DRUGS USED IN THE

TREATMENT OF HYPERTENSION
Dr. Monica Daniela Doa
25.03.2010

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Antihypertensive Drugs
Hypertension is the most common CV disease
The diagnosis is based on repeated, reproductible
measurements of elevated blood pressure and not on symptoms
reported by the patient
Normal regulation of blood pressure
BP is maintained by regulation of cardiac output CO and PVR,
exerted at three anatomic sites:
Arterioles
Postcapillary venules (capacitance vessels)
Heart
A fourth anatomic site is the kidney that contributes to maintenance
of BP by regulating the volume of intravascular fluid
Baroreflexes mediated by autonomic nerves act in combination with
humoral mechanisms including renin-angiotensin-aldosteron
system to coordinate function at these four control sites and to
maintain normal BP.

Antihypertensive Drugs

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Regulation of BP in hypertensive patients differs from healthy

patients in that the baroreceptors and the renal blood volumepressure control systems appear to be set at a higher level of
blood pressure.
All antihypertensive drugs act by interfering with these normal
mechanisms
A useful classification categorizes them according to the
principal regulatory site or mechanism on which they act

Antihypertensive Drugs
Four major pharmacological classes

Sympathetic nervous system suppressors:

that lower BP by reducing PVR, inhibiting cardiac

function, and increasing venous pooling in capacitance
vessels (the later two effects reduce CO).
Are subdivided according to their sites of action in the
symphatetic reflex arc.
Adrenoreceptors antagonists (1 and 1 antagonists)
Ganglion - blocking agents
Adrenergic neuron-blocking agents
2 agonists (centrally acting sympatholytic agents)

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Vasodilators:
Calcium channel antagonists
Arteriolar (directly) vasodilators

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Antihypertensive Drugs

Drugs that interfere with renin-angiotensin system:

Diuretics:

ACE inhibitors
Angiotensin II type 1 (AT1) receptor antagonists
Thiazides
Loop diuretics
K+ - sparing diuretics

Adrenoreceptors antagonists

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1-adrenergic antagonists
Prazosin, Terazosin

Prazosin- quinazoline derivative, it causes vasodilation of both

arteries and veins
Pharmacological effects
Reduces peripheral vascular resistance, it lowers arterial blood
pressure in both supine and erect patients
Unlike nonselective adrenergic blockers, it does not usually
produce reflex tachycardia
Unlike blockers, it does not adversely affect insulin sensitivity
or blood lipids
It does not increase plasma renin activity
It produce minimal changes in cardiac output, renal blood flow,
and glomerular filtration rate
Therapeutic uses- mild to moderate hypertension; CHF
- more effective in conjunction with a diuretic

Prazosin- Minipress, Adversuten

Route of administration- orally, 2 or 3 times daily, 2-10 mg/day
Adverse effects: dizziness, headache, drowsiness, palpitations, but
often disappear with continued therapy
- the initial dose, if larger than 1 mg. can induce postural
hypotension and syncope (probably as a result of decreased
venous return to the heart). It is, therefore best to give the initial
dose at bedtime (0,5 mg)

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- test for antinuclear factor may become positive with prazosin

therapy.

Terazosin
Mechanism of action- it is a postsynaptic 1 adrenergic
antagonist that rapidly relaxes smooth muscle tone in the
arteries, bladder neck, prostate capsule, and prostatic urethra
It has a longer half-life (12 h) and longer duration of action (24
h) than does prazosin
Therapeutic uses: hypertension
- benign prostatic hyperplasia (improves urine flow,
decreases symptoms of obstruction)

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Adverse effects: orthostatic hypotension, syncope with first dose

- Nasal congestion, impotence

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adrenergic antagonists
Have become increasingly important as antihypertensive
agents, are used alone or in combination antihypertensive
therapy
Mechanism of action and pharmacological effects:
As consequences of beta blockade: it decrease the cardiac
output, and inhibition of renin secretion.
Most used in hypertension are the beta 1 selective antagonists
such as: Metoprolol, Atenolol, Bisoprolol, Betaxolol
Labetalol, Carvedilol,: have both beta blocking effect and also
blocks vascular postsynaptic alfa1 adrenergic receptors
Adverse effects: can exacerbate CHF, asthma, chronic
obstructive pulmonary disease
They can mask symptoms of hypoglicemia in individuals with
diabetes mellitus
They can increase serum TG and decrease HDL cholesterol

Beta adrenergic antagonists

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Cont. adverse effects: when used chronically, labetalol causes

more frequent orthostatic hypotension and sexual dysfunction
than do other blockers.
Patients taking blockers who have allergic conditions may
develop more serious anaphylactic reactions to allergens
Therapeutic use: traditionally, they represent the first choice for the
initial treatment of chronic hypertension.
are effective in young persons, in hiperkinetic syndoms, in mild to
moderate hypertension. In severe hypertension, they prevent the
reflex tachycardia that often results from treatment with direct
vasodilators.
The effect appears after 7-10 days
The treatment with blockers is not interrupt suddenly: it may
cause angina, MI, arhythmias, increase of BP.

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Beta adrenergic antagonists

Relative cardioselectivity may be advantageous in treating
hypertensive patients who suffer from asthma, diabetes, or
peripheral vascular disease.
Betaxolol and Bisoprolol are beta1 selective blockers with long
half-lives, being admin.once daily: Betaxolol 10 mg/d
Bisoprolol 5 mg/d
Labetalol- useful in hypertensive emergencies, in repeated iv
bolus injections 20-80 mg
Carvedilol- usual starting dosage- 6,25 mg twice daily. ! It
reduces mortality in patients with CHF being particularly useful
in patients with both HF anf hypertension
Nebivolol- a beta 1 selective blocker with vasodilating properties
not mediated by alpha blockade, but due to an increase in
endothelial release of nitric oxide via induction of endothelial
nitric oxide synthase dose 5 mg/d to 40 mg/d if necessary

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Centrally acting sympatholytic agents

Clonidine, Methyldopa
Clonidine (Haemiton), Guanabenz, Guanfacine: act centrally on
the vasomotor centers of the brain predominantly by stimulating
2 adrenergic R. As result it decrease sympathetic outflow
from CNS.
Pharmacologic effects: reduction of CO due to decreased heart
rate and relaxation of capacitance vessels with reduction of
PVR. Lower AP and reduce secretion of renin.
Therapeutic uses: mild to moderate or severe hypertension
single or in combination (often diuretic coadministration,
because of the retention of sodium and water)
Adverse effects: dry mouth, drowsiness, sedation, rebound
hypertensive crises can result from abrupt cessation of clonidine
tablets or patches when the drug is used as a single agent.
Precaution and contraindications: cannot be administered to
patients taking tricyclic antidepressants, because these drugs
block clonidines hypotensive effect. Clonidine may worsen
depression, should not be given in such patients.

Clonidine

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Because of the risk of severe hypertensive crisis, mediated by

increased symphatetic nervous activity, when clonidine is
suddenly withdrawn, all patients should be warned of this
possibility
If the drug must be stopped it should be done gradually while
other antihypertensive agents are being substituted
Treatment of the hypertensive crisis: reinstitution of clonidine
therapy or administration of and adrenoreceptor- blocking
agents.

Methyldopa- Aldomet

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Mechanism of action: is an effective inhibitor of dopa

decarboxilase and was initially thought to act as an
antihypertensive agent by decreasing stores of NE in the SNS.
It is an analog of L-Dopa, and on a pathway parallels with the
synthesis of NE from dopa
Methyldopa is metabolised by decarboxylation and hydroxylation in adrenergic neurons of the CNS. The metabolite,
-methylnorepinephrine and -methyldopamine stimulates
AR in the brain, inhibiting sympathetic outflow
It reduces renal vascular resistance, possibly as a result of an
-methylnorepinephrine being a weaker vasoconstrictor than
NE in renal beds
Is thought to exert other direct actions on peripheral adrenergic
neurons that contribute to its antihypertensive effect

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Methyldopa
Pharmacologic effects
Decreases peripheral arteriolar resistance, and BP
It reduces renal vascular resistance
Little effect on cardiac output, renal blood flow, or glomerular
filtration rate
It does not abolish symphatetic reflexes, and BP reduction is not
markedly dependent on posture.
Therapeutic uses
Primarily for hypertension during pregnancy.
Orally in mild or moderate to severe hypertension, usually in
combination with a diuretic. Adverse effects limit its usefulness.
Adverse effects
Sedation, drug fever, positive direct Coombs test, hemolytic
anemia reversible on discontinuation of the drug, edema,
rebound hypertension, lactation, impotence (mediated by
inhibition of dopaminergic mechanisms in the hypothalamus)

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Adrenergic neuron- blocking agents

Reserpine, Guanethidine
Reserpine (Raunervil), a rauwolfia serpentina alkaloid (from
roots of an indian plant), was one of the first effective drugs
used on a large scale in the treatment of hypertension.
At present it is rarely used owing to its adverse effects.
Mechanism of action
depletes cathecolamines (NE, D) and serotonine stores in the
peripheral and CNS and causes impaired symphatetic nerve
discharge. It interferes with intracellular storage of CA by
inhibiting the binding of NE to neurosecretory vesicles at the
vesicle membrane (interfering with the vesicular membraneassociated transporter)
It decreases the synthesis of NE and increases its turnover rate
Depletion of peripheral amines accounts for much of the
beneficial antihypertensive effect of reserpine
Depletion of cerebral amine stores causes sedation, depression,
parkinsonism symptoms.

Reserpine

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Pharmacologic effects: it decreases BP, heart rate and cardiac

output, PVR. In usual therapeutic doses, only partially inhibits
CV reflexes. It exerts central actions that produce sedation.
Therapeutic use: low oral doses in combination with thiazide
diuretic or vasodilators to control moderate hypertension.
Adverse effects: sedation, depression, nightmares, parkinsonism
symptoms bradycardia, nasal congestion, increased GI activity:
diarrhea, cramps, increases acid secretion.
Daily dose start from 0,25/d.

Guanethidine- Ismelin

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Mechanism of action: it acts presinaptically to inhibit the release

of neurotransmitter from peripheral adrenergic neurons, thus
reducing the response to sympathetic nerve activation. To exert
an antihypertensive effect it must be taken up and stored in
adrenergic nerve terminals in a manner similar to NE uptake.
Agents that prevent this uptake such as cocaine and tryciclic
antidepressants, inhibit the therapeutic effect of guanethidine.
The drug does not cross the blood-brain barrier like reserpine
and it does not affect serotonin and NE stores in the CNS.
In high doses it can produce profound sympathoplegia, and for
this reason all the toxicities expected from pharmacologic
sympathectomymarked postural hypotension, diarrhea,
impaired ejaculation.
Because of these adverse effects is now rarely used

Guanethidine

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Pharmacologic effects
Initially it displaces and releases enough unchanged NE to cause
mild transient hypertension and cardiac stimulation.
Hypotension and bradycardia follow. Venous return and cardiac
output are decreased.
Therapeutic uses: moderate to severe hypertension in combination
with a thiazide diuretic or/and a vasodilator.
Adverse effects: significant orthostatic hypotension and syncope,
salt and water retention, GI hyperactivity

Antihypertensive Drugs:Vasodilators
Calcium channel blockers (= Calcium antagonists):
Inhibit calcium entry into cells of the arteries
=> decreased afterload

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Dihydropyridines:

Target specifically L-type channels on vascular smooth muscle cells

No cardiac effects (Vasoselective Ca ++ antagonists)
Can cause peripheral edema

Nifedipine

Nicardipine
Nimodipine
Nisoldipine
Amlodipine

Prototype

Ca-channel blockers

Verapamil

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Diltiazem
Depress A-V conduction and should not be used with blockers
Unlike blockers, they do not affect serum lipid concentrations or
cause sexual dysfunction.
. Nifedipine a dihydropyridine derivative, functions mainly as an
arteriolar vasodilator.
it has minimal effect on cardiac conduction or heart rate.
Nifedipine is administered orally, usually as extended-release
tablets
Side effects- flushing, headache, hypotension, reflex tachycardia
and peripheral edema due to its vasodilation activity.

Antihypertensive Drugs: Vasodilators

Potassium channel agonists:

Minoxidil directly relaxes arteriolar smooth muscle vasodilator

Mech.of action- it open K channels

Increases outward K+ current => membrane hyperpolarization, which inhibits Ca ++ channel activity make contraction less likely
It decreases PVR more than hydralzine does
It decreases renal vascular resistance while preserving renal blood flow and glomerular filtration rate
Used only for severe, treatment-resistant hypertension
Major side effect: Hirsutism => used topically to treat baldness (Rogaine)
tachycardia, palpitations, angina, edema, headache
Orally
in
single or divided doses

Should be used in combination with adrenergic antagonists and a diuretic to avert increased symphathetic activity and salt and
water retention

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Antihypertensive Drugs: Vasodilators

Sodium Nitroprusside
Very unstable being rapidly metabolised by uptake into red blood cells, with liberation of cyanide, further
metabolised by the mitocondrial enzyme rhodanase in less toxic thiocyanate (only iv infusion)
Metabolized by blood vessels into NO
=> activates cGMP production, through activation of the enzyme guanylyl cyclase, either via release of NO
=> vasodilation of both arterial and venous
It reduce PVR and venous return
Rapid action (30 sec !), short duration (effect ends after 3 min) => blood pressure titration
Used only to treat hypertensive emergencies in patients with coronary insufficiency or pulmonary edema
because it reduces cardiac preload

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Can also be used to produce controlled hypotension to minimize bleeding during surgery

Sodium Nitroprusside
Can improve left ventricular function in patients with MI, can be of benefit in
CHF
Acts directly on arterial and venous smooth muscle, it decreases BP in both
supine and upright positions
The increased venous capacitance that it produces results in decreased
preload, and thus decreases myocardial oxygen demand

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Renal blood flow is maintained and renin secretion is increased

Toxicity- excessive blood pressure lowering

- accumulation of cyanide
- metabolic acidosis
- arrhythmias
- death
Administration of sodium thiosulfate as a sufur donor, facilitates
metabolism of cyanide, hydroxocobalamin combines with
cyanide to form nontoxic cyancobalaminboth in prophylaxis of
poisoning during Nitroprusside infusion

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Diazoxide
Used as antihypertensive only in IV form
Similar chemically to the thiazide diuretics but has no diuretic
effect
Mechanism of action- it prevents vascular smooth muscle
contraction by opening K channels and stabilizing the membrane
potential at the resting level
Pharmacological effects
Is a vasodilator on arterioles and has little effect on capacitance
vessels
It increase the heart rate and cardiac output
It inhibits the release of insulin (probably by opening K channels
in the beta cells)
Therapeutic uses: iv in hypertensive emergencies, orally to treat
hypoglycemia that is caused by hiperinsulinemia
Adverse effects: severe hypotension, reflex sympathetic stimulation
which can cause angina and worsen myocardial ischemia,
hyperglycemia, edema

Drugs that interfere with renin-angiotensin system

Renin-angiotensin system

Important role in regulating blood volume,

arterial pressure, and cardiac and vascular
function.

Most important site for renin release is the

kidney: sympathetic stimulation (acting via

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-adrenoceptors), renal artery hypotension

(e.g. stenosis), and decreased sodium
delivery to the distal tubules stimulate the
release of renin by the kidney.

Renin acts upon a circulating substrate,

angiotensinogen (produced mainly by the
liver) which undergoes proteolytic cleavage
to form the decapeptide angiotensin I (AT I).

Vascular endothelium, particularly in the

lungs, contains angiotensin converting
enzyme (ACE), which cleaves off two amino
acids to form the octapeptide, angiotensin II
(AT II).

Drugs that interfere with renin-angiotensin system

Renin-angiotensin system

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Angiotensin II

Constricts vessels thereby increasing

vascular resistance and arterial pressure

Stimulates the adrenal cortex to release

aldosterone, which acts upon the kidneys to
increase sodium and fluid retention

Stimulates the release of vasopressin

(antidiuretic hormone, ADH) from the
pituitary which acts upon the kidneys to
increase fluid retention

Facilitates norepinephrine release and

inhibits re-uptake from nerve endings,
thereby enhancing sympathetic adrenergic
function

Stimulates cardiac and vascular

hypertrophy

Drugs that interfere with renin-angiotensin system

ACE - Inhibitors
Captopril
First ACE inhibitor
Given po
Frequent side effect: cough (reduced inactivation of kinins)

Enalapril

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Benazepril
Ramipril
Lisinopril
Etc

ACE inhibitors

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Mechanism of action: are specific competitive inhibitors of

peptidyl dipeptidase, the enzyme that converts angiotensin I in
angiotensin II- thus the drugs inhibit vasoconstriction, and inhibit
salt and water retention and slightly increase serum K levels.
Because peptidyl dipeptidase is necessary to catalyze the
degradation of bradykinin, the ACE inhibitors may increase the
concentration of bradykinin, which is a potent vasodilator.
Captopril- is rapidly absorbed after oral administration, and reaches
peak blood levels within 1 h
Enalapril- is more potent than captopril, its duration of action is
more than 24 h, twice as long as that of captopril.
Lisinopril- is absorbed more slowly than enalapril and has slower
onset of action

ACE inhibitors

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Quinapril is a prodrug that is rapidly converted to its active form

in the small intestine and liver
Pharmacological effects: a reduction in total PVR and mean arterial
blood pressure, and either no change or an increase in cardiac
output.
- These agents do not result in reflex symphatetic activation, can
be used safely in persons with ischemic heart disease
Route of administration
Captopril- orally 1 h before meals, the initial dose can be increased
at 1-2 week intervals.
Enalapril, benazepril, fosinopril, quinapril and ramipril are given
orally once or twice a day
Lisinopril is given orally once a day

ACE inhibitors

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Therapeutic uses:
Are increasingly used for treatment of mild to moderate
hypertension, because they are without the side effects
associated with adrenergic blockers
Are effective for low-renin as well as high-renin hypertension
Are effective when used alone but are often administered with a
thiazide diuretic (additive effect) or with a blocker (less additive
antihypertensive effect)
They relieve chronic CHF and afterload
Less effective than a diuretic for hypertension in black patients
A particularly useful role in patients with chronic kidney disease,
because they diminish proteinuria and stabilize renal functionvaluable in diabetes. These benefits result from improved
intrarenal hemodynamics with decreased glomerular efferent
arteriolar resistance and reduction of intraglomerular capillary
pressure

ACE inhibitors

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Adverse effects:
Proteinuria can occur, especially in patients with compromised
renal function- monitoring urinary protein levels is recommended
CI in patients with bilateral renal artery stenosis, because acute
renal failure may ensue
Dry cough is common, bronchospasm, angioedema
Neutropenia (to captopril), caution in patients with impaired
renal function or serious autoimmune disease
Reversible skin rashes, alteration in taste (incidence lower with
enalapril, lisinopril)
For enalapril most common: headache, dizziness and fatigue
hiperkalemia

ACE inhibitors

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Contraindicated in
Second and third trimesters of pregnancyrisk of fetal
hypotension, anuria, renal failure, fetal malformations- not even
in first trimester- teratogenic risk
Important drug interactions with potassium supplements or
potassium- sparing diuretics hyperkalemia
NSAIDs may impair the hypotensive effects of ACE
inhibitors by blocking bradikynin- mediated vasodilation, which
is at least in part prostaglandin mediated.

Antihypertensive Drugs: RAAS-targeting drugs

AT II type 1 (AT1) Receptor Antagonists
Do not interfer with kinin processing => no cough

Losartan
Candesartan
Eprosartan
Valsartan
Irbesartan
Telmisartan

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olmesartan

AT II Receptor Antagonists
Mecahnism of action: by blocking the AT 1 R for angiotensin II,
without having an effect on bradikinin, are more selective than
ACE inhibitors on angiotensin II effects
Much better tolerate than ACE inhibitors
No cough and angioedema
The same adverse effects and CI like ACE inhibitors

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Therapeutic use: hypertension, and CHF

Cardiac Arrhythmia
Arrhythmias:

Abnormal rhythms of the heart that cause the heart to pump less effectively
Arrhythmia occurs:

when the hearts natural pacemaker develops an abnormal rate or rhythm

when the normal conduction path is interrupted

when another part of the heart takes over as pacemaker

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Types of arrhythmia:

Tachycardia: unusually fast heartbeat

Bradycardia: unusually slow heartbeat

Atrial fibrillation: the atria quiver rather than contract normally because of rapid and irregular
electrical signals in the heart. Beside the abnormal heart beat, there is also a risk that blood
will pool in the atria, possibly causing the formation of blood clots.

Ventricular fibrillation: life threatening condition in which the heart ceases to beat regularly
and instead quivers or fibrillates very rapidly sometimes at 350 beats per minute or more
(causes 350,000 death/year in the US - sudden cardiac arrest)

Cardiac Arrhythmia

Arrhythmias:

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Drug Classes:

Class I: Sodium channel blockers

Class II: -blockers

Class III: Potassium channel blockers

Class IV: Calcium channel blockers

Other arrhythmic drugs

Cardiac Arrhythmia
Arrhythmias:
Class I - Sodium channel blockers:
Block Na+ entry during depolarization phase

For atrial and ventricular arrhythmias (all-purpose)

Procainamide

Quinidine

For acute treatment of ventricular arrhythmias

Lidocaine

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For chronic treatment of ventricular arrhythmias

Flecainide

Propofenone

Cardiac Arrhythmia
Arrhythmias:
Class II - -blockers:
For tachycardia

Propranolol

Class III - Potassium channel blockers:

Prolong repolarization phase by blocking outward potassium flux

For treatment of intractable ventricular arrhythmias

Bretylium

Amiodarone

Class IV - Calcium channel blockers:

Prolong repolarization phase by blocking inward calcium current

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Predominantly for treatment of atrial arrhythmias

Verapamil

Cardiac Arrhythmia
Arrhythmias:
Other antiarrhythmics:

Adenosine
For paroxysmal supraventricular tachycardia
iv only, extremely short half-life
used to terminate arrhythmias (blocks reentrant pathway)
(Paroxysmal = an arrhythmia that suddenly begins
and ends)

Digoxin
For atrial fibrillation

Epinephrine, Isoproterenol

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For bradycardia