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CHAPTER 8
ANTIHYPERTENSIVE DRUGS
Classification
-
Diuretics.
-
Beta adrenergic blockers.
-
Calcium channel blockers.
- Angiotensin converting enzyme inhibitors.
-
Angiotensin receptor blockers.
-
Sympatholytics and adrenergic blockers.
- Direct arterial vasodilators.
- Documented reduction in cardiovascular morbidity and mortality.
- Least expensive antihypertensive drugs.
- Best drug for treatment of systolic hypertension and for hypertension
in the elderly.
- Can be combined with all other antihypertensive drugs to produce synergetic
effect.
-
Metabolic effects (uncommon with small doses): hypokalemia,
hypomagnesemia, hyponatremia, hyperuricemia, dyslipidemia (increased
total and LDL cholesterol), impaired glucose tolerance, and hypercalcemia
(with thiazides).
-
Postural hypotension.
- Impotence in up to 22% of patients.
-
Moderate salt restriction is the key for effective antihypertensive
effect of diuretics and for protection from diuretic - induced hypokalaemia.
- Thiazides are not effective in patients with renal failure (serum
creatinine > 2mg /dl) because of reduced glomerular filtration rate.
- Frusemide needs frequent doses ( 2-3 /day ).Thiazides can be given
once daily or every other day.
-
Potassium supplements should not be routinely combined with thiazide
or loop diuretics. They are indicated with hypokalemia (serum potassium
< 3.5 mEq/L) especially with concomitant digitalis therapy or
left ventricular hypertrophy.
-
Nonsteroidal antiinflammatory drugs can antagonize diuretics
effectiveness.
- Diuretics should be the primary choice in all hypertensives.
-
They are indicated in:
- Volume dependent forms of hypertension:
blacks, elderly, diabetic, renal and obese hypertensives.
- Hypertension complicated with
heart failure.
- Resistant hypertension: loop
diuretics in large doses are recommended.
- Renal impairment: loop diuretics.
Preparations and Dosage: see table 12.
2. Beta - Adrenergic Blocking Agents
Mechanisms of Action
- Initial decrease in cardiac output, followed by reduction in peripheral
vascular resistance.
-
Other actions include decrease plasma renin activity, resetting
of baroreceptors, release of vasodilator prostaglandins, and blockade
of pre-junctional beta-receptors.
-
Documented reduction in cardiovascular morbidity and mortality.
-
Cardioprotection: primary and secondary prevention against coronary
artery events (i.e. ischemia, infarction, arrhythmias, death).
-
Relatively not expensive.
- Bronchospasm and obstructive airway disease.
- Bradycardia
-
Metabolic effects (raise triglyerides levels and
decrease HDL cholesterol; may worsen insulin sensitivity and cause
glucose intolerance). Increased incidence of diabetes mellitus.
- Coldness of extremities.
- Fatigue.
-
Mask symptoms of hypoglycemia.
-
Impotence.
- First line treatment for hypertension as an alternative
to diuretics.
- Hypertension associated with coronary artery disease.
- Hyperkinetic circulation and high cardiac output
hypertension (e.g., young hypertensives).
- Hypertension associated with supraventricular tachycardia,
migraine, essential tremors, or hypertrophic cardiomyopathy.
Preparations and Dosages: see table 12
3. Calcium channel blockers
Types
- Dihydropyridine: nifedipine, amlodipine, felodipine,
nicardipine, lacidipine.
-
Non dihydropyridine :
-
Phenylalkylamine: verapamil.
-
Benzothiazepine: diltiazem.
Mechanisms of action
-
Decrease in the concentration of free intracellular
calcium ions results in decreased contraction and vasodilation.
-
Diuretic effect through increase in renal blood
flow and glomerular filtration rate.
-
Inhibition of aldosterone secretion.
-
No metabolic distrubances: no change in blood glucose,
potassium, uric acid and lipids.
-
May improve renal function.
-
Maintain optimal physical, mental, and sexual activities.
-
Ischemic heart disease: when beta blockers are ineffective
or contraindicated and in vasospastic angina.
-
Elderly hypertensives: second agent of choice after
diuretics.
-
Peripheral vascular disease (e.g., Raynauld`s phenomenon).
-
Side Effects
-
Dihydropyridine: flushing, headache, and lower limb
oedema.
-
Non dihydropyridine: aggravation of heart failure
and heart block. Verapamil may cause constipation.
Practical Considerations
Short acting dihydropyridine should be combined with
beta blockers in coronary artery disease, and should be avoided in stroke,
and hypertensive crisis.
Peparations and Dosages: see table 12.
4. Angiotensin Converting Enzyme Inhibitors
Types
-
Class I: captopril
-
Class II (prodrug) : e.g., ramipril, enalapril,
perindopril
-
Class III ( water soluble) : lisinopril.
-
Inhibition of circulating and tissue angiotensin-
converting enzyme.
-
Increased formation of bradykinin and vasodilatory
prostaglandins.
-
Decreased secretion of aldosterone; help sodium
excretion.
-
Reduction of cardiovascular morbidity and mortality
in patients with atherosclerotic vascular disease, diabetes, and heart
failure.
-
Favorable metabolic profile.
-
Improvement in glucose tolerance and insulin resistance.
-
Renal glomerular protection effect especially in
diabetes mellitus.
-
Do not adversely affect quality of life.
-
Diabetes mellitus, particularly with nephropathy.
-
Congestive heart failure.
-
Following myocardial infraction.
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Cough (10 - 30%): a dry irritant cough with tickling
sensation in the throat.
-
Skin rash (6%).
-
Postural hypotension in salt depleted or blood volume
depleted patients.
-
Angioedema (0.2%) : life threatening.
-
Renal failure: rare, high risk with bilateral renal
artery stenosis.
-
Hyperkalaemia
-
Teratogenicity.
-
Contraindications include bilateral renal artery
stenosis, pregnancy, known allergy, and hyperkalaemia.
-
High serum creatinine (> 3 mg/dl) is an indication
for careful monitoring of renal function, and potassium. Benefits
can still be obtained in spite of renal insufficiency.
-
A slight stable increase in serum creatinine after
the introduction of ACE inhibitors does not limit use.
-
ACE-I are more effective when combined with diuretics
and moderate salt restriction.
Preparations and dosages: see table 12.
5. Angiotensin Receptor Blockers
Mechanism of action
They act by blocking type I angiotensin II receptors
generally, producing more blockade of the renin - angiotensin - aldosterone
axis.
Advantages
Practical Indications
Patients with a compelling indication for ACE-I and
who can not tolerate them because of cough or allergic reactions.
Preparations and Dosages: see table 12.
6. Sympatholytics And Alpha Adrenergic Blockers
Types
1. Alpha 1-receptor blockers:
prazocin,doxazocin.
2. Centrally acting alpha 2- agonists:
methyldopa, clonidine.
3. Peripherally acting adrenergic
antagonists: reserpine.
4. Imidazoline receptor agonists:
rilmenidine, moxonidine.
Advantages
-
Alpha1- receptor blockers and imidazoline receptor
agonists improve lipid profile and insulin sensitivity.
-
Methyldopa: increases renal blood flow. Drug of
choice during pregnancy.
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Reserpine: neutral metabolic effects and cheap.
-
Diabetes mellitus: alpha1- receptor blockers, imidazoline
receptor agonists.
-
Dyslipidemia: alpha 1- receptor blockers, imidazoline
receptor agonists.
-
Prostatic hypertrophy: alpha 1- receptor blockers.
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When there is a need for rapid reduction in blood
pressure: clonidine.
-
Prazocin: postural hypotension, diarrhea, occasional
tachycardia, and tolerance (due to fluid retention).
-
Methyldopa: sedation, hepatotoxicity, hemolytic
anemia, and tolerance.
-
Reserpine: depression, lethargy, weight loss, peptic
ulcer, diarrhea, and impotence.
-
Clonidine: dry mouth, sedation, bradycardia, impotence,
and rebound hypertension if stopped suddenly.
-
Prazocin, methyldopa, and reserpine should be combined
with a diuretic because of fluid retention.
-
In Egypt, reserpine is only available as combination
pill with thiazide (Brenardine) which contains 0.1 mg of reserpine
per tablet.
Preparations and Dosages: see table 12.
7. Direct Arterial Vasodilators
Types: hydralazine, diazoxide, nitroprusside,
and minoxidil (see chapter 10).
Patients’ compliance to antihypertensive medications
Poor adherence to antihypertensive therapy remains
a major therapeutic challenge contributing to the lack of adequate control
of blood pressure in more than two thirds of patients with hypertension.
One half of all patients discontinue antihypertensive medications within
one year.
Causes of Poor Compliance
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Hypertension has no symptoms and treatment has to
continue indefinitely.
-
Poor communication with the patient. Very long intervals
between follow-up visits, and frequent change of doctors impair the
doctor-patient relationship.
-
Logistic barriers e.g. expense of medications,
inability to read instructions, complicated multi-dose regimens, etc….
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Adverse drug effects.
Strategies to Improve Compliance
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Educate patients about the disease and involve their
families in the treatment.
-
Stress that treatment is life-long.
-
Consider cost while prescribing.
-
Consider adverse effects at initial prescription
and follow up visits.
-
Prescribe simple once-daily regimens.
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Allow extra visits for blood pressure measurement
at no extra charge to the patient.
-
Arrange follow-up visits at intervals no more than
three months apart, during the first year.
-
Encourage life style modifications.
| Table 12. Commonly Used Oral Antihypertensive
Medications |
| Class |
Generic Name |
Daily Dose (mg) |
Common Brand Name(s) |
Tablet Size (mg) |
| Diuretics |
Hydrochlorothiazide |
12.5-50 |
Hydrex |
25 |
| |
|
|
Aldactazide # |
25 |
| |
|
|
Moduretic ++ |
25 |
| |
Indapamide |
1.25-5 |
Natrilix |
2.5 |
| |
|
|
Natrilix SR |
1.5 |
| |
Chlorthalidone |
25-50 |
Hygrotone |
50 |
| |
Frusemide |
20-400 |
Lasix |
40 |
| |
Bumetanide |
1-4 ( or more ) |
Burinex |
1 |
| |
|
|
|
|
| Beta adrenergic blockers |
Atenolol |
25-100 |
Tenormin |
50, 100 |
| |
|
|
Blockium |
50, 100 |
| |
|
|
Blockium Diu * |
50 |
| |
Metoprolol |
50-200 |
Betaloc |
100 |
| |
Bisoprolol |
2.5-10 |
Concor |
5,10 |
| |
|
|
Concor 5 Plus* |
5 |
| |
|
|
|
|
| Calcium antagonists |
Verapamil |
120-480 |
Isoptin retard |
240 |
| |
|
|
Tarka *** |
120 |
| |
Diltiazem |
90-240 |
Tildium |
60 |
| |
|
|
Altiazem |
60 |
| |
|
|
Delaytiazem |
90, 120, 180 |
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Nifedipine |
20-80 |
Adalat retard |
20 |
| |
|
|
Epilat retard |
20 |
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Amlodipine |
2.5-10 |
Norvasc |
5, 10 |
| |
|
|
Amilo |
5 |
| |
Lacidipine |
2-4 (or more ) |
Lacipil |
2,4 |
| ACE inhibitors |
Captopril |
50-150 |
Capoten |
25, 50 |
| |
|
|
Capozide * |
50 |
| |
|
|
Captopril |
25, 50 |
| |
Enalapril |
2.5-40 |
Renetec |
10, 20 |
| |
|
|
Co-renetec |
10,20 |
| |
|
|
Ezapril |
10,20 |
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Lisinopril |
10-40 |
Zestril |
5,10,20 |
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|
|
Zestoretic |
20 |
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Ramipril |
2.5-20 |
Tritace |
1.25, 2.5, 5, 10 |
| |
|
|
Tritace comp * |
5 |
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|
|
Tritace comp LS * |
2.5 |
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Perindopril |
2-8 |
Coversyl |
2,4 |
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|
|
|
|
| Angiotensin Receptor blockers |
Losartan |
25-100 |
Cozaar |
50 |
| |
|
|
Hyzaar * |
50 |
| |
|
|
Losartan |
50 |
| |
|
|
Fortzar* |
100 |
| |
Valsartan |
80-320 |
Tareg |
80, 160 |
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|
|
Co-Tareg * |
80, 160 |
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|
|
Co-Diovan* |
160 |
| |
Candesartan |
4-32 |
Atacand |
8 |
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Telmisartan |
20-80 |
Micardis |
40, 80 |
| |
|
|
|
|
| Alpha-adrenergic blockers |
Prazocin |
1-16 |
Minipress |
1,2 |
| |
Doxazocin |
1-16 |
Cardura |
1,4 |
| |
|
|
|
|
| Centrally acting drugs |
Methyldopa |
500-2000 |
Aldomet |
250, 500 |
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Clonidine |
0.1-1.2 |
Catapres |
0.1, 0.2, 0.3 |
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Rilmenidine |
1-2 |
Rilmenidine |
1.0 |
| |
Reserpine |
0.1 |
Brenardine |
0.1 |
* Combination with hydrochlorothiazide
# Combination with spironolactone ++ Combination
with triametrene
*** Combination with ACE inhibitor
** Combination with thiazide & vasodilator
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