ANTIHYPERTENSIVE DRUGS

HYPERTENSION

Sustained, reproducible increase in blood pressure

One of the most common diseases affecting adults
Incidence increases with age
If left untreated cardiovascular problems (stroke, heart failure), renal

diseases, and blindness

Classification of BP:

Category
Optimal
Prehypertension
Hypertension
Stage 1
Stage 2

Systolic BP
(mmHg)
<120
120-139

Diastolic BP
(mmHg)
<80
80-90

140-159
>160

90-99
>100

Often described as SILENT KILLER because of the lack of symptoms

throughout most of the disease course

NORMAL CONTROL OF BLOOD PRESSURE

BP is normally maintained by the complex interaction of several physiologic

systems
Baroreceptor reflex
Kidneys
Humral factors
Circulating catecholamines
Arginine-vasopressin
Angiotensine II
Actual factors that determine BP:
BP = (CO) x (TPR)
BP can be maintained at a relatively constant level by changes in either CO or
TPR

PATHOGENESIS OF HYPERTENSION

HTN is divided into 2 major categories: ESSENTIAL (PRIMARY), or

SECONDARY

ESSENTIAL (PRIMARY)
95 %
exact cause unknown
genetic and environmental factors:
adaptive changes in cardiovascular
system
external factors: diet, stress, obesity
other: cigarette smoking, alcohol
abuse

SECONDARY
5%
attributed to some specific abnormalities:
renal artery stenosis
catecholamine-production tumor
endocrine d/o
cerebral damage
Tx: focused on the underlying pathology

Possible Mechanisms in Essential HTN

There

appears

to

be

rather

complex

interaction

of

genetic

and

environmental factors that ultimately leads to adaptive changes in the

cardiovascular system of the patient with essential hypertension
Essential hypertension is probably not caused by only one factor, but may be
caused by a subtle, complex interaction of many factors: diet, stress,
obesity, cigarette smoking, alcohol abuse may interact in such a way as to
cause a general increase in sympathetic activity: common denominator

underlying the elevated BP

Sympathetic nervous system may be a final common pathway in
mediating and perpetuating the hypertensive state

Elevation of BP:
-

Inc. sympathetic activity excitatory effect: heart & peripheral

vasculature initially inc. CO inc. BP later stages: CO normalizes inc.
BP d/t inc. vascular resist.

Once blood pressure does become elevated:

HTN become self-perpetuating: mechanisms that control BP (baroreceptor reflex for

example) may dec. in sensitivity blunting normal response to elevated BP
Increased discharge to kidneys and altered hemodynamics may also cause changes in
renal function contributing to sustained increase in BP
Chronic Elevations In BP metabolic impairement metabolic syndrome:
hyperinsulinemia, dyslipidemia, and abdominal obesity inc. risk for type 2 DM

Peripheral vasculature:
Adaptive changes: inc. pressure on vascular wall thickening of the wall less
compliant & further inc. resist. to blood flow

May also become more reactive to pressor substances such as norepinephrine &
angiotensine II
Defect in production of vasoactive substances by vascular endothelium: vasodilators
NITRIC OXIDE, bradykinin, prostaglandin I2; vasoconstrictors angiotensin II,
endothelin-I inc. vascular resist. HTN

DRUG THERAPY

Several major categories of drugs exist for the treatment of essential

hypertension:

Diuretics
Sympatholytic drugs
Vasodilators
Angiotensine-converting enzyme inhibitors
Calcium channel blockers

DIURETICS
Mechanism of Action and Rationle For Use

Diuretics increase the formation and excretion of urine. These drugs are used as
antihypertensive agents because of their ability to increase the renal
excretion of water and sodium, thus decreasing the volume of fluid within the
vascular system
Direct effect on blood pressure through their ability to simply decrease the
amount of fluid in the vascular system acting directly on kidneys
Thiazide diuretics might be superior to calcium channel blockers and
angiotensin converting enzyme inhibitors in preventing major cardiac events
such as myocardialinfarction, stroke, and heart failure in people with
hypertension

Classification of Diuretics

Thiazide Diuretics

Act primarily on the early portion of the distal tubule of the nephron, where they inhibit
sodium reabsorption.

Most frequently used type of diuretic for hypertension.

Loop Diuretics

Act primarily on the ascending limb of the loop of Henle.

They exert their diuretic effect by inhibiting the reabsorption of sodium and chloride from
the nephron, thereby preventing the reabsorption of water that follows these electrolytes.

Potassium-Sparing Diuretics

Several different drugs with diuretic properties are classified as potassium-sparing

because they are able to prevent the secretion of potassium into the distal tubule.

Potassium-sparing agents interfere with sodium-potassium exchange so that potassium is

spared from secretion and sodium remains in the tubule, where it is excreted.

Potassium-sparing drugs have the advantage of reducing potassium loss and thus
preventing hypokalemia.

Adverse Effects of Diuretics

Most serious side effects of diuretics are fluid depletion and electrolyte imbalance.

Diuretics decrease extracellular fluid volume as well as produce sodium depletion

(hyponatremia) and potassium depletion (hypokalemia).

Hypokalemia is a particular problem with the thiazide and loop diuretics, but occurs less
frequently when the potassium-sparing agents are used.

Decreased in blood volume may cause a reflex increase in cardiac output and peripheral
vascular resistance because of activation of baroreflex.

Decreased in blood volume may also activate the renin-angiotensin system, thereby
causing further peripheral vasoconstriction and increased cardiac workload.

Loop and thiazide diuretics may also impair glucose and lipid metabolism. High doses of
these agents may predispose some pts to type 2 DM.

Other side effects of diuretic therapy include GI disturbances, weakness-fatigue,

orthostatic hypotension & changes in mood and confusion.

SYMPATHOLYTIC DRUGS

Sympatholytic drugs used to treat hypertension include beta-adrenergic blockers,

alpha-adrenergic blockers, presynaptic adrenergic neurotransmitter depletors,
centrally acting drugs and ganglionic blockers.

BETA BLOCKERS
Mechanism of Action and Rationale for Use

Beta-adrenergic blockers have been used extensively to decrease blood pressure and a
mainstay of antihypertensive therapy in many pts.

Beta blockers exert their primary effect on the heart, where they decrease heart rate and
force myocardial contraction.

In hypertensive pts, these drugs lower BP by slowing down the heart and reducing
cardiac output.

Beta blockers also produce a general decrease in sympathetic tone.

Beta blockers may decrease sympathetic activity via the ff.:

Central inhibitory effect on the brainstem

Decrease renin release from the kidneys and within the CNS

Impaired sympathetic activity in the ganglia or at the presynaptic adrenergic terminals

Increase baroreceptor sensitivity

Beta blockers often compliment the effects of other antihypertensives (diuretics,

angiotensin converting enzyme (ACE) inhibitors) and are therefore included in the drug
regimen of pts with hypertension.

Specific Agents

Some beta blockers are relatively selective for beta-1 receptors (cardioselective) and tend
to affect the heart more than the lungs and other tissues.

Certain beta blockers such as pindolol and acebutolol function as partial agonists and are
said to have intrinsic sympathomimetic activity because they block the effects of
excessive endogenous catecholamines while producing a normal background level of
sympathetic stimulation to the heart.

Beta blockers such as labetalol and propanolol are able to normalize the excitability of
the cardiac cell membrane; these drugs are said to have membrane stabilizing activity.

Some newer third generation beta blockers such as carvedilol and nebivolol produce
peripheral vasodilation as well as a cardiac beta blockade, making these drugs especially
useful in decreasing BP.

Some newer agents may likewise have other beneficial effects such as antioxidant
properties and the ability to decrease lipid abnormalities and insulin resistance.

Adverse Effects

Nonselective beta blockers may produce bronchoconstriction in pts with asthma and
similar respiratory disorders.

Cardiovascular side effects include excessive depression of HR and myocardial

contractility as well as orthostatic hypotension.

Some of the traditional beta blockers may impair glucose and lipid metabolism.

Other side effects include depression, fatigue, GI disturbances and allergic reactions.

ALPHA BLOCKERS
Mechanism of Action and Rationale for Use

Drugs that block the alpha-1 adrenergic receptor on the vascular smooth muscle will
promote a decrease in vascular resistance.

Alpha blockers act directly on the tissues that ultimately mediate the increase in BP.
that is, the peripheral vasculature.

In the past, the use of alpha blockers in mild to moderate essential hypertension was
somewhat limited because these drugs are sometimes too effective and tend to cause
problems with hypotension.

Alpha-1 antagonists may offer specific advantages in treating hypertension, including an

ability to improve blood lipid profiles (decrease triglycerides and total cholesterol,
increase HDL-cholesterol ration) and produce a favorable effect on glucose metabolism
and insulin resistance.

Newer agents such as doxazosin (Cardura) also appear to have less adverse
cardiovascular side effects such as reflex tachycardia presumably because these agents
act longer and do not cause a sudden fall in BP.

Doxazosin gastrointestinal therapeutic system (GITS), allows slower drug absorption

into the bloodstream, thereby further reducing sudden adverse effects and improving
tolerability.

Alpha-1 blockers can also be used to treat the symptoms of benign prostatic hypertrophy
because they decrease sympathetic-mediated contraction of smooth muscle located in
prostate gland.

Specific Agents

Prazosin

- Primary alpha blocker used in the past, but newer agents such as doxazosin and terazosin
(Hytrin) are gaining acceptance in treating hypertension.
Adverse Effects

Reflex Tachycardia

When peripheral vascular resistance falls due to the effects of these drugs, the
baroreceptor reflex often responds by generating a compensatory increase in HR.

Use of a longer-acting or controlled-release drug (doxazosin) may reduce the risk of

reflex tachycardia because these agents produce a milder and more prolonged decrease in
BP following administration.

Orthostatic Hypotension

Blockade of apha-1 receptors in the peripheral arteries and veins often promotes pooling
of blood in the LE when pts stands up.

Alpha blockers may increase the risk of cardiac dse, including CHF

- By causing vasodilation, these drugs can increase plasma volume, thereby increasing the
workload on the heart and predisposing certain pts to heart failure and other cardiac events
(stroke, infarction)

Alpha blockers are not typically prescribed alone in treating hypertension, but are used in
advanced cases along with diuretics (to control fluid balance) or other antihypertensives
such as beta blockers and ACE inhibitors.

Alpha blockers may be a good choice for men with advanced hypertension and benign
prostatic hypertrophy because these drugs may help resolve both problems
simultaneously.

PRESYNAPTIC ADRENERGIC INHIBITORS

Mechanism of Action and Rationale for Use

Drugs that inhibit the release of norepinephrine from the presynaptic terminals of
peripheral adrenergic neurons may be used effectively in some individuals with
hypertension.
Reserpine inhibit the presynaptic synthesis and storage of norepinephrine in peripheral
and CNS adrenergic neurons
Guanadrel, Guanethidine
Decreased norepinephrine from the presynaptic terminal decreases sympathetic-mediated
excitation of the heart and peripheral vasculature Decreased BP

These agents are often used in conjunction with other agents in the steppedcare approach
to hypertension

Adverse Effects

Orthostatic Hypotension
GI Disturbances: Nausea, Vomiting and Diarrhea

CENTRALLY ACTING AGENTS

Mechanism of Action and Rationale for Use

Drugs - inhibit sympathetic discharge from the brainstem

2 types of neuronal receptors : alpha-2 adrenergic receptors & imidazoline type I1
receptors
Centrally acting sympatholytics - agonists for either one or possibly both
Clonidine - alpha-2 agonist ; has some ability to stimulate imidazoline receptors
Monoxidine and Rilmedine Imizadoline receptors
Decreased sympathetic outflow, cardiovascular stimulation and BP
Unique approach to Htn - limit sympathetic activity at the source (brainstem vasomotor
center) rather than at the periphery (cardiovascular neuroeffector junction)

Specific Agents

clonidine, guanabenz, guanfacine, and methyldopa

Adverse Effects

Dry mouth

Dizziness
Sedation

Note: Imidazoline receptors are more tolerated because patients are more alert and less
psychomotor slowing
GANGLIONIC BLOCKERS
Mechanism of Action and Rationale for Use

Drugs that block synaptic transmission at autonomic ganglia

Nicotinic cholinergic antagonists
Both divisions of ANS
Replaced by vasodilators (Nitropusside)
Acute aortic dissection or autonomic crisis in people with spinal cord injury

Specific Agents
Mecamylamine
Trimethaphan

Adverse Effects
GI discomfort (Nausea, constipation)
Urinary retension
Visual Disturbances
OH
VASODILATORS
Mechanism of Action and Rationale for Use
Drugs that directly vasodilate the peripheral vasculature
The vasodilators exert an inhibitory effect directly on vascular smooth-muscle cells
Increased amounts of cGMP
Specific Agents
Hydralazine (Apresoline) and minoxidil (Loniten)
Hydralazine - used to dec. BP in emergency situations: severe preeclampsia or malignant
hypertension
Diazoxide (Hyperstat) and nitroprusside (Nipride, Nitropress), - hypertensive crisis
Nitric oxide
Inhaled nitric oxide has been used to treat acute pulmonary hypertension
associated with respiratory distress syndrome in new borns and adults
Adverse Effects
Reflex tachycardia
dizziness, postural hypotension, weakness, nausea, fluid retention, and headache
Minoxidil - increases hair growth on the face, ears, forehead, and other hairy body
surfaces
Rogaine
INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM
Renin-angiotensin system is endogenous components that help regulate vascular tone
in various organs and tissues. Renin is an enzyme produced primarily in the kidneys. When
blood pressure falls, renin is released from the kidneys into the systemic circulation.
Angiotensinogen is a peptide that is produced by the liver and circulates continually in the
bloodstream. When renin contacts angiotensinogen, angiotensinogen is transformed into
angiotensin I. The circulating angiotensin I is then transformed by angiotensin-converting
enzyme into angiotensin II. The converting enzyme is located in the vasculature of many tissues,
especially the lung. Angiotensin II is an extremely potent vasoconstrictor. The fall in blood
pressure that activated the renin-angiotensin system is rectified by the min vascular resistance
caused by angiotensin II. Angiotensin II, or possibly its by-product angiotensin III, also increases
aldosterone secretion from the adrenal cortex. Aldosterone directly increases sodium
reabsorption from the kidneys, which creates osmotic forces in the kidneys that encourage water
reabsorption, thus helping maintain plasma volume.

Pharmacologic strategies to inhibit the effects of abnormal renin-angiotensin system

activation

Drugs that inhibit the enzyme that converts angiotensin I to angiotensin II (e.g. ACE
inhibitors )

Drugs that block angiotensin II receptors on various tissues (e.g. Angiotensin II

blockers)
Specific Agents
ACE inhibitors
Generic Name
Benazepril
Captopril
Lisinopril
Fosinopril
Quinapril
Enalapril
Moexipril

Trade Name
Lotensin
Capoten
Prinivil, Zestril
Monopril
Accupril
Vasotec
Univasc

Angiotensin II receptor blockers

Generic Name
Candesartan
Irbesartan
Telmisartan
Valsartan

Trade Name
Atacand
Avapro
Micardis
Diovan

Adverse Effects

Allergic Reaction
Persistent, Dry cough
Hematological effects (neutropenia, agranulocytosis)
Renal problems (glomerulonephritis, renal failure)
Other problems (gastrointestinal discomfort, dizziness, chest pain)

CALCIUM CHANNEL BLOCKERS

Calcium appears to play a role in activating the contractile element in smooth muscle much in
the same way that calcium initiates actin-myosin interaction in skeletal muscle cells. Drugs that
block calcium entry into vascular smooth muscle will inhibit the contractile process, leading to
vasodilation and decreased vascular resistance. CCB also tend to decrease heart rate and
myocardial contraction force, and some of their antihypertensive properties may derive from
their inhibitory effect on the heart.
Specific Agents
Generic Name
Amlodipine
Bepridil
Diltiazem
Felodipine
Isradipine

Trade Name
(Norvasc)
(Vascor)
(Cardizem)
(Plendil)
(DynaCirc)

Adverse Effect
Vasodilation
Orthostatic Hypotension
Abnormalities in heart rate (too fast, too slow, irregular)
Other bothersome side effects include dizziness, headache, and nausea.
STEPPED-CARE APPROACH TO HYPERTENSION
A stepped-care approach is generally regarded as an effective way to use different types of
antihypertensive drugs.
STEP 1: In patients with mild hypertension, drug therapy is usually initiated with a
single agent (monotherapy) from one of the following classes: a diuretic, a beta blocker,
an angiotensin converting enzyme (ACE) inhibitor, or a calcium channel blocker.
STEP 2: If a single drug is unsuccessful in reducing blood pressure, a second agent is
added. The second drug can be from one of the initial classes not used in step 1, or it can
be from a second group that includes the centrally acting agents (clonidine, guanabenz),
presynaptic adrenergic inhibitors (reserpine, guanethidine), alpha-1 blockers (prazosin,
doxazosin), and vasodilators (hydralazine, minoxidil).
STEP 3: A third agent is added, usually from one of the classes listed in step 2 that has
not already been used. Three different agents from three different classes are often
administered concurrently in this step.
STEP4: A fourth drug is added from still another class.
Nonpharmacologic Treatment of Hypertension
Dietary modifications, such as sodium restriction, low-fat diets, and diets high in certain
fish oils, have been helpful in some patients

Decreasing the use of alcohol and tobacco

Regular exercise
Patients should be encouraged to quit smoking, lose weight, manage stress, and modify
their diet, even if blood pressure is reduced pharmacologically.