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Antihypertensive Drugs Prof. Alhaider (1431H)

Antihypertensive Drugs Prof. Alhaider (1431H). 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?

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Antihypertensive Drugs Prof. Alhaider (1431H)

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  1. AntihypertensiveDrugsProf. Alhaider (1431H)

  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 (Sympathoplegics) • b-adrenergic Blockers • a-adrenergic Blockers • 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?

  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 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?

  6. B. Drugs that Inhibit Sympathetic System (Sympathoplegics) • 1. b-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 b-adrenergic blockers for patient • with hyperthyroidism?

  7. 2- a- 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 b and a-aderenergic antagonist • like labetalol and Carvedolol? • 3. Centrally acting Blockers (a2-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?

  8. 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?

  9. 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

  10. 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 b-adrenergic blockers or thiazides?

  11. 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 b-adrenergic blockers with CCB? • Fatigue, headache. • Constipation mainly with verapamil • Ankle or peripheral edema( nifedipine)

  12. 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

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

  14. 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?)

  15. 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?

  16. 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.

  17. 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.

  18. 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

  19. 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 diabetic • even 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)

  20. 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.

  21. 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.

  22. Drugs Used for Hypertensive CrisisCan you mention the Drugs that can be used for Management of Hypertensive Crisis?

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