Antihypertensive drugs
- Pharm. Adegbenga Adeoye, dept of Pharmacology&Toxicology, FUOye
Antihypertensive drugs, which act to reduce blood pressure, are used to treat hypertension, a disorder
characterized by elevation in systolic blood pressure, diastolic blood pressure, or both.
Treatment for hypertension typically begins with a thiazide diuretic or a calcium channel blocker.
The patient may also receive a beta-adrenergic antagonist, angiotensin-converting enzyme (ACE)
inhibitor, or an angiotensin II receptor blocker.
The choice of these drugs depends on whether the patient has a compelling indication, such as heart
failure, history of an MI, high risk of coronary artery disease (CAD), diabetes, or chronic kidney disease.
Other drugs used to treat hypertension include sympatholytic drugs (other than beta-adrenergic
blockers), and vasodilators. At times, a combination of drugs may be used.
Sympatholytic drugs
Sympatholytic drugs include several different types of drugs, but all reduce blood pressure by inhibiting
or blocking the sympathetic nervous system. They’re classified by their site or mechanism of action and
include:
• central-acting sympathetic nervous system inhibitors (clonidine and methyldopa) • alpha-adrenergic
blockers (doxazosin, phentolamine, prazosin, and terazosin)
• mixed alpha- and beta-adrenergic blockers (carvedilol and labetalol)
• norepinephrine depletors (guanadrel, guanethidine, and reserpine—these are rarely used).
Pharmacokinetics
Most sympatholytic drugs are absorbed well from the GI tract, distributed widely, metabolized in the
liver, and excreted primarily in urine.
Pharmacodynamics
All sympatholytic drugs inhibit stimulation of the sympathetic nervous system, causing dilation of the
peripheral blood vessels or decreased cardiac output, thereby reducing blood pressure.
Pharmacotherapeutics
If blood pressure fails to come under control with beta-adrenergic blockers and diuretics, an alpha-
adrenergic blocker, such as prazosin, or a mixed alpha- and beta-adrenergic blocker, such as labetalol,
may be used.
If the patient fails to achieve the desired blood pressure, the physician may add a drug from a different
class, substitute a drug in the same class, or increase the drug dosage.
Drug interactions
Sympatholytic drugs can create these drug interactions:
• Carvedilol taken with antidiabetics may result in increased hypoglycemic effect.
• Carvedilol taken with calcium channel blockers may result in increased conduction disturbances.
• Carvedilol taken with digoxin may result in increased digoxin levels.
• Carvedilol taken with rifampin decreases carvedilol levels.
• Clonidine plus tricyclic antidepressants may increase blood pressure.
• Clonidine taken with CNS depressants may worsen CNS depression.
• Reserpine taken with diuretics or other hypotensive agents can increase the hypotensive effects of
reserpine.
• Reserpine taken with cardiac glycosides can lead to cardiac arrthymias. Sympatholytic drugs can also
produce significant adverse reactions.
Vasodilating drugs
There are two types of vasodilating drugs—direct vasodilators and calcium channel blockers.
Both types decrease systolic and diastolic blood pressure.
Direct vasodilators act on arteries, veins, or both. They include: • diazoxide • hydralazine • minoxidil •
nitroprusside. Hydralazine and minoxidil are usually used to treat resistant or refractory hypertension.
Diazoxide and nitroprusside are reserved for use in hypertensive crisis.
No admittance: Calcium channel blockers produce arteriolar relaxation by preventing the entry of
calcium into the cells. This prevents the contraction of vascular smooth muscle.
Pharmacokinetics:
Most of these drugs are absorbed rapidly and well-distributed. They’re all metabolized in the liver, and
most are excreted by the kidneys.
Pharmacodynamics:
The direct vasodilators relax peripheral vascular smooth muscle, causing the blood vessels to dilate. The
increased diameter of the blood vessels reduces total peripheral resistance, which lowers blood
pressure.
Pharmacotherapeutics
Vasodilating drugs are rarely used alone to treat hypertension. They’re usually combined with other
drugs to treat the patient with moderate to severe hypertension (hypertensive crisis).
Calcium channel blockers are occasionally used alone to treat mild to moderate hypertension.
Drug interactions
• The antihypertensive effects of hydralazine and minoxidil are increased when they’re given with other
antihypertensive drugs, such as methyldopa or reserpine.
• Vasodilating drugs may produce additive effects when given with nitrates, such as isosorbide dinitrate
or nitroglycerin. • Few other drug interactions occur with vasodilating drugs. (See Adverse reactions to
direct vasodilators.)
Adverse reactions to direct vasodilators
Direct vasodilators commonly produce adverse reactions related to reflex activation of the sympathetic
nervous system. As blood pressure falls, the sympathetic nervous system is stimulated, producing
compensatory measures, such as vasoconstriction and tachycardia.
Other reactions to sympathetic stimulation include: • palpitations • angina • edema • breast tenderness
• fatigue • headache • rash • severe pericardial effusion.
ACE inhibitors
ACE inhibitors are typically used when beta-adrenergic blockers or diuretics are ineffective.
Commonly prescribed ACE inhibitors include: • benazepril • captopril • enalapril • enalaprilat •
fosinopril • lisinopril • moexipril • quinapril • ramipril • trandolapril.
Pharmacokinetics
ACE inhibitors are absorbed from the GI tract, distributed to most body tissues, metabolized somewhat
in the liver, and excreted by the kidneys.
Ramipril is also excreted in stool.
Enalaprilat is the only ACE inhibitor that’s administered I.V.
Pharmacodynamics
ACE inhibitors reduce blood pressure by interrupting the reninangiotensin-aldosterone system.
Normally, the kidneys maintain blood pressure by releasing the hormone renin. Renin acts on the
plasma protein angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II.
Angiotensin II, a potent vasoconstrictor, increases peripheral resistance and promotes the excretion of
aldosterone. Aldosterone, in turn, promotes the retention of sodium and water, increasing the volume
of blood the heart needs to pump.
Conversion diversion
ACE inhibitors prevent the conversion of angiotensin I to angiotensin II. As angiotensin II is reduced,
arterioles dilate, reducing peripheral vascular resistance.
Less water, less work
By reducing aldosterone secretion, ACE inhibitors promote the excretion of sodium and water, which
reduces the amount of blood the heart needs to pump, thereby lowering blood pressure.
Pharmacotherapeutics
ACE inhibitors may be used alone or with another drug, such as a thiazide diuretic, to treat
hypertension.
Certain ACE inhibitors— such as captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and
trandolapril—may also be used to treat patients with heart failure or following MI. Such situations
include: • left ventricular systolic failure (unless contraindicated or intolerant) • left ventricular systolic
dysfunction without symptoms of heart failure • reducing mortality following acute MI (especially in
patients with prior myocardial injury) • preventing or delaying the development of left ventricular
dilation and overt heart failure in patients with left ventricular dysfunction (recent or remote) • possible
production of complementary effects (combined with beta-blockade) • history of or present fluid
retention (combined with diuretics).
Ramipril is also indicated to prevent major cardiovascular events in patients with a history of vascular
disease or diabetes. It’s also used to reduce overall cardiovascular risk, including death, nonfatal MI,
nonfatal stroke, and complications of diabetes.
Captopril is also indicated for the long-term treatment of diabetic neuropathy.
Drug interactions
ACE inhibitors can cause several different types of interactions with other cardiovascular drugs.
All ACE inhibitors enhance the hypotensive effects of diuretics and other antihypertensives such as beta-
adrenergic blockers. They can also increase serum lithium levels, possibly resulting in lithium toxicity.
When ACE inhibitors are used with potassium-sparing diuretics, potassium supplements, or potassium-
containing salt substitutes, hyperkalemia may occur.
Individual items
ACE inhibitors interact with many other medications, prescription as well as over-the-counter (OTC).
For example, patients taking ACE inhibitors should avoid taking all NSAIDs. Besides decreasing the
antihypertensive effect of ACE inhibitors, NSAIDs may alter renal function. Also, antacids may impair the
absorption of fosinopril, and quinapril may reduce the absorption of tetracycline.
A patient taking ACE inhibitors shouldn’t take prescriptions or OTC medications or herbal products
without first consulting his physician.
Adverse reactions to ACE inhibitors
Angiotensin-converting enzyme (ACE) inhibitors can produce these adverse reactions:
• headache and fatigue • dry, nonproductive, persistent cough • angioedema • GI reactions • increased
serum potassium concentrations • tickling in the throat • transient elevations of blood urea nitrogen
and serum creatinine levels (indicators of kidney function).
Caused by captopril
Captopril may cause protein in the urine, reduced neutrophils and granulocytes (a type of white blood
cells), rash, loss of taste, hypotension, or a severe allergic reaction.
Angiotensin II receptor blockers
Angiotensin II receptor blockers (ARBs) lower blood pressure by blocking the vasoconstrictive effects of
angiotensin II.
Specific drugs include: • candesartan cilexetil • eprosartan • irbesartan • losartan • olmesartan •
telmisartan • valsartan.
Pharmacokinetics
ARBs have varying pharmacokinetic properties and all are highly bound to plasma proteins.
Pharmacodynamics
ARBs act by interfering with the renin-angiotensin-aldosterone system (RASS). Specifically, these drugs
block the binding of angiotensin II to the AT1 receptor. This prevents angiotensin II from exerting its
vasoconstricting properties and from promoting the excretion of aldosterone. Both of these actions
result in lowered blood pressure. ARBs don’t inhibit the conversion of angiotensin I to angiotensin II, nor
do they cause a breakdown in bradykinin (a vasodilator).
Pharmacotherapeutics
ARBs may be used alone or in combination with other drugs such as a diuretic. Valsartan may also be
used as an alternative to an ACE inhibitor or for the management of heart failure.
Because irbesartan and losartan protect the renal system, they’re often prescribed for patients with
type 2 diabetes.
Losartan is also used to reduce the risk of stroke in high-risk patients with hypertension and left
ventricular hypertrophy.
Drug interactions
ARBs can interact with other drugs in various ways.
• When losartan is taken with fluconazole, an increased blood level of losartan may result, leading to
hypotension.
• NSAIDs reduce the antihypertensive effects of ARBs.
• Rifampin may increase metabolism of losartan and decrease its antihypertensive effect.
Adverse reactions to ARBs
Adverse reactions to angiotensin II receptor blockers (ARBs) include:
• headache and fatigue
• cough and tickling in the throat
• angioedema
• GI reactions
• increased serum potassium level
• transient elevations of blood urea nitrogen and serum creatinine levels.
Warning!
• Candesartan may increase blood levels of lithium, leading to lithium toxicity.
• When digoxin is taken with telmisartan, an increased blood level of digoxin may occur, possibly
leading to digoxin toxicity.
• Potassium supplements may increase the risk of hyperkalemia when used with ARBs
Calcium channel blockers
Calcium channel blockers are commonly used to prevent angina that doesn’t respond to drugs in either
of the other antianginal classes.
They’re the drug of choice to treat Prinzmetal’s angina.
As mentioned earlier, several of the calcium channel blockers are also used as antiarrhythmics and to
treat hypertension.
Calcium channel blockers used to treat angina include:
• amlodipine
• diltiazem
• nicardipine
• nifedipine
• verapamil.
Pharmacokinetics
When administered orally, calcium channel blockers are absorbed quickly and almost completely.
Because of the first-pass effect, however, the bioavailability of these drugs is much lower.
The calcium channel blockers are highly bound to plasma proteins.
All calcium channel blockers are metabolized rapidly and almost completely in the liver.
Pharmacodynamics
Calcium channel blockers prevent the passage of calcium ions across the myocardial cell membrane and
vascular smooth-muscle
Calcium channel blockers increase the myocardial oxygen supply and slow the heart rate. Apparently,
the drugs produce these effects by blocking the slow calcium channel. This action inhibits the influx of
extracellular calcium ions across both myocardial and vascular smooth muscle cell membranes. Calcium
channel blockers achieve this blockade without changing serum calcium concentrations.
No calcium = dilation
This calcium blockade causes the coronary arteries (and, to a lesser extent, the peripheral arteries and
arterioles) to dilate, decreasing afterload and increasing myocardial oxygen supply.
How calcium channel blockers work
Some calcium channel blockers slow the heart rate but don’t change the level of calcium in the blood.
This causes dilation of the coronary and peripheral arteries, which decreases the force of the heart’s
contractions and reduces the workload of the heart.
The relaxation response
Also, by preventing arterioles from constricting, calcium channel blockers reduce afterload. Decreasing
afterload further decreases the oxygen demands of the heart.
Rate reductions
Some calcium channel blockers (diltiazem and verapamil) also reduce the heart rate by slowing
conduction through the SA and AV nodes. A slower heart rate reduces the heart’s need for additional
oxygen.
Pharmacotherapeutics
Calcium channel blockers are used for long-term prevention of angina only, not short-term relief of
chest pain. Calcium channel blockers are particularly effective for preventing Prinzmetal’s angina.
Drug interactions
• Calcium salts and vitamin D reduce the effectiveness of calcium channel blockers.
• Nondepolarizing blocking drugs may have an enhanced muscle relaxant effect when taken with
calcium channel blockers.
• Verapamil and diltiazem increase the risk of digoxin toxicity, enhance the action of carbamazepine,
and may cause myocardial depression.
Adverse reactions to calcium channel blockers
As with other antianginal drugs, cardiovascular reactions are the most common and serious adverse
reactions to calcium channel blockers.
These include orthostatic hypotension (a drop in blood pressure when a person stands up), heart failure,
and hypotension.
Diltiazem and verapamil can cause such arrhythmias as bradycardia, sinus block, and atrioventricular
block.
Others
Other possible adverse reactions include dizziness, headache, flushing, weakness, and persistent
peripheral edema.
Additional Side effects
Adverse reactions to sympatholytics
Alpha-adrenergic blockers • Hypotension
Central-acting drugs
• Depression • Drowsiness • Edema • Liver dysfunction • Numbness, tingling • Vertigo
Guanadrel
• Difficulty breathing • Excessive urination • Fainting • Orthostatic hypotension
Guanethidine
• Decreased heart contractility • Diarrhea • Fluid retention • Orthostatic hypotension
Reserpine
• Abdominal cramps, diarrhea • Angina • Blurred vision • Bradycardia • Bronchoconstriction •
Decreased libido • Depression • Drowsiness • Weight gain • Fatigue • Hypotension
Beta-adrenergic blockers may cause:
• bradycardia • angina • fluid retention • peripheral edema • heart failure • arrhythmias, especially
atrioventricular block • hypotension • dizziness • nausea and vomiting • diarrhea • significant
constriction of the bronchioles.
Quick stop causes concern:
Suddenly stopping a beta adrenergic blocker may trigger:
• angina • hypertension • arrhythmias • acute myocardial infarction.
Reference:
Lippincott Williams & Wilkins’s Clinical Pharmacology made Incredibly Easy.
