Etiology of hypertension (HTN)

90 % essential or primary while 10% secondary

(renal artery
constriction, pheochromocytoma, Cushings
disease, coarctation of the aorta)
Causes of Essential Hypertension. Unknown but
Weak epithelial elasticity ,genetics , stress, diet, environment
play a role.

Regulation of Blood Pressure

BP = CO X total peripheral vascular resistance
(PVR)

Thus, hypertensive patients can be classified as:

Hyprereninemic (White, young) : HTN because of renin
Nor-or hyporenenemic (Black, elderly, obese)
Salt sensitive (Black, elderly): increase Na influx into smooth muscles of blood
vessel Ca influx vasoconstriciton

Treatment of
Hypertension
Repeat Blood pressure
measurement
Start with low salt diet and
look for
any
secondary causes.
The goal of treatment with drugs is PVR

Best classification that depends on mechanism of

action
:and/or site of regulation
1) Drugs that alter sodium and water balance
(Diuretics)
2) Drugs that inhibit sympathetic system
(Sympatholytics)

-adrenergic Blockers
-adrenergic Blockers
C. Centrally acting Blockers (2adrenergic agonists)
3) Direct vasodilators (calcium channel
Blockers,
Hydralazine, Minoxidil)
4) Drugs that block production or action of
angiotensin
II (ACE
Having
many inhibitor)
different types of drugs permit the
combination between them to increase the efficacy or

Examples: Hydrochlorothiazide; Indapamide

Mechanism of Action:
Initially they increase sodium & water excretion, t
cause:
Reduction blood volume & C.O. (less important)
Late : Reduce peripheral resistance via negative
sodium
Balance (more important)
Indapamide has a direct vasodilating effect

Clinical Pharmacology of Diuretics in

Hypertension
Blacks & elderly patients best respond to this
treatment (salt sensitive)

Contraindicated in arrhythmia and ischemic heart

disease because of hypokalemia.
In diabetes because they produce hyperglycemia.
In pregnancy because of hypovolemia and perfusion to
the fetus. In case of arrhythmia and ischemic heart
disease:

(Sympatholytics)
-adrenergic Blockers
Examples: Atenolol; Metoprolol, Bisoprolol;
Esmilol
Mechanism of Action and Side Effects
(check the antiadrenergic lecture)
Clinical Pharmacology of B-adrenergic blockers:
Discontinuation after prolong use rebound tachycardia
Propranolol is not used for HTN because:
1.Its nonselective.
2.Short t1/2
3. CNS side effects
They can be used in heart failure
Don not produce postural hypotension
blockers can be used in patient with hyperthyroidism because
hyperthyroidism induces tachycardia .
blockers are used to treat hypertension in pregnant women .
blockers are not used to treat hypertension in patient with asthma.

Propranolol

atenolol

bisoprolol

Dose 40,80 mg

Dose 100,50,25

Dose 5

Three times
daily

Once daily

Once daily

Not practical

More practical

strongest

2- - adrenergic Blockers
e.g. : non-selective blockerslike phentolamine and
phenoxybenzamine; selective like prazosin, terazos
Mechanism of Action:
Dilation of arterial and venous vessels
Labetalol is used in
pheochromocytoma and HTN
crisis.

Advantages

Side effects

HDL

1st dose effect

Postural hypotension
Tolerance

3. Centrally acting agents (2-adrenergic agonists)

e.g: Clonidine and Methyldopa
MOA and Side Effects (see antiadrenergic lecture

Clinical Pharmacology of centrally acting antihypertensiv

Methyldopa used in pregnancy.

Methyldopa

clonidine

Sedation

Sedation

Depression

Rebound hypertension

Hypersensitivity

Dry mouth

Hepatitis

Fluid retention

Worsen heart failure

Hemolytic anemia

C. Direct vasodilators
1) Calcium Channel Blockers(CCB):
e.g: Nifedipine; Amlodipine; Diltiazem (not used in HTN) ;
Verapamil (not used in HTN)

Mechanism of Action :
There are two types of calcium channels T and L, the
latter (L) is
present in blood vessels.
CCB block transmembrane voltage-dependent Ca++
channels mainly on arterial smooth muscles & cardiac
muscles.
They have negligible effect on veins.
Vascular smooth muscles are more sensitive to CCB than
other smooth muscles e.g. (GI muscles, bronchioles)
Skeletal muscles depend on intracellular Ca++ to contract
so these drugs have no effect on them
They have effect on cerebral blood vessels so they can be used
in hemorrhagic stroke.
Not contraindicated in asthma because they have no action on

We
Wehave
haveto
touse
useblockers
blockersand
anddiuretics
diureticswith
with
vasodilator
vasodilatordrugs
drugsto
toovercome
overcomethe
thecompensatory
compensatory
mechanisms
mechanisms

Classification of Calcium channels Blockers:

1) Dihydropyridine group (Amlodipine, Nicardipine, Nifedip

Nimodipine) are more selective as vasodilators and have
cardiac depressant effect (used for hypertension).

2. Non- Dihydropyridine group like Verapamil (antiarryth

has the greatest depressant effect on the heart and sig
decreases heart rate and cardiac output. While Diltiaze
(antianginal agent) has intermediate action.

Vascular Slectivity=
dose which produces cardiac effect
dose which produces vasodilation

Clinical Uses of Calcium channel Blockers:

Hypertension (Amlodipine, Nifedipine) especially in

black, elderly, obese (salt sensitive)
Angina (Diltiazem)
Supraventricular tachycardia (Verapamil)
For cerebral hemorrhage (nimodipine)
Prophylactic of migraine (Nifedipine)
Peripheral vascular diseases (Raynaud's Phenomenon
Nifedipine; Amlodipine.
Hyporenenemic and salt sensitive patient respond better to CCB

They can be given to pregnant woman

They do not require adding diuretics
Generally, we add ACEI or blockers to prevent reflex
tachycardia produced by the action of CCB

Side Effects of CCBs:

Reflex tachycardia mainly with short acting
(like Nifedipine)
less with long acting like (Amlodipine) while
verapamil
induces severe bradycardia
Fatigue, headache.
Constipation mainly with verapamil (very
important)
Ankle or peripheral edema (nifedipine), less
edema with amlodipine

Direct arterial vasodilator works via increasing c-GMP and

NO.
PK: Given orally with 90% absorption but with significan
1st
pass effect (via acetylation). Given 3 times daily (TDS)

Side Effects:

Headache, sweating, flushing and Tachycardia (reflex)

therefore, should not given alone (see Figure) (what
figure ???)
Systemic Lupus erthymatosus(SLE) like symptoms
( arthralgia, myalgia and fever without kidney
involvement) .This occurs in slow
Acetylator patients because slow acetylator
hydralazine in blood SLE. Occurs more in women
9:1.
Hepatitis in fast acetylators. Fluid and salt retention

Which type of hypertensive patients can be

given hydralazine?
Hypertensive crisis
In pregnancy induced Hypertension
Essential hypertension (when patients have
hyperkalemia)
3)Minoxidil:
Unique arterial vasodilator
MOA: enhance potassium outflow leading to
hyperpolarization and arterial vasodilatation.
Advantages: Very potent arterial vasodilator used for
refractory HTN
(refractory means that HTN doesnt respond to normal
drugs).
Dose: orally , 5-10mg , taken twice daily. Can be taken
topically
(treatment of alopecia by increasing the

Disadvantage:
Produces salt and water retention and may
precipitate
pericardial effusion
Tachycardia
Hypertrichosis (increase hair length and
density) : can be used as a treatment for
alopecia (hair loss) by increasing blood flow
to the hair, leading to hair elongation.
Not good for pregnant women .
4)Sodium Nitroprusside
MOA: by releasing the inside NO (see the drug
structure in the next slide). Also, it releases cyanide
(CN).
PK:
sensitive to light and moisture.
given IV only , short t1/2 (1-10 min) , used in hypertensive crisis

Side Effects of Sodium nitroprusside:

Accumulation of Cyanide lead to metabolic acidosis and
arrhythmias low BP and coma.
Accumulation of thiocyanate during prolonged
administration or renal failure leads to weakness,
disorientation, psychosis and muscle spasm and convulsion.
Thiocyanate may inhibit iodide uptake by the thyroid
(hypothyroidism)

 Similar to thiazides diuretics with no diuretic

activity.
It causes water and salt retention
Inhibits the release of insulin (via opening
potassium
channels), leading to severe hyperglycemia.
Therefore, It is not now used for treatment of
hypertension. Instead, it is used for
hypoglycemia due to insulinoma (a tumor that
produces insulin).

or action of angiotensin II

A.angiotensin converting enzyme inhibitors(ACEI):

Examples: Captopril; Enalapril, Lisonopril, Fosinopril
MOA: see next slide.
They decrease peripheral vascular resistance (PVR)
(renal and venous action).

PK:
They are long acting (taken once daily) Except
captopril (TDS).
All are pro-drugs, converted to the active agents
by
hydrolysis in the liver except Captopril.
Enalaprilat is the active metabolite of enalapril and
is available
only for intravenous use for hypertensive
emergency.
All ACEI are distributed to all tissues except CNS.

Clinical Uses of (ACEIs)

More effective in treatment of hypertension in

conditions associated with high plasma renin activit
(young & white people ), but we can get the same
response with the majority.
ely used in patients with ischemic heart disease bec
They dont result in reflex sympathetic activation.
They are drugs of first choice for patients with diab
even without HTN, because they diminish proteinur
and stabilize renal function.
Afferent
arteriole

Glomerulu
s

Efferent arteriole

In diabetes efferent arteriole is

constricted result in GFR
hydrostatic pressure proteinuria

ACEI
Afferent
arteriole

Glomerulu
s

Efferent arteriole

With the use of ACEI

efferent arteriole dilate
and proeinuria is thus
treated

Treatment of heart failure also used after myocardial

infarction (MI) because they have an effect on veins
and can also decrease renin (aldosteron) decreasing
the load on heart muscles.
They also can be given to non-hypertensive patients
to
Decrease proteinurea (nephrotic syndrome or other
renal diseases)

Side Effects of ACEIs:

Severe hypotension at the beginning

(start with low

dose or start with captopril then use other ACEIs)
Acute renal failure (in patients with bilateral renal arterial
stenosis)
Stenosis (afferent vasoconstriction): by using ACEI efferent
vasoconstriction
GFR acute renal failure

Hyperkalemia
Dry cough, wheezing ,and angioedema (edema of the
dermis and subcutaneous tissue due to secretion of
bradykinin)
Captopril in high doses may cause neutropenia,
proteinuria, altered sense of taste, allergic skin rash, drug
fever .

Contraindications:

During the second and third trimesters of pregnancy

because of the risk of fetal hypotension, anuria, renal
failure.
They may cause fetal malformations and death.

B. Angiotensin Receptor Blockers (ARBs):

Losartan; Valsartan; Candesartan; Irbesartan
Mechanism of action:
Block AT1 receptors.
Advantages over ACEI:
They have no effect on the bradykinin
system: No cough, wheezing or angioedema.
Complete inhibition of angiotensin action
compared
with ACEI
Side Effects: Are similar to ACE Inhibitors but
with no cough or angioedema.

codiovan
codiovan =
=valsartan+
valsartan+thiazide
thiazidedieuretics
dieuretics
.We
.Weuse
usethiazide
thiazideto
totreat
treathyperkalemia
hyperkalemia