Antihypertensive Drugs

Hypertension & Antihypertensive Drugs: 

Hypertension & Antihypertensive Drugs Dr. Armaan

Objectives Of this class!!: 

Objectives Of this class!! Know mechanisms of blood pressure regulation and cardiovascular pathophysiology which chronically increase blood pressure Understand types and etiologies of major forms of clinical hypertension General treatment strategy for hypertension Know major classes of anti-hypertensive agents, their general sites and mechanisms of action Identify specific, widely used, antihypertensive agents, sites of action, mechanisms of action, indications and contraindications Understand strategies for hypertension management associated with other pathologies

What is Hypertension??: 

What is Hypertension?? It is defined as either.. “a sustained systolic blood pressure (SBP) of greater than 140 mm Hg or a sustained diastolic blood pressure (DBP) of greater than 90 mm Hg”

Blood Pressure Classification: 

Blood Pressure Classification SBP DBP mm Hg mmHg Normal Prehypertensive Stage 1 Hypertension Stage 2 Hypertension 120 and 80 120-139 or 80-89 140-159 or 90-99 > 160 or > 100

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The World Health Organization has estimated that high blood pressure causes one in every eight deaths , making hypertension the third leading killer in the world Globally ,there are one billion hypertensives and four million people die annually as a direct result of hypertension

Aetiology of Hypertension: 

Aetiology of Hypertension Primary – 90-95% of cases – also termed “essential” of “idiopathic” Secondary – about 5% of cases Renal or renovascular disease Endocrine disease Phaeochomocytoma Cusings syndrome Conn’s syndrome Acromegaly and hypothyroidism Coarctation of the aorta Iatrogenic Hormonal / oral contraceptive NSAIDs Lifestyle – influential risk factors ƒ smoking, heavy drinking, being overweight, sodium & calorie-rich diet, lack of physical activity, stress

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Determinants of BLOOD Pressure Mean Arterial Pressure MAP = X Arteriolar Diameter Blood Volume Stroke Volume Heart Rate Filling Pressure Contractility Blood Volume Venous Tone CRITICAL POINT! Change any physical factors controlling CO and/or TPR and MAP can be altered.

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Blood Pressure = Cardiac Output X Peripheral Resistance (BP) (CO) Flow (PR) Diameter of arterioles ■ BP depends on: 1. Cardiac output  CO = SV X HR 2. Peripheral resistance 3. Blood volume.

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Regulation of blood pressure

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■ Maintaining B.P. is important to ensure a steady blood flow (perfusion) to tissues. ■ B.P. is regulated neurally through centers in medulla oblongata 1. Vasomotor Center (V.M.C.), or ( pressor area)  Sympathetic fibers 2. Cardiac Inhibitory Center (C.I.C.), or (depressor area)  Parasympathetic fibers

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cardiac control centers in medulla oblongata 1. Cardiacaccelerator center (V.M.C) 2. Cardiacinhibitory center (C.I.C) Sympathetic n. fibers Parasympathetic n. fibers Regulatory mechanisms depend on: a. Fast acting reflexes: Concerned by controlling CO (SV, HR), & PR b. Long-term mechanism: Concerned mainly by regulating the blood volume

A. Regulation of Cardiac Output: 

A. Regulation of Cardiac Output ■ A fast acting mechanism ■ CO regulation depends on the regulation of: a. Stroke volume b. Heart rate

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Mean arterial pressure Cardiac output = Stroke volume X Heart rate End diastolic contraction Strength volume (EDV ) Stretch Sympathetic n Parasympathetic n

Regulation of Peripheral Resistance (PR): 

Regulation of Peripheral Resistance (PR) ■ A fast acting mechanism ■ Controlled by 3 mechanisms: 1. Intrinsic 2. Extrinsic ■ Extrinsic mechanism is c ontrolled through several reflex mechanisms, most important: 1. Baroreceptors reflex 2. Chemoreceptors reflex

1. Baroreceptors reflex: 

1. Baroreceptors reflex ■ Baroreceptors are receptors found in carotid sinus & aortic arch ■ Are stimulated by changes in BP  BP + Baroreceptors = V.M.C ++ C.I.C = Sympathetic Vasodilatation &  TPR + Parasympathetic Slowing of SA node ( HR) &  CO

2. Chemoreceptors reflex: 

2. Chemoreceptors reflex ■ Chemoreceptors are receptors found in carotid & aortic bodies ■ Are stimulated by chemical changes in blood mainly hypoxia (  O 2 ), hypercapnia (  CO 2 ), & pH changes  BP + Chemoreceptors ++ V.M.C = C.I.C + Sympathetic Vasoconstriction &  TPR = Parasympathetic  HR Hypoxia + Adrenal medulla

3. Other Vasomotor Reflexes: 

3. Other Vasomotor Reflexes 1. Atrial stretch receptor reflex:  Venous Return  ++ atrial stretch receptors  reflex vasodilatation &  BP 2. Thermoreceptors : (in skin/or hypothalamus) Exposure to heat  vasodilatation Exposure to cold  vasoconstriction 3. Pulmonary receptors: Lung inflation  vasoconstriction

4. Hormonal Agents: 

4. Hormonal Agents ■ NA  vasoconstriction ■ A  vasoconstriction (except in skeletal muscles) ■ Angiotensin II  vasoconstriction ■ Vasopressin  vasoconstriction

B. Regulation of Blood Volume: 

B. Regulation of Blood Volume ■ A long-term regulatory mechanism ■ Mainly renal 1. Renin-Angiotensin System 2. Anti-diuretic hormone (ADH) or vasopressin 3. Low-pressure volume receptors

1. Renin-Angiotensin System: 

1. Renin-Angiotensin System ■ Most important mechanism for Na + retention in order to maintain the blood volume ■ Any drop of renal blood flow &/or  Na + , will stimulate volume receptors found in juxtaglomerular apparatus of the kidneys to secrete Renin which will act on the Angiotensin System leading to production of aldosterone

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Renin Aldosterone Adrenal cortex Corticosterone Angiotensinogen (Lungs)  renal blood flow &/or  Na + ++ Juxtaglomerular apparatus of kidneys (considered volume receptors) Angiotensin I Converting enzymes Angiotensin II (powerful vasoconstrictor) Angiotensin III (powerful vasoconstrictor) Renin-Angiotensin System N.B. Aldosterone is the main regulator of Na + retention. Na+, water retention

2. Anti-diuretic hormone (ADH), vasopressin: 

2. Anti-diuretic hormone (ADH), vasopressin ■ Hypovolemia & dehydration will stimulate the osmoreceptors in the hypothalamus, which will lead to release of ADH from posterior pituitary gland ■ ADH will cause water reabsorption at kidney tubules

3. Low-pressure volume receptors: 

3. Low-pressure volume receptors ■ Atrial natriuritic peptide (ANP) hormone, is secreted from the wall of right atrium to regulate Na + excretion in order to maintain blood volume

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Mechanisms Controlling CO and TPR Artery Vein 2. Hormonal Renal Ang II Adrenal Catecholamines Aldosterone 3. Local Factors 1. Neural SymNS PSNS CRITICAL POINTS! 1. These organ systems and mechanisms control physical factors of CO and TPR 2. Therefore, they are the targets of antihypertensive therapy.

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Sympathetic activity Blood pressure Active β1 adrenoceptors on heart Active α1 adrenoceptors on heart Cardiac output Peripheral resistance Blood pressure Renal blood flow Renin Angiotensin II Aldosterone Sodium, water retention Glomerular filtration rate Blood volume

Antihypertensive drugs: 

Antihypertensive drugs Ace inhibitors Captopril enalapril Lisinopril Angiotensin (AT 1 ) antagonists Losartan candesartan irbesartan

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Calcium channel blockers Verapamil diltiazem nifedipine felodipine amlodipine nitrendipine Lacidipine Diuretics THIAZIDES hydrochlorothiazide chlorthalidone indapamide

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HIGH CEILING DIURETICS Furosemide Bumetanide K + SPARING DIURETICS Spironolactone triamterene amiloride β adrenergic blockers Propranolol metoprolol atenolol

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α +β adrenergic blockers Labetalol carvedilol α adrenergic blockers prazosin terazosin doxazosin phentolamine Phenoxybenzamine Central sympatholytics Clonidine Methyldopa

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Vasodilators ARTERIOLAR hydralazine minoxidil Diazoxide ARTERIOLAR + VENOUS Sodium nitroprusside

ACE INHIBITORS: 

ACE INHIBITORS Mechanism of action

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Adverse Effects hyperkalemia angiogenic edema persistent dry cough rash itching Contraindications pregnancy hypersensitivity bilateral renal stenosis

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Therapeutic Considerations use with diabetes or renal insufficiency adjunctive therapy in heart failure often used with diuretic Enalapril , iv for hypertensive emergency

Angiotensin (AT1) antagonists : 

Angiotensin (AT 1 ) antagonists Mechanism of action Competitive antagonists of Angiotensin II No inhibition of ACE

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2. Mechanism of Action- Blocks Ca++ channel decreases/prevents contraction 3. Effect on Cardiovascular system Vascular relaxation Decreased TPR 1. Site of Action- Vascular smooth muscle K+ Ca ++ Na+ Calcium channel blockers

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Contraindications Congestive heart failure pregnancy and lactation Post-myocardial infarction Adverse Effects bradycardia nausea vomiting constipation hypotension nifedipine –reflex Increase SymNS activity; tachycardia, increased contractility headache dizziness peripheral edema

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Therapeutic Considerations hypertension angina arrhythmias verapamil - mainly cardiac nifedipine - mainly arterioles diltiazem -both cardiac and arterioles at high doses, AV node block may occur nifedipine may increase heart rate (reflex)

diuretics: 

diuretics First-line drug for hypertension Relatively safe and effective. Suitable for older adults. Given orally, alone or together with other antihypertensive agents.

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2. Mechanism of Action Urinary Na+ excretion Urinary water excretion Extracellular Fluid and/or Plasma Volume 3. Effect on Cardiovascular System Acute decrease in CO Chronic decrease in TPR, normal CO Mechanism(s) unknown 1. Site of Action Renal Nephron

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4. Adverse Reactions dizziness electrolyte imbalance/depletion hypokalemia hyperlipidemia hyperglycemia ( Thiazides ) gout 5. Contraindications hypersensitivity compromised kidney function cardiac glycosides (K+ effects) hypovolemia hyponatremia

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6. Therapeutic Considerations Thiazides (most common diuretics for HTN) Generally start with lower potency diuretics Generally used to treat mild to moderate HTN Use with lower dietary Na+ intake, and K+ supplement or high K+ food K+ Sparing (combination with other agent ) Loop diuretics (severe HTN, or with CHF)

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Mechanism of Action: competitive antagonist at b- adrenergic receptors β adrenergic blockers

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Active β1 adrenoceptors on heart Cardiac output Blood pressure Renin Angiotensin II Aldosterone Sodium, water retention Blood volume β blockers Peripheral resistance

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Effects on Cardiovascular System a. Cardiac--  HR,  SV   CO b. Renal--  Renin   Angiotensin II   TPR Contraindications asthma; diabetes; bradycardia ; hypersensitivity Adverse Effects impotence; bradycardia ; fatigue; exercise intolerance;

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Therapeutic use: recommended as first-line antihypertensive agents combined use with diuretics are common young patients than elderly (due to high occurrence of chronic lung and heart diseases in the elderly) Especially useful in treating hypertension with preexisting conditions such as previous myocardia infarction, angina pectoris, migraine headache

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1. Site of Action- peripheral arterioles, smooth muscle CRITICAL POINT! Major mechanism/site of SymNS control of blood pressure. α adrenergic blockers

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2. Mechanism of Action Competitive antagonist at a-1 receptors on vascular smooth muscle. 3. Effects on Cardiovascular System Vasodilation , reduces peripheral resistance CRITICAL POINT! Blocking - receptors on vascular smooth muscle allows muscle relaxation, dilation of vessel, and reduced resistance.

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5. Contraindications Hypersensitivity 4. Adverse effects nausea; drowsiness; postural hypotenstion ; 1st dose syncope 6. Therapeutic Considerations no reflex tachycardia; small 1st dose; does not impair exercise tolerance useful with diabetes, asthma, and/or hypercholesterolemia use in mild to moderate hypertension often used with diuretic,  antagonist

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1. Site of Action CNS medullary cardiovascular centers clonidine; direct a -2 agonist methyldopa: “false neurotrans.” CNS a-2 adrenergic stimulation Peripheral sympathoinhibition Decreased norepinephrine release 2. Mechanism of Action 3. Effects on Cardiovascular System Decreased NE-->vasodilation--> Decreased TPR CRITICAL POINT! Stimulation of a-2 receptors in the medulla decreases peripheral sympathetic activity, reduces tone, vasodilation and decreases TPR. Central sympatholytics

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4. Adverse Effects dry mouth sedation impotence 5 . Therapeutic Considerations generally not 1st line drugs; methyldopa drug of choice for pregnancy prolonged use--salt/water retention, add diuretic Rebound increase in blood pressure

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Hydralazine Direct arteriolar vasodilator Release of nitric oxide cause the vasodilation of the arteries Reflex sympathetic system activation can cause tachycardia Norepinephrine release from nerve endings can increase myocardial contractility Vasodilators

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Adverse effects Throbbing headache , palpitation SLE ( Systemic Lupus Erythematosus ) – in slow acetylators or on prolonged use at a higher dose Precipitation of angina and MI Uses Hypertension not controlled by first line of anti hypertensives Can be used hypertension of pregnancy Hypertensive emergencies

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Hypertension treatment with some common co-existing conditions Heart Failure ACE inhibitors Diuretics Myocardial Infarction b -blockers ACE inhibitors Diabetes ACE Inhibitors AVOID- b- blockers Isolated systolic hypertension (Older persons) Diuretics preferred calcium channel antagonist

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Renal Insufficiency ACE Inhibitors Angina b- blocker Calcium channel antagonists Asthma Ca++ channel blockers AVOID- b- blockers Treatment Strategy with Some Common co-existing Conditions, cont

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Summary Important Points antihypertensive Agents Each class of antihypertensive agent: 1. has as specific mechanism of action, 2. acts at one or more major organ systems, 3. on a major physiological regulator of blood pressure, 4. reduces CO and/or TPR to lower blood pressure, 5. has specific indications, contraindications, and therapeutic advantages and disadvantages associated with the mechanism of action.

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Thank you