Drugs Acting on the Drugs Acting on the Cardiovascular SystemCardiovascular System

I. Agents Used to Treat Congestive Heart Failure (CHF)

Drugs for CCFDrugs for CCFHeart failure is the progressive inability of

the heart to supply adequate blood flow to vital organs.

It is classically accompanied by significant fluid retention.

It is a leading cause of mortality and morbidity.

Drugs for CCFDrugs for CCFThe most common symptoms of CCF

includes: ◦ shortness of breath ◦ edema◦ fatigue

Causes of heart failure includes:◦ Coronary artery disease (CAD)◦ Hypertension◦ Diabetes◦ Mitral valve disease ◦ Chronic alcohol use

OverviewOverview◦ CHF results when the output of the heart is

insufficient to supply adequate levels of oxygen for the body.

◦ Components of failure: Impaired contractility circulatory congestion

◦ Compensatory elevation in angiotensin II production results in sodium retention and vasoconstriction and increases both matrix formation and remodeling.

◦Therapeutic agents Increase cardiac contractility Reduce preload (left ventricular filling

pressure) and aortic impedance (systemic vascular resistance)

Normalize heart rate and rhythm

Drugs That Inhibit the Activity of Drugs That Inhibit the Activity of the Renin—Angiotensin Systemthe Renin—Angiotensin System

Drugs that either:

1.interfere with the biosynthesis of angiotensin II (angiotensin converting enzyme, [ACE] inhibitors) or

2.act as antagonists of angiotensin receptors (angiotensin receptor blockers, [ARBs])

◦ ACE inhibitors are indicated in all patients with LV dysfunction, whether symptomatic or asymptomatic.

◦ ACE inhibitors are becoming increasingly important in the treatment of CHF and have been shown to prevent or slow the progression of heart failure in patients with ventricular dysfunction.

Principles of the renin—angiotensin system

decapeptide

octapeptide

Several parameters regulate the release of renin from the kidney cortex. 1. Reduced arterial pressure 2. decreased sodium delivery to the cortex 3. increased sodium at the distal tubule 4. stimulation of sympathetic activity

All increase renin release.

Renin cleaves the protein angiotensinogen and releases the decapeptide angiotensin I.

Angiotensin I is converted enzymatically (mostly in the lung) to an octapeptide, angiotensin II, or the heptapeptide angiotensin III.

Both angiotensin II and angiotensin III stimulate the release of aldosterone.

Angiotensin II: ◦ is a vasoconstricting agent ◦ causes sodium retention via release of

aldosterone.

In the adrenal gland, angiotensin II is converted to angiotensin III, which is less active as a vasoconstricting agent than angiotensin II.

The actions of angiotensin II are mediated by:

◦ AT1◦ AT2 ◦ AT4 receptors located in most tissues.

The pressor actions of angiotensin II are mediated by AT1 receptors.

Angiotensin II can be produced1. ACE pathways2. locally (e.g. in the myocardium, kidney, adrenals

or in vessel walls by the action of non-ACE pathways) by the action of chymases and cathepsins

Because angiotensin II is produced via pathways other than the ACE pathway, angiotensin II receptor antagonists may be more effective and specific in reducing angiotensin II actions.

ACE inhibitorsACE inhibitors

Mechanism

ACE inhibitors inhibit the production of angiotensin II from angiotensin I.◦ These agents counteract:

elevated peripheral vascular resistance sodium and water retention

◦ resulting from angiotensin II and aldosterone.

ACE Inhibitors for CCFACE Inhibitors for CCF

◦ACE inhibitors increase cardiac output induce systemic arteriolar dilatation

(reduce afterload). ACE inhibitors cause venodilation induce natriuresis, thereby reducing

preload.

◦ These drugs are especially useful for long-term therapy.

Therapeutic uses

◦ Treatment of CHF◦ Reducing risk of recurrent post-myocardial

infarction (MI) ◦ Treating hypertension

Selected drugsSelected drugs

1. Enalapril is a prodrug that is deesterified in the liver to produce enalaprilat, which inhibits ACE.

Therapeutic uses. Enalapril is a first-line drug in the treatment of

CHF used to treat mild-to-severe hypertension. ACE inhibitors are also used to slow the

progression of renal disease, especially in diabetic patients.

Adverse effects and contraindications. ◦ Blood dyscrasias and aplastic anemia are rare but

serious◦ Renal function may be impaired.

2. Captopril

the first ACE inhibitor the only sulfur-containing ACE inhibitor is absorbed from the gastrointestinal (GI) tract adverse effects: rash, taste disturbance,

pruritus, weight loss, and anorexia.

3. Lisinopril

is an ACE inhibitor that permits once-a-day dosing.

The bioavailability of lisinopril is not affected by food.

Adverse effects common to all ACE all ACE inhibitorsinhibitors

a dry cough rarely angioedema hypotension Hyperkalemia Fetal toxicity

Angioedema: allergic disorder in which large, localized, painless swellings similar to hives appear under the skin.

ACE Inhibitors

Captopril

Enalapril (p)

Fosinopril (p)

Lisinopril

Quinapril (p)

Benazepril (p)

Moexipril (p)

Perindopril (p)

Ramipril (p)

Trandolapril (p)

Spirapril (p)

2.2. Angiotensin II receptor blockers Angiotensin II receptor blockers (ARBs)(ARBs)

Mechanism of actionMechanism of action◦ The actions of angiotensin II are

mediated by receptors that are 7-transmembrane proteins that couple to numerous signal transduction pathways.

◦ AT1 receptors are responsible for: 1. the pressor actions 2. increased aldosterone biosynthesis3. the proliferative and fibrotic actions

of angiotensin II.

◦In general, AT2 receptors antagonize the action of AT1 receptors.

◦AT4 receptors bind angiotensin IV and seem to be involved in memory and learning.

2.2. ARBs: ARBs: prototype drug: prototype drug: ValsartanValsartan

Mechanism◦ with high affinity for AT1 receptors (about

20,000-fold higher than for AT2 receptors).

◦ Oral doses are absorbed rapidly

◦ Peak levels of the drug are obtained in about 3 hours

◦ a half-life of about 6 hours.

◦ Valsartan is excreted in the feces, probably via biliary excretion.

Therapeutic uses.

◦ Left ventricular dysfunction following an MI.

◦ reducing blood pressure is available in combination with

hydrochlorothiazide for patients refractory to monotherapy. (Diovan)

Adverse effects and contraindications.

Dizziness and hyperkalemia can occur with valsartan.

Since ARBs do not lead to accumulation of kinins, the incidence of both the nonproductive cough and angioedema associated with ACE inhibitors is reduced

Other ARBs all have the same mechanism of action and adverse effect profile but have subtle pharmacokinetic differences.

They vary markedly in their relative affinity for AT1 and AT2 receptors

AT1/AT2 AffinityARBs

1,000Losartan (p)

20,000Valsartan

8,500Irbesartan

10,000Candesartan (p)

3,000Telmisartan

1,000Eprosartan

12,500Olmesartan (p)

3.3. Cardiac glycosidesCardiac glycosides

Cardiac glycosides are used for treatment of:

1. CHF 2. Arrhythmias (atrial fibrillation and

flutter and paroxysmal atrial tachycardias).

However, their use overall has diminished in the absence of data supporting a reduction in mortality.

The most common

digoxin digitoxin

the major active ingredients found in digitalis plants, which are collectively referred to as digitalis.

digitalis plants

1. Cardiac glycosides inhibit Na+/K+-ATPase, resulting in increased

• intracellular Na+ • decreased intracellular K+.

2. Increased Na+ reduces the normal exchange of intracellular Ca2+ for extracellular Na+ and yields somewhat elevated intracellular Ca2+.

Mechanism

◦ There are multiple isoforms of Na+/K+-ATPase;

◦ the cardiac isoform has the highest affinity for digitalis.

◦ Following treatment, each action potential produces a greater release of Ca2+ to activate the contractile process.

◦ The net result is a positive inotropic effect. (increase the strength of muscular

contraction)

Effects of cardiac glycosides

Cardiac glycosides have both: ◦direct effects on the heart ◦indirect effects mediated by an

increase in vagal tone.

Pharmacologic properties and selected Pharmacologic properties and selected drugsdrugsCardiac glycosides distribute to most body

tissues and accumulate in cardiac tissue.

The concentration of these drugs in the heart is twice that in skeletal muscle and at least 15 times that in plasma.

The dose of cardiac glycosides must be individualized.

Digoxin Digoxin

Digoxin has somewhat variable oral absorption; it can be given orally or intravenously.

The peak effect after an intravenous (IV) dose occurs in 1.5—2 hours

the half-life (t1/2) of digoxin is approximately 1.5 days.

The maintenance dose of digoxin is approximately 35% of the loading dose.

Digoxin produces a therapeutic effect (and its toxic effects disappear) more rapidly than digitoxin.

However, because of a relatively rapid clearance, lack of compliance may diminish the therapeutic effects.

Digoxin is eliminated by the renal route the t1/2 is prolonged in individuals with

impaired renal function.

Digoxin dosage can be adjusted on the basis of creatinine clearance.

Digitoxin Digitoxin Digitoxin is completely absorbed from the

gastrointestinal tract

its t1/2 is approximately 5—6 days.

Digitoxin is metabolized in the liver and excreted via the biliary route.

Impaired renal function does not alter the half-life of digitoxin.

Digitoxin should be administered cautiously in the presence of hepatic dysfunction.

Adverse effects and toxicityAdverse effects and toxicityNarrow therapeutic index

◦ Cardiac glycosides can cause fatal adverse effects.

◦ These drugs induce virtually every type of arrhythmia.

The most common site of action outside the heart is the GI tract (anorexia, nausea, vomiting, and diarrhea can occur) resulting either from direct action or through stimulation of the chemoreceptor trigger zone (CTZ).

Use of these drugs may result in disorientation and visual disturbances.

Toxicity is treated primarily by:

1. discontinuing the drug.2. Potassium may help in alleviating

arrhythmias.3. Antidigoxin antibodies (digoxin immune

Fab) or hemoperfusion are useful in acute toxicity.

4. Antiarrhythmic agents such as phenytoin and lidocaine may be helpful in treating acute digoxin-induced arrhythmias

Drug interactions

◦Drugs that bind digitalis compounds, such as cholestyramine and neomycin, may interfere with therapy.

◦Drugs that enhance hepatic metabolizing enzymes, such as phenobarbital, may lower concentrations of the active drug (especially digitoxin).

Other inotropic agentsOther inotropic agents

A.A. Phosphodiesterase inhibitorsPhosphodiesterase inhibitors Amrinone lactate Milrinone

◦ Bipyridine derivatives.

◦ Effects : Reduce left ventricular filling pressure Reduce vascular resistance Enhance cardiac output.

◦ MOA: they inhibit phosphodiesterases (PDE3) in cardiac and vascular muscle thereby increasing cAMP; this leads to elevated intracellular Ca2+ levels and excitation contraction.

◦ These drugs are used in: patients who do not respond to digitalis individuals with elevated left ventricular

filling pressure.

ToxicityToxicity::

◦ Should be given iv for short-term

◦ Adverse effects:

◦ The most common are: transient thrombocytopenia hypotension.

◦ Fever and GI disturbances occur occasionally.

◦ Fewer and less severe adverse effects are seen with milrinone than with amrinone

B.B. --Adrenergic agonistsAdrenergic agonists

Dobutamine hydrochloride

is a synthetic catecholamine derivative that

increases contractility; it acts primarily on myocardial 1-adrenoceptors with lesser effects on 2- and -adrenoceptors.

Dobutamine is the most commonly used inotropic agent other than digitalis

This drug is administered only by the IV route in hospitals to treat acute CHF.

Dobutamine hydrochloride is used in short-term therapy in individuals with severe chronic cardiac failure and for inotropic support after an MI and cardiac surgery.

C. Nesiritide

Nesiritide is a B-type natriuretic peptide approved for short-term use for acute decompensated heart failure.

Nesiritide: ◦ increases cGMP and thereby produces vasodilation. ◦ increases stroke volume.

Nesiritide is a peptide that must be given parenterally.

Adverse effects include headache, nausea, and hypotension.

D. Diuretics

1. reduce left ventricular filling pressure 2. decrease left ventricular volume 3. decrease myocardial wall tension (lower

oxygen demand).

Diuretics are frequently combined with an ACE inhibitor in mild

CHF they also are used for acute pulmonary

edema.

Aldosterone antagonists Spironolactone Eplerenone Canrenone Mexrenone

Antagonize the action of aldosterone at mineralocorticoid receptors.

In congestive heart failure, they are used in addition to other drugs for additive diuretic effect, which reduces edema and the cardiac workload.

E.Vasodilators

Effects:◦ Vasodilators reduce arterial resistance or ◦ increase venous capacitance

◦ the net effect is a reduction in vascular pressure.

Therapeutic use

◦ Vasodilators are used to treat severe, decompensated CHF refractory to diuretics and digitalis.

A.Agents used in short-term therapy include:

◦ Nitroprusside, which has a direct balanced effect on arterial and venous beds

◦ Nitroglycerin, which has more effect on venous beds than on arterial beds.

B. Agents used in long-term therapy include 1. Direct-acting vasodilators

isosorbide hydralazine

2. 1-adrenergic blocking agent (prazosin) produces arterial and minor venous dilation.

3. a combined - and nonselective -adrenoreceptor antagonist: Carvedilol