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ACEIs are cleared mainly by kidney except fosinopril (balanced bile and urine elimination), dose should be reduced in renal impairment. Pharmacodynamics: Mode of action: ACEIs act by competitive inhibition of ACE (=kininase II) resulting in: 1. Inhibit conversion of inactive Angioten...

ACEIs are cleared mainly by kidney except fosinopril (balanced bile and urine elimination), dose should be reduced in renal impairment. Pharmacodynamics: Mode of action: ACEIs act by competitive inhibition of ACE (=kininase II) resulting in: 1. Inhibit conversion of inactive Angiotensin I to active Angiotensin II➔ ↓synthesis of Angiotensin II leads to loss of vasoconstrictor effect of Angiotensin II, decrease aldosterone release, decrease noradrenaline release, Increase renin (compensatory feedback mechanism). Also, Angiotensin I is directed to synthesis of Ang. (1-7) by ACE2 (=carboxypeptidase) ➔VD, decrease hypertrophy& remodeling and antithrombotic effect. 2. Inhibit degradation of bradykinin➔increase bradykinin ➔Vasodilation 3. Inhibit degradation of substance P and stem cell regulator peptide → in part, responsible for their cardioprotective effect in CHF Pharmacological effects: o ↓ Blood pressure via ↓ peripheral resistance (mixed vasodilator) o ↓Salt and water retention due to ↑ Na+ excretion and ↓ aldosterone release. o ↓Cardiovascular remodeling and hypertrophy so ↓ mortality. o Cardiac output and heart rate are NOT affected. o NO reflex sympathetic activation (safe in ischemic heart diseases) o Reduce intraglomerular capillary pressure due to reduction of efferent VC so may diminish proteinuria. Therapeutic uses: 170 1. Hypertension: alone or in combination with either Ca++ channel blockers, β-blockers or diuretics. 2. Left ventricular systolic dysfunction: prevents and delays progression to heart failure, reduces ventricular dilation and reverse remodeling by decreasing fibrosis induced by Ag II and aldosterone in addition to ↓ preload and afterload. 3. Acute myocardial infarction: especially in hypertensive and diabetic patients. 4. Patients at high risk of cardiovascular events: ↓ myocardial infarction and stroke rates. 5. Diabetic nephropathy: via reduction of increased intraglomerular pressure and mesangial cell growth. 6. Scleroderma crisis: The marked rise in BP and deterioration of renal function in scleroderma crisis is mediated by Ang. II (life-saving). Adverse effects: 1. First-dose hypotension especially in hypovolemic patients due to multiple antihypertensives, diuretics, or patients having congestive heart failure. 2. Dry cough due to bradykinin accumulation (may be reduced by aspirin, iron, dose reduction or switching to ARBs). 3. Hyperkalemia: especially in renal impairment, diabetes 4. Acute renal failure: in bilateral renal artery stenosis, or stenosis in solitary kidney, volume depletion or heart failure. 5. Angioedema: rapid swelling of throat, mouths, lips and tongue, may disappear within hours of drugs stoppage 171  6. Use during first trimester causes teratogenicity and during second or third trimester cause risk of fetal hypotension, renal failure and death. 7. Captopril may cause proteinuria and neutropenia (high doses in renal patients). 8. Skin rash, dysgeusia, glycosuria. Drug interactions: Antacids ➔↓ bioavailability NSAIDs impair hypotensive effects of ACEIs (blocking bradykinin). Patients taking K supplements, β- blockers, K+ sparing diuretics or NSAIDs ➔ hyperkalemia. b) Angiotensin receptor blockers (ARBs) Include: losartan, valsartan, telmisartan, etc., Pharmacokinetics: Oral bioavailability is ranging from 90% Pharmacodynamics: Mode of action: Competitive antagonist selective for AT1 receptors ➔block all effects of Ang.II leading to :1. Vasodilation. 2. Block central & peripheral sympathetic stimulation. 3. Decrease release of aldosterone &release of adrenaline from adrenals. 4. Decrease salt &water retention and ↑K + level (hyperkalemia). 5. Inhibit hypertrophy &remodeling on heart & blood vessels. Can block thromboxane A2 receptor ➔ anti-platelet aggregation. Ang II activates the unblocked AT2 receptors ➔VD, inhibit hypertrophy &remodeling. 172  ↓ BP lasts for 24 hours, while HR remains unchanged. Losartan has a mild probenecid like uricosuric action. Differences from ACEIs: ACEIs ARBs Mechanism of action Decreases formation Block angiotensin AT2 of angiotensin II receptors Adverse effects Angioedema More Less Dry cough Present Absent GIT manifestation More Less Pancreatitis More Less Therapeutic uses: the same as ACEIs, losartan is approved for stroke prophylaxis due to antagonism of thromboxane A2 and ↓ platelet aggregation. Adverse effects: the same as ACEIs but with less incidence of cough and angioedema N.B: Sacubitril/Valsartan (neprilysin inhibitor): Sacubitril's active metabolite inhibits neprilysin, a neutral endopeptidase that cleaves natriuretic peptides [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP)]. ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down vasodilating peptides and vasoconstrictors such as angiotensin I and II. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased levels of vasoconstricting hormones such as angiotensin II. (So, when combined with 173  valsartan, result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) The most common adverse reactions include hypotension, hyperkalemia, cough, dizziness, and renal failure. Diuretics Especially loop diuretics (e.g. frusemide) as they counteract salt and water retention, edema, symptoms and ↓ preload. Thiazide (e.g. hydrochlorothiazide) has limited role in heart failure. may be combined with loop diuretics in patients who are refractory to loop alone. Minimal dose is required to maintain euvolemia in hypervolemic symptomatic patients. Avoid in asymptomatic left ventricular dysfunction as excessive diuresis may result in reduction of cardiac output Aldosterone antagonists (e.g. spironolactone): reduce mortality in severe heart failure as aldosterone may cause myocardial and vascular fibrosis. β-blockers Metoprolol, carvedilol and bisoprolol start with low dose and go slow (titrate) in compensated heart failure patients to counteract the harmful activation of sympathetic stimulation which causes remodeling of myocardium. Vasodilators Hydralazine (arterial VD ➔↓ afterload) - isosorbide dinitrate (venodilator➔↓ preload) combination is useful in chronic heart failure. 174  Hydralazine can be used in congestive heart failure with renal impairment not tolerant to ACEIs. IV nitroglycerine: acute congestive heart failure following acute myocardial ischemia. Na nitroprusside is used in acute congestive heart failure who have systemic emergency hypertension. Positive inotropic drugs: Cardiac glycosides: Digoxin Phosphodiesterase inhibitors (PDEI): milrinone Dobutamine Digoxin Chemistry: plant source steroid nucleus linked to a lactone ring and sugar Pharmacokinetics: Absorption: oral with 65%-80% oral bioavailability, or IV administration. Distribution: widely distributed Vd= 4-7L/kg, principal tissue reservoir is skeletal muscle Elimination: excreted unchanged by kidney, half-life is 36-40h in normal renal function (dose must be reduced in renal dysfunction and elderly) Steady state achieved 7 days after initiation of maintenance dose. Narrow therapeutic range: 0.8-2.0ng/ml Pharmacodynamics: Mechanism of positive inotropic effect: Digoxin binds and inhibit partially Na+/K+ ATPase in cardiac myocyte so ↑ cytosolic Na+➔ less Ca++ is removed from the cell and more Ca++ accumulates in the sarcoplasmic reticulum due to reduction of Na+ transmembrane gradient that is responsible for Na+/Ca++ exchange. 175 NB: K+ and Mg++reduce effect of digoxin on Na+/K+ ATPase, while Ca++ enhances its effect. Mechanism of positive inotropic action of digoxin Electrical effects: At low therapeutic doses: ❖ Cardio-selective vagal effect oDue to central vagal stimulation, sensitization of baroreceptors, facilitation of muscarinic transmission in cardiac cells oVagal effect is more prominent in atria and AV nodal tissue more than Purkinje and ventricles ➔ sinus bradycardia, decrease conduction through AV node and heart block, shorten APD of atrium. At high concentration: ❖ ↓ resting membrane potential due to inhibition of Na+ pump ❖ Overloading with intracellular calcium ➔delayed after-depolarization ➔elicit ectopic beats. ❖ Delayed after-depolarization ➔ self-sustained tachycardia➔ ventricular fibrillation, rapidly fatal if not corrected. ❖ Sympathetic outflow increases ➔ ↑ automaticity and exaggerate atrial and ventricular arrhythmia. 176  Other effects: o GIT: anorexia, nausea, vomiting and diarrhea occur directly and CNS effect due to stimulation of chemoreceptor trigger zone (CTZ) o CNS: stimulation of CTZ, vagal center, disorientation and hallucination in elderly o Visual disturbances, Gynecomastia due to steroid nucleus Therapeutic uses: 1. Heart failure a. Congestive heart failure in atrial fibrillation b. Patients with normal sinus rhythm who remain symptomatic despite maximal therapy with ACEIs and β-blockers. NB.: - It alleviates all signs and symptoms but does not reduce mortality. - Not effective in heart failure due to exhaustion of energy stores of myocardial fibers as: high output failure (e.g. Anemia, thyrotoxicosis), in ischemia, infection (acute rheumatic- diphtheritic) 2. Atrial arrhythmia as atrial flutter and fibrillation and paroxysmal atrial and AV nodal tachycardia owing to control of high ventricular rate through reduced conduction in AVN. NB: Contraindicated in Wolf-Parkinson-White syndrome. Adverse effects: GIT disturbances, and visual disturbances require dose reduction. Arrhythmia: bradycardia, heart block, ventricular arrhythmia. Digitalis-induced arrhythmia may become worse by cardioversion. Antidote for digoxin toxicity: Specific antidote: antidigoxin Fab fragment (Digibind, Digifab) purified antibodies bind to digoxin and enhance its renal excretion used in digoxin induced serious arrythmia. Drug interactions: 177  ↑ digoxin effects o Amiodarone, verapamil, quinidine, diltiazem, and flecainide decreases digoxin clearance by inhibiting P-glycoprotein. o Antibiotics may destruct bacteria responsible for metabolism of digoxin and enhance toxicity. o Drugs causing hypokalemia: e.g. loop diuretics. o IV Ca++ and sympathomimetics as they enhance arrhythmia. o β-blockers and verapamil as they cause heart block ↓ digoxin effects o ↓ absorption by antacids, neomycin, cholestyramine, kaolin & pectin o Hyperkalemia Phosphodiesterase inhibitors (ino-dilator) (Milrinone) Mode of action: selectively inhibits PDE-3 ➔ ↑ cAMP ➔ +ve inotropic effect in addition to arterial and venous dilation. Uses: IV for acute heart failure or severe exacerbation of chronic heart failure Adverse effect: favorable profile, less likely to cause bone marrow or liver toxicity as its withdrawn older congener (Amrinone) Dobutamine Used IV if rapid response is needed; as in acute decompensated heart failure to ↑ contractility and cardiac output. Agonist of β1 receptor ➔ ↑ contractility with minimal effect on heart rate Tolerance limit infusion efficacy after 4 days Recent β blocker therapy is a common cause of unresponsiveness to dobutamine. 178