Etiology of HTN 90 % essential while 10% secondary

Causes of Essential Hypertension. Unknown but

Regulation of Blood PressureBP = 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)

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

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 (Sympathoplegics)

a)-adrenergic Blockers)a-adrenergic Blockersc) Centrally acting Blockers (a2-adrenergic agonists)

3) Direct vasodilators (calcium channel Blockers, Hydralazine; Minoxidil) 4) Drugs that block production or action of angiotensin II

Why it is so fortunate that these drugs have different mechanisms and site of action?

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.•Late : Reduce peripheral resistance via negative sodium •balance•Indapamide has a direct vasodilating effect

Clinical Pharmacology of Diuretics in HypertensionWhich patients respond better and diuretics are drug of choice for them?Based on the side effects, which patients should not be treated with diuretics?Why potassium sparing diuretics mixed with thiazide as antihypertension medication?

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

Examples: Atenolol; Metoprolol, Bisoprolol; EsmilolMechanism 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 -adrenergic blockers for patient with hyperthyroidism?

2- a- adrenergic Blockerse.g: non-selective like phentolamine and phenoxybenzamine; selective like prazosin, terazosin

Mechanism of Action: dilate arterial and venous vesselsAdvantages and Side Effects of prazosin

What are the clinical uses of and a-aderenergic antagonist like labetalol and Carvedolol?

3. Centrally acting Blockers (a2-adrenergic agonists)e.g: Clonidine and MethyldopaMOA and Side Effects (see antiadrenergic lecture)Clinical Pharmacology of centrally acting antihypertensive agentsWhy these drugs are not commonly used as before?

•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?

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 angina) has intermediate action

Vascular Slectivity= a dose which produces cardiac effect/dose which produce vasodilation

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 -adrenergic blockers or thiazides?

Side Effects of CCBs: Reflex tachycardia mainly with short acting (like Nifedipine)

less with long acting like Amlodipine) while verapamil induces severe bradycardia

Can we add -adrenergic blockers with CCB? Fatigue, headache.

Constipation mainly with verapamil Ankle or peripheral edema( nifedipine)

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

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 vasodilatorMOA: 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?)

4. Sodium NitroprussideMOA: 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?

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.

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.

•4. Drugs that block production or action of angiotensin II• Examples: Captopril; Enalapril, Lisonopril, FosinoprilMOA: see FigureDo 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

•Clinical Uses of ACEIs) More effective in treatment of hypertension in conditions 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 diabeticeven with out HTN, because they diminish proteinuria, and

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)

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 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 bradykinin system: No cough, wheezing or angioedema. Complete inhibition of angiotensin action compared with ACEISide Effects: are similar to ACEIs but with no cough and Angioedema.