Antihypertensive agents

• Hypertension :BP SYSTOLIC DIASTOLIC

Normal < 120 < 80

Pre- hypertension

120 - 139 80 - 89

Stage 1 hypertension

140 - 159 90 - 99

Stage 2 hypertension

160 - higher 100 - higher

Antihypertensive agents - 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

Typical Diurnal Blood Pressure Rhythm in a "Dipper"

Paradigms of Antihypertensive Therapy

Antihypertensive agentsClassification of antihypertensives :• ACE inhibitors : Captopril, Enalapril.• Angiotensin receptor blockers: Losartan• Renin inhibitors: Aliskiren • Beta adrenergic blockers : Propranolol• Calcium channel blockers : Amlodipine• Alpha adrenergic blockers : Prazosin• Central alpha-2 agonist: Clonidine, Methyldopa• Diuretics: Chlorothiazides, Furosemide• Vasodilators

-Arterial (hydralazine, minoxidil, fenoldopam)-Arterial and venous (Nitroprusside)

Antihypertensive agents

Diuretics :• Thiazides or thiazides like:

Chlorothiazides, Indapamide, Metolazoneo These are the most effective diuretics to reduce

blood pressure in patients with normal renal function!!!

• High ceiling diuretics : Furesomide, Torsemide, Bumetanide

• Potassium sparing diuretics : Spironolactone, Amiloride

Diuretics

Thiazides or thiazides like diuretics:

• These are the first line of treatment in uncomplicated hypertension especially in elderly and African-American populations.

Potassium sparing diuretics are only used in combination with diuretics in hypertension to counteract hypokalemia.

Thiazides can improve the hypotensive effects of many antihypertensive agents like ACE inhibitors and ARBs.

• Mechanism of action is not clear and could be due to

a) Depletion of body Na+ stores leads to a fall in smooth muscle [Na+]. This in turn decreases intracellular [Ca ++] by activating the Ca/Na exchanger.

b) Induction of renal prostaglandin biosynthesis

Antihypertensive agents

Angiotensin Converting Enzyme (ACE) Inhibitors:

• Captopril, Lisinopril, Enalapril, Ramipril, Benazepril, Fosinopril

• Reduction in arterial resistance (after load)

• Reduction in venous tension (preload)

• Reduction in aldosterone secretion

Antihypertensive agents

Antihypertensive agents

Indications for ACE inhibitors includes:

• Congestive heart failure (CHF)• Post-myocardial infarction• Hypertension• Hypertensive emergencies –

enalaprilat.• Prevention of nephropathy in

diabetes mellitus

ACE Inhibitors

• ACE Inhibitors: Avoid in Bilateral renal artery stenosis

In bilateral renal artery stenosis and renovascular hypertension, glomerular filtration pressures are maintained by vasoconstriction of the efferent areteiole (post-glomerular arterioles), an effect mediated by angiotensin II.

ACE INHIBITORS

Antihypertensive agents

ANGIOTENSIN RECEPTOR

BLOCKERS ARBs (AT 1 BLOCKERS):

Losartan, Erbesartan, Candesartan• Competitive antagonists of

Angiotensin II• No inhibition of ACE or breakdown

of bradykinin

Antihypertensives agents agents

Antihypertensive agents

RENIN INHIBITORS: Aliskiren: • Aliskiren inhibits the activity of renin and

thus prevents the conversion of angiotensinogen to angiotensin-I

• Aliskiren may have renoprotective effects that are independent of its blood pressure lowering effect in patients with hypertension and type 2 diabetes

• Aliskiren is also available as combination therapy with hydrochlorothiazide.

• Adverse effects includes stroke, angioedema, hyperkalemia and hypotension

Antihypertensive agents

BETA BLOCKERS: Mechanism of action:

Atenolol, Propranolol• Decrease in cardiac output

(blockade of cardiac beta1 receptors)• Inhibition of renin release

(blockade of beta1 receptors on juxtaglomerular cells)

• Inhibition of NE release from presynaptic adrenergic terminals (blockade of presynaptic beta receptors)

• Reduction of central adrenergic tone

Antihypertensive agents

Guidelines for the use of Beta-Blockers in Hypertension– Patients benefit the most from a beta-blocker

drug therapy are those who have:a) hyperkinetic essential hypertension (associated high levels of catecholamines)b) hypertrophic obstructive cardiomyopathy.c) exertional angina.c) post myocardial infarction.d) hypertensive emergency (labetalol).

Antihypertensive agents

• BETA BLOCKERS: Adverse effects:

• Bradycardia is the most common adverse cardiac effect of beta-receptor blocking drugs. Sometimes, patients find cooling effect in hands and feet.

• Beta-receptor blockade with nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction without having these consequences in normal individuals.

Antihypertensive agentsREDUCING SYMPATHETIC OUTFLOW

FROM CNS:• Alpha2 receptor agonists: Clonidine,

Methyldopa Activation of α-2 receptors in NTS and in

RVLM.• Clonidine can cause hypertensive crisis

after abrupt withdrawal leading to tachycardia, tremors and anxiety and may be life-threatening.

• Methyldopa is often preferred for the treatment of gestational hypertension.

• Methyldopa causes hepatic injury and hemolytic anemia (Coombs’ test positive)

Antihypertensive agents

CALCIUM CHANNELS BLOCKERS : CCB

Types of calcium channels : L, N, T• Calcium channel blockers mainly block

L TYPE : SAN, AVN and smooth muscles• Amlodipine, Nifedipine, Diltiazem, Verapamil• Verapamil and diltiazem block Ca++channels

both in the heart and in the vessels• Dihydropyridines (DHP) like Nifedipine block

calcium channels in the vessels only.

Clinical uses of calcium channel - blocking drugs

Drug Indication

Amlodipine Angina, hypertension

Felodipine Hypertension, Raynaud’s disease

Nicardipine Angina, hypertension

Nifedipine Angina, hypertension, Raynaud’s disease

Nimodipine Subarachnoid hemorrhage

Diltiazem Angina, hypertension and Supraventricular arrhythmia

Verapamil Angina, hypertension, Supraventricular arrhythmias, Migraine

–Headache, dizziness, flushing and peripheral edema (DHP like nifedipine and amlodipine)–Tachycardia, palpitations and aggravation of

myocardial ischemia (nifedipine)–Gingival hyperplasia (nifedipine) –A-V block, bradycardia, arrhythmias (ver, dil)–Constipation (verapamil)–Verapamil can double the plasma

concentration of digoxin

Adverse effects of calcium channel blockers

Vasodilators Used in the Treatment of hypertension

Drug Site of action Mechanism of action

Sodium nitroprusside

Arterioles and veins

Production of nitric oxide

Hydralazine Arterioles

Stimulation of NO release, Inhibition of Ca++ release from SR

Minoxidil Arterioles K+ channel opening

Diazoxide Arterioles K+ channel opening

Fenoldopam Arterioles D1-receptor activation

Antihypertensive agentsSodium nitroprusside (SNP): Sodium nitroprusside (SNP) has potent

vasodilating effects in arterioles and venules.

SNP breaks down in circulation to release nitric oxide (NO).

Sodium nitroprusside is metabolized to release cyanide ions which is further converted by liver rhodanase to thiocyanate for excretion in urine.

Toxic accumulation of cyanide can cause severe lactic acidosis.

S/S of thiocyanate toxicity includes nausea, disorientation and psychosis.

Antihypertensive agents

Sodium nitroprusside: It is administered intravenously in

cases of hypertensive emergencies. It is also used in control of blood

pressure in vascular and neurosurgery.

Concomitant administration of sodium thiosulfate or hydroxocobalamin (Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin) can prevent cyanide accumulation in patients receiving more than usual dose of nitroprusside.

Antihypertensive agents

Hydralazine : • Direct arteriolar vasodilator.• Release of nitric oxide from vascular

endothelium cause the vasodilation of the arteries.

• Reflex tachycardia due to sympathetic stimulation may precipitate angina/MI in CAD patients.

Antihypertensive agents

Hydralazine : Adverse effects• Tolerance due to salt and water

retention and to baroreceptor-mediated activation of the SNS.

• Throbbing headache, palpitations.• SLE – in slow acetylators or on

prolonged use at a higher dose.

Antihypertensive agents

Hydralazine : Uses • Hypertension not controlled by first

line of antihypertensives agents.• Can be used in hypertension of

pregnancy Hypertensive emergencies. Heart failure (combined with

isosorbide dinitrate in African-American patients)

Antihypertensive agents

Minoxidil :• Arteriolar vasodilator - K channel

activator• Used in severe hypertension with renal

failure and not responding to other agents (given with diuretic and beta blocker).

• Hypertrichosis on chronic therapy – excess growth of hair on face, back and arms.

Topical minoxidil (ROGAINE) is marketed over the counter for the treatment of male pattern baldness, hair loss and thinning in women.

Effects of Minoxidil

Rationale for use of 1. Diuretics and 2. Beta blockers along with vasodilators.

Antihypertensive agents

• Diazoxide:• It is a rapidly acting and long acting

arterial dilator that is occasionally used to treat hypertensive emergencies.

• It acts by opening of potassium channels leading to relaxation of arteries.

• The most significant toxicity from diazoxide is excessive hypotension that can cause stroke and myocardial infarction. Other adverse effects includes hyperglycemia (inhibits insulin secretion)

Antihypertensive agents

• Fenoldopam is used as an antihypertensive agent postoperatively, and also to treat hypertensive crisis.

• It acts as a selective peripheral dopamine D1 receptor weak partial agonist.

• The drug is administered by continuous intravenous infusion.

• The major toxicities are reflex tachycardia, headache and flushing.

Antihypertensive agents

Hypertensive emergencies :• Sodium Nitroprusside• Nitroglycerine• Labetolol• Enalaprilat • Nicardipine• Esmolol • Diazoxide• Hydralazine

 

THE CHOICE OF THE ANTIHYPERTENSIVE IN PATIENTS WITH CONCOMITANT DISEASES.

 

Concomitantdisease

 

Antihypertensive drug

Diuretics ß-block. Ca-block. ACE-inhibitor

 

Diabetes

C.I

AVOID  

OK INDI CATED

 Gout

AVOID   

OK   

OK   

OK

 Dyslipidemia

C.I AVOID   

OK   

OK

 Angina pectoris

 

--   I I   

--

 Cardiac failure

I judicious OK   I

 Pregnancy

  C.I

 Cautious

  OK C.I

Pulmonary Hypertension

• Endothelin receptor antagonists – Bosentan, Sitaxentan

• Phosphodiesterase type 5 inhibitors - Sildenafil

• Prostacyclin derivatives – Epoprostenol (PGI2), Iloprost (PGI2)

Antihypertensives agents

• Diuretics often considered first choice to use in mild uncomplicated HTN.

• ACE inhibitors are the best choice in patients with hypertension and diabetes mellitus.

• Beta blockers are the best choice in hypertensive patient with history of CAD.

• Calcium channel blockers are suited for HTN with history of bronchial asthma.

• Methyldopa is often preferred for treatment of HTN in pregnancy.