DRUG USED IN HYPERTENSION

(HYPOTENSIVE DRUG)

Hypertension is defined as either

a sustained systolic blood pressure
of greater than 140 mmHg or
a sustained diastolic blood pressure
of greater than 90 mmHg

classification

etiology
Hypertension
results from
increased peripheral
vascular arteriolar
smooth muscle
tone, which leads to
increased arteriolar
resistance and
reduced
capacitance of the
venous system.

etiology
In most cases, the cause of the increased
vascular tone is unknown and hypertension of
unknown etiology is also called idiopathic,
primary or essential. 20% of cases of
hypertension are due to secondary factors that
can be clearly defined and corrected. This type of
hypertension is associated with
1.pheochromocytoma,
2.coaorctation of the aorta (also called aortic narrowing),
3.renal vascular disease,
4.adrenal cortical tumors, and a few other rare
conditions.

complications
Although many of individuals
with
hypertension
have
no
symptoms,
chronic
essential
hypertension can lead to
1.cerebrovascular
accidents
(strokes),
2.congestive heart failure,
3.myocardial infarction, and
4.renal damage.

Remember!
The incidence of morbidity and
mortality significantly decreases
when hypertension is diagnosed
early and is properly treated.

Endogenous and Exogenous predisposing

Factors:
A family history of hypertension increases
the likelihood of hypertensive disease.
The incidence of essential hypertension is
four-fold more frequent among blacks than
among whites.
It occurs more often among middle-aged
males than among middle-aged females,
and
its prevalence increases with age and
obesity.

Environmental factors,
such as
a stressful lifestyle,
high dietary intake of sodium, and
smoking,
further predispose an individual to
the occurrence of hypertension.

recommendations
In some patients with mild
hypertension,
1.weight
reduction,
if
appropriate,
2.reduced
alcohol
consumption and
3.moderate reduction in
salt consumption may be
sufficient,
but
usually
drug
treatment is required.

DRUG USED IN HYPERTENSION

Hypotensive drugs

Hypotensive drugs have a

variety of mechanisms of action
including
diuresis,
sympathoplegia,
vasodilation, and
antagonism of angiotensin.

TREATMENT STRATEGIES
Thus, the strategies for treating
idiopathic high blood pressure include
reductions of
blood volume,
sympathetic tone,
vascular smooth muscle tone, and
angiotensin effects.

TREATMENT STRATEGIES

Mild hypertension can sometimes

be controlled with a single drug, but
most patients require more than one
drug to achieve blood pressure
control.

Remember!
Certain subsets of the hypertensive
population respond better to one class of drug
than they do to another. For example,
black patients respond well to diuretics
and
calcium-channel
blockers,
but
monotherapy with -blockers or ACE
inhibitors is often less effective.
Similarly, calcium-channel blockers, ACE
inhibitors, and diuretics are favored for
treatment of hypertension in elderly patients,
whereas
that
-blockers and antagonists are less well tolerated.

General recommendation
Lack of patient compliance is the most
common reason for failure of antihypertensive
therapy. The hypertensive patient is usually
asymptomatic and is diagnosed by routine
screening before the occurrence of overs endorgan damage.

General recommendation
Thus, therapy is generally directed at
preventing future disease.
It is important to enhance compliance by
carefully selecting a drug regimen that both
reduces adverse effects and minimizes
the number of doses required daily.
Combining two or three drug classes in a
single pill, at a fixed-dose combination,
has been shown to improve patient
compliance and the number of patients
achieving goal blood pressure.

Compensatory responses
Initial treatment of hypertension
causes the compensatory responses
to
decreased
blood
pressure.
Therefore, the drugs should be used
regularly
to
minimize
the
compensatory responses.

SCHEME OF COMPENSATORY REACTIONS

DIURETICS

Diuretics can be used as first-line

drug therapy for hypertension in older
adults. These drugs lower blood
pressure by reduction of blood volume.
The most important diuretics for
treating hypertension are the
1. thiazides and the
2.loop diuretics (eg, furosemide).

Thiazides may be adequate in mild

hypertension, but the loop agents are
often used in moderate, severe and
malignant hypertension.

Thiazide diuretics:
Hydrochlorthiazide
Chlorthalidone
Thiazide diuretics cause
potassium loss. Potassium-sparing
diuretics are often used in
combination with thiazides to
reduce the amount of potassium
loss induced by the thiazide
diuretics.
Thiazide
diuretics
are
particularly useful in the treatment
of black and elderly patients.
Adverse effects: Thiazide
diuretics induce hypokalemia and
hyperuricemia in 70% of patients
and hyperglycemia in 10% of
patients.

Loop diuretics:
Furosemide
Bumetanide
Torsemide
act promptly, even in patients with renal function or
who have not responded to thiazides or other
diuretics.
Adverse effects:
1.Dehydration
2.Electrolyte disbalance
3.Arrhythmias
4.Hypotension
5.Fatigue
6.Ototoxic effect
7.hyperuricemia

Potassium-sparing diuretics:
Amiloride

Triamterene
Spironolactone
reduce potassium loss in the
urine.

CENTRAL NERVOUS SYSTEM-ACTIVE

AGENTS
2-selective agonists
clonidine,
methyldopa
cause a decrease in sympathetic
outflow by activation of 2 - receptors
in the CNS and the amount of
norepinephrine release. These drugs
readily enter the CNS when given
orally.

CENTRAL NERVOUS SYSTEM-ACTIVE

AGENTS

Methyldopa
Methyldopa is a predrug. Clonodine and
methyldopa both reduce blood pressure.
But methyldopa does not decrease
cardiac output and blood flow to vital
organs is not diminished. Therefore, it has
been used in hypertensive pregnant patients.
Clonodine is used primarily for the
treatment of hypertension that has not
responded adequately to treatment with two
or more drugs.

CENTRAL NERVOUS SYSTEM-ACTIVE AGENTS

Methyldopa

Sudden discontinuation of clonidine

causes rebound hypertension, which may be
severe.
Rebound hypertension elevated
blood pressure (usually above pretreatment
levels) resulting from loss of antihypertensive
drug effects.
Adverse effects: Methyldopa causes
hemolytic anemia and sedation.

Postganglionic sympathetic nerve

terminal blockers:
Reserpine
Guanethidine
Drugs that deplete the adrenergic nerve terminal of
its norepinephrine stores or that deplete and block
release of the stores can lower blood pressure.
Reserpine is used in low doses as an adjunct to
other agents. The most serious toxicity of
reserpine is behavioral depression, which may
require discontinuation of the drug. Reserpine
causes also diarrhea, nasal stuffiness, sedation.

SYMPATHOPLEGICS
Sympathoplegics (-lytic) drug that reduces
effects of the sympathetic nervous system.
ADRENOCEPTOR BLOCKERS
1 - SELECTIVE AGENTS:
prazosin,
doxazosin,
terazosin
are moderately effective antihypertensive drugs.
They are used from 2 to 3 weeks in patients
with hypertention and ischemic heart disease. They
cause orthostatic hypotension, especially with the
first few doses.

BETA BLOCKERS:

propranolol,
atenolol,
metoprolol,
carvedilol
nebivolol
are among the most popular (commonly
prescribed). They have hypotensive effect. Nebivolol
is a selective blocker of 1-receptors, which also
increases the production of nitric oxide leading to
vasodilation.

side effects
Beta-blocker therapy
is associated with
1.slightly
elevated
glucose,
2.elevated
lowdensity lipoprotein, and
3.diminished
highdensity
lipoprotein
levels in the blood;
4.sleep disturbances,

side effects
1.sedation,
2.impotence,
3.cardiac disturbances (bradycardia,
blockades),
4.bronchospasm
5.heart failure
6.Peripheral vasoconstriction.

Therefore, the -blockers should

used cautiously in the treatment
patients with acute heart failure
peripheral vascular disease.

be
of
or

Remember!
-blockers are more effective
for treating hypertension in white
than in black patients and in young
compared to elderly patients
-blockers are orally active.
The
-blockers may take
several weeks to develop their full
effects.

Withdrawal syndome
Abrupt withdrawal with
-blockers may induce angina,
myocardial infarction, and even
sudden death in patients with ischemic
heart disease. Therefore, the dose of
these drugs must be tapered.

VASODILATORS:
HYDRALAZINE,
NITROPRUSSIDE,
CA-CHANNEL ANTAGONISTS
VERAPAMIL, DILTIAZEM, NIFEDIPINE.

Hydralazine is the direct-acting smooth

muscle relaxant. It is rarely used at
high dosage because of its toxicity,
which include reflex tachycardia, salt
and water retention, drug induced
lupus
erythematosus
(which
is
reversible upon stopping the drug).

It is almost always administered

in combination with a -blockers, such
as propranolol, atenolol (to balance
the reflex tachycardia) and a diuretic
(to decrease sodium retention).

Nitroprusside
is used in hypertensive emergencies,
it is a short-acting agent that must be
infused continuously. The mechanism
of action involves the release of nitric
oxide, which increases cyclic guanine
monophosphate
concentration
in
smooth muscle and decrease BP
(blood pressure)

nitroprusside
The toxicity includes:
excessive hypotension
tachycardia
accumulation of cyanide in the
blood.

Calcium channel blocking agents:

Verapamil,
diltiazem and
dihydropyridines - nifedipine,
amlodipine,
isradipine,
nicardipine

are effective vasodilators.

All dihydropyridines have a much

greater affinity for vascular calcium
channels than for calcium channels in the
heart. They are, therefore, particularly
attractive in treating hypertension.

Because they produce fewer

compensatory
calcium

responses,

channel

blockers

the
are

much more commonly used than

hydralazine or minoxidil.

Calcium channel blocking agents

General recommendation

Calcium-channel blockers are

recommended when the first-line agents are
contraindicated or ineffective.
These agents are effective in the treatment
of hypertensive patients who also have asthma,
diabetes, angina, and/or perifeheral vascular
disease.
High doses of short-acting calcium channel
blockers (such as nifedipine) should be avoided
because of increased risk of myocardial
infarction due to excessive vasodilation and
marked reflex cardiac stimulation.

Calcium channel blocking agents

General recommendation

Calcium-channel blockers have an

intrinsic natriuretic effect and, therefore, do
not usually require the addition of a diuretic.

Black hypertensive patients respond

well to calcium-channel blockers.

Adverse effects
of
calcium
channel
includes:
Constipation,
flushing,
cardiac disturbances.

blockers

Angiotensin antagonists (ACE-inhibitors)

The
2
primary
groups
of
angiotensin
antagonists
are
recognized:
angiotensin converting enzyme
(ACE - inhibitors) and
angiotensine - receptors blockers
(ARBs).

Angiotensin antagonists Ace-inhibitors

The first group (enalapril, lisinopril) causes a
reduction in blood levels of angiotensin (the potent
vasoconstrictor) and aldosterone.
They are recommended when the diuretics or
blockers are contraindicated or ineffective.

ACE-INHIBITORS

effects
ACE-inhibitors reduce both cardiac preload and
afterload, thereby decreasing cardiac work.
Like -blockers, ACE inhibitors are most
effective in hypertensive patients who are white and
young.
Chronic treatment with ACE inhibitors achieves
sustained blood pressure reduction, regression of
left ventricular hypertrophy, and prevention of
ventricular remodeling after a myocardial infarction.

Clinical use
ACE-inhibitors are first-line drigs for
treating heart failure,
hypertensive patients with chronic renal
disease,
for patients with increased risk for
coronary artery disease.
ACE inhibitors have a low incidence of
adverse effects (except in pregnancy).

toxicities of ACE-inhibitors
include
dry cough (in about 10% of
patients due to increased levels of
bradykinin in the pulmonary tree),
rash, fever, altered taste;
renal damage (in patients with
bilateral renal artery stenosis)
renal damage in the fetus;
hypotension;
hyperkalemia (use of potassiumsparing
diuretics
are
contraindicated).

toxicities of ACE-inhibitors
Remember!

These
drugs
are
contraindicated
in
(teratogen, ACE-inhibitors
fetal malformations).

absolutely
pregnancy
can induce

angiotensine- receptors blockers

Second group (angiotensine- receptors
blockers) is represented by the orally active
agents:

losartan,
valsartan,
irbesartan,
which competitively inhibit angiotensin at its
AT1-receptor site. ARBs are also
fetotoxic and should not be used by women
who are pregnant.

Treatment strategy
Therapy of hypertension is c o m p l e x
because the disease is symptomless until far
advanced and because the drug can cause
major compensatory responses and
significant toxicities.
Typically, drugs are added to a patients
regimen in stepwise fashion, each additional
agent is chosen from a different subgroup
until adequate blood pressure control has
been achieved.

Treatment strategy
The usual steps include:
lifestyle measures (such
as salt restriction and weight
reduction)
diuretics (a thiazide)
sympathoplegics
(,
- blockers)
ACE inhibitors
Vasodilators (usually a
calcium channel blocker)

Treatment guideline for hypertension

Malignant hypertension
Age and ethnicity
Older patients of most races respond
better to diuretics and blockers than
to ACE - inhibitors.

Malignant hypertension
-is an accelerated form of severe
hypertension associated with rising
blood
pressure
and
rapidly
progressing damage to vessels and
end organs.
End-organ damage - Vascular
damage in heart, kidney, retina, or
brain.

Malignant hypertension
Complications
This condition may be signaled
deterioration of

renal function,
encephalopathy and
retinal hemorrhages or
by angina, stroke, or
myocardial infarction.

by

Malignant hypertension Management

Management
of
malignant
hypertension must be carried out on
an emergency basis in the hospital.
Nitroprusside is combined with diuretics
and blockers to lower blood pressure
to the 140-160/90-110 mm. Hg range
promptly. Further reduction is then
pursued more slowly.