Antihypertensive Drugs Prof Alhaider 1431 H Etiology of

Antihypertensive Drugs Prof. Alhaider (1431 H)

üEtiology of hypertension (HTN) 90 % essential or primary while 10% secondary (renal artery constriction, pheochromocytoma, Cushing’s disease, coarctation of the aorta) üCauses of Essential Hypertension. Unknown but üWeak epithelial elasticity , genetics , stress, diet, environment play a role. üRegulation 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 (a 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; Indapamide Mechanism of Action: • Initially they increase sodium & water excretion, this cause: üReduction blood volume & C. O. (less important) üLate : Reduce peripheral resistance via negative sodium Balance (more important) üIndapamide has a direct vasodilating effect Clinical Pharmacology of Diuretics in Hypertension üBlacks & 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: Adding K sparing diuretics to for hypokalemia compensate

• 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: üDiscontinuation after prolong use rebound tachycardia üPropranolol is not used for HTN because: 1. It’s nonselective. 2. Short t 1/2 3. CNS side effects ü They can be used in heart failure ü Don not produce postural hypotension ü β blockers can be used in patient with hyperthyroidism because hyperthyroidism induces tachycardia. üβ blockers are used to treat hypertension in pregnant women. üβ blockers are not used to treat hypertension in patient with asthma. ü Does β blockers cause postural hypotension? üNo.

Propranolol atenolol bisoprolol Dose 40, 80 mg Dose 100, 50, 25 Dose 5 Three times 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 1 st dose effect Postural hypotension Tolerance 3. Centrally acting agents (a 2 -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.

Side effects of centrally acting agents Methyldopa clonidine 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 ↑ dose that produce heart effect ↑vascular selectivity

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. ü Hyporenenemic and salt sensitive patient respond better to CCB ü They can be given to pregnant woman ü They do not require adding diuretics ü 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 1 st 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 -10 mg , 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 t 1/2 (1 -10 min) , used in hypertensive crisis CN will be converted to thiocyanate in the liver. Thyiocyanate will be eliminated in the kidney

Accumulation of CN occurs in patient with 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, psychosis and muscle spasm and convulsion. disorientation, 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 In diabetes efferent arteriole is constricted result in ↑GFR ↑hydrostatic pressure proteinuria Efferent arteriole

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 AT 1 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.

ﻧﺼﺎﺋﺢ ﺟﻮﻫﺮﻳﺔ You can use ACEI and CCB together or CCB and diuretics. You cannot use ACEI with β blockers

Drugs Used for Hypertensive Crisis The drugs should have Drugs that can be used ↓t 1/2 Fast onset Gradual decrease to prevent shock? ? • • • Hydralazine Sodium nitroprusside Labetalol Enalaprite CCB Fenoldopam