2. Etiology of HTN
90%essential while 10% secondary
Causes of Essential Hypertension. Unknown but
Regulation of Blood Pressure
BP = CO X PVR
What are the factors that determine the PVR?
Thus, hypertensive patients can be classified as:
Hyprereninemic (White, young) Vs Nor-or
hyporenenemic (Black, elderly, obese)
Salt sensitive (Black, elderly)

3. Treatment of Hypertension
 Repeat Blood pressure measurement
 Start with low salt diet and look for
any secondary causes.
 Look for age, race, live style etc

4. Classifications of Antihypertensive drugs:
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 (Sympathopleg
α) β-adrenergic Blockers
β) α-adrenergic Blockers
c) Centrally acting Blockers (α2-adrenergic agonists)
3) Direct vasodilators (calcium channel Blockers,
Hydralazine; Minoxidil)
4) Drugs that block production or action of angiotensin I
Why it is so fortunate that these drugs have different
mechanisms and site of action?

5. A. Drugs that Alter Sodium and Water Balance (Diuretics)
Examples: Hydrochlorothiazide; Indapamide
Mechanism of Action:
•Initially they increase sodium & water excretion, this cause:
•Reduction blood volume & C.O.
•Late : Reduce peripheral resistance via negative sodium
•balance
•Indapamide has a direct vasodilating effect
Clinical Pharmacology of Diuretics in Hypertension
Which patients respond better and diuretics are drug of choic
for them?
Based on the side effects, which patients should not be
 treated with diuretics?
Why potassium sparing diuretics mixed with thiazide

7. •B. Drugs that Inhibit Sympathetic System (Sympathoplegics)
1. β-adrenergic Blockers
Examples: Atenolol; Metoprolol, Bisoprolol; Esmilol
Mechanism of Action and Side Effects
(from the antiadrenergic lecture)
Clinical Pharmacology of B-adrenergic blockers:
Doses and stopping medication?
Why propranolol is not commonly used for Rx of HTN
as compared to Atenolol or Bisoprolol?
 Can we prescribed β-adrenergic blockers for patien
with hyperthyroidism?

8. 2- α- adrenergic Blockers
e.g: non-selective like phentolamine and phenoxybenzamine;
selective like prazosin, terazosin
Mechanism of Action:
dilate arterial and venous vessels
Advantages and Side Effects of prazosin
What are the clinical uses of β and α-aderenergic antagonist
like labetalol and Carvedolol?
3. Centrally acting Blockers (α2-adrenergic agonists)
e.g: Clonidine and Methyldopa
MOA and Side Effects (see antiadrenergic lecture)
Clinical Pharmacology of centrally acting antihypertensive agents
Why these drugs are not commonly used as before?

9. •C. Direct vasodilators (calcium channel Blockers,
Hydralazine;Minoxidil)
• 1) Calcium Channel Blockers:
e.g: Nifedipine; Amlodipine; Diltaizem; Verapamil
(not used for HTN)
Mechanism of Action :
There are two types of calcium channels T and L, the latter is
present in blood vessels. CCB block transmembrane
voltage-dependent calcium channels mainly on arterial
smooth muscles & cardiac muscles
What is the effect of CCB on veins?
What is the effect on other smooth muscle like bronchioles
or even skeletal muscles? Calcium influx vs intracellular
calcium store!!
What is the effect of CCB on cerebral blood vessels?

11. Classification of Calcium channels Blockers:
•1) Dihydropyridine group (Amlodipine, Nicardipine, Nifedipine;
Nimodipine) are more selective as vasodilators and have less
cardiac depressant effect (used for hypertension).
•2. Non- Dihydropyridine group like Verapamil (antiarrythmic agent)
has the greatest depressant effect on the heart and significantly
decreases heart rate and cardiac output. while Diltiazem (as anti angi
has intermediate action
Vascular Slectivity=
a dose which produces cardiac effect/dose which produce vasodila

12. Clinical Uses of Calcium channel Blockers:
 Hypertension (Amlodipine, Nifedipine)
 Angina (Diltaizem)
 Supraventricular tachycardia (Vearapamil)
 Prophylactic of migraine
•
 Peripheral vascular diseases (Raynaud's Phenomenon)
Nifedipine; Amlodipine
 Which type of hypertensive patients respond better to CHB?
 Can CCB be given for pregnant women?
Can CCBs be given with β-adrenergic blockers or thiazides?

13. Side Effects of CCBs:
Reflex tachycardia mainly with short acting (like Nifedipin
less with long acting like Amlodipine) while verapamil
induces severe bradycardia
Can we add β-adrenergic blockers with CCB?
 Fatigue, headache.
 Constipation mainly with verapamil
 Ankle or peripheral edema( nifedipine)

14. 2. Hydralazine:
Direct arterial vasodilator works via increasing c-GMP and NO.
PK: Given orally with good absorption 90% but with significant first
pass effect (via acetylation). Thus given TDS.
Side Effects:
 Sweating, flushing and Tachycardia (reflex); therefore, should not
given alone (see Figure)
 Systemic Lupus like symptoms ( arthralgia, myalgia and fever
without kidney involvement) . This occurs in slow acetylator
patients. Why?
Occurs more in women 9:1.
 Hepatitis in fast acetylators. How?
 Fluid and salt retention

15. Which type of hypertensive patients can be given
hydralazine?
 Hypertensive crisis
 In pregnancy induced Hypertension
 Essential hypertension (when patients have
hyperkalemia)

16. •3. Minoxidil:
Unique arterial vasodilator
MOA: enhance potassium outflow leading to
hyperpolarization and arterial vasodilation.
Advantages: Very potent arterial vasodilator used for
refractory HTN (dose; 5-10 mg P.O. BID)
Disadvantage:
 Produces salt and water retention and may precipitate
pericardial effusion
 Tachycardia
 Hypertrichosis (useful for Rx of alopecia How?)

17. 4. Sodium Nitroprusside
MOA: Chemical structure is very important (see Figure)
Release of NO.
PK:
 Light and moisture sensitive and should be given i.v. only
(for hypertensive crisis). Very short t1/2 (1-10 minutes)
 CN will be converted to thiocyanate in the liver.
 Thiocyanate will be eliminated in the kidney.
What will happen if patients have liver or renal impairment?

19. 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.
 Methemoglobenemia during infusion may occur.

20. 5. Diazoxide:
 Similar to thiazides diuretics with no diuretic activity
but incontrast produce salt and water retention.
 Inhibits the release of insulin (via opening potassium
channels), leading to hyperglycemia. Therefore,
 It is not now used for treatment of hypertension and
used for hypoglycemia due to insulinoma.

21. •4. Drugs that block production or action of angiotensin II
•
Examples: Captopril; Enalapril, Lisonopril, Fosinopril
MOA: see Figure
Do they decrease peripheral resistance?
PK:
 They are long acting (O.D) 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 is available
only for intravenous use for hypertensive emergency.
 All ACEI are distributed to all tissues except CNS.
 All ACEI are eliminated by the kidney except
fosinopril & moexpril

24. •Clinical Uses of ACEIs)
 More effective in treatment of hypertension in condition
associated with high plasma renin activity (young &
white people ). But response can occur with the majority.
 Safely used in patients with ischemic heart disease.why?
 They are drugs of first choice for patients with diabetic
even with out HTN, because they diminish proteinuria, a
stabilize renal function. How?
 Treatment of heart failure and used after MI.
 Also they can be given to non-hypertensive patients to
 Decrease proteinurea (nephrotic syndrome or some
renal diseases)

25. Side Effects of ACEIs:
 Severe hypotension at the beginning (start with low dose)
 Acute renal failure (in patients with bilateral renal artery stenosis)
 Hyperkalemia
 Dry cough, wheezing ,and angioedema
 Captopril in high doses may cause neutropenia,
proteinuria, altered sense of taste, allergic skin rash, drug fe
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.
 Bilateral renal artery stenosis or stenosis of the artery of
a solitary kidney.

26. B. Angiotensin Receptor Blockers (ARBs):
Losartan; Valsartan; Candesartan; Irbesartan
•Mechanism of action :
Block AT1
receptors.
•Advantages over ACEI :
 They have no effect on bradykinin system: No cough,
wheezing or angioedema.
 Complete inhibition of angiotensin action compared
with ACEI
Side Effects: are similar to ACEIs but with no cough and
Angioedema.