Transcript THE THERAPY OF HYPERTENSION

(Anti-hypertensive drugs)
Dr. Fayhaa
Assistant professor of pharmacology
Definition
 Hypertension: is a multifactorial disease,
Characterized by elevated systolic &/ or diastolic
arterial blood pressure above normal on repeated,
reproducible measurements.
CLASSIFICATION OF BLOOD PRESSURE IN ADULTS
SBP
DBP
Normal
< 120
< 80
Prehypertension 120-139
80-89
Stage 1
140-159
90-99
Stage 2
≥ 160
≥ 100
(mmHg)
(mmHg)
Classification
1. Essential hypertension: sustained,
elevated blood pressure for which no
cause is apparent.
2. Secondary hypertension: results
from known disorder, such as renal
and vascular disease.
MAP = CO × TPR
REGULATION OF Blood Pressure
Physiologically,in both normal and
hypertensive individuals,blood pressure is
maintained by moment-to-moment
regulation of cardiac output and peripheral
vascular resistance.
REGULATION OF Blood Pressure
 Regulatory mechanisms:
1.
Short-term control afforded by the sympathetic
nervous system (Baroreflexes)
2.
Long-term control, which is the function of the
renal system (kidney)
Baroreflex
 The baroreflex or baroreceptor reflex is one of the
body's homeostatic mechanisms for maintaining
blood pressure. It provides a negative feedback loop in
which an elevated blood pressure reflexively causes
heart rate to decrease and also causing blood pressure
to decrease; likewise, decreased blood pressure
activates the baroreflex, causing heart rate to increase,
and also causing an increase in blood pressure.
Baroreflex
THE MANAGEMENT OF
Hypertension
 There are over 100 drug products that are available
for the treatment of hypertension.
 In addition to pharmacologic means to lower
blood pressure, life-style modifications can also
decrease blood pressure.
General Aims of Anti-hypertensive drug Therapy
 The goal of therapy is not the reduction in blood
pressure . Rather, it is to decrease the end organ
damage and subsequent pathophysiology that
occurs with sustained, untreated elevated blood
pressure.
General Aims of Anti-hypertensive drug Therapy
 Another goal of therapy is minimize the number
of drugs prescribed as well as the times that drugs
have to be taken.
 Hypertension is a unique clinical
problem because it is an asymptomatic
disease. Therefore, therapy with
antihypertensive drugs can cause a
variety of unpleasant side effects which
can reduce patient compliance.
The categories include the following
1. Diuretics, which lower blood
pressure by depleting the body of
sodium and reducing blood
volume.
2. Sympathoplegic agents, which
lower blood pressure by reducing
peripheral vascular resistance,
inhibiting cardiac function, and
increasing venous pooling in
capacitance vessels.
3. Direct vasodilators, which reduce
pressure by relaxing vascular
smooth muscle, thus dilating
resistance vessels and—to varying
degrees—increasing capacitance as
well.
4. Agents that block production or
action of angiotensin and thereby
reduce
peripheral
vascular
resistance and blood volume.
Classification of
Antihypertensive Drugs
1. Diuretics
4. Alpha1 receptor
blockers.
 —Thiazides
 —Loop diuretics 5. ACE inhibitors
 —Potassium6. Calcium
sparing diuretics
antagonists
2. Beta blockers
7. Direct vasodilators
3. Alpha-beta
blockers
how drugs act:
1. Dilatation of arteriolar resistance
vessels; the heart pumps against
lower resistance (after load), with
more rapid run-off of pressure.
2. Dilatation of venous capacitance
vessels; reduced venous return to the
heart (preload) leads to reduced
cardiac output, especially in the
upright position
how drugs act:
Reduction of cardiac contractility and
rate leads to reduced output at lower
pressure, especially in response to stress,
e.g. upright posture, exercise
4.
Depletion of body sodium reduces
plasma volume (transiently), and reduces
arteriolar response to norepinephrine.
3.
how drugs act:
5. Inhibition of angiotensin II formation
or action leads to vasodilatation.
Diuretics
 The major diuretic class used in the
long term treatment of hypertension
are the thiazides. K+ sparing and loop
diuretics can also be used.
 Numerous clinical studies have shown
these agents to decrease the risks of
other cardiovascular diseases.
 Diuretics
lower
blood
pressure
primarily by depleting body sodium
stores.
Mechanism of action
 The diuretics reduce plasma volume by
increasing Na+ and water excretion.
 This effect lowers blood pressure by
decreasing CO initially.
Mechanism of Action
 The hypotensive effect persist because
of a reduction in the peripheral
resistance (electrolyte changes in
vascular smooth muscle account for
vasodilation).
Clinical Uses
Diuretics can be used as
monotherapy for mild hypertension
as well as in combination with other
antihypertensives.
Side Effects
 Hyponatremia.
 Hypokalemia.
 These agents increase uric acid levels,
and should be used carefully in
individuals with gout.
Glucose intolerance and a reduction in
the efficacy of oral hypoglycemic
agents.
 increases in lipid and cholesterol
levels.

Angiotensin Converting Enzyme (ACE)
Inhibitors and Angiotensin (AT1)-Receptor
Antagonists.
 ACE inhibitors( Captopril, & Enalapril)
and AT1- receptor antagonists
(Losartan ) are first line agents for the
treatment of hypertension.
Mechanism of action
 The ACE inhibitors lower blood pressure by
reducing peripheral vascular resistance
without reflexly increasing cardiac output,
rate, or contractility.
 These drugs block the ACE that cleaves
angiotensin I to form the potent
vasoconstrictor, angiotensin II .
 These inhibitors also diminish the rate of
bradykinin inactivation.
 Vasodilation occurs as a result of the
combined effects of lower vasoconstriction
caused by diminished levels of angiotensin II
and the potent vasodilating effect of increased
bradykinin.
Side Effects
 dry cough.
 Rashes.
 Fever.
 Altered taste or loss of taste.
 Hypotension (in hypovolemic states) .
 Hyperkalemia.
 Angioedema is a rare but potentially life-
threatening reaction.
Non-inflammatory edema involving
skin, subcutaneous tissue, underlying
muscle & mucous membranes.
 Occurs in response to allergen
Most critical in the larynx
ANGIOTENSIN II ANTAGONISTS (ARBs)
 losartan , a highly selective, orally
active, angiotensin II receptor blocker,
has recently been approved for
antihypertensive therapy.
Mechanism of Action
 They are selective inhibitors of the AT1
receptor.
 Bind to the receptor and competitively
inhibit the action of angiotensin II and
IIІ.
Pharmacologic Effects
 Its pharmacologic effects are similar to
ACE inhibitors in that it produces
vasodilation and blocks aldosterone
secretion.
Calcium Channel Blockers
 Calcium channel blockers are
recommended when the preferred
first-line agents are contraindicated or
ineffective.
Mechanism of Action
 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 vasculature.
 This causes vascular smooth muscle to
relax, dilating mainly arterioles.
Classes of calcium channel blockers
 The calcium channel blockers are
divided into :three chemical classes,
each with different pharmacokinetic
properties and clinical indications.
 Benzothiazepines: Diltiazem
 Diphenylalkylamines: Verapamil
 Dihydropyridines: nifedipine ,
amlodipine, isradipine, nicardipine.
Pharmacologic Effects
 Verapamil is the least selective of any
calcium channel blocker, and has
significant effects on both cardiac and
vascular smooth-muscle cells.
 It is used to treat angina,
supraventricular tachyarrhythmia's,
and migraine headache
 Like verapamil, diltiazem affects both
cardiac and vascular smooth-muscle
cells.
 All the 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.
Clinical Uses
 These agents are useful in the
treatment of hypertensive patients who
also have asthma, diabetes, angina,
and/or peripheral vascular disease.
Side Effects
Headache.
2. Flushing.
3. Dizziness.
4. Palpitations.
5. Hypotension may occur during the first few
hours after dosing, as the plasma concentration
is increasing, particularly if the initial dose is too
high or increased too rapidly.
1.
6. Ankle edema also develop. This is due to
a rise in intracapillary pressure as a
result of the selective vasodilatation by
calcium blockers.
7. The edema is not a sign of Na+ retention.
It is not therefore relieved by diuretics
but disappears after lying flat (e.g.
overnight).
8. Bradycardia and dysrhythmia may
occur.
9. Gastrointestinal effects include
constipation, nausea and vomiting;
palpitation and lethargy may be felt.
Beta Blockers
 Beta blockers are first line agents in the
treatment of hypertension. These drugs
have diverse effects on cardiovascular
function and have a variety of
cardiovascular and noncardiovascular
uses.
Mechanism of Action
 The β-blockers reduce blood pressure
primarily by decreasing cardiac output
.
 They also block the release of renin
(mediated by β1-receptors).
Classes of Beta Blockers
 There are selective and nonselective
beta blockers
 The prototype β-blocker is propranolol,
which acts at both β1- and β2 receptors.
 Newer agents, such as atenolol and
metoprolol, are selective for β1
receptors.
Therapeutic uses
1. Subsets of the hypertensive
population: The β-blockers are more
effective for treating hypertension in
white than in black patients, and in
young patients compared to the
elderly.
Therapeutic uses
2. Hypertensive patients with
concomitant diseases: The β-blockers
are useful in treating conditions that
may coexist with hypertension, such
as supraventricular tachyarrhythmia,
previous myocardial infarction,
angina pectoris, glaucoma (applied
topically), and migraine headache.
Side Effects
 Common effects: The β -blockers may
cause CNS side effects such as fatigue,
lethargy, insomnia, and hallucinations;
these drugs can also cause
hypotension.
 Alterations in serum lipid patterns: The
β-blockers may disturb lipid
metabolism, decreasing high-density
lipoproteins (HDL) and increasing
plasma triacylglycerol.
Side Effects
 Drug withdrawal: Abrupt withdrawal
may cause rebound hypertension,
probably as a result of up-regulation of
β-receptors.
 Patients should be tapered off of β1blocker therapy in order to avoid
precipitation of arrhythmias.
Side Effects
 The β-blockers should be avoided in
treating patients with asthma,
congestive heart failure, and peripheral
vascular disease.
α -ADRENERGIC BLOCKING AGENTS
Prazosin, oxazosin and terazosin
produce a competitive block of α1
adrenoceptors.
They decrease peripheral vascular
resistance and lower arterial blood
pressure by causing the relaxation of
both arterial and venous smooth
muscle.
α -ADRENERGIC BLOCKING
AGENTS
 These drugs cause only minimal
change in cardiac output, renal blood
flow, and glomerular filtration rate.
 Postural hypotension is the most
common side effect.
Prazosin
 Prazosin is used to treat mild to
moderate hypertension and is
prescribed in combination with
propranolol or a diuretic for additive
effects.
 Reflex tachycardia and first dose
syncope are almost universal adverse
effects.
CENTRALLY-ACTING ADRENERGIC DRUGS
A. Clonidine:
 This α 2-agonist diminishes central adrenergic
outflow.
 Clonidine is used primarily for the treatment
of mild to moderate hypertension that has not
responded adequately to treatment with
diuretics alone.
 Clonidine does not decrease renal blood flow
or glomerular filtration and therefore is useful
in the treatment of hypertension complicated
by renal disease.
Side Effects
 Adverse effects are generally mild, but
the drug can produce sedation and
drying of nasal mucosa.
 Rebound hypertension occurs
following abrupt withdrawal of
clonidine.
 The drug should therefore be
withdrawn slowly if the clinician
wishes to change agents.
B. α-Methyldopa
 This α2-adrenergic agonist diminishes the
adrenergic outflow from the CNS, leading to
reduced total peripheral resistance and a
decreased blood pressure.
 Cardiac output is not decreased and blood flow to
vital organs is not diminished ( it is especially
valuable in treating hypertensive patients with
renal insufficiency ).
Side Effects
 The most common side effects of α -
methyldopa are sedation and
drowsiness
VASODILATORS
. VASODILATORS
 The direct-acting smooth muscle
relaxants, such as hydralazine and
minoxidil, have traditionally not been
used as primary drugs to treat
hypertension.
. VASODILATORS
 Vasodilators act by producing
relaxation of vascular smooth muscle,
which decreases resistance and
therefore decreases blood pressure.
 These agents produce reflex
stimulation of the heart, resulting in
the competing symptoms of increased
myocardial contractility, heart rate, and
oxygen consumption.
A. Hydralazine
 This drug causes direct vasodilatation,
acting primarily on arteries and
arterioles.
 This results in a decreased peripheral
resistance, which in turn prompts a
reflex elevation in heart rate and
cardiac output.
Clinical Uses
 Hydralazine is used to treat
moderately severe hypertension.
Clinical Uses
 It is almost always administered in
combination with a β-blocker such as
propranolol (to balance the reflex
tachycardia) and a diuretic (to decrease
NA+ retention).
 Together, the three drugs decrease cardiac
output, plasma volume, and peripheral
vascular resistance.
Side Effects
 Adverse effects of hydralazine therapy
include headache, nausea, sweating,
arrhythmia, and precipitation of
angina.
 A lupus-like syndrome can occur with
high dosage, but it is reversible on
discontinuation of the drug.
B. Minoxidil
 This drug causes dilation of resistance
vessels (arterioles) but not of
capacitance vessels (venules).
B. Minoxidil
 Minoxidil is administered orally for
treatment of severe to malignant
hypertension that is refractory to other
drugs.
 Reflex tachycardia may be severe and
may require the concomitant use of a
diuretic and a β-blocker.
Side Effect
 Minoxidil causes serious NA+ and water
retention, leading to volume overload,
edema, and congestive heart failure.
 [Note: Minoxidil treatment also causes
hypertrichosis (the growth of body
hair). This drug is now used topically to
treat male pattern baldness.]
TREATMENT OF HYPERTENSIVE
CRISIS
 Hypertensive crisis is an elevation in blood
pressure in which diastolic pressure exceeds 120
mmHg. In the presence of ongoing end-organ damage
this is referred to as a hypertensive
emergency. Without such complications, it is
referred to as a hypertensive urgency.
TREATMENT OF HYPERTENSIVE
CRISIS
 Hypertensive emergencies require blood pressure
to be reduced within a few hours.
 The blood pressure in hypertensive urgencies can
be lowered over a period of 1-2 days.
 Intravenous medications are often used to treat
these conditions.
 Some agents are used
A. Sodium nitroprusside
 Nitroprusside is administered intravenously, and
causes prompt vasodilatation, with reflex tachycardia.
 It is capable of reducing blood pressure in all patients,
regardless of the cause of hypertension.
Notes
 Nitroprusside is metabolized rapidly (t1/2 12 of
minutes) and requires continuous infusion to
maintain its hypotensive action.
Mechanism of Action
 The drug has little effect outside the vascular system,
acting equally on arterial and venous smooth muscle.
 [Note: Because nitroprusside also acts on the veins, it
can reduce cardiac preload.]
Side Effect
 Sodium nitroprusside exerts few adverse effects except
for those of hypotension caused by overdose.
Side Effect
 Nitroprusside metabolism results in cyanide ion
production, although cyanide toxicity is rare and
can be effectively treated with an infusion of
sodium thiosulfate to produce thiocyanate, which
is less toxic and is eliminated by the kidneys .
 [Note: Nitroprusside is poisonous if given orally
because of its hydrolysis to cyanide.)
B. Diazoxide
 Diazoxide is a direct-acting arteriolar vasodilator. It
has vascular effects like those of hydralazine.
 For patients with coronary insufficiency, diazoxide is
administered intravenously with a β-blocker, which
diminishes reflex activation of the heart.
Therapeutic Uses

1.
2.
3.
Diazoxide is useful in the treatment of:
hypertensive emergencies.
hypertensive encephalopathy.
eclampsia.
Side Effect
 Excessive hypotension is the most serious toxicity.
C. Labetalol
 Labetalol is both an α1- and β-blocker that has been
successfully used in hypertensive emergencies.
C. Labetalol
 Labetalol does not cause the reflex tachycardia that
may be associated with diazoxide.
 Labetalol carries the contraindications of a
nonselective β-blocker.
Implications for Dentistry
Antihypertensive drugs are able to induce a
series of adverse effects with the oral cavity:
patients can present oral manifestations
in the form of xerostomia, lichenoid
reactions,burning mouth sensation,
loss of taste sensation or gingival
hyperplasia, as well as extraoral
manifestations such as sialadenosis.
Drug Interactions:
Certain nonsteroidal antiinflammatory drugs
(NSAIDs), such as ibuprofen, indomethacin or
the
naproxen,
can
interact
with
antihypertensive
drugs
(beta-blockers,
diuretics,(ACEIs),thereby
lowering
their
antihypertensiveaction.
Normally more than five days of treatment
with both types of drugs are required for
interactions to manifest; as a result, NSAIDs
should not be prescribed for longer than this
five-day period.
Drug Interactions:
 Aspirin & other NSAIDs antagonize the
antihypertensive effect of ACE & diuretics, due to
inhibition of prostaglandin synthesis.
 Vasoconstrictor in local anesthesia) amount & type )
should be considered, especially in patient receiving
propranolol
Notes:
 the use of the aspiration technique to avoid
intravascular injection can reduce the chance of
vasoconstrictor adverse reactions.
Adverse Effects
1.
2.
3.
4.
Xerostomia ( reserpine & the centrally Acting drug(.
Dysgeusia ( ACE ).
Gingival hyperplasia ( ca channel blocker).
Postural hypotension.