ANTI-HYPERTENSIVE AGENTS

Dr.V.V.Gouripur, B.Sc, MBBS, MD

Hypertension

• Elevation of arterial blood pressure above 140/90 mm Hg. Can be caused by:– an underlying disease process (secondary

hypertension) • Renal artery stenosis

• Hyperaldosteronism

• pheochromocytoma

– idiopathic process (primary or essential hypertension)

Hypertension-Persistent high blood pressure

• What is Blood Pressure?– Pressure created by the heart as it pumps blood

through the arteries and the circulatory system

• What do Blood Pressure Numbers Mean?– Top number (Systolic)= Pressure while heart is

beating– Bottom number (Diastolic)= Pressure while heart

is resting between beats

Hypertension

• What Causes High Blood Pressure?– Cause unknown in 90 to 95% of cases =

Primary Hypertension– Secondary Hypertension = 5 to 10%

• Kidney Abnormalities• Narrowing of certain arteries• Rare tumors• Adrenal gland abnormalities• Pregnancy

Regulation of blood pressure

• Arterial blood pressure (BP) is equal to the product of the rate of blood flow (cardiac output [CO]) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance [PR]).

• BP = CO x PR.

: Autonomic and Renal Regulation of Blood Pressure

• Postural Baroreflex (Autonomic Feedback Loop)– Baroreceptors (e.g., carotid sinus) sense reduction in BP

caused by pooling of blood below the heart.– Vasomotor and cardio regulatory centers in the brain stem

are activated resulting in increased sympathetic output.» Increase in peripheral vascular resistance (PR;

constriction of arterioles).» Increased cardiac output (direct stimulation of the heart).» Increased venous return to the heart (constriction of

postcapillary venules or capacitance vessels).

Baroreflex acts in response to any event that lowers blood pressure including

•Primary reduction in PR (e.g., vasodilating agent).•Reduction in intravascular volume.•Decreased rate and/or contractility of heart.

Role of kidneys

(Renal Hormonal Control Loop)– Long-term control of B.P. via regulation of blood volume

» Reduction in renal perfusion causes intrarenal redistribution of blood flow and increased reabsorption of salt and water and production of renin.

– Renin» Enzyme that increases production of Angiotensin II.» Renin production is stimulated by decreased pressure in renal arterioles

as well as sympathetic neural activity (via beta-adrenergic receptors).– Angiotensin II causes:

» Direct constriction of resistance vessels» Stimulates synthesis of aldosterone in the adrenal cortex.

– Aldosterone - increases renal sodium absorption and intravascular blood volume.

Treatment Rationale

Short-term goal of antihypertensive therapy:

Reduce blood pressure

• Primary (essential) hypertension

• Secondary hypertension

Treatment Rationale

Long-term goal of antihypertensive therapy:Reduce mortality due to hypertension-induced disease

• Stroke • Congestive heart failure • Coronary artery disease• Nephropathy• Peripheral artery disease• Retinopathy

Ways of Lowering Blood Pressure

• Reduce cardiac output (ß-blockers, Ca2+ channel blockers)

• Reduce plasma volume (diuretics)

• Reduce peripheral vascular resistance (vasodilators)

Drugs used in treating hypertension

• Drugs used in treating hypertension act by altering normal homeostatic mechanisms.

• Efficacy, toxicity, and suitable combinations of drugs can often be predicted by consideration of both the sites and the mechanisms of action of the agents.

• An understanding of the pharmacology of the agents provides the rationale for drug therapy in hypertension

Antihypertensive Drugs

Drugs used in hypertensionDrugs used in hypertension

DiureticsDiuretics Angiotensin antagonistsAngiotensin antagonists

Receptor blockersReceptor blockersACE inhibitorsACE inhibitors

Sympathoplegics-Sympathoplegics- VasodilatorsVasodilators

Alpha or beta receptors

Alpha or beta receptors

Nerve terminalNerve terminal

gangliaganglia

Older oralVasodilatorsOlder oral

Vasodilators

Calcium blockersCalcium blockers

Parenteral VasodilatorsParenteral

Vasodilators

CNS Sympatheticoutflow

CNS Sympatheticoutflow

classification• Diuretics-Lower blood pressure by depleting the body of

sodium and reducing blood volume.• Sympatholytic nAgents -Lower blood pressure by reducing

peripheral resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessel (i.e., reducing venous return).Direc

• Vasodilators -Lower blood pressure by relaxing vascular smooth muscle.

• Agents which Decrease Action of Angiotensin Reduce peripheral resistance from angiotensin action; angiotensin also decreases aldosterone release, which will lower blood volume.

Thiazides and Other Diuretic Agents

• Chlorothiazide• hydrochlorothiazide• Benzfluothiazide• Chlorthalidone• Metalozone Antihypertensive action

– Prevent Na+ retention and reduce plasma and extracellular fluid volumes.

– Direct vasodilator action,

Site of action of diuretics

Diuretics play an extremely important role in antihypertensive therapy.

– Usually well tolerated and accepted by patients.

– Lower B.P. both at rest and during exercise, regardless of body position.

– Favorable hemodynamic effects

Enhance action of other antihypertensive drugs»When non-diuretic antihypertensive agents are used

alone to lower B.P., the kidney responds to the decreased perfusion pressure by retaining Na+, Cl-, and H20 (leads to expansion of plasma and extracellular fluid volumes which tends to offset the original decrease in B.P.).

»Concomitant administration of a diuretic with other antihypertensive agents is important

Absorption, Metabolism and Excretion

– All absorbed orally but hydrochlorothiazide absorbed more readily than chlorothiazide.

– Excreted by kidney by the some mechanism responsible for secretion of uric acid.

» May cause elevated serum uric acid.

» Use with caution in gout.

Use

– Treatment of essential hypertension

– Treatment of edema

– Treatment of diabetes insipidus

– Treatment of hypercalciuria

Adverse Effects–Hypokalemia –

drowsiness, dizziness, sometimes fainting, muscle weakness, loss of deep tendon reflexes.Cardiovascular complications - arrhythmias, hypotension.(May have to administer K+.)

–Hyperuricemia - may aggravate gout.

–May induce hyperglycemia and aggravate diabetes mellitus.

Cautions and contraindications

• May aggravate renal and/or hepatic insufficiency.

• May aggravate gout and diabetes mellitus.• May intensify arrhythmias of digitalis

toxicity.• May worsen other fluid/electrolyte

imbalances.• Direct and indirect effects on fetus.

Sympatholytic Drugs that alter SNS function

• There are a number of different sites of action for "sympatholytic" antihypertensives which act to interfere with some aspect of

sympathetic nervous system (SNS) activity, including:• A) outflow of SNS activity from the brain;• B) antagonism of α or β adrenergic receptors; • C) decreased availability of neurotransmitter released from

adrenergic [postganglionic sympathetic] neurons; and,• D) blockade of SNS neurotransmission at the level of

autonomic ganglia.

Centrally Acting Sympatholytics

• Drugs that decrease sympathetic nervous system outflow from the central nervous system).

• Eg. Clonidine,moxanidine,

Methyl dopa

Methyldopa (Aldomet®)

Mechanism of action - major antihypertensive action is on the CNS to decrease SNS outflow from the brainstem.

Effect due to a metabolite, -methyl norepinephrine that stimulates presynaptic 2-adrenergic receptors to inhibit sympathetic outflow from vasopressor centers in brainstem.

Side Effects and ToxicityBradycardia, diarrhea, dry mouth, failure of ejaculationEdemaPostural hypotension can develop, but considerably less frequent and less

severe than with reserpine, guanethidine, ganglionic blocking agentCNS effects(Unpleasant sedation; persistent lassitude and drowsiness;

vertigo.Extrapyramidal signs, nightmares, psychic depression (less common than with reserpine).

Lactation - associated with high concentration of prolactin in plasma.Idiosyncratic reactionsDrug fever, liver damageHemolytic anemicSudden withdrawal can cause "rebound" hypertension.

Pharmacokinetics

» Absorbed well from G.I.T. but there is a large variability of the extent of absorption among patients.

» Elimination is largely renal.» The drug and its metabolites may

interfere with some of the standard chemical tests for catecholamines.

Clonidine (Catapres®)

• Mechanism - Like methyldopa, clonidine is a central 2-adrenergic agonist.

– Direct stimulation of -adrenergic receptors in

the vasomotor centers of brainstem.– Results in inhibition of sympathetic activity– Predominance of parasympathetic activity

PharmacokineticsAbsorbed well from G.I.T.

Largely excreted by kidney

(60% excreted unchanged,

remainder as metabolites).

–Use»Treatment of essential hypertension»Other

–Side Effects and Toxicity»Similar to those seen with methyldopa; i.e., bradycardia, dry

mouth, sedation, etc.»Fluid and sodium retention.»Occasionally impotence or postural hypotension may occur.»Sudden withdrawal can result in hypertensive crisis.

Sympatholytics Acting on Postganglionic Sympathetic Neurons

Reserpine (Rauwolfia Alkaloid;

Mechanism - depletion of catecholamines (NE, DA, Epi) and 5-HT (serotonin) in both the central and peripheral nervous system and some other sites.

» Antagonizes the uptake and binding of NE by storage granules (vesicles).

» NE is then metabolized by MAO in the neuron.

» Once NE is depleted, sympathetic discharge is decreased.

» Central as well as peripheral action.

Side Effects and Toxicity»CNS-Unpleasant sedation and lethargy. Nightmares, dreams.Depression and suicide.»Extrapyramidal signs (rare).»Increases tone and motility of G.I.T. with

abdominal cramps and diarrhea.»Bradycardia, miosis, nasal congestion, flushing.»Orthostatic (postural) hypotension - may be

severe.

Adrenergic neuron blockers

• Guanethidine (Ismelin®)– Mechanism

» Prevents release of NE from vesicles.

» Actions are primarily peripheral ( unlike reserpine, guanethidine doesn't cross B.B.B.).

» Actively taken up by adrenergic neuron, replaces NE in vesicle, and causes gradual NE depletion.

Use - treatment of moderately severe to severe hypertension.

Side Effects and Toxicity»Postural hypotension»May be severe»Dizziness, weakness»Intestinal cramping and diarrhea.»Ejaculatory failure»Other minor effects - edema, nasal congestion.»Drug interactions for guanethidine

Sympatholytics Acting on Autonomic Ganglia

• Trimethaphan (Arfonad®)

Mechanism-block nicotinic receptors at autonomic ganglia

Side Effects & Toxicity

Severe postural hypotension

Diarrhoea

Sympatholytics Which Block Adrenergic Receptors

Beta receptor blockers;

Mechanism - -adrenergic blocking agent» Decreases C.O. via 1-blocking action on heart.» There is evidence that it decreases sympathetic

outflow from CNS but this is not likely to be primary site of action.

1-blocking action inhibits renin production by juxtaglomerular cells in kidney.

Beta-receptor blockers1. (Nonselective) Beta-1 and Beta-2 blockade » PROPRANALOL» Timolol (Blocadren®)» Nadolol (Corgard®)» Penbutolol (Levatol®)

2. Relatively selective beta-1 blockade (preferred for patients with asthma or diabetes)» Metoprolol (Lopressor®)» Atenolol (Tenormin®)

3 Beta blockers with "Intrinsic Sympathomimetic Activit- Have less effect on resting heart rate and cardiac output; also less likely to cause a decrease in HDL cholesterol/LDL cholesterol

» Pindolol (Visken®)» Acebutolol (Sectral®)

4. Combined α &βreceptor blockade -Labetalol (Normodyne

Uses

»Treatment of hypertension

»Treatment of supraventricular and ventricular arrhythmias

»Angina pectoris

»Migraines

»Other

• Proven benefit in reduction of stroke, MI

• Commonly used as first line therapy

• When used alone effective in 50-60% of patients

• When used in conjunction with a diuretic increase response rate to 60-80%

Role of beta blockers in hypertension

Side Effects and Toxicity» Bradycardia» Development of heart failure (usually in patients with compromised heart function or on

other drugs).» Sudden discontinuation may precipitate rebound hypertension» Exacerbation of asthmatic symptoms» Hypotension» A.V. block» May be detrimental to diabetics because of two actions:» masks tachycardia which usually signals hypoglycemia» intensified hypoglycemic response in diabetics because of suppression of

glycogenolysis.» Elevated triglycerides and decreased HDL-cholesterol» Diminished exercise tolerance

Contraindications

–Asthma Never use in asthmatic patients

–Heart failure, Bradycardia

–Intermittent claudication

–Raynauds

Alpha blockers

Non selective alpha blockers» phentolamine » phenoxybenzamine» dibenamine

Selective alpha1blockers» Prazosin (Minipress®) » doxazosin (Cardura®)» terazosin (Hytrin®)» trimazosin

Alpha Blockers– Mechanism

» Blocks postsynaptic alpha adrenoreceptors (1) in arterioles and venules.

» Selective 1 block allows norepinephrine to act on presynaptic 2 receptors to exert negative feedback on its own release.

» Prazosin produces less reflex tachycardia than nonselective alpha-blockers such as phentolamine, which blocks 2 receptors as well as 1 receptors.

» Block of presynaptic 2 “auto-receptors” by nonselective blockers allows more NE release following nerve stimulation. Therefore, there is more NE available to stimulate the heart.

Use

» Essential hypertension; effectiveness may be increased, if necessary, by use in combination with other agents, such as diuretics and beta-blockers, to offset compensatory actions, i.e., edema, tachycardia.

» Chronic congestive heart failure (CHF); used to dilate both resistance and capacitance vessels (decreases both afterload and preload).

Side Effects and ToxicityUsually well tolerated

“First-dose phenomenon” with postural hypotension and syncope occurring shortly after the first dose.

First dose should be given at bedtime

» Others - dizziness, palpitations, lassitude, headache.

Doesn't alter plasma lipid concentration

Sexual dysfunction is uncommon

Calcium Channel Blockers [ “Cardioactive”

• i. Verapamil (Calan®)

• ii. Diltiazem (Cardizem®)

“Vasoactive” – Dihydropyridines• Nifedipine-( Procardia®)

• Amlodipine (Norvasc®)

• Felodipine (Plendil®)

• Nimodipine (Nimotop®)

Mechanism of action(Calcium antagonists; slow channel

blockers)– Inhibits calcium influx in arterial smooth

muscle causing dilation of peripheral arterioles and reduction of blood pressure.

– Also inhibits movement of calcium through channels in myocardial and specialized conducting tissues of the heart.

• . Use–Treatment of hypertension

–Treatment of angina

–Antiarrhythmic

Calcium Channel Blockers

Concern over the use of short acting CCBs

• May increase rate of MI in hypertensive patients

• The FDA have said that “ short acting dihydropyridines should not be used as first line therapy to treat hypertension.”

• Long acting dihydropyridines such as AMLODIPINE appear safe

• Rate limiting CCBs such as VERAPAMIL, DILTIAZEM also safe

• CCBs work by– blocking the L type calcium channels– selectivity between vascular and cardiac L

type channels– relaxing large and small arteries and

reducing peripheral resistance– reducing cardiac output

Side Effects and Toxicity

– Constipation– Hypotension– Atrioventricular block– Decreased cardiac output leading to, or

worsening, heart failure– Ankle Edema– Other

Contraindications

– Acute MI– Heart failure, (rate limiting CCBs)– bradycardia (rate limiting CCBs)

Vasodilators (act directly on vascular smooth muscle)

Hydralazine (Apresoline®)• Mechanism

– Direct relaxation of vascular smooth muscle is major effect (arteriole effect greater than effect on veins).

– Causes reflex cardiac stimulation.– Increases renin secretion (reflex

sympathetic discharge).

Use

–Used in hypertensive emergencies.–Used in treatment of essential hypertension.

»Antihypertensive effect is optimized by concurrent administration of a -adrenergic blocker, (eg, propranolol) to prevent tachycardia and increased renin secretion and a diuretic to counter sodium and water retention and increased plasma volume.

-adrenergic blockers and thiazide diuretics also limit symptoms.

Side Effects and Toxicity–Headache, palpitation, anorexia, nausea, dizziness, and

sweating are common.–Nasal congestion, flushing, lacrimation, conjunctivitis,

paresthesias, edema, tremors, and muscle cramps occur less frequently.

–Myocardial stimulation - can produce anginal attacks.–Drug fever, urticaria, skin rash, polyneuritis, anemia, and

certain other idiosyncratic reactions are rare, but require termination of therapy.

–Drug-induced lupus-like syndrome occurs in 10-20% of patients receiving prolonged therapy with high doses

minoxidil (Rogaine®)

Side Effects and Toxicity– Tachycardia, palpitations, angina and

edema when doses of beta-blockers and diuretics are inadequate.

– Headache, sweating, and hypertrichosis are relatively common.

.

minoxidil - used topically to stimulate hair growth

• A 2% solution of minoxidil (Rogaine®) is used topically to stimulate hair growth in treatment of male pattern baldness

Vasodilators Used in Treating Hypertensive Emergencies

• Diazoxide (Hyperstat I.V.®) - parenterally administered arteriolar dilator used to treat hypertensive emergencies; structurally related to -thiazide diuretics but is devoid of diuretic activity.

• Nitroprusside (Nipride®) - parenterally administered vasodilator used in treating hypertensive emergencies and severe cardiac failure; dilates both arterioles and venules resulting in decreased peripheral resistance and venous return. Solutions are light sensitive and metabolized to cyanide.

• Fenoldopam (Corlopam®) - Dopamine receptor agonist; Administered by continuous IV infusion

Angiotensin Converting Enzymes

ENALAPRIL, LISINOPRIL, RAMIPRIL

• Competitively inhibit the actions of angiotensin converting enzyme (ACE)

• ACE converts angiotensin I to active angiotensin II

• Angiotensin II is a potent vasoconstrictor and hypertrophogenic agent

GFRProteinuriaAldosterone releaseGlomerular sclerosis

Angiotensin-II plays a central role in organ damage

A-II AT1 receptor

Atherosclerosis*VasoconstrictionVascular hypertrophyEndothelial dysfunction

LV hypertrophyFibrosisRemodelling

Stroke

DEATH

*Preclinical dataLV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

Hypertension

Heart failureMI

Renal failure

• Contraindications– Renal artery stenosis– Renal failure– Hyperkalaemia

• Adverse Drug reactions– Cough– first dose hypertension– taste disturbance– renal impairment– Angioneurotic oedema

Drug-Drug Interactions

• NSAIDs– Precipitate acute renal failure

• Potassium supplements – Hyperkalaemia

• Potassium sparing diuretics– Hyperkalaemia

Angiotensin II Antagonists

• LOSARTAN, VALSARTAN, CANDESARTAN, TELMISARTANand

IRBESETRAN

MECHANISM-angiotensin II antagonists competitively block the actions of angiotensin II at the angiotensin AT1 receptor

• Advantage over ACE inhibitors – No cough

Use

• Treatment of hypertensionManagement of congestive heart failureAcute MI

BHS Guidelines

Young Elderly(low renin)

A B C D

A ACE Inhibitor/AT II Blockers

B Beta Blocker

C Calcium Channel Blocker

D Diuretic

Less commonly used agents

• Alpha-adrenoceptor antagonists– Doxazosin

• Centrally acting agents– Methyldopa– Moxonidine

• Vasodilators– Hydralazine– Minoxidil

• If there are no contraindications start treatment according to age and other pathology

• If elderly with a low dose of – a thiazide diuretic– a calcium channel blocker

• If young– An ACEI– or beta-blocker

If a single agent doesn’t control BP– Then use the two together

• A single agent will control BP in 40-50% of patients

Some Considerations for Choosing Treatments (unless

otherwise contraindicated).

–Diabetes mellitis

• ACE inhibitors, alpha-antagonists, and calcium antagonists can be effective, and have few adverse effects on carbohydrate metabolism.

– Hyperlipidemic • Low dose diuretics have little effect on

cholesterol and triglycerides. • Alpha-Blockers decrease LDL/HDL ratio.

Calcium-channel blockers, ACE inhibitors, angiotensin II receptor blockers have little effect on lipid profile.( Beta blockers ^lipids)

– Obstructive airway disease • Avoid beta-blockers.

–Pregnancy

»If taken before pregnancy, most antihypertensives can be continued except ACE inhibitors and angiotensin II receptor blockers.

»Methyldopa is most widely used when hypertension is detected during pregnancy.

»Beta-Blockers are not recommended early in pregnancy.

–African origin• Diuretics have been demonstrated to decrease morbidity and mortality, and hence should be first choice.

• Ca++ blockers and alpha/beta blockers are effective.

• Patients may not respond well to monotherapy with beta-blockers or ACE inhibitors.

–Elderly • Smaller doses, slower incremental increases in dosing, and simple regimens should be used.

• Close monitoring for side effects (i.e., deficits in cognition after methyldopa; postural hypotension after prazosin) is appropriate.

• BPH-ALPHA BLOCKERS

THE END

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