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Antihypertensive agents. Hypertension :. 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.

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Antihypertensive agents
Antihypertensive agents

  • Hypertension :


Antihypertensive agents rationale
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




Antihypertensive agents1
Antihypertensive agents

Classification 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 agents2
Antihypertensive agents

Diuretics :

  • Thiazides or thiazides like: Chlorothiazides, Indapamide, Metolazone

  • 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
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 improvethe hypotensive effects of many antihypertensive agents like ACE inhibitors and ARBs.

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

  • 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.

  • Induction of renal prostaglandin biosynthesis


Antihypertensive agents3
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 agents5
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

  • 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.



Antihypertensive agents6
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



Antihypertensive agents7
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 agents8
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 agents9
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 agents10
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 agents11
Antihypertensive agents

REDUCING 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 agents12
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.



Adverse effects of calcium channel blockers
Adverse effects of calcium channel blockers

  • 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



Antihypertensive agents13
Antihypertensive agents blockers

Sodium 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 agents14
Antihypertensive agents blockers

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 agents15
Antihypertensive agents blockers

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 agents16
Antihypertensive agents blockers

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 agents17
Antihypertensive agents blockers

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 agents18
Antihypertensive agents blockers

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.



Antihypertensive agents

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


Antihypertensive agents19
Antihypertensive agents 2. Beta blockers along with vasodilators

  • 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 agents20
Antihypertensive agents 2. Beta blockers along with vasodilators

  • 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 agents21
Antihypertensive agents 2. Beta blockers along with vasodilators

Hypertensive emergencies :

  • Sodium Nitroprusside

  • Nitroglycerine

  • Labetolol

  • Enalaprilat

  • Nicardipine

  • Esmolol

  • Diazoxide

  • Hydralazine


Antihypertensive agents

THE CHOICE OF THE ANTIHYPERTENSIVE IN PATIENTS WITH CONCOMITANT DISEASES.

Pregnancy

C.I

Cautious

OK

C.I

Concomitant

disease

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


Pulmonary hypertension
Pulmonary Hypertension CONCOMITANT DISEASES

  • Endothelin receptor antagonists – Bosentan, Sitaxentan

  • Phosphodiesterase type 5 inhibitors - Sildenafil

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


Antihypertensives agents
Antihypertensives agents CONCOMITANT DISEASES

  • 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.