Drug Therapy of Hypertension

Physiologically, the cardiac output as well as peripheral resistance are controlled mainly by three overlapping mechanisms:

a. The baroreflexes, mediated by the autonomic nervous system

b. The renin-angiotensin-aldosterone system

C. A local release of hormones from vascular endothelium, e.g.nitric oxide (NO) which dilates and endothelin 1 which constricts blood vessels

Joint National Committee (JNC) classifies hypertension as follows Category SBP mmHg DBP mmHgNormal <120 and <80Prehypertension 120–139 or 80–89Hypertension, Stage 1 140–159 or 90–99Hypertension, Stage 2 ≥160 or ≥100

General approaches to the treatment of hypertension:

The use of diuretics to reduce the blood volume.

Drugs that interfere with the RAAS and Drug induced reduction in PVR, Cardiac output

or both.

Beta – blocking drugs

• In Mild to moderate hypertension.• Mechanism: Reduction in heart rate and myocardial contractility. Reduced renin secretion Reduction in central sympathetic outflow by blocking

presynaptic β-receptors centrally. Stimulation of prostacyclin synthesis in vascular beds. Blockade of peripheral facilitatory presynaptic β2- receptors to

reduce NE release and Increase in natriuretic peptide secretion caused by β-blockade. Blockade of ADH from posterior pituitary. Β1 action.

• Earlier, these were employed as a first step in the management of essential hypertension.

• However, now these are often used in conjunction with a diuretic when monotherapy is not satisfactory.

• The combination of β-blockers, a diuretic and a vasodilator is very effective in patients who are resistant to other antihypertensive regimens.

• Besides HT, β-blockers are also used for the treatment of:o supraventricular tachyarrhythmiaso previous MI ando angina pectoris.

Should not be used in :• Insulin dependent diabetes, • Bronchial asthma or • COPD• Raynaud’s phenomenon, • Variant angina and • Acute congestive cardiac failure.

Adverse effects:• Fatigue, lethargy, decreased libido and

unfavourable lipid profile. • May produce rebound hypertension,

tachycardia and anginal pain , upon sudden withdrawal of β – blockers. The withdrawal syndrome involves up – regulation and hyper – responsiveness of β – adrenoceptors

• The non – selective (β1+ β2) beta – blockers:propranolol, sotalol, nadolol, pindolol and oxprenolol.

Salient features about non selective blockers:• Sotalol has low lipid solubility with negligible first –pass

metabolism. It has an additional K+ channel blocking and class III antiarrhythmic property independent of β-blocking property.

• Nadolol has longer half life and once daily dosage. It does not cross BBB and has least first pass metabolism.

• Pindolol and oxprenolol possess some inherent intrinsic sympathomimetic actions useful in patients prone to bradycardia or those with low cardiac reserve.

Selective β1-blockers used therapeutically:• Metoprolol, atenolol, esmolol, acebutolol, celiprolol and nebivolol.

Salient Features: CARDIOSELECTIVE Acebutolol and celiprolol possess ISA. Safer in patients having concomitant asthma, diabetes, Raynaud’s

phenomenon and in those who have unfavourable lipid profile. Atenolol does not cross BBB and has longer duration of action

than metoprolol. Nebivolol is a new hybrid drug possessing β1 adrenoceptor blockade plus vasodilating properties(3 rd generation)

Esmolol is an ultrashort acting β1-adrenoceptor antagonist.

Mixed (α+β) Antagonists

Labetalol exhibits:• selective blockade of α1 adrenoceptor, • inhibition of neuronal uptake of NE, • blockade of β1 receptors,• partial agonist activity at β2 and • some direct vasodilator properties.

• Useful in phaeochromocytoma and for controlling rebound HT after clonidine withdrawal. Treatment of black hypertensive patients

• Postural hypotension and hepatotoxicity are main side effects.

• Carvedilol is a β1+ β2 and α1 adrenoceptor blocker• It inhibits free radical induced lipid peroxidation and also prevents

vascular smooth muscle mitogenesis.• Therefore cardioprotective in patients of CCF

Alpha - Blockers• Phenoxybenzamine, is non selective.• α1-selective receptor antagonists like prazosin, terazosin and doxazosin

produce lesser tachycardia than non selective α blockers, so more used now.• These drugs reduce arterial pressure by dilating both the resistance and

capacitance vesselsCommon adverse effects includes:• Postural hypotension • Retention of salt and water

• Terazosin and doxazosin have a longer duration of action• Useful in patients with concomitant complications such as gout, diabetes

and hyperlipidaemia and male hypertensive patients having benign prostatic hyperplasia

Centrally Acting Antihypertensive Agents

• These agents reduce sympathetic outflow from vasopressor Centre

Methyldopa:• Stimulates central α2 receptors to inhibit adrenergic

neuronal outflow from the brainstem• Valuable in HT complicated by renal insufficiency• It is the drug of choice for treating HT during

pregnancy• The drug should be used in conjunction with a diuretic

CLONIDINE: • At lower plasma concentration, has lesser intrinsic activity on

postsynaptic α1 receptors.

Antihypertensive effect of clonidine is exerted by-activation of α2 receptors at vasopressor centre.

Clonidine binds to and activates imidazoline I receptor which may modulate the central α2 receptor activity

Clonidine also activates the presynaptic α2 receptors on sympathetic post ganglionic neurons which suppresses further release of NE from peripheral nerve endings.

Reduces renin release also and decreases renal vascular resistance.

• The principal difference between clonidine and α-methyldopa is that clonidine acts directly on central α2 – adrenoceptors (AUTORECEPTOR) whereas α-methyldopa must be converted to α-methyl NE to exert its antihypertensive effects.

• A vasodilator can be added to the clonidine + diuretic combination to treat the cases of refractory HT.

• It is also useful for HT complicated by renal disease, to control diarrhea in patients with autonomic neuropathy, in migraine prophylaxis, treatment of nicotine, alcohol & opioid withdrawal.

• Not used as a first-line antihypertensive drug because of its side effects and risk associated with rebound hypertension after its abrupt withdrawal.

Adverse Effects: Rebound hypertension due to supersensitivity of newly formed α

receptors-so its withdrawal to be gradual. Dry mouth Sedation Nasal stuffiness Constipation Impotence Contact dermatitis when used as patch

Moxonidine and Rilmenidine:• Newer congeners of clonidine• Longer plasma half-life and are said to be

selective for imidazoline (I 1) receptor• Rebound hypertension is much less frequent

DIURETICS• Na+ contributes to vascular resistance by increasing vessel stiffness.• These effects are reversed by diuretics and salt restriction.THIAZIDES:• Thiazides are generally the diuretic of choice for essential hypertension• Indapamide is more potent and longer acting than hydrochlorothiazide

and possesses some intrinsic vasodilator activity also.• The main adverse effects of thiazides are:

• Hypokalaemia, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyperlipidaemia and hypochloraemic alkalosis.

• Thiazides should be avoided in hypertensive cases with concomitant Diabetes mellitus, gout, hyperlipidaemia, renal insufficiency and pregnancy. Indapamide can be used in diabetic hypertensives.

Loop Diuretics• They are preferred in severe HT with cardiac and renal

insuffuciency.• Loop diuretics promptly reduce pulmonary oedema in CHF

due to rapid diuresis which results in the decrease in venous return and subsequently in the reduction in right ventricular output. These drugs can convert oliguric renal failure to non-olguric failure which helps in management of renal failure.

• Adverse effects include hyperuricaemia, hypercalciuria, hypomagnesaemia and hypokalaemia

• Indacrinone is useful for hypertensive patients having gout as it inhibits proximal tubular uric acid absorption also

k+ sparing diuretics

• Spironolactone is an aldosterone receptor antagonist and hence antagonises Na+ retaining and K+ excreting actions of aldosterone.

• They are usually given along with thiazides to avoid excess potassium depletion

• Concomitant use with ACE inhibitors should be avoided because it will aggravate hyperkalemia.

ACE Inhibitors

• Angiotensin Converting Enzyme Inhibitors• Enalapril, Ramipril, Captopril, Lisinopril, Benazepril,

Perindopril• All ACEI are prodrugs except captopril and lisinopril• Ang – II is a vasoconstrictor and stimulates aldosterone

release and thus promotes Na+ retention.• These are the drugs of first choice for treating all grades of

essential as well as renovascular hypertension.• Most useful in diabetic nephropathy, left venticular

hypertrophy, CHF and in cases of post-myocardial remodeling.• Adverse effects include: • Hypotension after first dose, dry cough, angioneurotic

oedema, hyperkalemia, foetal hypotension with a risk of foetal malformations administered during II and III trimester of pregnancy and altered sense of taste (ageusia)

ARB s• Angiotensin Receptor Blockers• Specific antagonists of angiotensin II receptors( AT 1

receptor)• ARBs have no effect on bradykinin metabolism and their

use is generally restricted to patients who do not tolerate ACEIs because of dry cough or angioneurotic oedema.

• Adverse effect- Hazardous during pregnancy• Losartan is also effective in portal hypertension due to

cirrhosis of liver

CCB s

• Calcium channel blockers• Block voltage dependent L-type Ca2+ channels and thus

reduce the frequency of the opening of these channels response to depolarisation

• Four types: • Voltage-sensitive Ca2+ channels• L-type Ca2+ channels dominant in cardiac and smooth

muscles are blocked by CCBs.• Currently CCBs enjoy the status of first-line antihypertensive

drugs.• Also used in treatment of angina and cardiac arrhythmias

Advantages of CCBs:• Their relaxant effects on large arteries is more beneficial in

elderly patients.• They improve arterial compliance and retard atherogenesis• These can be used safely in patients with asthma, angina and

PVD.• No adverse effects on lipid profile, uric acid levels or glucose

metabolism.• Postural hypotension, first dose effect or rebound

phenomenon are not observed• These neither impair male sexual activity nor the physical

work capacity.• They have no adverse effects on foetus

ALL THESE FACTORS MAKE CCBs 1St LINE ANTIHYPERTENSIVE DRUGS

Classification of CCBs

Dihydropyridines (DHPs)• Short acting: Nifedipine, Nicardipine and Nimodipine• Intermediate acting: Nisoldipine, Nitrendipine,

Lacidipine, Cilnidipine• Long acting: Felodipine, Benindipine and Amlodipine

Non- dihydropyridines (Non – DHPs)• Short acting: Verapamil, diltiazem• Long acting: Bepridil

Pharmacological Characteristics:• Verapamil is relatively cardioselective, nifedipine is relatively

vascular smooth muscle selective while diltiazem exhibits intermediate selectivity.

• Coronary artery dilator effects, including dilatation of both epicardial and intramyocardial arteries which prevent coronary spasm:

• Vasodilatory effects on peripheral and pulmonary blood vessels

• All CCBs decrease heart rate contractility and conduction velocity to a varied extent.

• Coronary vasodilation and reduction in peripheral arterial resistance (↓in afterload)

• Used to treat HT and angina.• Verapamil and diltiazem have nodal depressant effects.• Reduce myocardial O2 demand and make them suitable

for treating angina, HT and supraventricular tachycardias.• CCBs are excellent antihypertensive drugs in (1) low renin

hypertensive patients• (2)Elderly patients and (3) in pregnancy as well. • Their antihypertensive effect is independent of Na-intake

or of concurrent use of NSAIDs (unlike ACEIs)

Adverse effects

• Headache, flushing and peripheral oedema.• Reversible gingival hyperplasia (on Prolonged

use)• Its negative inotropic effects are unsuited for

patients with LV dysfunction• Contraindications: Unstable angina• LV failure, aortic stenosis and obstructive

cardiomyopathy.

Amlodipine

• Amlodipine has a longer t1/2• It has lesser first – pass metabolism, hence

bioavailability is consistent.• Ankle oedema• Approved for effort angina as well as for

hypertension

Nicardipine

• Shorter t1/2• Coronary dilatation effect with lesser effect on

cardiac contractility as compared to nifedipine• Angina and HT

Hypertension II

Drugs for Hypertension

• Diuretics– Thiazide– Loop diuretics– Aldosterone antagonists– K-sparing

• Adrenergic inhibitors– Peripheral agents– Central (α-agonists)– alpha -blockers*– beta-blockers– Alpha+beta-blockers

• Direct Vasodilators *

• Calcium channel blockers– Dihydropyridine– Non dihydropyridine

• ACE-inhibitors

• Angiotensin-II blockers

* Usually not monotherapy

Vasodilators

• Direct vasodilators• Vasodilators decrease the total peripheral

resistance• Relax arterial smooth muscle to a greater

extent than venous smooth muscle.On chronic use

• Neuroendocrine and sympathetic reflexes tend to counteract the fall in BP

Arteriolar vasodilators

• These include hydralazine, minoxidil, diazoxide and fenoldopam

• Hydralazine and minoxidil, are used orally for long-term outpatient therapy of HT

• Diazoxide and fenoldopam, are given parenterally to treat hypertensive emergencies.

• An increase in the k+ conductance results in hyperpolarisation of cell membrane which causes relaxation of vascular smooth muscle.

• These are usually administered in combination with a diuretic and a β - blocker

• Triple combination -decrease in cardiac output reduction in plasma volume and decrease in TPR

Hydralazine

• Besides activating K+ channels, vasodilatation due to hydralazine is partly endothelium dependent and may involve generation of nitric oxide and stimulation of cGMP

Use :Moderately hypertensive ambulatory patients: second line in comb with diuretic/B blocker

HT in preg , HT emergency(iv).

Adverse effects:-Facial flushing,headache,dizziness,nasal stuffiness,edema,CHF-tachycardia and angina/MI precipitated-tremor,muscle cramps-Reduced when it is administered in conjunction with a diuretic and a β-blockerOn prolonged use in high doses, it causes reversible disseminated lupus erythematosus or RA like syndrome

Minoxidil

• Active metabolite minoxidil sulfate which activates k+ channel opening

• Severe HT that may be life- threatening or HT associated with chronic renal failure or HT that is resistant to other forms of therapy

• Side effects: headache, nasal congestion, tachycardia and precipitation of anginal attacks.local irritation,itching, burning sensation

• Always administered in combination with a β-blocker and a diuretic

• Topical minoxidil is now marketed as a stimulant of hair growth for correcting male type baldness

Diazoxide

• It opens k+ channels to produce long lasting arteriolar dilatation with no effect on venules

• Slow I.V. injection or infusion is less effective as the drug exhibits rapid and extensive protein binding.

• Long – term oral or parenteral use is not suitable because it causes hyperuricaemia, hyperglycaemia and fluid retention.

• Diazoxide is used for the treatment of hypertensive emergencies such as malignant HT, hypertensive encephalopathy and eclampsia

Fenoldopam

• Agonist of dopamine receptor(D1) leading to dilatation of peripheral arteries and natriuresis.

• Urine output, creatinine clearance, and Na+ excretion are increased by fenoldopam.

• Hypertensive emergency associated with impaired renal function.

• Caution is required for its use in patients in whom hypotension could be deleterious such as those with acute cerebral infraction or haemorrhage.

Arteriolar+venous vasodilators• Sodium nitroprusside : nitrovasodilator as it

releases nitric oxide• Sodium nitroprusside activates guanylyl

cyclase either directly or through release of nitric oxide.

• This results in an increase in the intracellular levels of cGMP which provides vascular smooth muscle relaxation.

• Decrease in peripheral vascular resistance and in venous return.

• In patients with refractory heart failure, even in absence of HT, it improves ventricular performance, by reducing preload and afterload

• Treatment of severe HT with acute MI or LVF.• The aqueous solutions of sodium

nitroprusside are unstable and sensitive to light.

Adrenergic blocking agents

• Reserpine • Guanethedine

Drug Therapy of the Hypertensive Pregnant Patient

• Methyldopa: Drug of choice.• Beta blockers (not early pregnancy).• Hydralazine is the parenteral drug of choice.• DHP CCB- • Prazosin/clonidine • Most agents if used prior to pregnancy may be

continued – (except ACE-I OR A-II BLOCKERS)

Emergencies & Urgencies

• HYPERTENSIVE EMERGENCIES – Require immediate blood

pressure reduction (not necessarily to normal range) to prevent or limit target organ damage.

• HYPERTENSIVE URGENCIES– Require reduction of

blood pressure within a few hours

Hypertensive emergency• Hypertensive emergency is a situation in which BP must be

reduced by 25mm Hg within one to two hours to avoid the risk of severe morbidity and death.

• Progressive target organ damage.• Emergencies include -hypertensive encephalopathy-Hypertensive nephropathy-Intracranial haemorrhage, dissecting aneurysm, pulmonary Oedema, unstable angina, myocardial infraction or malignant hypertension (hypertension associated with vascular damage and Papilloedema).• Rapid and complete normalization of BP should be avoided

Treatment of Hypertensive emergency

• Changes in cerebral blood flow • Rapid normalization of BP would lead to

cerebral, coronary or renal ischaemia• Oral –nifedipine , captopril, clonidine• Parenteral

Parenteral Drugs For Treatment of Hypertensive Emergencies

VASODILATORS• Nitroprusside• Nitroglycerine• Enalaprilat• Nicardipine• Hydralazine• Fenoldopam

ADRENERGIC INHIBITORS• Labetalol• Esmolol• Phentolamine

Sodium Nitroprusside

• Predictable titratable effect- doc• It is an effective drug in treating hypertensive

crisis associated with encephalopathy, nephropathy, pulmonary oedema and MI.

• used in combination with a β-blocker especially in patients with aortic dissection.

• Needs infusion pump & cont monitoring

• GTN- venodialator, lowering BP after cardiac surgery and in acute LVF; tolerance

• Hydralazine – used esp in eclampsia • Esmolol – rapid action ; aortic dissection; also

used during surgery; along with Sod nit• Labetalol-used in MI angina,eclampsia• Phentolamine – hyperadrenergic states- pheo,

cheese reac,clonidine withdrawal

• Other drugs• -furosemide- vol overload, edema• -fenoldopam• Clevidipine/nicardipine• enalaprilat• trimethaphan

Treatment of HT

Target Organ Damage

• Heart Disease– CAD (Angina, myocardial infarction, coronary

revascularization– Left Ventricular Hypertrophy– Heart Failure

• Stroke/TIA• Chronic kidney disease• Peripheral arterial disease• Retinopathy

Joint National Committee (JNC) classifies hypertension as follows Category SBP mmHg DBP mmHgNormal <120 and <80Prehypertension 120–139 or 80–89Hypertension, Stage 1 140–159 or 90–99Hypertension, Stage 2 ≥160 or ≥100

Goals of Therapy

BP <140/90 mmHg

BP <130/80 mmHg in patients with diabetes or chronic kidney disease.

Achieve SBP goal especially in persons >50 years of age.

Lifestyle ModificationModification Approximate SBP

reduction(range)Weight reduction 5–20 mmHg/10 kg weight loss

Adopt DASH eating plan 8–14 mmHg

Dietary sodium reduction

2–8 mmHg

Physical activity 4–9 mmHg

Moderation of alcohol consumption

2–4 mmHg

Drugs for Hypertension

• Diuretics– Thiazide– Loop diuretics– Aldosterone antagonists– K-sparing

• Adrenergic inhibitors– Peripheral agents– Central (α-agonists)– alpha -blockers*– beta-blockers– Alpha+beta-blockers

• Direct Vasodilators *

• Calcium channel blockers– Dihydropyridine– Non dihydropyridine

• ACE-inhibitors

• Angiotensin-II blockers

* Usually not monotherapy

Algorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99 mmHg)

Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB,

or combination.

Without Compelling Indications

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

Classification and Management of BP for adults

*Treatment determined by highest BP category.†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.

BP Class SBP DBP Lifestyle

Initial drug therapy Without compelling

indication Compelling indications

Normal <120 <80 Encourage

None None

Pre-hypertension

120–139

or 80–89

Yes No antihypertensive drug indicated.

Drug(s)

Stage 1 Hypertension

140–159

or 90–99

Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Stage 2 Hypertension

>160 or >100

Yes Two-drug combination (usually thiazide and ACEI or ARB or BB or CCB).

• Start with single dose ;Thiazide – doc• ABCD• Initiate therapy at lose• If partial response, add another drug• If no response, change the drug• If side effect occurs, reduce dose or alter drug• Majority of stage 2 HT start two drug comb

• White coat HT• Resistant HT- despite full dose of three drug

goal BP not acheived

Conclusions

The initial approach to hypertension should start with ruling out secondary causes, detecting and treating other cardiovascular risk factors, and looking for target organ damage.

Treatment should always include lifestyle changes. Medication use should be guided by the severity of HTN and the

presence of “compelling” indications. Thiazide-type diuretics should be initial drug therapy for most, either

alone or combined with other drug classes. Most patients will require two or more antihypertensive drugs

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