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)

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. -adrenergic BlockersB. -adrenergic BlockersC. Centrally acting Blockers (2-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; IndapamideMechanism 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 HypertensionBlacks & 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:

•B. Drugs that Inhibit Sympathetic System (Sympatholytics).-adrenergic Blockers

Examples: Atenolol; Metoprolol, Bisoprolol; EsmilolMechanism of Action and Side Effects (check the antiadrenergic lecture)

Clinical Pharmacology of B-adrenergic blockers:Discontinuation after prolong use rebound tachycardiaPropranolol is not used for HTN because:1.It’s nonselective.2.Short t1/2

3. CNS side effectsThey can be used in heart failureDon 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.

Propranololatenolol bisoprolol

Dose 40,80 mgDose 100,50,25Dose 5

Three times daily

Once dailyOnce daily

Not practicalMore practical strongest

2- - adrenergic Blockerse.g. : non-selective blockerslike phentolamine and phenoxybenzamine; selective like prazosin, terazosin Mechanism of Action: Dilation of arterial and venous vessels

3. Centrally acting agents (2-adrenergic agonists)e.g: Clonidine and MethyldopaMOA and Side Effects (see antiadrenergic lecture)Clinical Pharmacology of centrally acting antihypertensive agentsMethyldopa used in pregnancy.

AdvantagesSide effects

↑HDL1st dose effect

Postural hypotension

Tolerance

Labetalol is used in pheochromocytoma and HTN crisis.

Methyldopaclonidine

SedationSedation

DepressionRebound hypertension

HypersensitivityDry mouth

HepatitisFluid 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

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 slowAcetylator 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, FosinoprilMOA: 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. 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.

Glomerulus

Afferent arteriole

Efferent arteriole

In diabetes efferent arteriole is constricted result in ↑GFR

↑hydrostatic pressure proteinuria

Glomerulus

Afferent arteriole

Efferent arteriole

ACEI

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 failureHyperkalemia 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 ACEISide Effects: Are similar to ACE Inhibitors but with no cough or angioedema.

codiovan® = valsartan+ thiazide dieureticsWe use thiazide to treat hyperkalemia.

codiovan® = valsartan+ thiazide dieureticsWe use thiazide to treat hyperkalemia.

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