Drugs used for the Treatment of

Hypertension/ Antihypertensive Agents/

 Drugs for Hypertension
 Hypertension is defined as either a sustained systolic blood pressure
of greater than 140 mm Hg or a sustained diastolic blood pressure of
greater than 90 mm Hg.

 Hypertension results from increased peripheral vascular arteriolar

smooth muscle tone, which leads to increased arteriolar resistance
and reduced capacitance of the venous system

 Left untreated, hypertension can lead to heart disease, kidney

disease, and stroke.

 Hypertension is also an important risk factor in the development of

chronic kidney disease and heart failure
 Types of hypertension

Primary (Essential) Hypertension

 Defined as hypertension that has no identifiable cause.

 Chronic, progressive disorder. In the absence of treatment,

patients will experience a continuous, gradual rise in BP over
the rest of their lives.
 Types of hypertension
Secondary Hypertension

 defined as an elevation of BP brought on by an identifiable

primary cause.

 The most common are Chronic renal disease, Renovascular

disease , Oral contraceptive–induced, Coarctation of the aorta,
Primary aldosteronism, Cushing's syndrome, Pheochromocytoma
 Types of hypertension
 Because secondary hypertension results from an identifiable
cause, it may be possible to treat that cause directly, rather than
relying on antihypertensive drugs for symptomatic relief.

 As a result, some individuals can actually be cured. For

example, if hypertension occurs secondary to
pheochromocytoma (a catecholamine-secreting tumor), surgical
removal of the tumor may produce permanent cure.

 When cure is not possible, secondary hypertension can be

managed with the same drugs used for primary hypertension.
Classification of blood pressure
Primary determinants of arterial blood pressure.
 Treatment strategies
 The ultimate goal in treating hypertension is to reduce
cardiovascular and renal morbidity and mortality.

 For most patients with stage 1 or stage 2 hypertension, the goal is

to maintain systolic BP below 140 mm Hg and diastolic BP below
90 mm Hg.

 For patients with diabetes or chronic kidney disease, the target BP

is lower: 130/80 mm Hg

 Drug therapy, together with lifestyle modifications, can control

BP in all patients with chronic hypertension.
 Drug therapy: Diuretics
 Regardless of class, the initial mechanism of action of diuretics is
based upon decreasing blood volume, which ultimately leads to
decreased blood pressure.

 Low-dose diuretic therapy is safe, inexpensive, and effective in

preventing stroke, myocardial infarction, and heart failure.

 Thiazide diuretics, such as hydrochlorothiazide and

chlorthalidone, lower blood pressure initially by increasing
sodium and water excretion.

 This causes a decrease in extracellular volume, resulting in a

decrease in cardiac output and renal blood flow
 Diuretics
 Thiazides are useful in combination therapy with a variety of
other antihypertensive agents, including β-blockers, ACE
inhibitors, ARBs, and potassium-sparing diuretics.

 With the exception of metolazone , thiazide diuretics are not

effective in patients with inadequate kidney function (estimated
glomerular filtration rate less than 30 mL/min).

 Loop diuretics may be required in these patients.

 Thiazide diuretics can induce hypokalemia, hyperuricemia and,

to a lesser extent, hyperglycemia in some patients
Actions of thiazide diuretics
 High-Ceiling (Loop) Diuretics.
 High-ceiling diuretics (eg, furosemide) produce much greater
diuresis than the thiazides.

 The loop diuretics (furosemide, torsemide, bumetanide, and

ethacrynic acid) act promptly by blocking sodium and chloride
reabsorption in the kidneys, even in patients with poor renal
function or those who have not responded to thiazide diuretics.

 Loop diuretics cause decreased renal vascular resistance and

increased renal blood flow.
 High-Ceiling (Loop) Diuretics.
 Like thiazides, they can cause hypokalemia. However, unlike
thiazides, loop diuretics increase the Ca2+ content of urine,
whereas thiazide diuretics decrease it.

 These agents are rarely used alone to treat hypertension, but

they are commonly used to manage symptoms of heart failure
and edema

 They are reserved for (1) patients who need greater diuresis
than can be achieved with thiazides and (2) patients with a low
GFR (because thiazides won't work when GFR is low).
 Potassium-sparing diuretics
 Amiloride and triamterene (inhibitors of epithelial sodium
transport at the late distal and collecting ducts) as well as
spironolactone and eplerenone (aldosterone receptor
antagonists) reduce potassium loss in the urine.

 Aldosterone antagonists have the additional benefit of

diminishing the cardiac remodeling that occurs in heart failure.

 Potassium-sparing diuretics are sometimes used in combination

with loop diuretics and thiazides to reduce the amount of
potassium loss induced by these diuretics.
 β-Adrenoceptor–blocking agents
 β-Blockers are a treatment option for hypertensive patients with
concomitant heart disease or heart failure

 The β-blockers reduce blood pressure primarily by decreasing

cardiac output

 They may also decrease sympathetic outflow from the central

nervous system(CNS) and inhibit the release of renin from the
kidneys, thus decreasing the formation of angiotensin II and the
secretion of aldosterone
Actions of β-adrenoceptor–blocking agents.
 Therapeutic uses
 The primary therapeutic benefits of β-blockers are seen in
hypertensive patients with concomitant heart disease, such as
supraventricular tachyarrhythmia (for example, atrial
fibrillation), previous myocardial infarction, angina pectoris,
and chronic heart failure.

 Conditions that discourage the use of β-blockers include

reversible bronchospastic disease such as asthma
Adverse effects
 The β-blockers may cause bradycardia, hypotension, and CNS
side effects such as fatigue, lethargy, and insomnia

 The β-blockers may decrease libido and cause erectile

dysfunction, which can severely reduce patient compliance.

 Alterations in serum lipid patterns: Noncardioselective β-

blockers may disturb lipid metabolism, decreasing high-density
lipoprotein cholesterol and increasing triglycerides.
 Adverse effects
 Drug withdrawal: Abrupt withdrawal may induce angina,
myocardial infarction, and even sudden death in patients with
ischemic heart disease.

 Therefore, these drugs must be tapered over a few weeks in

patients with hypertension and ischemic heart disease.
 ACE Inhibitors
 ACE catalyzes the conversion of angiotensin I (inactive) into
angiotensin II (highly active).

 ACE is located on the luminal surface of all blood vessels, the

vasculature of the lungs being especially rich in the enzyme

 Because ACE is abundant, conversion of angiotensin I into

angiotensin II occurs almost instantaneously after angiotensin I
has been formed.

 ACE is a relatively nonspecific enzyme that can act on a variety

of substrates in addition to angiotensin I.
 ACE Inhibitors

• The ACE inhibitors, such as enalapril and lisinopril are

recommended as first-line treatment of hypertension in patients
with a variety of compelling indications, including high coronary
disease risk or history of diabetes, stroke, heart failure,
myocardial infarction, or chronic kidney disease
 Actions
 ACE inhibitors produce their beneficial and adverse effects by

 (1) reducing levels of angiotensin II (through inhibition of ACE)

and

 (2) increasing levels of bradykinin (through inhibition of kinase

II).
 Actions
 By reducing levels of angiotensin II, ACE inhibitors

 can dilate blood vessels (primarily arterioles and to a lesser extent

veins), reduce blood volume (through effects on the kidney), and,
importantly, prevent or reverse pathologic changes in the heart
and blood vessels mediated by angiotensin II and aldosterone.
Inhibition of ACE can also cause hyperkalemia and fetal injury.

 Elevation of bradykinin causes vasodilation (secondary to

increased production of prostaglandins and nitric oxide), and can
also lead to cough and angioedema.
Effects of various drug classes on the renin–
angiotensin–aldosterone system
 Therapeutic uses
 ACE inhibitors slow the progression of diabetic nephropathy and
decrease albuminuria and, thus, have a compelling indication for
use in patients with diabetic nephropathy.

 ACE inhibitors are a standard in the care of a patient following a

myocardial infarction and first-line agents in the treatment of
patients with systolic dysfunction
 Therapeutic uses
 Chronic treatment with ACE inhibitors achieves sustained blood
pressure reduction,

 ACE inhibitors are first-line drugs for treating heart failure,

hypertensive patients with chronic kidney disease, and patients
at increased risk of coronary artery disease.

 All of the ACE inhibitors are equally effective in the treatment

of hypertension at equivalent doses.
 Pharmacokinetics
 All of the ACE inhibitors are orally bioavailable as a drug or
prodrug.

 All but captopril and lisinopril undergo hepatic conversion to

active metabolites, so these agents may be preferred in patients
with severe hepatic impairment.

 Fosinopril is the only ACE inhibitor that is not eliminated

primarily by the kidneys and does not require dose adjustment in
patients with renal impairment.

 Enalaprilat is the only drug in this class available intravenously.

 Adverse effects
 Common side effects include dry cough, rash, fever, altered taste,
hypotension (in hypovolemic states), and hyperkalemia

 The dry cough, which occurs in up to 10% of patients, is thought

to be due to increased levels of bradykinin and substance P in the
pulmonary tree and resolves within a few days of discontinuation.

 Angioedema is a rare but potentially life-threatening reaction that

may also be due to increased levels of bradykinin.
 Adverse effects
 Potassium levels must be monitored while on ACE inhibitors, and
potassium supplements and potassium-sparing diuretics should be
used with caution due to the risk of hyperkalemia.

 ACE inhibitors during the second and third trimesters of

pregnancy can injure the developing fetus
 Angiotensin II Receptor blockers
 The ARBs, such as losartan and irbesartan , are alternatives to the
ACE inhibitors.

 These drugs block the AT1receptors, decreasing the activation of

AT1 receptors by angiotensin II.

 Their pharmacologic effects are similar to those of ACE inhibitors

in that they produce arteriolar and venous dilation and block
aldosterone secretion, thus lowering blood pressure and
decreasing salt and water retention

 ARBs do not increase bradykinin levels.

 Angiotensin II Receptor blockers
 They may be used as first-line agents for the treatment of
hypertension, especially in patients with a compelling indication of
diabetes, heart failure, or chronic kidney disease.

 Adverse effects are similar to those of ACE inhibitors, although the

risks of cough and angioedema are significantly decreased.

 ARBs should not be combined with an ACE inhibitor for the

treatment of hypertension due to similar mechanisms and adverse
effects.

 These agents are also teratogenic and should not be used by

pregnant women.
 Angiotensin II Receptor blockers
 Like the ACE inhibitors, ARBs decrease the influence of
angiotensin II. However, the mechanisms involved differ:
Whereas ACE inhibitors block production of angiotensin II, ARBs
block the actions of angiotensin II.

 Because both groups interfere with angiotensin II, they both have
similar effects.

 ARBs do not inhibit kinase II, and hence do not increase levels of
bradykinin in the lung. As a result, ARBs do not promote cough,
the most common reason for stopping ACE inhibitors.
 Angiotensin II Receptor blockers
 By blocking angiotensin II receptors on blood vessels, ARBs
cause dilation of arterioles and veins.

 By blocking angiotensin II receptors in the heart, ARBs can

prevent angiotensin II from inducing pathologic changes in
cardiac structure.

 By blocking angiotensin II receptors in the adrenals, ARBs

decrease release of aldosterone, and can thereby increase renal
excretion of sodium and water. Sodium and water excretion is
further increased through dilation of renal blood vessels.
 Angiotensin II Receptor blockers
 Like the ACE inhibitors, ARBs can injure the developing fetus if
taken during the second or third trimester of pregnancy, and
hence are contraindicated during this period.

 Also, there is concern that ARBs and ACE inhibitors may harm
the fetus earlier in pregnancy, and hence should be discontinued
as soon as pregnancy is discovered.
 Renin inhibitor
 A selective renin inhibitor, aliskiren , is available for the
treatment of hypertension.

 Aliskiren directly inhibits renin and, thus, acts earlier in the

renin–angiotensin–aldosterone system than ACE inhibitors or
ARBs .

 It lowers blood pressure about as effectively as ARBs, ACE

inhibitors, and thiazides.

 Direct renin inhibitors (DRIs) are drugs that act on renin to

inhibit the conversion of angiotensinogen into angiotensin I.
 Renin
 catalyzes the formation of angiotensin I from angiotensinogen.

 This reaction is the rate-limiting step in angiotensin II formation.

 Renin is produced by juxtaglomerular cells of the kidney and

undergoes controlled release into the bloodstream, where it cleaves
angiotensinogen into angiotensin I.

 Release increases in response to a decline in blood pressure, blood

volume, plasma sodium content, or renal perfusion pressure

 Aliskiren causes less cough and angioedema than the ACE

inhibitors, but poses similar risks to the developing fetus.
 Renin
 Aliskiren binds tightly with renin, and thereby inhibits the
cleavage of angiotensinogen into angiotensin I.

 Since this reaction is the first and rate-limiting step in the

production of angiotensin II and aldosterone, aliskiren can reduce
the influence of the entire RAAS.
 Renin inhibitor
 Aliskiren should not be routinely combined with an ACE inhibitor
or ARB.

 Aliskiren can cause diarrhea, especially at higher doses, and can

also cause cough and angioedema, but probably less often than
ACE inhibitors.

 As with ACE inhibitors and ARBs, aliskiren is contraindicated

during pregnancy.
 Calcium channel blockers
 a recommended treatment option in hypertensive patients with
diabetes or angina.

 High doses of short-acting calcium channel blockers should be

avoided because of increased risk of myocardial infarction due
to excessive vasodilation and marked reflex cardiac stimulation.

 Drugs that prevent calcium ions from entering cells.

 These agents have their greatest effects on the heart and blood
vessels.
 Calcium channel blockers
 The calcium channel blockers (CCBs) fall into two groups:
dihydropyridines (e.g., nifedipine) and nondihydropyridines
(verapamil and diltiazem).

 Drugs in both groups promote dilation of arterioles.

 Verapamil is the least selective of any calcium channel blocker

and has significant effects on both cardiac and vascular smooth
muscle cells.

 blocks calcium channels in blood vessels and n the heart

 Calcium channel blockers
 Like verapamil, diltiazem affects both cardiac and vascular
smooth muscle cells,

 Diltiazem has a favourable side effect profile.

 Calcium channel blockers
 Dihydropyridines: This class of calcium channel blockers
includes nifedipine (the prototype), amlodipine , felodipine ,
isradipine , nicardipine , and nisoldipine .

 These agents differ in pharmacokinetics, approved uses, and drug

interactions.

 All dihydropyridines have a much greater affinity for vascular

calcium channels than for calcium channels in the heart.

 Particularly beneficial in treating hypertension.

 Calcium channel blockers
 The dihydropyridines have the advantage in that they show little
interaction with other cardiovascular drugs, such as digoxin or
warfarin, which are often used concomitantly with calcium
channel blockers.
 Actions
 The intracellular concentration of calcium plays an important role in
maintaining the tone of smooth muscle and in the contraction of the
myocardium.

 Calcium enters muscle cells through special voltage sensitive

calcium channels.

 Calcium channel antagonists block the inward movement of

calcium by binding to L-type calcium channels in the heart and in
smooth muscle of the coronary and peripheral arteriolar vasculature.

 This causes vascular smooth muscle to relax, dilating mainly

arterioles. Calcium channel blockers do not dilate veins.
 Therapeutic uses
 In the management of hypertension, CCBs may be used as an
initial therapy or as add-on therapy.

 They are useful in the treatment of hypertensive patients who

also have asthma, diabetes, and/or peripheral vascular disease,
because unlike β-blockers, they do not have the potential to
adversely affect these conditions.
 Adverse effects
 Verapamil and diltiazem should be avoided in patients with
heart failure

 Dizziness, headache, and a feeling of fatigue caused by a

decrease in blood pressure are more frequent with
dihydropyridines.

 Peripheral edema is another commonly reported side effect of

this class.

 Nifedipine and other dihydropyridines may cause gingival

hyperplasia
 α-Adrenoceptor–blocking agents

 Prazosin , doxazosin , and terazosin produce a competitive block

of α1-adrenoceptors.

 They decrease peripheral vascular resistance and lower arterial

blood pressure by causing relaxation of both arterial and venous
smooth muscle.

 These drugs cause only minimal changes in cardiac output, renal

blood flow, and glomerular filtration rate.
 α-Adrenoceptor–blocking agents
 Reflex tachycardia and postural hypotension often occur at the
onset of treatment and with dose increases, requiring slow
titration of the drug in divided doses.

 Due to weaker outcome data and their side effect profile, α-

blockers are no longer recommended as initial treatment for
hypertension.

 Other α1-blockers with greater selectivity for prostate muscle are

used in the treatment of benign prostatic hyperplasia
 α-/β-Adrenoceptor–blocking agents
 Labetalol and carvedilol block α1, β1, and β2 receptors.

 Carvedilol, although an effective antihypertensive, is mainly

used in the treatment of heart failure.

 Carvedilol, as well as metoprolol succinate, and bisoprolol have

been shown to reduce morbidity and mortality associated with
heart failure.

 Labetalol is used in the management of gestational hypertension

and hypertensive emergencies.
 α-/β-Adrenoceptor–blocking agents
 Blood pressure reduction results from a combination of actions:

 (1) alpha1 blockade promotes dilation of arterioles and veins,

 (2) blockade of cardiac beta1 receptors reduces heart rate and

contractility, and

 (3) blockade of beta1 receptors on juxtaglomerular cells

suppresses release of renin. Presumably, these drugs also share
the ability of other beta blockers to reduce peripheral vascular
resistance
 Centrally acting adrenergic drugs
A. Clonidine acts centrally as an α2 agonist to produce inhibition of
sympathetic vasomotor centers, decreasing sympathetic outflow to
the periphery.

 This leads to reduced total peripheral resistance and decreased

blood pressure.

 Clonidine is used primarily for the treatment of hypertension that

has not responded adequately to treatment with two or more drugs.

 Clonidine does not decrease renal blood flow or glomerular

filtration and, therefore, is useful in the treatment of hypertension
complicated by renal disease
 Centrally acting adrenergic drugs
 Act within the brainstem, to suppress sympathetic outflow to the
heart and blood vessels.

 The result is vasodilation and reduced cardiac output, both of

which help lower BP.

 All central alpha2 agonists can cause dry mouth and sedation.

 In addition, clonidine can cause severe rebound hypertension if

treatment is abruptly discontinued.

 The drug should, therefore, be withdrawn slowly if

discontinuation is required.
 Centrally acting adrenergic drugs
B. Methyldopa
 α2 agonist that is converted to methyl norepinephrine centrally to
diminish adrenergic outflow from the CNS.

 The most common side effects of methyldopa are sedation and

drowsiness.

 Its use is limited due to adverse effects and the need for multiple
daily doses.

 Mainly used for management of hypertension in pregnancy,

where it has a record of safety.
 Vasodilators
 The direct-acting smooth muscle relaxants, such as hydralazine
and minoxidil are not used as primary drugs to treat hypertension.

 These vasodilators act by producing relaxation of vascular smooth

muscle, primarily in arteries and arterioles.

 This results in decreased peripheral resistance and, therefore,

blood pressure.

 Both agents produce reflex stimulation of the heart, resulting in

the competing reflexes of increased myocardial contractility, heart
rate, and oxygen consumption.
 Vasodilators
 Vasodilators differ from one another with respect to the types of
blood vessels they affect.

 Some agents (e.g., hydralazine) produce selective dilation of

arterioles. Others (e.g., nitroglycerin) produce selective dilation
of veins.

 Still others (e.g., prazosin) dilate arterioles and veins.

 Vasodilators
 These actions may prompt angina pectoris, myocardial infarction,
or cardiac failure in predisposed individuals.

 Vasodilators also increase plasma renin concentration, resulting in

sodium and water retention.

 These undesirable side effects can be blocked by concomitant use

of a diuretic and a β-blocker.

 For example, hydralazine is almost always administered in

combination with a β-blocker, such as propranolol, metoprolol, or
atenolol (to balance the reflex tachycardia) and a diuretic
(todecrease sodium retention).
 Vasodilators
 Hydralazine is an accepted medication for controlling blood
pressure in pregnancy induced hypertension.

 Adverse effects of hydralazine include headache, tachycardia,

nausea, sweating, arrhythmia, and precipitation of angina.

 A lupus-like syndrome can occur with high dosages, but it is

reversible upon discontinuation of the drug.

 Minoxidil treatment causes hypertrichosis (the growth of body

hair).

 This drug is used topically to treat male pattern baldness.

 Hypertensive emergency
 Hypertensive emergency is a rare but life-threatening situation
characterized by severe elevations in blood pressure (systolic
greater than180 mm Hg or diastolic greater than 120 mm Hg)
with evidence of impending or progressive target organ damage
(for example, stroke, myocardial infarction).

 A severe elevation in blood pressure without evidence of target

organ damage is considered a hypertensive urgency.

 Hypertensive emergencies require timely blood pressure

reduction with treatment administered intravenously to prevent
or limit target organ damage
 Hypertensive emergency
 A variety of medications are used, including calcium channel
blockers (nicardipine and clevidipine), nitric oxide vasodilators
(nitroprusside and nitroglycerin), adrenergic receptor
antagonists (phentolamine, esmolol, and labetalol), the
vasodilator hydralazine, and the dopamine agonist fenoldopam.

 Treatment is directed by the type of target organ damage present

and/or comorbidities present.
 Resistant hypertension
 Resistant hypertension is defined as blood pressure that remains
elevated (above goal) despite administration of an optimal three-
drug regimen that includes a diuretic.

 The most common causes of resistant hypertension are poor

compliance, excessive ethanol intake, concomitant conditions
(diabetes, obesity, sleep apnea, hyperaldosteronism, high salt
intake, and/or metabolic syndrome), concomitant medications
(sympathomimetics, nonsteroidal anti-inflammatory drugs,),
insufficient dose and/or drugs, and use of drugs with similar
mechanisms of action.
 Combination therapy

 Combination therapy with separate agents or a fixed-dose

combination pill may lower blood pressure more quickly with
minimal adverse effects.

 A variety of combination formulations of the various

pharmacologic classes are available to increase ease of patient
adherence to treatment regimens that require multiple
medications to achieve the blood pressure goal.