Anti-Hypertensive Drugs

By

Dr. Srujana Ashok

TOPICS TO BE DISCUSSED

▪ Diuretics

▪ ACE inhibitors

▪ Angiotensin receptor blockers

▪ Calcium channel blockers

Diuretics

First line of drugs for mild to moderate Hypertension Used in patients with adequate renal function.They do not lower BP in normotensives.

Diuretics-Definition And Classification

Def : These are the drugs which cause a net loss of sodium and water in urine.

Classification :

1) Thiazides : Hydrochlorothiazide, Chlorthalidone, Indapamide.

2) High ceiling : Furosemide.

3) Potassium sparing : Spironolactone , Amiloride.

Thiazides-Mechanism of Action

inhibit Na+ and Cl- transporter in distal convoluted tubules

increased Na+ and Cl- excretion

ADVANTAGES OF USING THIAZIDES

▪ During long term treatment with thiazides – heart rate and cardiac output remain unaffected.

▪ It has no effect on capacitance vessels .

▪ Sympathetic reflexes are not impaired.

▪ Postural hypotension is rare.

Pharmacokinetics

orally administered

poor absorption

onset of action in ~ 1 hour

wide range of T 1/2 amongst different thiazides, longer then loop diuretics

free drug enters tubules by filtration and by organic acid secretion

Therapeutic Uses

hypertension

congestive heart failure

hypercalciuria: prevent excess Ca2+ excretion to form stones in ducts

osteoperosis

nephrogenic diabetes insipidus

treatment of Li+ toxicity

Side Effects

hypokalemia

increased Na+ exchange in CCD

hyponatremia

hyperglycemia

diminished insulin secretion

elevated plasma lipids

hyperuricemia

hypercalcemia

Contraindications

▪ Pregnancy

▪ Gout

▪ Severe renal or hepatic impairment

▪ Pre-existing hypercalcaemia

▪ Hypokalemia

Drug interactions

▪ NSAIDs

▪ Lithium

▪ Digoxin

▪ k+ depleting agents

▪ Antidiabetics

Loop Diuretics

▪ The loop diuretics act promptly, even in patients with poor renal function or who have not responded to thiazides or other diuretics.

▪ Loop diuretics cause decreased renal vascular resistance and increased renal blood flow.

▪ Loop diuretics increase the Ca2+ content of urine, whereas thiazide diuretics decrease it.

Loop diuretics-mechanism of action

inhibits apical Na-K-2Cl transporter in thick ascending loop of henle

competes with Cl- binding site

enhances passive Mg2+ and Ca2+ excretion

increased K+ and H+ excretion in CCD

inhibits reabsorption of ~25% of glomerular filtrate

Pharmacokinetics

orally administered, rapid absorption

rapid onset of action

bound to plasma proteins

Therapeutic Uses

edema: cardiac, pulmonary or renal

chronic renal failure or nephrosis

hypertension

Hypercalcemia

acute and chronic hyperkalemia

Adverse Effects

hypokalemia

Hyperuricemia

metabolic alkalosis

hyponatremia

ototoxicity

Mg2+ depletion

Contraindications

▪ Hypersensitivity

▪ Hypokalaemia

▪ pericardial tamponade

▪ dehydration

Drug interactions

▪ NSAIDs

▪ Lithium

▪ K+ depleting agents

▪ Antidiabetic drugs

▪ Thiazides

▪ Captopril

▪ Cephalosporins

K+ sparing diuretics

▪ Spironolactone or Amiloride lower B.P slightly

▪ They are used only in conjugation with thiazide diuretics to prevent K+ loss

augment anti-hypertensive action

used in HTN due to primary hyperaldosteronism

Mechanism of Action

K+ sparing diuretics function in CCD

decrease Na+ transport in collecting tubule

Triamterene/Amiloride

inhibit apical Na+ channel

Spironolactone

competitive antagonist for mineralocorticoid receptor

prevents aldosterone stimulated increases in Na+ transporter expression

Pharmacokinetics

Spironolactone

orally administered

Amiloride

•oral administration, 50% effective

•not metabolized

•not bound to plasma proteins

•Triamterine

•oral administration, 50% effective

•60% bound to plasma proteins

•liver metabolism, active metabolites

Therapeutic Uses

primary hyperaldosteronism

congestive heart failure

cirrhosis

nephrotic syndrome

in conjunction with K+ wasting diuretics

Adverse Effects

hyperkalemia: monitor plasma [K+]

spironolactone: gynecomastia

triamterene: megaloblastic anemia in cirrhosis patients

amiloride: increase in blood urea nitrogen, glucose intolerance in diabetes mellitus

RENIN ANGIOTENSIN-ALDOSTERONE SYSTEM

RENIN ANGIOTENSIN-ALDOSTERONE SYSTEM

▪ A system which works to increase Blood pressure when the pressure within the kidney drops.

▪ As a result of low blood pressure and/or oxygenation in the nephron, renin is released from Juxtaglomerular cells.

▪ Renin travels to the liver via the cardiovascular system and combines with angiotensinogen to form Angiotensin 1.

▪ Angiotensin 1 travels through the cardiovascular system and arrives at the lungs where it is changed into Angiotensin 2.

▪ The alveoli use Angiotensin Converting Enzyme also known as Kinase2 to cause this conversion.

CONTD...

▪ Angiotensin 2 is a powerful vasoconstrictor which causes a rise in peripheral resistance and increases pressure.

▪ Angiotensin 2 works to increase the release of Aldosterone from the adrenal glands.

▪ Aldosterone causes renal retention of sodium and water, which further increases blood pressure by increasing volume.

And 2 types of Drugs Act on This Renin AngiotensinAldosterone system

1.ACE Inhibitors

2.ARBs

Angiotensin 1 converting enzyme inhibitors

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Introduction

These drugs block the ACE that cleaves Angiotensin-1 to form potent vasoconstrictor Angiotensin-2.

These are first choice of drugs in All grades of essential as well as Reno-Vascular Hypertension.

These drugs lower BP by reducing peripheral vascular resistance without reflexively increasing Cardiac output rate or contractility.

They have Renal blood flow improving action and also have potential to retard Diabetic Nephropathy

More effective in younger hypertensives than in elderly.

More effective when given in conjugation with Diuretics or Beta blockers.29

Drugs

▪ Captopril

▪ Enalapril

▪ Lisinopril

▪ Perindopril

▪ Ramipril

▪ Fosinopril

Mechanism of Action

Pharmacokinetics

▪ All ACEs except Captopril and Lisinopril are connverted to active metabolites.

▪ Enalapril : Converted to Enalaprilat, t ½ is 11 hours, renallyexcreted , unchanged .

▪ Captopril Short t ½ of 3 hours.

▪ lisinopril : water soluble , not hepatically metabolised.

Clinical uses of ACEIs

▪ Treatment of hypertension .

▪ Treatment of heart failure .

▪ Secondary prevention after myocardial infarction .

▪ Diabetic nephropathy in insulin dependent diabetes .

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Side effects

▪ Cough that is nonproductive not dose related caused by accumulation of kinins in the lung .

▪ Postural hypotension can occur , particularly after the first dose .

▪ Rashes .

▪ Angioedema .

▪ Hyperkalemia.

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Contraindications

▪ Pregnancy

▪ Bilateral renal Artery Stenosis

▪ Aortic Valve Stenosis

▪ K+ supplements

Interactions

▪ Drug-drug :

Digoxin: may increase digoxin level by 15% to 30%.

Iithium :increase lithium levels and symptoms of toxicity possible.

K sparing diuretics , K supplements may cause hyperkalemia.

▪ Drug-food:

salt substitutes containing K : increase K level .

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Angiotensin 2 receptor blockers

Introduction

▪ Angiotensin 2 is a very potent chemical that causes the muscles surrounding the blood vessels to contract, thus narrowing of vessels causing high Blood pressure.

▪ The angiotensin II receptor blockers (ARBs) are alternatives to the ACE inhibitors.

▪ These drugs allow angiotensin1 to be converted to angiotensin2 but block the receptors that receive Angiotensin2

▪ block vasoconstriction and release of Aldosterone

▪ ARBs decrease the nephrotoxicity of diabetes, making them an attractive therapy in hypertensive diabetics.

Angiotensin Receptor

▪ Distinct subtypes of Ang2 receptors are designated as AT1 and AT2.

▪ The AT1 receptor subtype is located predominantly in vascular and myocardial tissue and also in the brain, kidney, and adrenal glomerulosa cells , which secretes Aldosterone.

ACTION OF ANGIOTENSIN2 ON AT1 AND AT2

vasoconstriction

AT 1 Receptor AT2 Receptor

Site of Action of ARBs

Mechanism of Action

▪ Block AT1 receptors in

Vascular Smooth muscle Adrenal Cortex

Vaso dilatation Reduced Aldosterone Secretion

Contd...

▪ they do not inhibit AT2 receptors.

▪ Have no effect on bradykinin metabolism and are more selective blockers of angiorensin effects than ACE inhibitors.

DRUGS

LosartanCandesartanTelmisartanIrbesartanValsartanEposartan

Therapeutic uses

Hypertension

Treatment of congestive heart failure

May be used alone or with other agents such as Diuretics.

Adverse effects

▪ Dizziness

▪ headche

▪ skin rash

▪ fatigue

▪ taste disturbances

no cough or angioedema

Advantages of ARBs over ACE inhibitors

Do not induce cough

Low incidence of Angioedema, rash , dysguesia.

They are as effective as ACE inhibitors in CHF, MI and Diabetic Nephropathy.

Calcium channel blockers

Introduction

▪ Calcium-channel blockers are recommended when the preferred first-line agents are contraindicated or ineffective.

▪ They are effective in treating hypertension in patients with angina or diabetes.

▪ High doses of short-acting calcium channel blockers should be avoided because of increased risk of myocardial infarction due to excessive vasodilation and marked reflex cardiac stimulation.

Calcium Channel Blockers -Classification

CCBs – Mechanisms of Action

They act by inhibiting L type of voltage sensitive calcium channels in smooth muscles and heart.

This causes decreased peripheral smooth muscle tone, decreased systemic vascular resistance

Result : decreased blood pressure

Why Do CCBs Act Selectively on Cardiac and Vascular Muscle?

CCBs Act Selectively on Cardiovascular Tissues

Neurons rely on N-and P-type Ca2+ channels

Skeletal muscle relies primarily on [Ca]i

Cardiac muscle requires Ca2+ influx through

L-type Ca2+ channels- contraction - upstroke of AP

Vascular smooth muscle requires Ca2+ influx

through L-type Ca2+ channels for contraction

Pharmacokinetics

▪ Well absorbed through GIT.

▪ First pass metabolism.

▪ Highly bound to plasma proteins.

▪ Metabolism in liver.

▪ Excreted through urine.

USES OF CCBs..

1. angina pectoris - Due to decrease in myocardial oxygen consumption, and dilatation of

coronary arteries.

2. supraventicular arrhythmias - because of its depressant action on S-A and A-V nodes.

3. hypertension - they control blood pressure by their vasodilatory effect.

4. Migraine

5. raynaud’s phenomenon - due to their vasodilatory property.

Side Effects of calcium antagonists1. Arterial dilation: headache, flush, dizziness,ankle swelling2. Bradycardia and AV block 3. cardiodepression.4. Constipation5. Haemorrhagic gingivitis

ADVERSE EFFECTS..

Postural hypotension

palpitation

reflex tachycardia

edema

dizziness

constipation

sedation

A-V block

headache

fatigue

lowered B.P.

CONTRAINDICATIONS

o Heart failure

o Bradycardia

oAtrioventricular block.

o Dihydropyridine calcium-channel blockers should not be used in people with uncontrolled heart failure.

ConcomitantDisease

Diuretics ACE inhibitors ARBs Calcium channel blockers

High risk Angina Pectoris

Diabetes

Recurrent Stroke

Heart Failure

Previous MI

Chronic Renal Disease

Thank you...