
because longer-acting drugs (e.g., chlorthalidone) may increase potassium loss.
Restrict sodium intake to less than 100 mmol/day (i.e., 2.4 g sodium).
Increase dietary potassium intake.
Restrict concomitant use of laxatives.
Use a combination of a thiazide with a potassium-sparing agent except in patients with
renal insufficiency or in association with an ACE inhibitor or angiotensin II–receptor
blocker.
Concomitant use of a beta blocker or an ACE inhibitor diminishes potassium loss by
blunting the diuretic-induced rise in renin-aldosterone.
HYPERLIPIDEMIA.
Serum cholesterol levels often rise after diuretic therapy, but after 1 year, no adverse
effects were noted in those who responded to smaller doses.
HYPERGLYCEMIA AND INSULIN RESISTANCE.
High doses of diuretics may impair glucose tolerance and precipitate diabetes mellitus,
probably because they increase insulin resistance and hyperinsulinemia. The manner by which
diuretics increase insulin resistance is uncertain, but in view of the many potential pressor actions
of hyperinsulinemia, this could be a significant problem.
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Conf. dr. Laurenţiu Şorodoc MD, PhD
ADRENERGIC INHIBITORS
A number of drugs that inhibit the adrenergic nervous system are available, including some
that act centrally on vasomotor center activity, peripherally on neuronal catecholamine discharge,
or by blocking alpha- and/or beta-adrenergic receptors
ADRENERGIC INHIBITORS
ADRENERGIC INHIBITORS USED IN TREATMENT OF HYPERTENSION
Peripheral Neuronal Inhibitors
Reserpine
Guanethidine (Ismelin)
Guanadrel (Hylorel)
Bethanidine (Tenathan)
Central Adrenergic Inhibitors
Methyldopa (Aldomet)
Clonidine (Catapres)
Guanabenz (Wytensin)
Guanfacine (Tenex)
Alpha-Receptor Blockers
Alpha1 and alpha2 receptor
Phenoxybenzamine (Dibenzyline)
Phentolamine (Regitine)
Alpha1 receptor
Doxazosin (Cardura)
Prazosin (Minipress)
Terazosin (Hytrin)
Beta-Receptor Blocker
Acebutolol (Sectral)
Atenolol (Tenormin)
Betaxolol (Kerlone)
Bisoprolol (Zebeta)
Carteolol (Cartrol)
Metoprolol (Lopressor, Toprol)
Nadolol (Corgard)
Penbutolol (Levatol)
Pindolol (Visken)
Propranolol (Inderal)
Timolol (Blocadren)
Alpha- and Beta-Receptor Blocker
Labetalol (Normodyne, Trandate)
Carvedilol (Dilatrend)
When the nerve is stimulated, norepinephrine, which is synthesized intraneuronally and stored
in granules, is released into the synaptic cleft. It binds to postsynaptic alpha- and beta-adrenergic
receptors and thereby initiates various intracellular processes. In vascular smooth muscle, alpha
stimulation causes constriction and beta stimulation causes relaxation. In the central vasomotor
centers, sympathetic outflow is inhibited by alpha stimulation; the effect of central beta
stimulation is unknown.
An important aspect of sympathetic activity involves the feedback of norepinephrine to alphaand beta-adrenergic receptors located on the neuronal surface, i.e., presynaptic receptors.
Presynaptic alpha-adrenergic receptor activation inhibits release, whereas presynaptic beta
activation stimulates further norepinephrine
release. The presynaptic receptors probably
has a role in the action of some of the drugs to
be discussed
Simplified schematic view of the adrenergic nerve
ending showing that norepinephrine (NE) is released
from its storage granules when the nerve is stimulated
and enters the synaptic cleft to bind to alpha 1 and beta
receptors on the effector cell (postsynaptic). In
addition, a short feedback loop exists, in which NE
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binds to alpha2 and beta receptors on the neuron (presynaptic), to inhibit or to stimulate further release, respectively.
Drugs That Act Within the Neuron
Reserpine, guanethidine, and related compounds act differently to inhibit the release of
norepinephrine from peripheral adrenergic neurons.
RESERPINE.
1. Reserpine, the most active and widely used of the derivatives of the rauwolfia
alkaloids, depletes the postganglionic adrenergic neurons of norepinephrine by
inhibiting its uptake into storage vesicles, exposing it to degradation by cytoplasmic
monoamine oxidase.
2. The peripheral effect is predominant, although the drug enters the brain and depletes
central catecholamine stores as well. This probably accounts for the sedation and
depression accompanying reserpine use.
3. The drug has certain advantages: only one dose a day is needed; in combination with a
diuretic, the antihypertensive effect is significant, greater than that noted with
nitrendipine in one comparative study; little postural hypotension is noted; and many
patients experience no side effects.
4. The drug has a relatively flat dose-response curve, so that a dose of only 0.05 mg/day
gives almost as much antihypertensive effect as 0.125 or 0.25 mg/day but fewer side
effects.
5. Although it remains popular in some places and is recommended as an inexpensive
choice where resources are limited, reserpine has progressively declined in use because
it has no commercial sponsor.
GUANETHIDINE.
1. This agent acts by inhibiting the release of norepinephrine from the adrenergic neurons,
perhaps by a local anesthetic-like effect on the neuronal membrane. In order to act, the
drug must be transported actively into the nerve through an amine pump.
2. Their low lipid solubility prevents guanidine compounds from entering the brain, so
that sedation, depression, and other side effects involving the central nervous system
do not occur.
3. The initial predominant hemodynamic effect is decreased cardiac output: after
continued use, peripheral resistance declines.
4. Blood pressure is reduced further when the patient is upright, owing to gravitational
pooling of blood in the legs, because compensatory sympathetic nervous system–
mediated vasoconstriction is blocked. This results in the most common side effect,
postural hypotension.
5. Unlike reserpine, guanethidine has a steep dose-response curve, so that it can be
successfully used in treating hypertension of any degree in daily doses of 10 to 300 mg.
6. Like reserpine, it has a long biological half-life and may be given once daily.
7. Guanethidine has been relegated mainly to the treatment of severe hypertension
unresponsive to all other agents.
Drugs That Act on Receptors
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Conf. dr. Laurenţiu Şorodoc MD, PhD
Predominantly Central Alpha Agonists
Until the mid-1980's, methyldopa was the most widely used of the adrenergic receptor
blockers, but its use has declined as beta blockers and other drugs have become more popular. In
addition, three other drugs—clonidine, guanabenz, and guanfacine, which act similarly to
methyldopa but have fewer serious side effects—have become available.
METHYLDOPA.
1. The primary site of action of methyldopa is within the central nervous system, where
alpha-methylnorepinephrine, derived from methyldopa, is released from adrenergic
neurons and stimulates central alpha-adrenergic receptors, reducing the sympathetic
outflow from the central nervous system.
2. The blood pressure mainly falls as a result of a decrease in peripheral resistance with
little effect on cardiac output.
3. Renal blood flow is well maintained, and significant postural hypotension is
unusual.
4. The drug has been used in hypertensive patients with renal failure or cerebrovascular
disease and remains the most commonly used agent for pregnancy-induced
hypertension.
5. Methyldopa need be given no more than twice daily, in doses ranging from 250 to 1000
mg/day.
6. Side effects include some that are common to centrally acting drugs that reduce
sympathetic outflow: sedation, dry mouth, impotence, and galactorrhea. However,
methyldopa causes some unique side effects that are probably of an autoimmune
nature, because a positive antinuclear antibody test result occurs in about 10 percent of
patients who take the drug, and red cell autoantibodies occur in about 20 percent.
Clinically apparent hemolytic anemia is rare, probably because methyldopa also
impairs reticuloendothelial function so that antibody-sensitized cells are not removed
from the circulation and hemolyzed. Inflammatory disorders in various organs have
been reported, most commonly involving the liver (with diffuse parenchymal injury
similar to viral hepatitis).
CLONIDINE.
1. Although of different structure, clonidine shares many features with methyldopa. It
probably acts at the same central sites, has similar antihypertensive efficacy, and causes
many of the same bothersome but less serious side effects (e.g., sedation, dry mouth). It
does not, however, induce the autoimmune and inflammatory side effects.
2. As an alpha-adrenergic receptor agonist, the drug also acts on presynaptic alpha
receptors and inhibits norepinephrine release, and plasma catecholamine levels fall.
3. The drug has a fairly short biological half-life, so that when it is discontinued, the
inhibition of norepinephrine release disappears within about 12 to 18 hours, and plasma
catecholamine levels rise. This is probably responsible for the rapid rebound of the
blood pressure to pretreatment levels and the occasional appearance of withdrawal
symptoms, including tachycardia, restlessness, and sweating. If the rebound requires
treatment, clonidine may be reintroduced or alpha-adrenergic receptor antagonists
given.
4. Clonidine is available in a transdermal preparation, which may provide smoother blood
pressure control for as long as 7 days with fewer side effects. However, bothersome
skin rashes preclude its use in perhaps one-fourth of patients.
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Alpha1-adrenoceptor blocking agents. Alpha1 blockers (doxazosin, prazosin, terazosin) lower blood pressure by
preventing catecholamine-induced vasoconstriction. In this illustration, norepinephrine released from the
sympathetic nerve ending is depicted as circles, and the alpha 1-adrenergic blocking agent as an oval. The competitive
action is confined to the vascular smooth muscle cell. These agents selectively block postsynaptic alpha1
adrenoceptors. Catecholamines can still activate presynaptic alpha 2 receptors and thus exert an inhibitory action on
norepinephrine release by the sympathetic nerve terminal. This probably accounts for the lack of reflex heart rate
acceleration during alpha1-adrenoceptor blockade. Alpha1 blockers induce dilation of both arteries and veins. The
effect on the capacitive system accounts for the prominent fall in postural blood pressure that occurs in some
patients; this effect often limits the utility of these agents. Alpha 1 blockers are effective in reducing the symptoms of
benign prostatic hypertrophy, which makes them an attractive choice in hypertensive elderly men with that disorder.
Alpha-Adrenergic Receptor Antagonists
Before 1977, the only alpha blockers used to treat hypertension were phenoxybenzamine
(Dibenzyline) and phentolamine (Regitine). These drugs are effective in acutely lowering blood
pressure, but their effects are offset by an accompanying increase in cardiac output, and side
effects are frequent and bothersome. Their limited efficacy may reflect their blockade of
presynaptic alpha-adrenergic receptors, which interferes with the feedback inhibition of
norepinephrine release. Increased catecholamine release would then blunt the action of
postsynaptic alpha-adrenergic receptor blockade. Their use has largely been limited to the
treatment of patients with pheochromocytomas.
PRAZOSIN.
1. This was the first of a group of selective antagonists of the postsynaptic alpha1
receptors.
2. By blocking alpha-mediated vasoconstriction, prazosin induces a decline in
peripheral resistance with both venous and arteriolar dilation.
3. Because the presynaptic alpha-adrenergic receptor is left unblocked, the feedback loop
for the inhibition of norepinephrine release is intact, an action that is also certainly
responsible for the greater antihypertensive effect of the drug and the absence of
concomitant tachycardia, tolerance, and renin release.
4. Inhibition of norepinephrine release may also account for the propensity toward greater
first-dose reductions in blood pressure.
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Conf. dr. Laurenţiu Şorodoc MD, PhD
Beta-Adrenergic Receptor Antagonists



In the 1980's, beta-adrenergic receptor blockers became the most popular form of
antihypertensive therapy after diuretics.
For the majority of patients, beta-blockers are usually easy to take, because somnolence, dry
mouth, and impotence are seldom encountered.
Because beta-blockers have been found to reduce mortality if taken either before or after acute
myocardial infarction (i.e., secondary prevention), it was assumed that they might offer special
protection against initial coronary events, i.e., primary prevention.
Classification of beta-adrenergic receptor blockers based on cardioselectivity and intrinsic sympathomimetic activity
(ISA). Those not approved for use in the United States are in italics. (From Kaplan NM: Clinical Hypertension. 7th
ed. Baltimore, Williams & Wilkins, 1998, p 206.)
Clinical Effects.
1. Even in small doses, beta-blockers begin to lower the blood pressure within a few hours.
2. Although progressively higher doses have usually been given, careful study has shown a
near-maximal effect from smaller doses.
3. The degree of blood pressure reduction is at least comparable to that noted with other
antihypertensive drugs.
4. Beta blockers may be particularly well suited for younger and middle-aged hypertensive
patients, especially nonblacks, and for patients with myocardial ischemia and high levels
of stress.
5. Because the hemodynamic responses to stress are reduced, however, they may interfere
with athletic performance.
SPECIAL USES FOR BETA BLOCKERS
1.
2.
3.
4.
5.
14
COEXISTING ISCHEMIC HEART DISEASE.
COEXISTING HEART FAILURE.
PATIENTS WITH HYPERKINETIC HYPERTENSION.
PATIENTS WITH MARKED ANXIETY.
PERIOPERATIVE STRESS.
Braunwald 6th ed. 2001
Conf. dr. Laurenţiu Şorodoc MD, PhD
SIDE EFFECTS.
Most of the side effects of beta blockers relate to their major pharmacological action, the
blockade of beta-adrenergic receptors. Certain concomitant problems may worsen when betaadrenergic receptors are blocked, including peripheral vascular disease and bronchospasm.
1. The most common side effect is fatigue, which is probably a consequence of decreased
cardiac output and the decreased cerebral blood flow that may accompany successful
lowering of the blood pressure by any drug.
2. More direct effects on the central nervous system—insomnia, nightmares, and
hallucinations—occur in some patients.
3. An association with depression appears to be accounted for by various confounding
variables.
4. Diabetic patients may have additional problems with beta blockers, more so with
nonselective ones. The responses to hypoglycemia, both the symptoms and the
counterregulatory hormonal changes that raise blood glucose levels, are partially
dependent on sympathetic nervous activity. Diabetic patients who are susceptible to
hypoglycemia may not be aware of the usual warning signals and may not rebound as
quickly. The majority of noninsulin-dependent diabetic patients can take these drugs
without difficulty, although their diabetes may be exacerbated, probably from beta blocker
interference with insulin sensitivity.
5. When a beta blocker is discontinued, angina pectoris and myocardial infarction may
occur. Because patients with hypertension are more susceptible to coronary disease, they
should be weaned gradually and given appropriate coronary vasodilator therapy.
6. Perturbations of lipoprotein metabolism accompany the use of beta blockers.
Nonselective agents cause greater rises in triglycerides and reductions in cardioprotective
high-density lipoprotein-cholesterol levels, whereas ISA agents cause less or no effect and
some agents such as celiprolol may raise high-density lipoprotein cholesterol levels.
7. Caution is advised in the use of beta blockers in patients suspected of harboring a
pheochromocytoma, because unopposed alpha-adrenergic agonist action may precipitate
a serious hypertensive crisis if this disease is present.
8. The use of beta blockers during pregnancy has been clouded by scattered case reports of
various fetal problems. Moreover, prospective studies have found that the use of beta
blockers during pregnancy may lead to fetal growth retardation
General overview of beta blockers in hypertension:
1. Beta blockers are specifically recommended for hypertensive patients with
concomitant coronary disease, particularly after a myocardial infarction,
congestive heart failure, or tachyarrhythmias.
2. If a beta blocker is chosen, those agents that are more cardioselective and
lipid insoluble offer the likelihood of fewer perturbations of lipid and
carbohydrate metabolism and greater patient adherence to therapy; only one
dose a day is needed, and side effects probably are minimized.
3. In patients with heart failure, the initial dose should be very small (e.g.,
metoprolol 12.5 mg twice daily) and gradually increased to the maintenance
dose (100 to 200 mg twice daily).
Braunwald 6th ed. 2001
15
Conf. dr. Laurenţiu Şorodoc MD, PhD
Alpha- and Beta-Adrenergic Receptor Antagonists
1. The combination of an alpha and a beta-blocker in a single molecule is available in the
forms of labetalol and carvedilol, the latter agent approved for treatment of heart failure
as well.
2. The fall in pressure mainly results from a decrease in peripheral resistance, with little or
no decline in cardiac output.
3. The most bothersome side effects are related to postural hypotension; the most serious
side effect is hepatotoxicity.
4. Intravenous labetalol is used to treat hypertensive emergencies.
VASODILATORS
Direct Vasodilators
 Hydralazine is the most widely used agent of this type.
 Minoxidil is more potent but is usually reserved for patients with severe, refractory
hypertension associated with renal failure.
 Nitroprusside and nitroglycerin are given intravenously for hypertensive crises.
HYDRALAZINE.
1. From the early 1970's, hydralazine, in combination with a diuretic and a beta blocker, was
used frequently to treat severe hypertension.
2. The drug acts directly to relax the smooth muscle in precapillary resistance vessels,
with little or no effect on postcapillary venous capacitance vessels.
3. As a result, blood pressure falls by a reduction in peripheral resistance, but in the process a
number of compensatory processes, which are activated by the arterial baroreceptor arc,
blunt the decrease in pressure and cause side effects.
4. With concomitant use of a diuretic to overcome the tendency for fluid retention and an
adrenergic inhibitor to prevent the reflex increase in sympathetic activity and rise in
renin, the vasodilator is more effective and causes few, if any, side effects.
5. Without the protection conferred by concomitant use of an adrenergic blocker, numerous
side effects (tachycardia, flushing, headache, and precipitation of angina) may occur.
6. The drug need be given only twice a day. Its daily dose should be kept below 400 mg to
prevent the lupus-like syndrome that appears in 10 to 20 percent of patients who receive
more. This reaction, although uncomfortable to the patient, is almost always reversible.
The reaction is uncommon with daily doses of 200 mg or less.
MINOXIDIL.
1. This drug vasodilates by opening potassium channels in vascular smooth muscle.
2. Its hemodynamic effects are similar to those of hydralazine, but minoxidil is even more
effective and may be used once a day.
3. It is particularly useful in patients with severe hypertension and renal failure.
4. Even more than with hydralazine, diuretics and adrenergic receptor blockers must be used
with minoxidil to prevent the reflex increase in cardiac output and fluid retention.
5. Pericardial effusions have appeared in about 3% of those given minoxidil, in some
without renal or cardiac failure. The drug also causes hair to grow profusely, and the facial
hirsutism precludes use of the drug in most women.
16
Braunwald 6th ed. 2001
Conf. dr. Laurenţiu Şorodoc MD, PhD
Calcium Antagonists
1. These drugs have become the most popular class of agents used in the treatment of
hypertension.
2. Dihydropyridines have the greatest peripheral vasodilatory action, with little effect on
cardiac automaticity, conduction, or contractility.
3. However, comparative trials have shown that verapamil and diltiazem, which do affect
these properties, are also effective antihypertensives, and they may cause fewer side
effects related to vasodilation, such as flushing and ankle edema.
PHARMACOLOGICAL EFFECTS OF CALCIUM ANTAGONISTS
DILTIAZEM VERAPAMIL DIHYDROPYRIDINES
Heart rate


–
Myocardial contractility


–
Nodal conduction


–
Peripheral vasodilation



 Indicates decrease; , increase; –, no change.
4. Calcium antagonists are effective in hypertensive patients of all ages and races and in
hypertensive diabetics.
5. Calcium antagonists may cause at least an initial natriuresis, probably by producing renal
vasodilation, which may obviate the need for concurrent diuretic therapy.
Renin-Angiotensin Inhibitors
Activity of the renin-angiotensin system may be inhibited in four ways, three of which can be
applied clinically:
 The first, use of beta-adrenergic receptor blockers to inhibit the release of renin,
was discussed earlier.
 The second, direct inhibition of renin activity by specific renin inhibitors, is being
investigated.
 The third, inhibition of the enzyme that converts the inactive decapeptide
angiotensin I to the active octapeptide angiotensin II, is being widely used with
orally effective ACE inhibitors.
 The fourth approach to inhibiting the renin-angiotensin system, blockade of
angiotensin's actions by a competitive receptor blocker, is now the basis for the
fastest growing class of antihypertensive agents. The AII receptor blockers (ARBs)
may offer additional benefits, but their immediate advantage is the absence of
cough that often accompanies ACE inhibitors, as well as less angioedema.
*In the absence of outcome data, both JNC-6 and WHO-ISH guidelines recommend their
use only if an ACE inhibitor cannot be tolerated. The ARBs are considered after the ACE
inhibitors.
MECHANISM OF ACTION.

The first of these ACE inhibitors, captopril, was synthesized as a specific inhibitor of the
converting enzyme that, in the classical pathway, breaks the peptidyldipeptide bond in
angiotensin I, preventing the enzyme from attaching to and splitting the angiotensin I
structure.
Braunwald 6th ed. 2001
17
Conf. dr. Laurenţiu Şorodoc MD, PhD

Because angiotensin II cannot be formed and angiotensin I is inactive, the ACE inhibitor
paralyzes the classical renin-angiotensin system, thereby removing the effects of most
endogenous angiotensin II as both a vasoconstrictor and a stimulant to aldosterone
synthesis.
Overall scheme of the renin-angiotensin mechanism indicating the site of action of angiotensin II type I
receptor antagonist.
The four sites of action of inhibitors of the renin-angiotensin system. J-G = Juxtaglomerular apparatus; CE
= converting enzyme.
18
Braunwald 6th ed. 2001
Conf. dr. Laurenţiu Şorodoc MD, PhD
Dual role of ACE inhibitors, both in preventing and treating cardiovascular disease. Note multiple sites of
action in both primary and secondary prevention. ACE inhibitors have an indirect effect in primary
prevention by lessening hypertension and by decreasing left ventricular hypertrophy. They protect the
blood vessels indirectly by an antihypertensive effect and directly inhibit carotid atherogenesis and
thrombogenesis. Given at the start of myocardial infarction, they improve mortality in high-risk patients. By
an antiarrhythmic effect, they may act to prevent postinfarct sudden death. By lessening wall stress, they
beneficially improve postinfarct remodeling and decrease the incidence of left ventricular failure. LVH = left
ventricular hypertrophy.

Interestingly, with long-term use of ACE inhibitors, the plasma angiotensin II levels
actually return to previous level while the blood pressure remains lowered; this
suggests that the antihypertensive effect may involve other mechanisms:
o Because the same enzyme that converts angiotensin I to angiotensin II is also
responsible for inactivation of the vasodilating hormone bradykinin, by inhibiting
the breakdown of bradykinin, ACE inhibitors increase the concentration of a
vasodilating hormone while they decrease the concentration of a vasoconstrictor
hormone.
o The increased plasma kinin levels may contribute to the vasodilation and
improvement in insulin sensitivity observed with ACE inhibitors, but they are
also responsible for the most common and bothersome side effect of their use, a
dry, hacking cough.
o ACE inhibitors may also vasodilate by increasing levels of vasodilatory
prostaglandins and decreasing levels of vasoconstricting endothelins.

Regardless of their mechanism of action, ACE inhibitors lower blood pressure mainly
by reducing peripheral resistance with little, if any, effect on heart rate, cardiac
output, or body fluid volumes, likely reflecting preservation of baroreceptor reflexes.
Their vasodilating effect may also involve restoration of endothelium-dependent
relaxation by nitric oxide. As a consequence, resistance arteries become less thickened and
more responsive.

Braunwald 6th ed. 2001
19
Conf. dr. Laurenţiu Şorodoc MD, PhD
ACE inhibitors have dual vasodilatory actions, chiefly on the renin-angiotensin system with ancillary effects
on the breakdown of bradykinin. The result of the former action is the inhibition of the vasoconstrictory
systems and the result of the latter is the formation of vasodilatory nitric oxide and prostacyclin. These
effects of bradykinin may protect the endothelium. A-II = angiotensin II; AT1 = angiotensin II subtype 1.
CLINICAL USE:
1. In patients with uncomplicated primary hypertension, ACE inhibitors provide
antihypertensive effects that are equal to those with other classes, but they are less
effective in blacks, perhaps because blacks tend to have lower renin levels.
2. They are equally effective in elderly and younger hypertensive patients.
3. The WHO-ISH guidelines include ACE inhibitors as a choice for initial therapy.
4. In view of the impressive reduction in morbidity and mortality with ramipril in the
HOPE trial of high-risk patients, the use of ACE inhibitors will almost certainly
increase.
5. The initial dose of ACE inhibitor may precipitate a rather dramatic but transient fall in
blood pressure that likely reflects a higher level of renin-angiotensin and that could be a
harbinger of the presence of renovascular hypertension (simple diagnostic test for the
disease).
6. The removal of the high levels of angiotensin II that they produce may deprive the stenotic
kidney of the hormonal drive to its blood flow, thereby causing a marked decline in renal
perfusion so that patients with solitary kidneys or bilateral disease may develop acute and
sometimes persistent renal failure.
7. Patients with intraglomerular hypertension, specifically those with diabetic
nephropathy or reduced renal functional mass due to other forms of renal parenchymal
disease, may benefit especially from the reduction in efferent arteriolar resistance that
follows reduction in angiotensin II.
8. ACE inhibitors are the best tolerated antihypertensive agents (along with ARBs), so their
use will continue to grow.
20
Braunwald 6th ed. 2001
Conf. dr. Laurenţiu Şorodoc MD, PhD
SIDE EFFECTS.
1. Cough (10 percent of women and about half as many men). If a cough appears in a patient
who needs an ACE inhibitor, an ARB should be substituted !
2. Rash.
3. Loss of taste.
4. Leukopenia (neutropenia).
5. Hyperkalemia.
6. Angioneurotic edema.
ANGIOTENSIN II RECEPTOR BLOCKERS (ARBs)
CLINICAL PHARMACOLOGY OF AVAILABLE ANGIOTENSIN II RECEPTOR BLOCKERS
ACTIVE
METABOLITE
FOOD EFFECT
HALF-LIFE
(hr)
Prodrug
No
9–10
Irbesartan (Avapro)
No
No
11–15
Losartan (Cozaar)
Yes
Modest
2–4
Telmisartan (Micardis)
No
No
18–24
Valsartan (Diovan)
No
Moderate
6–8
COMPOUND
Candesartan (Atacand)
Schematic representation of a possible mechanism of action of the AT 1 receptor antagonist. Blockade of
the AT1 receptor is accompanied by increased circulating angiotensin II (Ang II) plasma levels, which
stimulate the unblocked AT2 receptor. This induces a rise in cyclic guanosine monophosphate (cGMP)
formation. L NAME = NG-nitro-L-arginine methyl ester; NOS = nitric oxide synthase; HOE = code number
of Hoechst 140, at present also known as I cantilant.
Braunwald 6th ed. 2001
21
Conf. dr. Laurenţiu Şorodoc MD, PhD
Other Vasodilators
Various other forms of antihypertensive therapy are under investigation:
 endothelin receptor antagonists
 agents that inhibit both the ACE and neutral endopeptidase, thereby increasing atrial
natriuretic hormone.
The distant future may see the application of gene therapy.
SPECIAL CONSIDERATIONS IN THERAPY
HYPERTENSION IN THE ELDERLY.
 A few elderly persons may have high blood pressure as measured by the
sphygmomanometer but may have less or no hypertension when direct intraarterial
readings are made, i.e., pseudohypertension due to rigid arteries that do not collapse under
the cuff.


22
If either the systolic pressure alone or both systolic and diastolic levels are elevated,
careful lowering of blood pressure with either diuretics or dihydropyridine calcium
antagonists has been unequivocally documented to reduce cardiovascular morbidity in
older hypertensive patients extending to those older than 80 years.
In view of the reduced effectiveness of the baroceptor reflex and the failure of peripheral
resistance to rise appropriately with standing, drugs with a propensity to cause postural
Braunwald 6th ed. 2001
Conf. dr. Laurenţiu Şorodoc MD, PhD

hypotension should be avoided, and all drugs should be given in slowly increasing doses
to prevent excessive lowering of the pressure.
For those who start with systolic pressures exceeding 160 mm Hg, the goal of therapy
should be a level around 140 mm Hg with little concern about further reductions in already
low diastolic levels.
FACTORS THAT MIGHT CONTRIBUTE TO INCREASED RISK OF PHARMACOLOGICAL
TREATMENT OF HYPERTENSION IN THE ELDERLY
POTENTIAL
COMPLICATIONS
FACTORS
Diminished baroreceptor activity
Orthostatic hypotension
Decreased intravascular volume
Orthostatic hypotension, dehydration
Sensitivity to hypokalemia
Arrhythmia, muscle weakness
Decreased renal and hepatic function
Drug accumulation
Polypharmacy
Drug interaction
Central nervous system changes
Depression, confusion
PATIENTS WITH HYPERTENSION AND DIABETES.
 Most diabetic hypertensive patients need two or more antihypertensive drugs to bring their
pressure to below 130/85 mm Hg, which is likely the highest level that should be tolerated.


An ACE inhibitor should be included if proteinuria is present.
A diuretic and a beta-blocker are appropriate, and a long-acting dihydropyridine will
likely be required.
HYPERTENSIVE PATIENTS WITH IMPOTENCE.
 Erectile dysfunction is common in hypertensive patients, even more so in those who are
also diabetic.
 The problem may be exacerbated by diuretic therapy, even in appropriately low doses.
Braunwald 6th ed. 2001
23
Conf. dr. Laurenţiu Şorodoc MD, PhD

Fortunately, sildenafil (Viagra) usually returns erectile ability, but caution is advised with
antihypertensive drugs.The potential for hypotension, well recognized with concomitant
nitrate therapy, may also appear with other vasodilators, although to a lesser degree.
HYPERTENSION WITH CONGESTIVE HEART FAILURE.
 Lowering the blood pressure may, by itself, relieve the heart failure.
 Chronic unloading has been most efficiently accomplished with ACE inhibitors, and beta
blockers have been shown to
further reduce morbidity and
mortality in ACE inhibitor–treated
patients in heart failure.
 Caution is needed for those elderly
hypertensive patients with diastolic
dysfunction related to marked left
ventricular hypertrophy, because
unloaders may worsen their status,
whereas beta blockers or calcium
antagonists may be beneficial.
 All
antihypertensive
drugs
except direct vasodilators have
been shown to regress left
ventricular hypertrophy and
regression may continue for as
long as 5 years of treatment.
(Jennings G, Wong J: Regression of left ventricular hypertrophy in hypertension: Changing patterns with successive meta-analyses. J
Hypertens 16:S29, 1998)
HYPERTENSION WITH ISCHEMIC HEART DISEASE.
 The coexistence of ischemic heart disease makes antihypertensive therapy even more
essential, because relief of the hypertension may ameliorate the coronary disease.
 Beta
blockers
and
calcium
antagonists are particularly useful if
angina or arrhythmias are present.
24
Braunwald 6th ed. 2001
Conf. dr. Laurenţiu Şorodoc MD, PhD
THERAPY FOR HYPERTENSIVE CRISES


When DBP exceeds 140 mm Hg, rapidly progressive damage to the arterial vasculature is
demonstrable experimentally, and a surge of cerebral blood flow may rapidly lead to
encephalopathy
If such high pressures persist or if there are any signs of encephalopathy, the pressures
should be lowered using parenteral agents in those patients considered to be in immediate
danger or with oral agents in those who are alert and in no other acute distress.
PARENTERAL DRUGS FOR TREATMENT OF HYPERTENSIVE EMERGENCY (IN ORDER OF
RAPIDITY OF ACTION)
DRUG
ONSET
ACTION
DOSAGE
OF
ADVERSE EFFECTS
Vasodilators
Nitroprusside (Nipride, 0.25–10
Nitropress)
infusion
mg/kg/min
as
IV Instantaneous
Nausea,
vomiting,
muscle
twitching,
sweating,
thiocyanate
intoxication
Nitroglycerin
5–100 mg/min as IV infusion
2–5 min
Tachycardia,
flushing,
headache,
vomiting,
methemoglobinemia
Nicardipine (Cardene)
5–15 mg/hr IV
5–10 min
Tachycardia,
flushing,
phlebitis
Hydralazine
(Apresoline)
10–20
10–50 mg IM
Enalapril (Vasotec IV)
1.25–5 mg q 6 hr
15 min
Precipitous fall in blood
pressure
in
high
renin states; response variable
Fenoldopam (Corlopam)
0.1–0.3 mg/kg/min
<5 min
Tachycardia, headache, nausea,
flushing
Phentolamine (Regitine)
5–15 mg IV
1–2 min
Tachycardia, flushing
Esmolol (Brevibloc)
500 mg/kg/min for 4 min, then 1–2 min
150–300 mg/kg/min IV
mg
IV 10–20
20–30 min
headache,
local
min Tachycardia,
flushing,
headache,
vomiting,
aggravation of angina
Adrenergic inhibitors
Labetalol
Trandate)
(Normodyne, 20–80 mg IV bolus every 10 min 5–10 min
2 mg/min IV infusion
Hypotension
Vomiting,
scalp
tingling,
burning
in
throat, postural hypotension,
dizziness,
nausea
1. If diastolic pressure exceeds 140 mm Hg and the patient has any complications, such as
an aortic dissection, a constant infusion of nitroprusside is most effective and almost
always lowers the pressure to the desired level. Constant monitoring with an intraarterial
line is mandatory because a slightly excessive dose may lower the pressure abruptly to
Braunwald 6th ed. 2001
25
Conf. dr. Laurenţiu Şorodoc MD, PhD
levels that induce shock. The potency and rapidity of action of nitroprusside have made it
the treatment of choice for life-threatening hypertension. However, nitroprusside acts as a
venous and arteriolar dilator, so that venous return and cardiac output are lowered and
intracranial pressures may increase.
2. Other parenteral agents are being more widely used. These include labetalol and the
calcium antagonist nicardipine.
3. With any of these agents, intravenous furosemide is often needed to lower the blood
pressure further and prevent retention of salt and water. Diuretics should not be given if
volume depletion is initially present.
For patients in less immediate danger, oral therapy may be used.
 Almost every drug has been used and most will, with repeated doses, reduce high
pressures.
 The prior preference for liquid nifedipine by mouth or sublingually has been deflated
because of occasional ischemic complications from too rapid reduction in blood pressure.
 Oral doses of other short-acting formulations may be used, including furosemide,
propranolol, captopril, or felodipine.
26
Braunwald 6th ed. 2001