Antihypertensive Antihypertensive DrugsDrugs

Dr. Yahya Ibn Ilias

What is hypertention?

WHO standard:WHO standard:

Hypertension:Hypertension: People whose blood pressure is People whose blood pressure is elevated to More than 140/90mmHg require elevated to More than 140/90mmHg require antihypertensive agents.antihypertensive agents.

The diagnosis of The diagnosis of hypertensionhypertension is based on repeated, rep is based on repeated, reproducible measurements of elevated blood pressure.roducible measurements of elevated blood pressure.

U Hv Got HTN !!

Normal Systolic Blood Pressure 90—140 mmHg

Normal Diastolic Blood Pressure 60—90 mmHg

Etiology of hypertension

Classification of hypertension: Classification of hypertension:

Essential hypertensionEssential hypertension and and secondary secondary hypertensionhypertension

Essential hypertension:Essential hypertension: Patients with arterial Patients with arterial hypertension and no definable cause are said to have Primary, or hypertension and no definable cause are said to have Primary, or Essential hypertension.Essential hypertension.

Secondary hypertension:Secondary hypertension: A specific cause of A specific cause of hypertension hypertension

can be established in only 10-15% of patients.can be established in only 10-15% of patients. it is important to consider specific causes in each case, it is important to consider specific causes in each case, some of them are amenable to definitive some of them are amenable to definitive surgical treatmentsurgical treatment:: Renal artery constrictionRenal artery constriction, , Coarctation of the aortaCoarctation of the aorta, , PheochromocytomaPheochromocytoma 。。

The category of hypertension when the cause is unknown.

There are probably several different genetic causes. Includes approximately 90% of cases.

Also referred to as Idiopathic hypertension. Approximately 20% of all adults in US are affected.

Even though the underlying cause usually is not known,hypertension can usually be very effectively treated.

Normal Regulation of Blood Pressure :-

Arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR):

BP = CO X PVR

In both normal and hypertensive individuals, blood pressure is maintained by:

Cardiac output and peripheral vascular resistance, exerted at three anatomic sites:

Arterioles, postcapillary venules (capacitance vessels), and heart.

A fourth site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid.

Baroreflexes, mediated by autonomic nerves

Act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure.

Finally, local release of hormones from vascular endothelium may also be involved in the regulation of vascular resistance. For example, nitric oxide : dilates and endothelin-1 constricts blood vessels.

Therapeutic goals in hypertension To lower the high blood pressure and

reduced cardiovascular morbidity and mortality by least intrusive means.

For most of the patients: life-long treatment of an asymptomatic disease.

Antihypertensive AgentsAntihypertensive Agents

Antihypertensive AgentsAntihypertensive Agents

6. Sympatholytic Drugs

Centrally acting agents(Alpha-2 Agonists)

Ganglionic Inhibitors (Mecamylamine)

Adrenergic Neural Terminal Inhibitors (reserpine)

Adrenergic receptor blockers - Alpha- Blockers - Beta –Blockers - Alpha and Beta –Blockers

1. Diuretics

2. Calcium Channel Blockers

3. Angiotensin Converting Enzyme Inhibitors

4. Angiotensin Receptor Antagonists

5. Peripheral Vasodilators

Classification :

Diuretics: thiazide and loop diuretics

B-blockers: atenolol, labetalol, metoprolol, propanolol

ACE Inhibitors: captopril,enalapril,lisinopril

Angiotensin receptor blockers: losartan

Ca-channel blockers: amlodipine, nifedipine, diltiazem, verapamil

Alpha blockers: prazosin, doxazocin, terazocin

Centrally acting Alfa agonist: clonidine, methyldopa

Direct Vasodilators: hydralizine, nitroprusside, minoxidil, diazoxide.

Renin angiotensin aldosterone sRenin angiotensin aldosterone system, RAASystem, RAAS

AgⅠ AgⅡACE BP↑

Aldosterone ↑

Angiotensinogen

ReninDecomposition

BP↓

BradykininBradykinin

A n g i o t e n s i n II

Peripheral resistance Renal function Cardiovascular structure

RapidPressor Response

1. Direct vasoconstriction

2. Enhancement of peripheral noradrenergic neurotransmission 3. Increased central (CNS) sympathetic discharge

4. Release of catecholamines from adrenal medulla

1. Releases aldosterone from adrenal cortex

2. Increases Na+ reabsorption

3. Altered renal hemodynamics: - renal vasoconstriction - increased noradrenergic neurotransmission in kidney - Increased renal sympathetic tone (CNS)

SlowPressor Response

Cardiovascular Hypertrophy and Remodeling

1. Non-hemodynamic effects: - Increased expression of proto-oncogenes - Increased production of growth factors - Increased synthesis of extracellular matrix proteins

2. Hemodynamic effects: - Increased afterload (cardiac) - Increased wall tension (vascular)

Inhibitors of Angiotensin

Mechanism & Sites of Action :

Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and reduced sodium delivery.

Renin acts upon angiotensinogen to split off the inactive precursor decapeptide angiotensin I.

Angiotensin I is then converted, primarily by

Endothelial ACE, to the arterial vasoconstrictor octapeptide angiotensin II ,which is in turn converted in the adrenal gland to angiotensin III.

Juxtaglomerular apparatus

Angiotensin II has vasoconstrictor and sodium-retaining activity.

Angiotensin II and III both stimulate aldosterone release.

Two classes of drugs act specifically on the renin-angiotensin system: the ACE inhibitors and the competitive inhibitors of angiotensin at its receptors

ACE Inhibitors Antihypertensive

Mechanisms

Angiotensin-Converting Enzyme (ACE) Inhibitors

1. Captopril ** 2. Enalapril 3. Fosinopril 4. Lisinopril **5. Ramipril

Benazepril, fosinopril, moexipril, perindopril, quinapril, and trandolapril

Captopril

Inhibit the converting enzyme angiotensin I to angiotensin II .

Inhibit the inactivation of Bradykinin, a potent vasodilator, which works at least in part by stimulating release of nitric oxide and prostacyclin.

Hypotensive activity of Captopril results both from an inhibitory action on the renin-angiotensin system and a stimulating action on the kallikrein-kinin system

Enalapril

Is a prodrug that is converted by deesterification to a converting enzyme inhibitor, Enalaprilat, with effects similar to captopril.

Available only for intravenous use,

Use : primarily for hypertensive emergencies.

Lisinopril is a lysine derivative of enalaprilat.

Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class.

All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver.

Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance.

Cardiac output and heart rate are not significantly changed.

Useful role in treating patients with diabetic nephropathy because they diminish proteinuria and stabilize renal function.

Indication of ACE Inhibitors:

Hypertension

Congestive heart failure (CHF)

Left ventricular dysfunction

Prevention of nephropathy in diabetes mellitus

Following myocardial infarction.

In the treatment of essential hypertension, captopril is considered first choice therapy, either alone or in combination with a thiazide diuretic.

If the patient is asymptomatic, captopril can be used as monotherapy in the treatment of congestive heart failure.

In symptomatic patients captopril should be used in conjunction with a diuretic because of the weak natriuretic properties of ACE inhibitors.

In the treatment of diabetic nephropathy associated with type I insulin-dependent diabetes mellitus, captopril decreases the rate of progression of renal insufficiency and retards the worsening of renal function.

Adverse effect :

Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic due to diuretics, salt restriction, or gastrointestinal fluid loss.

Acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney),

hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema.

Hyperkalemia is more likely to occur in patients with renal insufficiency.

Contraindication

During the second and third trimesters of pregnancy because of the risk of fetal hypotension, sometimes associated with fetal malformations or death.

All converting enzyme inhibitors are

contraindicated in patients with bilateral renal artery disease or with unilateral renal artery disease and one kidney.

Angiotensin Receptor Blockers

(ARBs)

Angiotensin II is a very potent chemical that causes the muscles surrounding the blood vessels to contract, which thereby narrows the blood vessels.

This narrowing increases the pressure within the vessels and can cause high blood pressure (hypertension).

ANGIOTENSIN RECEPTOR

Distinct subtypes of AngII receptors are designated as AT1 and AT2.

The AT1 receptor subtype is located predominantly in vascular and myocardial tissue and also in brain, kidney, and adrenal glomerulosa cells, which secrete aldosterone.

•Vasoconstriction •Vascular proliferation •Aldosterone secretion •Cardiac myocyte proliferatio

n •Increased sympathetic tone

•Vasodilation •Antiproliferation •Apoptosis

AT1AT2

Angiotensin II

Different Roles of ATDifferent Roles of AT11 and ATand AT22 Receptors Receptors

Ang II Receptor Blockers (...sartans)

Sartans are selective and competitive antagonists of angiotensin II type 1 (AT1) receptors and do not inhibit AT2 receptors.

The physiological function of angiotensin II is mediated by AT1 receptors (vasoconstriction, catecholamine release, aldosterone synthesis, and renal sodium and water retention)

Angiotensin Receptor-Blocking Agents

Losartan and valsartan were the first blockers of the angiotensin II type 1 (AT1) receptor.

More recently, candesartan, eprosartan, irbesartan, and telmisartan.

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

Angiotensin receptor blockers (ARBs) are medications that block the action of angiotensin II.

As a result, the blood vessels dilate and the blo

od pressure is reduced.

The lower blood pressure makes it easier for the heart to pump blood and can improve heart failure.

Angiotensin I

Angiotensinogen (Liver)

AT1 AT2

Angiotensin II

ACE inhibitor

Valsartan AT1 receptor blocker

Renin inhibitor

Bradykinin

Peptides

Inhibitors of renin-angiotensin-alInhibitors of renin-angiotensin-aldosterone System(RAS) dosterone System(RAS)

Aldosterone

IndicationsIndications::

HypertensionHypertension

Heart FailureHeart Failure

Adverse effects

Similar to those described for ACE inhibitors, including the hazard of use during pregnancy.

Cough and angioedema can occur but are less common with angiotensin receptor blockers than with ACE inhibitors.

Calcium channel blockers

The largest chemical class of calcium-channel blockers is the dihydropyridines:

Amlodipine, Felodipine, Isradipine, and Nifedipine.

Non-dihydropyridine calcium-channel blockers:

Diltiazem Verapamil

Calcium channel blockers are a class of drugs that block the entry of calcium into the muscle cells of the heart and the arteries.

It is the entry of calcium into these cells that causes the heart to contract and arteries to narrow.

By blocking the entry of calcium, CCBs decrease contraction of the heart and dilate (widen) the arteries.

Uses:

High blood pressure

Chest pain (angina)

Migraines

Irregular heartbeats (arrhythmia)

Side effects

Constipation,

Headache,

Rapid heartbeat,

Drowsiness, and

Swelling in the feet and lower legs.

Direct Acting Vasodilators

Hydralazine and nitroprusside act through NO.

Minoxidil and Diazoxide act by opening K+ channel.

Arteriolar- hydralazine, minoxidil, diazoxide.

Arteriolar + venous- sodium nitroprusside.

Hydralazine stimulates the formation of nitric oxide by the vascular endothelium, leading to vasodilation.

The arterial vasodilator action of hydralazine reduces systemic vascular resistance and arterial pressure.

Sodium Nitroprusside Sodium nitroprusside is used for the short-term control of severe hypertension

and can improve cardiac function in patients with left ventricular failure.

Nitroprusside acts by releasing nitric oxide (NO).

Nitroprusside activate soluble guanylate cyclase in vascular smooth muscle, which brings about an increase in the intracellular levels of cyclic guanosine monophosphate (cGMP).

Increases in cGMP are associated with vascular smooth muscle relaxation.

The action of the nitrovasodilators appears to be quite similar to that of the endogenous vasodilator released by a variety of stimuli from endothelial cells of blood vessels.

This substance, originally named endothelial-derived relaxing factor, or EDRF, is nitric oxide.

Pharmacological Actions

In contrast to hydralazine, minoxidil, and diazoxide, sodium nitroprusside relaxes venules as well as arterioles.

Thus, it decreases both peripheral vascular resistance and venous return to the heart.

This action limits the increase in cardiac output that normally follows vasodilator therapy.

Sodium nitroprusside does not inhibit sympathetic reflexes, so heart rate may increase following its administration even though cardiac output is not increased.

Renal blood flow remains largely unaffected by sodium nitroprusside, because the decrease in renal vascular resistance is proportional to the decrease in mean arterial pressure.

As with all vasodilators, plasma renin activity increases.

K+ ATPChannel Openers: Minoxidil

Minoxidil is efficacious in patients with the most severe and drug-resistant forms of hypertension.

Minoxidil sulfate activates the ATP-modulated K+channel in smooth muscle, causing hyperpolarization and relaxation of arteriolar smooth muscle. Minoxidil produces arteriolar vasodilation with essentially no effect on capacitance vessels.

Potassium-Channel Openers

Minoxidil and Diazoxide

Potassium-channel openers are drugs that activate (open) K+-channels in vascular smooth muscle, thus hyperpolarizes the smooth muscle, which closes voltage-gated calcium channels and decreases intracellular calcium.

This leads to relaxation and vasodilation, decreasing systemic vascular resistance, and lowering arterial pressure.

The fall in arterial pressure leads to reflex cardiac stimulation (baroreceptor-mediated tachycardia).

Uses: Hypertensive emergencies(diazoxide) Severe hypertension(minoxidil) Baldness (topical minoxidil)A/E: Headaches, flushing and reflex tachycardia.

most noted side effects of minoxidil is hypertrichosis (hair growth on the body)-hirsutism: topical minoxidil

Hyperglycemia(decrease insulin release by diazoxide)

Centrally-acting drugs

Centrally-acting drugs

Clonidine Alfa-methyldopa

These drugs act on the central nervous system, decreasing the activity of the sympathetic nervous system.

The end result is that blood vessels relax and blood pressure decreases; also decreases heart rate.

Alfa-methyldopa dopa

Mechanism of Action: Systemically administered α-methyldopa rapidly enters th

e brain, where it accumulates in noradrenergic nerves, is converted to α-methylnorepinephrine, and is released.

Released α -methylnorepinephrine activates CNS α-adrenoceptors whose function is to decrease sympathetic outflow.

Why α -methylnorepinephrine decreases sympathetic outflow more effectively than does the naturally occurring transmitter is not entirely clear.

Uses:

Mild to moderate HTN.

Opiate withdrawal (clonidine)

Hypertensive management in pregnancy (methyldopa)

A/E

In addition to lowering blood pressure, the active metabolite of methyldopa acts on a2 adrenergic receptors in the brainstem to inhibit the centers that are responsible for wakefulness and alertness, producing sedation that is largely transient.

Decreased mental acuity and depression occurs occasionally.

Medullary centers that control salivation are inhibited by a adrenergic receptors, and methyldopa may produce dry mouth.

Other side effects related to pharmacological effects in the CNS include decreased libido, parkinsonian signs, and hyperprolactinemia that may become sufficiently pronounced to cause galactorrhea.

SYMPATHOLYTIC AGENTS

SYMPATHOLYTIC AGENTS reduce blood pressure by depressing the activity of the sympathetic nervous system.

This is accomplished in four ways:

(1) by reducing the number of impulses traveling in the sympathetic nerves,

(2) by inhibiting neurotransmitter release,

(3) by depleting the stores of norepinephrine, and

(4) by antagonizing the actions of norepinephrine on effector cells.

ADRENOCEPTOR ANTAGONISTS

Drugs of this group are subdivided into

a-adrenoceptor antagonists (a-blockers) and

β-adrenoceptor antagonists(β-blockers).

Alpha 1 selective

Prazosin : highly selective alpha 1 blockers

Fall in BP (venodilatation is much less than arteriolar dilatation). Because of lack alpha 2 antagonism, tachycardia is only mild.

Effective orally (bioavailability 60%), highly bound to plasma protein, metabolized in liver and excreted in bile, plasma half life 2-3 hours, effect of a single dose lasts for 6-8 hours.

Uses : antihypertensive, BPH (improve urine flow)

Dose : 0.5, 1, 2 mg tab, start with 0.5 – 1 mg at bed time

Prazosin that are relatively selective for α1-receptors.

α1-receptors selective antagonists will not potentiate the release of norepinephrine from sympathetic nerves.

The α1-receptors– selective antagonists can be used alone in mild hypertension.

When hypertension is moderate or severe, prazosin is generally administered in combination with a thiazide and a beta blocker.

Prazosin can cause “first dose effect” ie, postural hypotension is less marked, dizziness and fainting can develop after 1st dose, but if the drug is persistent, tolerance develops. Therefore, the rule is,

1. Very low dose at first

2. Administered at night

3. The patient should be warned of the first dose effect.

Clinical use

Prazosin may be particularly useful when patients cannot tolerate other types of antihypertensive agents or when blood pressure is not well controlled by other drugs.

Since prazosin does not significantly influence blood uric acid or glucose levels, it can be used in hypertensive patients whose condition is complicated by gout or diabetes mellitus.

Prazosin treatment is associated with favorable effects on plasma lipids.

Thus,it may be of particular importance in managing patients with hyperlipidemia.

Terazosin

Chemically and pharmacologically similar to prazosin; differences are higher biovailability (90%) and longer plasma half life (12 hrs), a single dose lowers BP over 24 hrs.

Uses : BPH (popular for use), antihypertensive Dose : 1, 2 and 5 mg (2-10 mg od)

Doxazosin : longer acting (t1/2 18 hrs), used in HTN and BPH, dose : 1, 2 , 4 mg (1 mg od)

To be continue……