Antihypertensives Alia Shatanawi Associate Professor Department of Pharmacology School of Medicine University of Jordan [email protected] ta-Adrenergic Receptor Block -Adrenoceptor Antagonists Blockers 1 adrenergic receptor Cardiac effects:

Increase cardiac output Increase heart rate Increase heart contractility History Raymond Ahlquist (MCG) in 1948 was searching for a drug to relieve menstrual cramps and coincidently found epinephrine stimulated heart rate through a distinct set of receptors () in the heart

By 1964, a research chemist, Sir James Black, having read these published observations developed -blockersblockers Mechanism of Action: Effect on the cardiac myocyte Sympathetic Nerve NE -blocker Ca

++ 2 1 ATP cAMPPK Ca /CaM A MLC ++

P (contractile elements) Contraction cardiac myocyte The endogenous pathway Beta-AR are coupled to Gs-proteins Gs-proteins activate adenylyl cyclase to form cAMP Increased cAMP activates PK-A PK-A phosphorylates L-type

calcium channels and MLCK, 1. Increase inotropy (contractility). 2. Gs-protein activation also increases heart rate (chronotropy) Mechanism of Action: Effect on the blood vessel The endogenous pathway Beta-AR are again coupled VSMC, smooth muscle cell 2 AR 2-AR to Gs-proteins However, in contrast to heart, increased cAMP

contraction MLCK inhibits MLC-K in VSMC 1. A modest effect (relative to other vasoactive (increase vessel tone) autocoids) causing blood AT2 vessel relaxation Renin blocker A Beta blocker will also block b1-AR in the kidney which will decrease B1-AR renin production, and (decrease vessel tone) decrease vessel tone Propranolol (Inderal):

Mechanisms of Action Nonselective, competitive antagonist of 1 and 2 adrenergic receptors (block binding of NE) Cardioprotective

Decreases heart rate Decreases contractile force Decreases cardiac output Delays AV node conduction Neutralize reflex tachycardia induced by vasodilators Reduces central sympathetic nervous system output Small vasoconstrictive effect (Increase PVR) Reduces renin release (1) (effective in patients with high renin activity as is common in younger patients having hypertension) Propranolol: Side-effects

Hypotension, AV block, severe bradycardia (negative chronotrope), possibly HF Bronchial constriction/spasm Do not use in asthmathic patients Acute withdrawal syndrome (receptor

supersensitivity) in patients, predisposing to myocardial ischemia Increase triglyceride levels and decrease HDL levels Induce glucose intolerance Careful consideration in patients with conduction problems/bradycardia Careful usage in diabetic and obese patients Lipid soluble, cross BBB-blockersNightmares/depression Propranolol:

Contraindications Bronchial asthma Peripheral vascular disease AV (heart) block Other blockers Atenolol (Tenormin) 1 selective antagonist Administered once daily Less lipid soluble than other antagonists Metoprolol (Lopressor) Selective inhibitor to 1 Useful in asthmatic patients

Nadolol (Corgard) Non-blockersselective antagonist Administered once daily Blockers: Indications Mild and moderate hypertensives Useful in patients receiving vasodilators to prevent sympathetic reflex tachycardia Also useful in controlling BP in patients with underlying heart disease (congestive HF, ischemia, MI)

giotensin Converting Enzyme Inhibit ACE Inhibitors History Workers in the banana plantations of Brazil were known to collapse after being bitten by a specific viper A Brazilian biochemist Maricio Rocho e Silva purified the venom extracts and sent

his post-blockersdoc with extracts to study their effects in the lab of Sir John Vane (London) By 1970, the lab of Sir John Vane found the effect was on ACE, ultimately leading to the development of ACE inhibitors Renin-Angiotensin-Aldosterone System (RAAS) Angiotensinogen ACE Inhibitors Inhibit conversion of inactive angiotensin I to angiotensin II which: reduces Na+ retention via aldosterone

reduces vessel tone Angiotensin I blocks degradation of bradykinin, a vasodilator Angiotensin II Very useful in diabetic patients Slows progression of renal disease Vasodilation Renin

ACE (inhibitor) AT1 Vasoconstriction Thus RAAS pathway has multiple effects via discrete pathways which are important in blood pressure control, but which act to increase Bradykinin Inactive peptide Aldosterone

Na+ retention pril suffix=ACE-I Enalapril Excretion is primarily renal dose should be reduced in patients with renal insufficiency Ramipril Peak plasma concentration within 1 hour t1/2 2-blockers4 hrs Lisinopril Slowly absorbed; plasma t1/2 12 hrs; administered once daily Captopril

Sulfhydryl containing moiety causes some taste changes ACEI: Side-effects Severe hypotension in hypovolemic patients Hyperkalemia Angioedema (0.1-blockers0.5%)

rapid swelling of nose, throat, mouth, larynx, lips, or tongue may relate to inhibitory effect bradykinin catalysis Greater risk in African Americans Cough (10-blockers20%) Skin rash (10%) Taste alterations (6%) ACE inhibitors: Contraindications

ACE Inhibitor Can cause hyperkalemia Hyperkalemia can be exacerbated with potassium sparing diuretic Some studies indicate that ACEI are not effective in lowering BP in the African American population Pregnancy ACEI suppresses cell

proliferation which will impair embryonic development; should not be administered in second or third trimester Angiotensin I Receptor Blockers (ARBs) Angiotensinogen Renin Losartan (Cozaar) Decreases TPR Inhibits Aldosterone

release Block Na+ reabsorption Angiotensin I Losartan Angiotensin II AT1 Vasoconstriction Aldosterone Na+ retention Blocking AT1 receptor is antihypertensive

ATI Prototype antagonist=Losartan ANG II ANG II AT1 receptor AT2 receptor Vasoconstriction Vasodilation Cell Growth and Proliferation Restrains cell growth and proliferatio Aldosterone release Mediates NO and PGI2 release in kidn

Central Sympathetic activation Renal sodium excretion Sodium and water retention Dilates afferent renal arteriole Losartan: Side Effects Angioedema Subcutaneous swelling of eyes and lips Not to be administered during

pregnacy (first trimester) AT receptors important in embryonic renal development Dizziness ACEI versus ARB Use ACEI and ARB in hypertensive patients with heart failure, renal disease, and diabetes ACEI costs $0.11/cap vs. $0.48-blockers0.90/cap for ARB

Use ACEI as first choice vs. ARB, unless patients cannot tolerate ACEI (angioedema), then use ARB ipheral 1 Adrenergic Receptor Block Peripheral 1 Blockers Prazosin (Minipres): Mechanism of Action Blocks 1-blockersAR on resistance vessels from binding NE released from nerve terminals

Decreases vascular tone (vasodilates) Prazosin: Side effects Postural dizziness (14%) Headaches (8%) Drowsiness (8%) first dose phenomenon

Syncopal reaction-blockersorthostatic hypotension (upon standing) After first dose, tolerance to this reaction Other selective 1adrenergic receptor blockers Doxazosin and Terazosin longer t1/2 than prazosin used for treatment of benign prostate hypertrophy

Recent Recommendations on blockers -blockersblockers are less effective than diuretics in preventing cardiovascular events, mainly heart failure (ALLHAT clinical study) NIH recommends NOT to use -blockersblocker as the first drug of choice in hypertension (it is safe, just not effective in preventing heart failure) A reasonable addition, to facilitate blood

pressure control energic Neuron-Blocking Age Sympatholytics Adrenergic Neuron-Blocking Agents Deplete norepinephrine from presynaptic, postganglionic sympathetic nerve terminals Inhibit release of norepinephrine in response to sympathetic nerve stimulation

Reduce cardiac output and total peripheral resistance Gaunethidine (Ismelin): Mechanism of action anethidine enters peripheral nerve terminals e transporter as NE pletes NE stores in vesicles Guanethidine: Pharmacokinetics

Effective orally (takes 72 hrs to reach maximum effect) Plasma t1/2 approximately 5 days Guanethidine is indicated only for moderate to severe hypertension Reserpine (Serpasil): Mechanism of Action

Blocks transport of dopamine into storage granules in nerve terminals Depletes stores of catecholamines and serotonin in CNS and PNS Decreases sympathetic tone, total peripheral resistance and cardiac output Reserpine: Pharmacokinetics Absorbed from GI tract (2-blockers6 wks to achieve maximal effect)

Plasma t1/2 11.5-blockers16 days Largely hepatic metabolism Guanethidine and Reserpine: Side Effects

Orthostatic hypotension (Guanethidine) Depression Nasal Congestion Bradycardia Impotence (Guanethidine) Diarrhea (Guanethidine) Salt and water retention Guanethidine and Reserpine: Drug Interactions Drugs that alter function of the amine pump can block uptake to site of action:

tricyclic antidepressants, monoamine oxidase inhibitors, ephedrine, amphetamines, phenothiazines After chronic use of guanethidine, the above agents could cause hypertension due to development of receptor supersensitivity Rarely indicated

The a adrenergic blocking agents are not frequently prescribed because of their adverse effects Can be a last resort in refractory (unmanageable) hypertension Reserpine is cost-blockerseffective tral 2-Adrenergic Receptor Agon ntrally Acting Sympathoplegic Dr Central 2 Agonists Central 2-Adrenergic Agonists Vasomotor center VN=ventral nucleus RVLM=rostral ventrolateral medulla

Methyldopa and clonidine cross BBB to stimulate 2 receptors in vasomotor center in brainstem Inhibit sympathetic and increase parasympathetic outflow to periphery Decrease BP Central 2-AR Agonists: Mechanism of Action Heart rate, cardiac output, total peripheral resistance, plasma renin activity, and

baroreceptor function are reduced. Vascular smooth muscle: 2 adrenergic receptors located on vascular smooth muscle open Ca2+ channels and cause vasoconstriction. Not evident clinically unless given intravenously Central 2-AR Agonists Clonidine, (guanabenz and guanfacine): Direct acting 2 adrenergic receptor agonists.

-methyldopa: Prodrug taken up by central adrenergic neurons and converted to the 2 adrenergic receptor agonist -blockers methylnorepinephrine. Clonidine (Catapres): Pharmacokinetics Oral plasma t1/2 12-blockers16 hrs Transdermal administration of clonidine by patch (replaced once per week) useful in patients unable

to take oral medication Clonidine: Side Effects Dry mouth (44%) Drowsiness (50%) Dizziness (15%) Clonidine can cause sodium retention, but may be used at low doses w/o addition of diuretic Clonidine:

Drug Interactions Tricyclic antidepressants can reverse the antihypertensive effects of clonidine Methyldopa (Aldomet): Side Effects Like Clonidine, causes sedation, dry mouth, sodium retention, and dizziness

With prolonged use, hemolytic anemia is a rare side effect Clonidine and Methyldopa: Drug interactions Tricyclic antidepressants may prevent the antihypertensive effect Barbiturates may reduce the efficacy of through induction of hepatic microsomal enzymes Monoamine oxidase inhibitors when

coadministered may produce hypertension and CNS stimulation Indications Methyldopa is a first choice for hypertension during pregnancy Clonidine is useful in the diagnosis of pheochromocytoma (adrenal tumor) in hypertensive patients; it will reduce NE to lower then 500 pg/mL in tumor-blockersfree patients

Vasodilators Vasodilators: Mechanism of Actio Relax Vascular smooth muscle cells Vasodilate Arterioles Decrease PVR Decrease Blood Pressure Hydralazine Minoxidil Smooth Muscle cell + + +

+ + K+ Ca 2+ + + contract Contractile elements Hydralazine (Apresoline): Mechanism of Action Direct vasodilatory action on

arterioles altering smooth muscle cell Ca2+ by hyperpolarizing cell Decreases total peripheral resistance Sympathetic activity (Reflex responses) Increased heart rate Increased heart contractility Increased plasma renin activity

Hydralazine: Pharmacokinetics Plasma t1/2 1 hr, but antihypertensive action of 12 hrs possibly due to storage in arterial wall Hydralazine: Side-effects Reflex tachycardia

Can precipitate MI in elderly patients or patients with coronary artery disease Reflex response can be blocked by addition of propranolol Sodium and water retention can be prevented by addition of a diuretic Headache, Nausea, Dizziness Lupus syndrome Minoxidil (Loniten) : Mechanism of Action

Activates ATP-blockerssensitive K+ channels to cause hyperpolarization and smooth muscle cell relaxation Arteriolar vasodilation Decrease in total peripheral resistance Minoxidil: Pharmacokinetics

Plasma t1/2 -blockers 4 hrs, but hypotensive effect for 12-blockers24 hrs Must be metabolized by the liver to form the active metabolite, minoxidil N-blockersO sulfate Minoxidil: Side effects Similar to hydralazine Hypertrichosis accentuated hair growth

Minoxidil is reserved for treatment of severe hypertension and must be given with a diuretic and a sympatholytic agent (usually a -blockersadrenergic receptor antagonist). Indications Severe, resistant hypertension Vasodilators in Treatment of Hypertensive Crisis Vasodilators: Mechanism of Actio

Relax Vascular smooth muscle cells Vasodilate Arterioles Decrease PVR Decrease Blood Pressure HydralazineNE Labetolol Minoxidil Carvedilol Smooth Muscle cell 1AR K+ Ca

2+ contractrelax N O Contractile elements SNP Sodium Nitroprusside (SNP, Nipride): Mechanism of Action Liberates nitric oxide which dilates vascular smooth muscle

Thereby, decreases total peripheral resistance SNP: Pharmacokinetics Given by I.V. infusion Is light sensitive and unstable in aqueous

solution Antihypertensive effect ceases upon stopping infusion Metabolized to sodium thiocyanate slowly cleared by kidneys Toxic accumulation of cyanide can lead to lactic acidosis SNP: Side-effects Rebound hypertension Tolerance Diazoxide (Hyperstat):

Mechanism of Action Dilates arterial smooth muscle through activation of KATP channels Little or no effect on venous smooth muscle Decreases total peripheral resistance Diazoxide: Pharmacokinetics

Administered I.V. Onset of action within 2 min. Duration of action 6-blockers24 hrs Diazoxide: Side-effects Tachycardia Angina

Labetalol (Normodyne) and Carvedilol (Coreg) : Mechanism of Action Mixture of 1 and non-blockersselective adrenergic receptor antagonist Block adrenergic receptors in blood vessels and heart

Labetolol 1:3 selectivity 1AR: AR Carvedilol 1:10 selectivity 1AR: AR Decrease total peripheral resistance w/o reflex tachycardia Labetalol & Carvedilol: Pharmacokinetics Administered orally or i.v. (for hypertensive crisis) Useful in pheochromocytoma

(Labetalol) Plasma t1/2 2 hrs (p.o.) and 5 hrs (i.v.)

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