Download 1. antihypertensive

Etiology of hypertension (HTN)
90 % essential or primary while 10% secondary (renal artery
constriction, pheochromocytoma, Cushing’s 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)
Factors
determine
PVR
Vascular
tone
elasticity
Deficient NO
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.
 Look for age, race, lifestyle, etc
The goal of treatment with drugs is ↓PVR
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 (Sympatholytics)
A. b-adrenergic Blockers
B. a-adrenergic Blockers
C. Centrally acting Blockers (a2-adrenergic agonists)
3) Direct vasodilators (calcium channel Blockers,
Hydralazine, Minoxidil)
4) Drugs that block production or action of angiotensin II
(ACE inhibitor)
Having many different types of drugs permit the combination between
them to increase the efficacy or decrease toxicity (side effect)
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. (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
Diabetes
Ischemic heart
disease
Renal
impairment
Pregnancy
(important)
gout
•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:
•B. Drugs that Inhibit Sympathetic System (Sympatholytics)
1. b-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. It’s nonselective.
2. Short t1/2
3. CNS side effects
 They can be used in heart failure
 Don not produce postural hypotension
 β blockers can be used in patient with hyperthyroidism because hyperthyroidism
induces tachycardia .
β blockers are used to treat hypertension in pregnant women .
β blockers are not used to treat hypertension in patient with asthma.
 Does β blockers cause postural hypotension?
No.
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- a- adrenergic Blockers
e.g. : non-selective blockerslike phentolamine and
phenoxybenzamine; selective like prazosin, terazosin
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 (a2-adrenergic agonists)
e.g: Clonidine and Methyldopa
MOA and Side Effects (see antiadrenergic lecture)
Clinical Pharmacology of centrally acting antihypertensive agents
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
bronchiols
We have to use β blockers and diuretics with vasodilator
drugs to overcome the compensatory mechanisms
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
(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 β 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
2) Hydralazine:
•Direct arterial vasodilator works via increasing c-GMP and NO.
•PK: Given orally with 90% absorption but with significant 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 doesn’t respond to normal drugs).
•Dose: orally , 5-10mg , taken twice daily. Can be taken topically
(treatment of alopecia by increasing the blood flow to the hair beds)
•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
 CN will be converted to thiocyanate in the liver.
Thyiocyanate will be eliminated in the kidney
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)
Methemoglobinemia during infusion may occur.
5)Diazoxide:
 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).
•D. Drugs that block production 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) 
venous action).
(renal and
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.
 All ACEI are eliminated by the kidney except
fosinopril & moexpril
•Clinical Uses of (ACEIs)
 More effective in treatment of hypertension in
conditions associated with high plasma renin activity
(young & white people ), but we can get the same
response with the majority.
 Safely used in patients with ischemic heart disease because
They don’t result in reflex sympathetic activation.
 They are drugs of first choice for patients with diabetic
even without HTN, because they diminish proteinuria,
and stabilize renal function.
Afferent
arteriole
Glomerulus
Efferent arteriole
In diabetes efferent arteriole is constricted
result in ↑GFR  ↑hydrostatic pressure
 proteinuria
ACEI
Afferent
arteriole
Glomerulus
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.
 Bilateral renal artery stenosis or stenosis of the artery of a solitary
kidney.
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® = valsartan+ thiazide dieuretics
We use thiazide to treat hyperkalemia.
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