IN THE NAME OF GOD

ANTI HYPERTENSIVE DRUGS

A.Soleimani MDCardiologist at Emam Khomeini

hospital, Flavarjan

Anti Hypertensive Drugs

Direct vasodilators Calcium channel blockers

DHP CCB : amlodipine NDHP CCB: diltizem, verapamil

Angiotensin converting enzyme inhibitors(ACE inh)

Angiotensin receptor blockers(ARB) Direcr renin inhibitors: aliskiren

Direct Vasodilators

Hydralazine Minoxidil Nitroprusside Nitroglycerin

HYDRALAZINE Hydralazine: in combination with a

diuretic and beta blocker. The drug acts directly to relax the smooth

muscle in precapillary resistance vessels, with little or no effect on postcapillary venous capacitance vessels.

BP falls by a reduction in peripheral resistance .Should use with combination with a diuretic to overcome the tendency for fluid retention and an adrenergic inhibitor to prevent the reflex increase in sympathetic activity and rise in the renin level, more effective and causes few side effects.

HYDRALAZINE

Dosing: twice a day. Its daily dose should be < 400

mg to prevent lupus-like syndrome the that appears in 10 to 20 percent of patients who receive more than 400 mg : almost always reversible.

The reaction happens seldom with daily doses of 200 mg or less and is more common in slow acetylators of the drug.

MINOXIDIL This drug vasodilates by opening potassium

channels in vascular smooth muscle. Its hemodynamic effects are similar to those of hydralazine, but minoxidil is more effective and may be used once daily.

It is particularly useful for patients with severe hypertension and renal failure.

Diuretics and adrenergic receptor blockers must be used with minoxidil to prevent the reflex increase in cardiac output and fluid retention.

Pericardial effusions have appeared in about 3 percent , in some without renal or cardiac failure. The drug also causes hair to grow profusely, and the facial hirsutism precludes use of the drug in most women.

NitroprussideIf diastolic pressure exceeds 140 mm Hg and

the patient has any complications, such as an aortic dissection, a constant infusion of nitroprusside is most effective.

Constant monitoring with an intraarterial line is mandatory because a slightly excessive dose may lower the pressure abruptly to levels that induce shock.

The potency and rapidity of action of nitroprusside have made it the treatment of choice for life-threatening hypertension. However, because nitroprusside acts as a venous and arteriolar dilator, venous return and cardiac output are lowered and intracranial pressures may increase.

Calcium Channel Blockers

These drugs are among the most popular classes of agents used in the treatment of hypertension.

All currently available CCBs interact with the same L-type voltage-gated plasma membrane channel but at different sites and with different consequences.

CCBs: Dihydropyridines (DHPs)

Dihydropyridines (DHPs) have the greatest peripheral vasodilatory action, with little effect on cardiac automaticity, conduction, or contractility.

Nifedipine Amlodipin Nicardipine Nitrendipine

CCBs: Non Dihydropyridines (NDHPs)

Verapamil and diltiazem, are also effective antihypertensives and may cause fewer side effects related to vasodilation, such as flushing and ankle edema.

They induce slight bradycardia and should be used carefully with a beta blocker or in patients with a conduction defect.

CCBs

CCBs are effective in all ages and races.

DHP-CCBs reduced cardiovascular events and death.

Compared with other classes of drugs, they may protect better against stroke but less well against heart failure.

CCBCCBs appear particularly effective in

prevention of stroke in older adult hypertensives, perhaps because they tend to have a greater antihypertensive effect than seen in younger patients.

They also appear to lower blood pressure in blacks better than in other racial groups but, with equal degrees of blood pressure reduction, they are no better in cardioprotection than a diuretic or ACEI

Calcium antagonists Calcium antagonists may cause an

initial natriuresis by producing renal afferent vasodilation, which may lessen the need for concurrent diuretic therapy.

Unlike all other antihypertensive agents, they may have their effectiveness reduced rather than enhanced by concomitant dietary sodium restriction, whereas most careful studies show an enhancement of their effect by concomitant diuretic therapy.

CCBdiabetes Nitrendipine, provided excellent

protection in those enrolled in the Systolic Hypertension in Europe (Syst-Eur) trial, even better than that provided by a diuretic in the SHEP trial.

Felodipine provided a 51 percent reduction in major cardiovascular events in the 1501 patients with diabetes enrolled in the HOT trial.

Among the almost 12,000 diabetics in the ALLHAT trial, amlodipine was as protective as the ACEI or diuretic.

CCB Nephropathy An ACEI or ARB should be the first

drug used. A CCB is an appropriate choice as the

third drug, with a diuretic as the second.

If needed to achieve the goal of therapy, a CCB is an appropriate addition.

On the basis of greater reduction in proteinuria seen with non–DHP-CCBs, some researchers think that a non–DHP-CCB should be used. However, the addition of a DHP-CCB does not interfere with the renoprotective effect of ACEIs or ARBs.

CCB: SIDE EFFECTS Side effects : 10 percent of patients. Most side effects, such as headaches,

flushing, and local ankle edema, are related to the vasodilation for which the drugs are given.

With slow-release and longer acting formulations, vasodilative side effects are reduced.

the antihypertensive effect of the short-acting agents, liquid nifedipine, may be so marked as to reduce blood flow and induce ischemia of vital organs.

CCBlocker

Calcium antagonists may be unique in not having their antihypertensive effi-cacy blunted by nonsteroidal antiinflammatory drugs (NSAIDs).

OVERVIEW OF CCB. CCBs reduce stroke more but heart attacks less

than other therapies while having similar effects on overall mortality. They work well and are usually well tolerated across the entire spectrum of hypertensives. They are good option for coexisting angina and cyclosporine use or NSAID use.

If chosen, an inherently long-acting, second-generation DHP such as amlodipine seems the best choice because it maintains better blood pressure control in the critical early morning hours and on throughout the next day if the patient misses a dose.

Rate-slowing CCBs, such as verapamil or diltiazem, may be preferable in certain circumstances.

RAS Inhibition

Activity of the renin-angiotensin system may be inhibited in four ways, all of which can be applied clinically.

The first, use of beta-adrenergic receptor blockers to inhibit the release of renin.

The second, direct inhibition of renin activity by a selective renin inhibitor, aliskiren, has now become available.

RAS Inhibition

The third, inhibition of the enzyme that converts the inactive decapeptide angiotensin I (A I) to the active octapeptide angiotensin II (A II), has achieved widespread use with orally effective ACEIs.

The fourth, blockade of angiotensin's actions by a competitive receptor blocker, the ARBs. ARBs may offer additional benefits, but their immediate advantage is the absence of cough that often accompanies ACEIs, as well as less angioedema

Angiotensin-Converting Enzyme Inhibitors

Because A II cannot be formed and A I is inactive, the ACEI paralyzes the classic renin-angiotensin system, thereby removing the effects of most endogenous A II as both a vasoconstrictor and stimulant of aldosterone synthesis.

with long-term use of ACEIs, the plasma A II levels actually return to previous values but the blood pressure remains lowered, which suggests that the antihypertensive effect may involve other mechanisms.

Angiotensin-Converting Enzyme Inhibitors

The same ACE enzyme that converts A I to A II also inactivates the vasodilating hormone bradykinin. By inhibiting the breakdown of bradykinin, ACEIs increase the concentration of a vasodilating hormone while decreasing the concentration of a vasoconstrictor hormone. they are also probably responsible for the most common side effects of their use, a dry hacking cough and, less frequently, angioedema.

ACE Inh

ACEIs lower blood pressure mainly by reducing peripheral resistance with little, if any, effect on heart rate, cardiac output, or body fluid volumes, probably reflecting preservation of baroreceptor reflexes. As they restore endothelium-dependent relaxation, resistance arteries become less thickened and more responsive.

ACE Inhibitor

In patients with uncomplicated primary hypertension, ACEIs as monotherapy provide antihypertensive effects equal to those of other classes, but they are somewhat less effective in blacks and older adults because of their lower renin levels.

Addition of a diuretic, even as little as 6.25 mg of hydrochlorothiazide, enhances the efficacy of an ACEI.

ACE InhibitorACEI-based therapy has provided

significant protection against cardiovascular disease and death when compared against placebo and comparable if not better protection than other classes of drugs

In the ALLHAT trial, involving predominantly elderly, high-risk hypertensives, ACEI-based therapy was equal to diuretic- or CCB-based therapies in most respects except against strokes in the black enrollees, probably because of less antihypertensive efficacy.

ACE InhibitorACEIs have proven impressively effective for

treatment of hypertensives (and nonhypertensives) with coronary disease or congestive heart failure.

They have become the drug of choice for chronic renal disease, whether diabetic or nondiabetic in origin. The high levels of renin, arising in the juxtaglomerular cells within the renal afferent arterioles, flood the glomeruli and renal efferent arterioles, providing ACEIs (and ARBs) the opportunity to dilate these vessels selectively and lower intraglomerular pressure more effectively than other classes of drugs.

ACE Inhibitor

These hemodynamic effects may lower renal perfusion and glomerular filtration. However, because acute increases of serum creatinine levels, up to 30 percent, that stabilize within the first 2 months of ACEI therapy are associated with better long-term renoprotection, such increased levels should not prompt withdrawal of the drug.

ACE InhibitorThese drugs have been a mixed blessing

for patients with renovascular hypertension. they usually control blood pressure effectively. On the other hand, the removal of the high levels of A II that follow their use may deprive the stenotic kidney of the hormonal drive to its blood flow, thereby causing a marked decline in renal perfusion; consequently, patients with solitary kidneys or bilateral disease may develop acute and sometimes persistent renal failure.

ACE InhibitorSpecific side effectse: rare rashes, loss

of taste, leukopenia. hypersensitivity reaction with

angioneurotic edema, most frequently in blacks, or a cough, most frequently in Asians.ACEI with Glitazone: angioedema( increased substanse P)

The cough is infrequently associated with pulmonary dysfunction but may not disappear until 3 weeks after the ACEI is discontinued. If a cough appears in a patient who needs an ACEI, an ARB or DKInh should be substituted.

ACE InhibitorIn women during pregnancy side effect on

the fetus. The interference with renal development with their use in the second and third trimesters. Their use during the first trimester may cause major cardiac and central nervous system malformations.

The antihypertensive efficacy of ACEIs may be blunted by large (300-mg) doses of aspirin and most NSAIDs.

Patients with renal insufficiency or those taking potassium supplements or potassium-sparing agents may not be able to excrete potassium loads and therefore may develop hyperkalemia.

ACE Inhibitor They are the drugs of choice for

three large groups of patients, those with heart failure, coronary ischemia, or nephropathy.

The evidence from the Heart Outcomes Prevention Evaluation (HOPE) trialhas led to the recommendation that an ACEI be given to all patients at high risk for coronary disease, whether hypertensive or not.

Angiotensin II Receptor Blockers

ARBs displace A II from its specific AT1 receptor, antagonizing all of its known effects and resulting in a dose-dependent fall in peripheral resistance and little change in heart rate or cardiac output.

circulating levels of A II increase but, at the same time, the blockade of the renin-angiotensin mechanism is more complete, including any A II that is generated through pathways that do not involve the ACE enzyme.

ARB The major obvious difference between

ARBs and ACEIs is the absence of an increase in kinin levels, which may be responsible for some of the beneficial effects of ACEIs and probably more of their side effects.

Direct comparisons between the two types of drugs show little difference in antihypertensive efficacy, but cough is not provoked by the ARB, although angioedema has been reported .As with ACEIs, ARBs have been found to improve endothelial dysfunction and correct the altered structure of resistance arteries in patients with hypertension

Angiotensin II Receptor Blockers The dose-response curve is fairly flat ARBs have cardiovascular and renal

protective effects equal to others. The addition of an ARB to a presumed

maximal dose of an ACEI has not been shown to increase the antihypertensive effect but increase renal dysfunction. ARB-based therapy reduces the progress of renal damage in patients with type 2 diabetes with nephropathy .

Therapy based on the ARB losartan caused LVH to regress and reduced the number of cardiovascular events more than therapy based on the beta blocker atenolol in the LIFE trial of hypertensives with LVH.

Angiotensin II Receptor Blockers Whether or not they are more

effective than ACEIs, ARBs are easier to take. In various clinical trials, side effects were generally no greater than with placebo, and the agent was better tolerated than other antihypertensive agents.

Fetal toxicity, hyperkalemia, hypotension, and renal impairment are almost certain to be noted occasionally because they are expected consequences of blockade of the renin-angiotensin mechanism

Direct Renin Inhibitor

ALISKIRENLong half life (>40h), minimally

metabolized.Blocks renin catalytic site .(Production

of AT1)Combination of aliskiren with ARB:

Increase antihypertensive effect.Contraindicated during pregnancy.

THANKS FOR YOUR ATTENTION