Pharmacology of drugs used for

treatment of
hypertension and hypotension
 Introduction
Definition:
Persistent diastolic blood pressure (BP) greater than 90
mm Hg and systolic pressure greater than 140 mm Hg
Stages of hypertension:
Stage 1, mildsystolic BP 140-159 or diastolic BP 90-99
Stage 2, moderatesystolic BP 160-179 or diastolic BP
100-109
Stage 3, severesystolic BP > 180 or diastolic BP > 110
 The most common presenting sign?
Is sometimes referred as "The Silent Killer
b/s it usually causes NO SYMPTOMS!
May have: Headache, Blurry vision, Chest Pain, Frequent
urination at night
Potential complications?
Why we fear hypertension?
b/s it causes dangerous complications (Target Organ
Damage such as:
Myocardial infarction
Heart failure
Retinopathy
Stroke and renal failure
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 Types & etiology of HTN
Primary hypertension
Accounts for 90-95% of HTN cases
Also termed essential Hypertension
Refers to HTN which has no identifiable cause.
It can be treated, however, the treatment is not curative
(instead it is symptomatic treatment)
We cant eliminate the underlying cause
Risk factors include:
Increased salt intake
Obesity, genetics
Alcohol, stress
lack of exercise, age, cigarette smoking, diabetes,
hyperlipidemia 4
 Secondary Hypertension
Accounts only for about 5-10% of HTN cases
It results from an identifiable cause
So it may be possible to treat that cause directly,
rather than relying on drugs for symptomatic relief
As a result, some individuals can actually be cured
Cause could be:
Secondary to renal diseases
Pheochromocytoma
Hyperladosteronism
Cushing's syndrome
Aortic constriction
Secondary to drugs
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 The hydraulic equation for BP?
BP is the product of cardiac out put & peripheral resistance

BP = CO x TPR

Strategies to reduce BP?

Drugs that reduce either CO or TPR will produce a reduction in BP

Regulation of normal BP

There are four anatomical regulating sites

1. Arterioles

2. Post-capillary Venules

3. The heart

4. The kidneys
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Main sites and mechanisms of BP control
1. Baroreceptor reflex:
Is mediated by autonomic nerves
Works for rapid and moment to moment adjustment of BP
Receptors found on carotid sinus and aortic arc control BP by sensing
the stretch on their wall

If BP is increased:
Carotid receptors are stimulated by stretch of blood vessels which results in the
inhibition of sympathetic discharge

If BP is decreased:
Stretch of blood vessels is reduced ed baroreceptor activity which leads to
disinhibition of sympathetic discharge 8
2. Humoral mechanism (RAAS system)
Used for long term control of BP

Mediated by the Jaxutaglomerular apparatus of kidney

If mean arterial BP is reduced, the JGA detects:

Reduction in the renal perfusion pressure & initiates a

number of responses including:
Increased reabsorption of salt & water

Increased secretion of renin and the resulting increase in

Angiotensin II, which in turn causes
Direct arteriolar vasoconstriction

Increased secretion of aldosterone 9

 Major classes of drugs used to treat
hypertension
(1) Diuretics
(2) Sympathoplegic agents
(3) Direct vasodilators
(4) Agents that block production or action of AGII
Diuretics
They reduce blood volume => reduction in CO
Thiazide diuretics
Loop diuretics
K+ sparing diuretics
Thiazide diuretics are the most commonly used
antihypertensive diuretics
Loop diuretics are used in patients with severe
edema
K+ sparing diuretics are used with other diuretic
agents to prevent excessive K+ loss
 Thiazide diuretics
Includes: Chlorothiazide, Hydrochlorothiazide,
Indapamide
Site of action: distal convoluted tubule

Mechanism of action: inhibit Na+-Cl- symporter

Used in treatment of mild to moderate HTN

Along with other antihypertensive agents

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 Side effects & precautions
hyperuricemia => gout
Hyponatremia => Volume depletion
Hypercalcemia (thiazides inhibit Ca++ excretion)
Hypokalemia

Thiazides appear in breast milk, so they should be

avoided in breast feeding mothers

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 Loop Diuretics
Includes: Furosemide, Torsemide, Ethacrynic acid
Site of action: - thick ascending limb (ThAL)
Mechanism of action: inhibit Na+-K+-2Cl- symporter in the
ThAL
Thiazides are more effective antihypertensive agents than loop
diuretics for two reasons
Short duration of action of loop diuretics requiring beyond
once daily dosing
Can cause excessive diuresis & lead to more SEs than
thiazide diuretics
Used in severe HTN
When multiple drugs with Na+ retaining properties are used
In case of renal insufficiency
In case of CHF or cirrhosis 15
 Side effects
Hypokalemia
Fluid volume depletion
Cardiac arrhythmias: from the hypokalemia
Should be used with K+ sparing diuretics or K+
supplements
Hypomagnesaemia
Hypocalcemia
Ototoxicity (due to inner ear electrolyte imbalance)
Hyperuricemia (can lead to gout)

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 K+ sparing diuretics
Includes: Spiranolactone, amiloride, triamterene
Site of action: collecting duct system
Mechanism of action:
Inhibit the binding of aldosterone to Mineralocorticoid
Receptors (spiranolactone)
Inhibit Na+ conductance channels (amiloride & triamterene)
Pharmacological effect:
Cause mild increase in Na+ & Cl- excretion
Decrease excretion of H+ & K+
Therapeutic uses:
Usually used with other diuretic agents to prevent excessive
K+ loss (prevent hypokalemia)
To treat hyperladosteronism
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 Side effects
Hyperkalemia
Metabolic acidosis (accumulation of acids in body
fluids): mainly occurs in Patients with liver disease
Drowsiness, lethargy, headache
Gynacomasteia, impotence (spiranolactone)
Diarrhea, gastritis

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 QQQQQQQ
What are the effects of thiazide and loop
diuretics on uric acid and calcium excretion?
Sympatholytic agents
Works by blunting the sympathetic nervous system
effect on the cardiovascular system
Includes:
-antagonists
E.g. Propranolol, metoprolol, pindolol, atenolol etc
1 antagonists
E.g. prazosin, terazosin, doxazosin
Non selective & antagonists
E.g. labetalol, Carvedilol
Centrally acting antihypertensive agents
E.g. methyldopa, clonidine, Guanfecine
All of these agents reduce PVR or CO
 -antagonists
Two MOA for their antihypertensive effects have been
postulated
Antagonizing the 1 receptors leading to reduced HR, FC
which finally reduces CO
Antagonizing the 1 receptors of the renal system (JGA)
reduces renin release which finally leads to reduction in AGII
production
 antagonists
These drugs my be of particular use in high renin states
because they reduce renin release.
Examples of -blockers
Propranolol, atenolol, metoprolol, etc
The use of antagonists should be avoided in patients
with:
Asthma
Diabetes mellitus
Sino atrial or atrio-ventricular dysfunction
In combination with other drugs that inhibit AV
conduction
o 1receptorantagonist
Includes:prazosin,terazosin,doxazosin,
alfuzosin
MOA:decreaseperipheralvascular
resistance
Thiscausessympatheticallymediatedreflex
increaseinheartrate&plasmareninactivity
Butduringlongtermtherapy,vasodilatory
effectpersistswhileCO,HR&reninactivity
returntonormallevel
ThesedrugsexertminimaleffectsonCO
 1 blockers are used to:
Treatment of hypertension
Hypertension of Pheochromocytoma

1 blockers are not recommended as monotherapy for

hypertensive patients,
so they are used in conjunction with diuretics, -blockers or
other agents
Side effects
First dose phenomenon: refers to orthostatic
hypotension
 QQQ?
Phenoxybenzamine blocks both 1 and 2 receptors.
Could it be very nice drug for hypertension?
o Non selective & antagonists
Includes: labetalol, Carvedilol
MOA: blocks both the & receptors producing vasodilation
& reduced CO
Labetalol, when given IV reduces BP sufficiently rapidly which
makes it useful in management of hypertensive crises
Have more profound effect on the receptors than receptors
More selective blockade to 1 than 2 receptors
Side effects
Postural hypotension
GI distress
Tiredness
Sexual dysfunction
Skin rashes
 Centrally acting antihypertensive agents
Includes: methyldopa, clonidine, guanfacine
Methyldopa
Stimulates central presynaptic 2-adrenergic receptors and
inhibits the release of norepinephrine
Is a prodrug & produces its antihypertensive effect via
active metabolite (-methyl NE)
Methyldopa is preferred drug for treatment of HTN during
pregnancy
b/s it is safe for both the mother & infant
Clonidine, guanbenze & guanfacine
Are all 2 receptor agonists
MOA:theystimulatepresynaptic2Areceptorsreducing
sympatheticoutflowfromtheCNS
ReduceBPbyaneffectonbothCO&peripheralresistance
Athigherdoses,thesedrugscanstimulatepostsynaptic2B
receptors(foundonthevascularsmoothmuscles)causing
vasoconstriction
Thisexplainstheinitialvasoconstrictionthatisseenwhenthesedrugs
aretaken
Suddenwithdrawalofclonidine&other2agonistsmaycause
withdrawalsyndromeconsistingof:
Headache,sweating,tremors,abdominalpain,tachycardia&rebound
HTN
 Angiotensin converting enzyme inhibitors
Reduced blood volume or hypotension stimulates the
receptors in JGA of the kidney
Then, the JGA cells synthesize & release Renin
Renin activates angiotensinogen w/h is synthesized in
the liver to angiotensin I
Angiotensin I is then cleaved by angiotensin
converting enzymes to angiotensin II
Ag II causes:
Direct vasoconstriction of the blood vessels
Secretion of aldosterone
Causes salt & water retention
Causing rise in the BP
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Sites of action of drugs that interfere with the renin-angiotensin-aldosterone system. ACE, angiotensin-
converting enzyme; ARBs, angiotensin receptor blockers
 ACEIs
Includes: Captopril, Lisinopril, enalapril (enalaprilat),
fosinopril (fosinoprilat), Ramipril (ramiprilat)
MOA: inhibits ACE, reducing the concentration of Ag
II and increasing that of bradykinin
Pharmacokinetics
Are orally active drugs
Most are prodrugs that require hydrolysis in liver or
intestine (those ending with -at); except captopril and
lisinopril
Enalapril is an oral prodrug that is converted by hydrolysis
to active metabolite, enalaprilat
Enalaprilat itself is available only for intravenous use,
primarily for hypertensive emergencies
ACEIs are eliminated primarily by the kidneys;
Doses of these drugs should be reduced in patients with
renal insufficiency
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 Adverse effects
Hypotension, dry Cough, Angioedema, hyperkalemia, Acute
renal failure, Fetal damage, Skin rashes
Dry Cough and Angioedema are due to elevation of bradykinin
Contraindication
All ACEIs are contraindicated during pregnancy b/s they cause
fetal anomalies
Drug interaction
With potassium supplements or potassium sparing diuretics,
ACEIs can cause hyperkalemia
NSAIDs can blunt the antihypertensive effect of ACEIs by

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 Angiotensin receptor blockers
Losartan, valsartan
They block angiotensin II at its receptor site,
thus inhibiting both the
Vasoconstriction and
Aldosterone-secreting effects of ANG II
They do not affect the bradykinin system
 Some adverse effects of ARBs
Headache
hyperkalemia-especially in patients taking
potassium sparing diuretics
Hypotension
CI- pregnancy
Calcium channel blockers
Are important groups of drugs used for long term treatment of HTN

Includes:
Cardioselective CCBs: verapamil & diltiazem

Vessel selective CCBs: amlodipine, felodipine, isradipine & nifedipine (all are c/d
dihydropyridines)

MOA: block voltage gated Ca++ channels & cause vasodilation leading to
reduced PVR

Verapamil & diltiazem have direct negative effect on the heart while the
dihydropyridines dont
So concurrent use of -blockers with verapamil or diltiazem can magnify the
negative chronotropic effect of these drugs & cause heart block
 Dihydropyridines cause reflex tachycardia
But verapamil & diltiazem dont cause reflex tachycardia due to their
negative chronotropic effect
All CCBs are effective when used alone for treatment of mild to
moderate HTN
But now days, CCBs are usually used along with other agents

Side effects
Varies among the drugs in this class
Nifedipine (immediate release capsules): cause headache, flushing, dizziness &
peripheral edema
Verapamil: constipation, exacerbation of GERD, urinary retention
Both verapamil & diltiazem can lead to bradycardia but not the dihydropyridines
Vasodilators
Includes: hydralazine, minoxidil, sodium nitroprusside &
diazoxide
Produce vasodilation by d/f mechanisms

Hydralazine
MOA: it causes direct arteriolar smooth muscle relaxation by
unknown molecular mechanisms
It doesnt dilate venous smooth muscles & epicardial coronary
arteries
b/s of preferential dilation of arteries over veins, postural
hypotension is not common problem of hydralazine
 Vasodilation is associated with profound stimulation of SNS
resulting in:
Reflex tachycardia & force of contraction
Increased plasma renin activity & fluid retention
Both effects counteract the antihypertensive effect of hydralazine
So it is usually given with sympatholytics (-blockers) & diuretics
Well absorbed from GIT & metabolized in the liver & bowel by N-
acetylation
Rate of acetylation is genetically determined
A patient could be fast or slow acetylator
Larger doses are to be used in fast acetylators & vice versa
Hydralazine is no longer 1st line drug for treatment of HTN
It is used for treatment of sever HTN & hypertensive emergencies in
pregnant women
 Side effects & precautions
Headache, nausea, flushing, hypotension, dizziness, palpitations, myocardial
ischemia, hemolytic anemia, Vasculitis, glomerulonephritis
Myocardial ischemia occurs as result of:

Reflex tachycardia (increases O2 demand)

Hydralazine dont dilate epicardial coronary arteries

For this reason parenteral administration of hydralazine isnt advisable in

patients with:
Coronary artery disease
Hypertensive patients with multiple CVS disorders
Old age

When combined with -blockers & diuretics, hydralazine is well

tolerated
 Minoxidil
Efficacious in treating sever & resistant type of HTN
MOA: it is a prodrug which is converted to active metabolite c/d minoxidil
sulfate
Then, minoxidil sulfate causes K+ efflux leading to hyperpolarization of
smooth muscles leading to vasodilation
Produces arteriolar vasodilation with essentially no effect on the
capacitance vessels

Minoxidil is reserved for sever HTN that responds poorly to other

antihypertensive drugs
Should never be given alone
Should be given concurrently with diuretic & -blockers
 Side effects
SEs of minoxidil can be classified into 3
CVS effects
Are consequences of reflex SNS activation
Increased HR, FC & O2 consumption
Myocardial ischemia can be induced by minoxidil in patients with
coronary artery disease
Attenuated by concurrent administration of -blockers
Fluid & water retention
Minoxidil increases salt & water retention by:
Increasing renin & aldosterone secretion
Controlled by using diuretics
Hypertrichosis: refers to excessive hair growth on face, back,
arms & legs
 Sodium Nitroprusside
Is used for short term treatment of severe HTN

MOA: works by releasing nitric oxide (NO) which leads to

vasodilation
Is non selective vasodilator

Given by continuous IV infusion

Its primary use is to treat hypertensive emergencies

Onset of action occurs with in 30 seconds & effect stays only

for 2 minutes
Metabolically it is degraded by the liver to thiocyanate, w/h is
excreted by the kidney
Patients with impaired renal function are likely to develop
toxicities from thiocyanate
 Side effects: are secondary to:
Excessive lowering of BP; and

Accumulation of CN-

Metabolic acidosis, arrhythmias etc

Hypothyroidism (thiocyanate inhibits uptake of iodine)

 Diazoxide is also useful for treatment of
hypertensive emergencies
Diazoxide works by activating ATP sensitive K+
channels & cause hyperpolarization
 Hypotension
It is due to blockade of sympathetic
vasoconstrictor outflow to blood vessels
Sympathomimetics especially those with
prominent effect on veins (ephedrine,
mephentermine) effectively prevent and
counteract hypotension.