CVS(2).pdf

Pharmacotherapy of
Hypertension (HTN)
1

Definition
A sustained increase in blood pressure (130/80
mm Hg) [on repeated BP measurement]
Criteria for HTN in Adults
2
Classification Blood Pressure (mm Hg)
Systolic Diastolic
Normal < 120 & < 80
Elevated 120 – 129 / < 80
Hypertension, Stage 1 130 – 139 / 80 – 89
Hypertension, Stage 2  140 /  90

Sustained arterial hypertension damages blood
vessels in kidney, heart and brain and leads
to an increased incidence of renal failure,
cardiac failure, and stroke.
Effective pharmacologic lowering of blood
pressure prevents the damage to blood vessels
and reduces the morbidity and mortality rate.

 Two factors which determine blood pressure are cardiac out put (stroke
volume x heart rate) and total peripheral resistance of the vasculature.
 Blood pressure is regulated by an interaction between nervous, endocrine
and renal systems
 Elevated blood pressure is usually caused by a combination of several
abnormalities such as psychological stress, genetic inheritance,
environmental and dietary factors and others.
 Patients in whom no specific cause of hypertension can be found are said to
have essential hypertension or primary hypertension (accounts for more
than 90 % of cases).
 Secondary hypertension arises as a consequence of some other conditions
such as, atherosclerosis, renal disease, endocrine diseases and others.
 The central issue of antihypertensive therapy is to lower arterial blood
pressure, irrespective of the cause.
 The choice of therapy of a patient with hypertension depends on a variety
of factors: age, sex, race, body build, life-style of the patient, cause of the
disease, other co-existing disease, rapidity of onset and severity of
hypertension, and the presence or absence of other risk factors for
cardiovascular disease (e.g. smoking, alcohol consumption, obesity, and
personality type).

Antihypertensive therapies.
Non pharmacological therapy of hypertension
 Several non-pharmacological approaches to therapy of hypertension
are available.
 Low sodium chloride diet
 Weight reduction
 Exercise
 Cessation of smoking
 Decrease in excessive consumption of alcohol
 Psychological methods (relaxation, meditation …etc)
 Dietary decrease in saturated fats.
 On the average, only modest reductions (5 to 10 mmHg) in blood
pressure can be achieved.
 This may be sufficient for the treatment of some mild hypertensive
cases.
 The major advantage of non-pharmacological approaches is the
relative safety and freedom from side effects, compared with drug
therapy.

Pharmacological therapy of hypertension.
Currently available drugs lower blood pressure
by decreasing either cardiac output (CO) or
total peripheral vascular resistance (PVR) or
both
A) Diuretics, which lower blood pressure by
depleting the body sodium and reducing blood
volume.
Diuretics are effective in lowering blood
pressure by 10 – 15 mmHg in most patients.

B) Sympathoplegic agents (Depressants of sympathetic activity).
 sympathoplegic drugs are divided into:
a) Centrally acting antihypertensive agents e.g. methyldopa, clonidine
 Centrally acting sympathetic depressants act by stimulating α2 -
receptors located in the vasomotor centre of the medulla.
 As a result, sympathetic out flow from the medulla is diminished
and either total peripheral resistance or cardiac out put decreases.
 Methyldopa is useful in the treatment mild to moderately severe
hypertension.
 Methyldopa is a prodrug and must be converted in the CNS to active
α – methylnorepinephrine to exert the effect on blood pressure.
 The side effects of methyldopa include sedation, vertigo, dry mouth,
nausea, vomiting, diarrhea, postural hypotension, impotence,
haemolytic anemia, weight gain and hypersensitivety reactions
(fever, liver damage, thrombocytopenia).

b) Adrenoceptor antagonists, e.g propranolol (beta blocker), prazosin
(alpha
blocker), labetalol (alpha and beta blocker).
 β – Blockers antagonize beta, receptors located on the myocardium and prevent the
cardio acceleration, which follows sympathetic stimulation.
 The rate and force of myocardial contraction is diminished, decreasing cardiac out
put and thus, lowering blood pressure.
 An additional effect which can contribute to a reduction of blood pressure is that
renin release is mediated by β receptors.
 Therefore, receptor blockade prevents angiotensin II formation and associated
aldosterone secretion, resulting in a decrease in total peripheral resistance and blood
volume.
 The principal action of alpha adrenergic blocking drugs is to produce peripheral
vasodilation.
 Alpha blockers reduce arterial pressure by dilating both resistance and capacitance
vessels.
 Treatment with prazosin should be initiated with low dose (1mg 3 times daily) to
prevent postural hypotension and syncope or be given at bed time.
c) Adrenergic neuron – blocking agents, e.g. guanethidine
 Guanethidine is an adrenergic neuron-blocking drug recommended for treatment of
severe forms of hypertension.
 Guanethidine blocks adrenergic nerve transmission, preventing the release of
transmitter.
 It lowers blood pressure by reducing both cardiac out put and total peripheral
resistance.

d) Drugs which deplete catecholamine stores, e.g. reserpine.
Reserpine interferes with the storage of endogenous
catecholamines in storage vesicles as a result of which
little neurotransmitter is released upon stimulation.
It leads to reduction of cardiac out put and peripheral
vascular resistance.
Reserpine is a second-line drug for treatment of
hypertension.
e) Ganglion blockers, e.g. trimethaphan
Trimethaphan is ganglion blocking drug which is
reserved for use in hypertensive emergencies only.
C) Direct vasodilators. These include:-
 Arterial vasodilators, e.g. hydralazine
 Arteriovenous vasodilators, e.g. sodium nitroprusside

Hydralazine: It dilates arterioles but not veins.
 It is used particularly in severe hypertension.
 The most common adverse effects are headache,
nausea, anorexia, palpitations, sweating and flushing
which are typical to vasodilators.
Sodium nitroprusside: It is a powerful vasodilator that
is used in treating hypertensive emergencies as well as
severe cardiac failure.
 It dilates both arterial and venous vessels, resulting in
reduced peripheral vascular resistance and venous
return.
 Nitroprusside rapidly lowers blood pressure and it is
given by intravenous infusion.
 The most serious toxicities include metabolic acidosis,
arrhythmias, excessive hypotension and death.

 D) Angiotensin converting enzyme inhibitors, e.g. captopril, enalapril, etc.
 The prototype is captopril.
 Captopril inhibits angiotensin converting enzyme that hydrolyzes
angiotensin I (Inactive) to angiotensin II (Active), a potent vasoconstrictor,
which additionally stimulates the secretion of aldosterone.
 It lowers blood pressure principally by decreasing peripheral vascular
resistance.
 The adverse effects include maculopapular rash, angioedema, cough,
granulocytopenia and diminished taste sensation.
 Enalapril is a prodrug with effects similar to those of captopril.

E) Calcium channel blockers, e.g. nifedipine,
verapamil, nicardipine, etc.
The prototype is verapamil.
The mechanism of action in hypertension is
inhibition of calcium influx in to arterial smooth
muscle cells, resulting in a decrease in peripheral
resistance.
Verapamil has the greatest cardiac depressant
effect and may decrease heart rate and cardiac out
put as well.
The most important toxic effects for calcium
channel blockers are cardiac arrest, bradycardia,
atrioventricular block and congestive heart
failure.

Lines of treatment of primary hypertension
 The initial step in treating hypertension may be non-
pharmacologic.
 Dietary salt restriction may be effective treatment for about
half of the patients with mild hypertension.
 Weight reduction even without salt restriction normalizes
blood pressure in up to 70% of obese patients with mild to
moderate hypertension.
 Regular exercise may also be helpful in some hypertensive
patients.
 When non-pharmacologic approaches do not satisfactorily
control blood pressure, drug therapy begins in addition to
non-pharmacological approaches.
 The selection of drug(s) depends on various factors such as
the severity of hypertension, patient factors (age, race,
coexisting diseases, etc.).

 For most patients with mild hypertension and some
patients with moderate hypertension monotherapy with
either of the following drugs can be sufficient.
 Thiazide diuretics
 Beta blockers
 Calcium channel blockers
 Angiotensin converting enzyme inhibitors
 Central sympathoplegic agents
 Beta-blockers are preferred in young patients, high
renin hypertension and patients with tachycardia or
angina and hypertension.
 Black patients respond well to diuretics and calcium
channel blockers than to beta-blockers and ACE
inhibitors.

 If mono-therapy is unsuccessful, combination of two
drugs with different sites of action may be used.
 Thiazide diuretics may be used in conjunction with a beta-
blocker, calcium channel blocker or an angiotensin
converting enzyme inhibitor.
 If hypertension is still not under control, a third drug
e.g. vasodilator such as hydralazine may be combined.
 When three drugs are required, combining a diuretic, a
sympathoplegic agents or an ACE inhibitor, and a direct
vasodilator or calcium channel block is effective.
 The treatment of hypertensive emergencies is usually
started with furosemide given by parenteral route at
dose of 20-40mg.
 In addition, parenteral use of diazoxide, sodium
nitroprusside, hydralazine, trimethaphan, labetalol can
be indicated.

Drug used in heart failure
 Congestive heart failure occurs when there is an
inability of the heart to maintain a cardiac out put
sufficient to meet the requirements of the metabolising
tissues.
 Heart failure is usually caused by one of the following:
 Ischaemic heart disease,
 Hypertension,
 Heart muscle disorders, and
 Valvular heart disease.
 Drugs used to treat heart failure can be broadly divided
into:
A. Drugs with positive inotropic effect.
B. Drugs without positive inotropic effect.

A. Drugs with positive inotropic effect:-
Drugs with positive inotropic effect increase
the force of contraction of the heart muscle.
These
include:
Cardiac glycosides,
Bipyridine derivatives,
Sympathomimetics, and
Methylxanthines

Cardiac glycosides.
 Cardiac glycosides comprise a group of steroid compounds that can
increase cardiac out put and alter the electrical functions.
 Commonly used cardiac glycosides are digoxin and digitoxin.
 The mechanism of inotropic action of cardiac glycosides is
inhibition of the membrane-bound Na+/K+ ATPase often called the
“Sodium Pump”.
 This results in an increased intracellular movement of sodium and
accumulation of sodium in the cells.
 As a consequence of the higher intracellular sodium, decreased
transmembrane exchange of sodium and calcium will take place
leading to an increase in the intracellular calcium that acts on
contractile proteins.
 All cardiac glycosides exhibit similar pharmacodynamic properties
but do differ in their pharmacokinetic properties.
 For example, digitoxin is more lipid soluble and has long half-life
than digoxin.

Therapeutic uses of cardiac glycosides include:
 Congestive heart failure
 Atrial fibrillation,
 Atrial flutter, and
 Paroxysmal atrial tachycardia.
Toxicity of cardiac glycosides include:
 Gastrointestinal effects such as anorexia, nausea,
vomiting, diarrhoea Cardiac effects such as
bradycardia, heart block, arrhythmias CNS effects such
as headache, malaise, hallucinations, delirium, visual
disturbances (yellow vision) Mild toxicities such as
gastrointestinal and visual disturbance can be managed
by reducing the dose of the drug.

 For the management of arrhythmias or serious toxicity,
potassium supplementation, administration of anti-
arrhythmic drugs (e.g. lidocaine), and use of digoxin
antibodies can be helpful.
Bipyridine derivatives, e.g. amrinone, milrinone.
 These drugs possess both positive inotropic effect and
vasodilator effects.
 The suggested mechanism of action is inhibition of an
enzyme known as phophodiesterase, is responsible for
the inactivation of cyclic AMP.
 Inhibition of this enzymes result in an increase in
cAMP.
 Bipyridine derivatives are used in cases of heart failure
resistant to treatment with cardiac glycosides and
vasodilators.

 Beta - adrenergic stimulants e.g. dobutamine, dopamine
 The increase in myocardial contractility by beta stimulants
increase the cardiac out put.
 However, positive chronotropic effect of these agents
minimizes the benefit particularly in patients with ischaemic
heart disease.
 The positive inotropic effect of dobutamine is
proportionally greater than its effect on heart rate.
 It is reserved for management of acute failure or failure
refractory to other oral agents.
 Methylxanthines, e.g. theophylline in the form of
aminophylline
 Aminophylline has a positive inotropic effect,
bronchodilating effect and a modest effect on renal blood
flow.
 It is used for management of acute left ventricular failure or
pulmonary edema.

B. Drugs without positive inotropic effect.
 These include:
 Diuretics, e.g. hydrochlorothiazide, furosemide
 Vasodilators, e.g. hydralazine, sodium nitroprusside
 Angiotensin converting enzyme inhibitors e.g. captopril, enalapril
Diuretics
 Diuretics are first – line drugs for treatment of patients with heart
failure. In mild failure, a
 thiazide may be sufficient but are ineffective at low glomerular
filtration rates.
 Moderate or severe failure requires a loop diuretic.
 In acute failure, diuretics play important role by reducing ventricular
preload.
 The reduction in venous pressure causes reduction of edema and its
symptoms and reduction of cardiac size which leads to improved
efficiency of pump function.

Vasodilators.
 Vasodilators are effective in acute heart failure because
they provide a reduction in preload (through venous
dilation), or reduction in after-load (through arteriolar
dilation), or both.
 Hydralazine has a direct vasodilator effect confined to
arterial bed.
 Reduction in systemic vascular resistance leads to a
considerable rise in cardiac out put.
 Sodium nitroprusside is a mixed venous and arteriolar
dilator used also for acute reduction of blood pressure.
 Vasodilator agents are generally reserved for patients
who are intolerant of or who have contraindications to
ACE inhibitors.

Angiotensin converting enzyme (ACE) inhibitors.
 Because of the pervasive involvement of angiotensin II in the undesirable
compensatory responses to heart failure, reduction of this peptide has
positive effects on the course of the disease.
 These drugs reduce after load by reducing peripheral resistance and also
reduce preload by reducing salt and water retention by way of reduction in
aldosterone secretion.
 They are nowadays considered a head of cardiac glycosides in the
treatment of chronic heart failure.
 The following are essential for long-term management of chronic heart
failure:
 Modify cardiovascular risk factor profile, e.g. cigarette smoking, obesity,
salt intake Underlying
 causes should be treated, e.g. anemia, hypertension, valvular disease If this
proves inadequate, diuretic should be given.
 Give ACE inhibitor and digitalis (ACE inhibitors may be used before
digitalis). In patients with persisting symptoms give vasodilators besides
increasing the dose of diuretic and ACE inhibitors.

Pharmacotherapy of Angina pectoris
Angina pectoris develops as a result of an
imbalance between the oxygen supply and the
oxygen demand of the myocardium.
It is a symptom of myocardial ischemia.
When the increase in coronary blood flow is
unable to match the increased oxygen demand,
angina develops.
It has become apparent that spasm of the coronary
arteries is important in the production of angina.

Drugs used in angina pectoris
 Organic nitrates e.g. nitro-glycerine, isosorbide dinitrate, etc.
 Beta adrenergic blocking agents e.g. propranolol, atenolol, etc.
 Calcium channel blocking agents e.g. verapamil, nifedipine, etc.
 Miscellaneous drugs e.g. aspirin, heparin, dipyridamole.
 Organic nitrates: organic nitrates are potent vasodilators and successfully used in
therapy of angina pectoris for over 100 years.
 The effects of nitrates are mediated through the direct relaxant action on smooth
muscles.
 Nitrates are believed to act by mimicking the vasodilator action of endothelium
derived relaxing factor (EDRF) identified as nitric oxide.
 Vasodilating organic nitrates are reduced to organic nitrites, which is then
converted to nitric oxide.
 The action of nitrates begins after 2-3 minutes when chewed or held under tongue
and action lasts for 2 hours.
 The onset of action and duration of action differs for different nitrates and varying
pharmaceutical preparations.
 Adverse effects include flushing, weakness, dizziness, tachycardia, palpitation,
vertigo, sweating, syncope localized burning with sublingual preparation and
contact dermatitis with ointment.
 Therapeutic uses: prophylaxis and treatment of angina pectoris, post myocardial
infarction, coronary insufficiency, acute LVF (left ventricle failure)

Adrenergic blocking agents
 Exercise and emotional excitement induce angina in
susceptible subject by the increase in heart rate, blood
pressure and myocardial contractility through increased
sympathetic activity.
 Beta receptor blocking agents prevent angina by blocking
all these effects.
 In most patients the net effect is a beneficial reduction in
cardiac workload and myocardial oxygen consumption e.g.
atenolol, propranolol metoprolol, labetolol.
 Adverse effects: Lethargy, fatigue, rash, cold hands and
feet, nausea, breathlessness, nightmares and bronchospasm.
Selective beta blockers have relatively lesser adverse
effects.
 Therapeutic uses other than angina include hypertension,
Cardiac arrhythmias, post myocardial infarction and
pheochromocytoma

Calcium channel blockers:
 Calcium is necessary for the excitation contraction coupling in both
the cardiac and smooth muscles. Calcium channel blockers appear to
involve their interference with the calcium entry into the myocardial
and vascular smooth muscle, thus decreasing the availability of the
intracellular calcium e.g. nifedipine, felodipine, verapamil and
diltiazem.
 Other therapeutic uses: hypertension, acute coronary insufficiency,
tachycardia,
 Adverse effects: flushing nausea/vomiting, headache, Ankle
swelling, dizziness, constipation, etc.
 Miscellaneous drugs,e.g. Acetylsalicylic acid
 Acetylsalicylic acid (aspirin) at low doses given intermittently
decreases the synthesis of thromboxne A2 without drastically
reducing prostacylin synthesis. Thus, at the doses of 75 mg per day
it can produce antiplatelet activity and reduce the risk of myocardial
infarction in anginal patients.

Anti - arrhythmics
Electrophysiology of cardiac muscle: the
pathophysiological mechanisms responsible
for the genesis of cardiac arrhythmias are not
clearly understood.
However, it is generally accepted that cardiac
arrhythmias arise as the result of either of
a) Disorders of impulse formation and/ or
b) Disorders of impulse conduction.

Pharmacotherapy of cardiac arrhythmias
 Antiarrhythmic drugs are used to prevent or correct
cardiac arrhythmias (tachyarrhythmias).
 Drugs used in the treatment of cardiac arrhythmias are
traditionally classified into:
 Class (I): Sodium channel blockers which include
quinidine, lidocaine, phenytion, flecainide, etc.
 Class (II): Beta adrenergic blockers which include
propranolol, atenolol, etc.
 Class (III): Potassium channel blockers e.g. amiodarone,
bretylium.
 Class (IV): Calcium channel blockers e.g. verapamil, etc.
 Class (V): Digitalis e.g.digoxin.

Class – I drugs
 Quinidine: It blocks sodium channel so that there is an increase in
threshold for excitability.
 It is well absorbed orally
 Adverse effects: It has low therapeutic ratio. Main adverse effects
are SA block, cinchonism, severe headache, diplopia and
photophobia.
 Lidocaine, which is used commonly as a local anaesthetic blocks
both open and inactivated sodium channel and decreases
automaticity.
 It is given parenterally.
 Adverse effects: excessive dose cause massive cardiac arrest,
dizziness, drowsiness, seizures, etc.
 Flecainide: It is a procainamide analogue and well absorbed orally.
 It is used in ventricular ectopic beats in patients with normal left
ventricular function.

Class –II drugs:
Beta-adrenergic receptor blockers
 Propranolol: Myocardiac sympathetic beta receptor
stimulation increases automaticity, enhances A.V.
conduction velocity and shortens the refractory period.
 Propranolol can reverse these effects.
 Beta blockers may potentiate the negative inotropic
action of other antiarrhythmics.
 Therapeutic uses: This is useful in tachyarrhythmias, in
pheochromocytoma and in thyrotoxicosis crisis.
 It is also useful in patients with atrial fibrillation and
flutter refractory to digitalis.

Class – III: Potassium channel blockers
 AMIODARONE: This drug is used in the treatment of
refractory supraventriculat tachyarrhythmias and ventricular
tachyarrhythmias.
 It depresses sinus, atrial and A.V nodal function.
 The main adverse effects of this drug are anorexia, nausea,
abdominal pain, tremor, hallucinations, peripheral
neuropathy, A.V. block
Class IV drugs: Calcium channel blockers
 Verapamil: this drug acts by blocking the movement of
calcium ions through the channels.
 It is absolutely contraindicated in patients on beta blockers,
quinidine or disopyramide.
 It is the drug of choice in case of paroxysmal
supraventricular tachycardia for rapid conversion to sinus
rhythm.

Class - V drugs:
Digoxin causes shortening of the atrial
refractory period with small doses (vagal
action) and a prolongation with the larger
doses (direct action).
It prolongs the effective refractory period of
A.V node directly and through the vagus.
This action is of major importance in slowing
the rapid ventricular rate in patients with atrial
fibrillation

Drugs used in hypotensive states and shock
 Antihypotensive drugs or agents are used to elevate a low
blood pressure and may be classified as follows:
I. Agents intended to increase the volume of blood in activ
circulation.
 These include intravenous fluids such as whole blood,
plasma, plasma components, plasma substitutes and solution
of crystalloids
II. Vasoconstrictor drugs
 these include: Peripherally acting vasoconstrictors which
are further divided into sympathomimetic drugs and direct
vasoconstrictors.
 Sympathomimetics used to elevate the blood pressure
include adrenaline, noradrenaline, methoxamine,
phenylephrine, mephentermine and ephedrine.
 Direct vasoconstrictors include vasopressin and angiotensin.

Treatment of shock
 Shock is a clinical syndrome characterized by decreased blood
supply to tissues.
 Common signs and symptoms include oliguria, heart failure,
disorientation, mental confusion, seizures, cold extremities, and
comma.
 Most, but not all people in shock are hypotensive.
 The treatment varies with type of shock.
 The choice of drug depends primarily on the patho-physiology
involved.
 For cardiogenic shock and decreased cardiac out put, dopamine or
other cardiotonic drug is indicated.
 With severe CHF characterized by decreased CO and high PVR,
vasodilator drugs (nitropruside, nitroglycerine) may be given along
with the cardiotonic drug.
 Diuretics may also be indicated to treat pulmonary congestion if it
occurs.

•For anaphylactic shock or neurogenic shock
characterized by severe vasodilation and
decreased PVR, a vasoconstrictor drug (e.g.
levarterenol) is the first drug of choice
•For hypovolemic shock, intravenous fluids that
replace the type of fluid lost should be given
•For septic shock, appropriate antibiotic therapy
in addition to other treatment measures.

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