Clinical Pharmacology for Second Years

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Heart Failure
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Compensatory physiological responses in CHF

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Decompensated heart failure

If these mechanisms adequately restore cardiac output,

the heart failure is said to be compensated.

However, these compensations increase the work of

the heart and contribute to further decline in cardiac performance.

If the adaptive mechanisms fail to maintain cardiac

output, the heart 5/24/12 failure is termed decompensated.

Drugs commonly used in management of HF

1. Angiotensin-Converting Enzyme (ACE) Inhibitors: Captopril 2. Angiotensin II receptor blockers: Losartan, candesartan, irbesartan 3. Diuretics: Thiazides (eg, hydrochlorothiazide) and furosemide 4. Inotropic-cardiotonic drugs: Digoxin, Inamrinone and Nesiritide 5. Aldosterone Antagonist: Spironolactone 6. Vasodialators: Nitrates, hzdralayine and isosorbide dinitrate 7. Beta adrenergic blocking agents: Propranolol, atenolol, metoprolol 8. Adrenergics : Dopamine or dobutamine
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Angiotensin- Converting Enzyme (ACE) Inhibitors

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Angiotensin Converting Enzyme Inhibitors (ACE-I)

Introduction

Treatment of hypertension and heart failure Captopril and enalapril the fore-runners, followed by several others such as perindopril, lisinopril, cilazapril, quinapril, fosinopril, ramipril, trandolapril and zofenopril

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Mechanism of action of ACE -I

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Mechanism of action of ACE -I

ACE inhibitors inhibit the conversion of Angiotensin I to Angiotensin II, which results in vasodilation and less sodium and water retention via the kidneys.

Angiotensin converting enzyme inhibitors work best when the renin-angiotensin system is activated

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Angiotensin Converting Enzyme Inhibitors (ACE-I)

Individual Members
1.

Captopril

- Was the first ACE-inhibitor to become available - Characterized by a much shorter half-life than other ACE inhibitors (2 hs) Enalapril active enalaprilic acid during its first passage through the liver. - enalaprilic acid has a half life of approximately 10 hours compared with two hours for captopril. More recently released ACE-inhibitors
.

2. -.

Differs from captopril in that it is a prodrug, converted to the

longer elimination half-lives. Otherwise, similar in terms of their clinical properties and side effects.
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Angiotensin Converting Enzyme Inhibitors (ACE-I)

Pharmacokinetics

Poor relationship between plasma concentration of ACE inhibitor and its action action dependent to large extent on the state of activation of the renin-angiotensin system (RAS)

Bioavailability varies between 25 and 80% All excreted via the kidneys but some also undergo hepatic metabolism, such as fosinopril, perindopril, ramipril, spirapril and trandolapril

Captopril has a short half-life, therefore dosing 2-3 times daily is required. Most others have half-lives in excess of 10 hours. Captopril bioavailability is reduced by 30-40% if co-administered with food.

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Clinical Uses

Angiotensin Converting Enzyme Inhibitors (ACE-I)

Hypertension Cardiac Failure Diabetes Myocardial infarction

1. Cardiac Failure

Prolong survival as well as improve exercise tolerance and quality of life Reduce the mortality of moderate to severe cardiac failure by 20-30% Delay progression of heart failure in those with asymptomatic left ventricular dysfunction Introduce with caution to avoid hypotension, test dose and monitor BP, increase dose slowly if tolerated.
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Angiotensin Converting Enzyme Inhibitors (ACE-I)

Clinical Uses 2. Hypertension Relatively weak anti-hypertensive effect when administered alone. Synergistic when administered with diuretics or vasodilators. First-line agents in those with concomitant heart failure or type I diabetes 3. Diabetes Reduce proteinuria and slow the progression of nephropathy in diabetes Used as first-line therapy in diabetics with hypertension Increasingly as first-line therapy in diabetics with early renal disease who are normotensive 4. Myocardial Infarction ACE inhibitors improve survival after MI in those with left ventricular failure (even if transient) - Study - 26% reduction in mortality
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Angiotensin Converting Enzyme Inhibitors (ACE-I)

Adverse Effects

First dose hypotension -more likely if RAS activated i.e. elderly, sodium and water depletion, diuretic use, renal artery stenosis. Initiate therapy with a test dose. Exacerbation of hypotension Renal failure - 0.5-1% Cough -20% Rash, taste disturbance, neutropenia Angioedema - rare but life-threatening Reproductive effects -oligohydramnios, delayed fetal growth and decreased fetal survival

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Angiotensin Converting Enzyme Inhibitors (ACE-I)

DRUG INTERACTIONS

Potassium-sparing diuretics - Severe hyperkalaemia may result if these drugs are used in combination with potassium sparing diuretics (eg amiloride) especially if the patient has some pre-existing degree of renal insufficiency.

Beta-blockers : because beta blockers suppress renin release, they reduce sensitivity to the effect of ACE-inhibitors.

Diuretics : potentiate the hypotensive activity of ACE inhibitors.

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Angiotesin II Receptor Blockers

Mode of Action

Competitively block binding of Angiotensin II (AT II) to ATII receptors Blocks the vasoconstrictor and growth-promoting effects of AT II Reduce sodium reabsorption and aldosterone release.

Available agents Losartan, candesartan, irbesartan Pharmacokinetics

Oral bioavailability of losartan 33%, therefore considerable FPM Undergoes hepatic metabolism so reduce dose in hepatic dysfunction Once daily dosing with all agents

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Angiotesin II Receptor Blockers

Clinical uses

Hypertension Similar efficacy to ACE inhibitors and beta-blockers Reduces blood pressure without any change in heart rate Synergistic with thiazides Alternative to those who have ACE inhibitor intolerance CHF, post-MI, diabetic nephropathy - studies ongoing

Adverse Effects Similar to ACE inhibitors but cough less frequent Avoid during pregnancy
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Drugs commonly used in management of HF

2. Diuretics

Diuretics are used in treating both acute and chronic HF. Thiazides (eg, hydrochlorothiazide) can be used for mild diuresis in clients with normal renal function;

loop diuretics (eg, furosemide) should be used in clients who need strong diuresis or who have impaired renal function.

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3. Cadiotonic-inotropic drugs

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What are cadiotonic-inotropic drugs?

Inotropics and cardiotonics are medications that increase the strength of the muscle contractions that pump blood from the heart. They are mainly used for treatment for heart failure.

What are the different classes of inotropics?

1.

Digitalis glycosides (Mainly Digoxine) Phosphodiestrase inhibitors e.g Inamrinone (Inocor), and milrinone IV (Primacor)

2.

3. Human Natriuretic Peptide B-type e.g Nesiritide (Natrecor) 4. Endothelin Receptor Antagonists

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Pharmacology of digoxin on CVS:

A. Digoxin (Lanoxin)

Positive inotropic action - inhibits Na+/K+ ATPase Suppression of sympathetic nervous system activity Increase of parasympathetic activity. Negative chronotropic effect

Actions in Heart Failure

In HF, digoxin exerts a cardiotonic or positive inotropic effect that improves the pumping ability of the heart. Increased myocardial contractility allows the ventricles to empty more completely with each heartbeat. Improved cardiac output leads to decrease in all the following: heart size, heart rate, end-systolic and end-diastolic pressures, vasoconstriction, sympathetic nerve stimulation, and venous congestion.
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Mechanism of action of digoxin

Na-K-ATPase

Cardiac cell membrane

(Na-K-ATPase), an enzyme in cardiac cell membranes that stimulates the movement of sodium out of myocardial cells after contraction.

Digoxin indirectly increases intracellular calcium levels by binding to the Na-K-ATPase 5/24/12

Mechanism of action of digoxin in arrhythmia

In atrial dysrhythmias, digoxin slows the rate of ventricular contraction (negative chronotropic effect). This effect is caused by several factors: 1. First, digoxin has a direct depressant effect on cardiac conduction tissues, especially the atrioventricular node. This action decreases the number of electrical impulses allowed to reach the ventricles from supraventricular sources. 2. Second, digoxin indirectly stimulates the vagus nerve. 3. Third, increased efficiency of myocardial contraction and vagal stimulation decrease compensatory tachycardia that results from the sympathetic nervous system in response to inadequate circulation.
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Pharmacokinetics of digoxin

Medium lipid solubility and is relatively water soluble Oral availability 70% Protein-binding 20-40% Large volume of distribution and high concentrations are found in the myocardium, brain, liver, and skeletal muscle It also crosses the placenta, and serum levels in neonates are similar to those in the mother. 20% metabolized - renal excretion 60%, largely unchanged Dosage must be reduced in the presence of renal failure to prevent drug accumulation and toxicity. Half-life 36-40 hours with normal renal function Narrow therapeutic range 0.8-2.0 ng/ml Therapeutic serum levels of digoxin are 0.5 to 2 ng/mL; toxic serum levels are above 2 ng/mL. However, toxicity may occur at virtually any serum

level.

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Digoxin Dosages

Oral or intravenous Loading dose for rapid "digitalization" only if patient can be monitored closely for toxicity. Steady-state plasma levels take about 7 days to achieve due to slow elimination, longer if renal impairment. Usual maintenance dose 0.125-0.25 mg/day Trough plasma levels to monitor for toxicity

Therapeutic Uses of Digoxin

Management of HF, Atrial fibrillation, and atrial flutter.

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Contraindications to Digoxin use

Digoxin is contraindicated in: Severe myocarditis, ventricular tachycardia, or ventricular fibrillation and must be used cautiously in clients with acute myocardial infarction, heart block, Wolff-Parkinson-White syndrome (risk of fatal dysrhythmias), electrolyte imbalances (hypokalemia, hypomagnesemia, hypercalcemia), and renal impairment

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Administration and Digitalization

Digoxin is given orally or intravenously (IV). I.M route is not recommended because pain and muscle necrosis may occur at injection sites.

When given orally, onset of action occurs in 30 minutes to 2 hrs, and peak effects occur in approximately 6 hrs.

When given IV, the onset of action occurs within 10 to 30 minutes, and peak effects occur in 1 to 5 hours.

In the heart, maximum drug effect occurs when a steady-state tissue concentration has been achieved. This occurs in approximately 1 week unless loading doses are given for more rapid effects.

Traditionally, a loading dose is called a digitalizing dose.

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Digoxin Toxicity

Narrow therapeutic range 0.8-2.0 ng/ml Risk of toxic effects at levels above 2.0 ng/ml Severe toxicity at levels above 3.5 ng/ml GIT and CNS S/E are commonest and include anorexia, nausea, vomiting, diarrhoea, abdominal cramps, visual disturbance, disorientation, hallucinations and convulsions

Cardiac toxicity includes bradycardia, heart block and ventricular tachyarrhythmias

Others - gynaecomastia, allergic skin reactions

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Management of Toxicity
Mild to moderate toxicity without serious arrhythmia

Withdrawal of digoxin Correction of electrolyte disturbance

Moderate to severe toxicity with arrhythmia

Withdrawal of digoxin Correction of electrolyte disturbance (K+, Ca++ and Mg++) Cardiac pacing for bradyarrhythmias Antiarrthymic drugs, lidocaine, phenytoin and propranolol Digoxin antibodies (Digibind)

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B. Phosphodiesterase Inhibitors
Inamrinone (Inocor), and milrinone IV (Primacor) Cardiotonic-inotropic agents used in short-term management of acute, severe HF that is not controlled by digoxin, diuretics, and vasodilators. Mechanism of action - The drugs increase levels of cyclic adenosine monophosphate (cAMP) in myocardial cells by inhibiting phosphodiesterase, the enzyme that normally metabolizes cAMP. - They also relax vascular smooth muscle to produce vasodilation and decrease preload and afterload.

cAMP & cGMP effect

cyclic nucleotide phosphodiesterases

Positive inotropic Inamrinone milrinone Vasodialation

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Degradation

B. Phosphodiesterase Inhibitors
Inamrinone (Inocor), and milrinone IV (Primacor) Kinetics and Toxicity - There is a time delay before the drugs reach therapeutic serum levels as well as inter-individual variability in therapeutic doses. - Both drugs are given IV by bolus injection followed by continuous infusion. - Dose-limiting adverse effects of the drugs include tachycardia, atrial or ventricular dysrhythmias, and hypotension.

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C. Human Natriuretic Peptide B-type

Nesiritide (Natrecor)
The first in this class of drugs to be used in the management of acute HF. Nesiritide is identical to endogenous human B-type natriuretic peptide, which is secreted primarily by the ventricles in response to fluid and pressure overload. Mechanism of action This drug acts to compensate for deteriorating cardiac function by: 1. Reducing preload and afterload, 2. Increasing diuresis and secretion of sodium, 3. Suppressing the reninangiotensinaldosterone system, and 4. Decreasing secretion of the neurohormones endothelin and norepinephrine. Onset of action is immediate with peak effects attained in 15 minutes with a 5/24/12

D. Endothelin Receptor Antagonists

This new class of drugs relaxes blood vessels and improves blood flow by targeting endothelin-1 (a neurohormone) that is produced in excess in HF. Endothelin-1 causes blood vessels to constrict, forcing the ailing heart to work harder to pump blood through the narrowed vessels. Studies indicate that endothelin antagonist drugs improve heart function, as measured by cardiac index; animal studies indicate that structural changes of heart failure (eg, hypertrophy) may be reversed by the drugs. Currently, one endothelin receptor antagonist, bosentan (Tracleer), is Food and Drug Administration (FDA) approved but only for treatment of pulmonary hypertension. Additional data are being collected to support specific indications for these drugs in the management of heart failure
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Drugs commonly used in management of HF

Adrenergics : Dopamine or dobutamine may be used in acute, severe heart failure (HF) when circulatory support is required, usually in a critical care unit. Aldosterone Antagonist Increasingly, spironolactone is also being added for clients with moderate to severe HF. Spironolactone is an aldosterone antagonist that reduces the aldosteroneinduced retention of sodium and water and impaired vascular function. Although ACE inhibitors also decrease aldosterone initially, this effect is transient. Spironolactone is given in a daily dose of 12.5 to 25 mg, along with standard doses of an ACE inhibitor, a loop diuretic, and usually digoxin.
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Drugs commonly used in management of HF

Vasodilators Vasodilators are essential components of treatment regimens for HF, and the beneficial effects of ACE inhibitors and angiotensin receptor antagonists stem significantly from their vasodilating effects . Other vasodilators may also be used. Venous dilators (eg, nitrates) decrease preload Arterial dilators (eg, hydralazine) decrease afterload. Isosorbide dinitrate and hydralazine may be combined to decrease both preload and afterload. The combination has similar effects to those of an ACE inhibitor or an ARB, but may not be as well tolerated by clients. Oral vasodilators usually are used in clients with chronic HF and parenteral agents are reserved for those who have severe HF or are unable to take oral medications.
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HYPERTENSION
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Cardiovascular Pharmacology Management of hypertension

Hypertension is a major health problem with prevalence rate of 25% among adults, increasing to 50% among those above 60 years. Hypertension causes dangerous Click to edit Master subtitle style complications (Target Organ Damage [TOD]) such as myocardial infarction, heart failure, aortic aneurysm, stroke and renal failure. 5/24/12 These

The cause of hypertension is unknown and only less than 5% of cases are secondary to renal diseases, pheochromocytoma, hyperaldosteronism, aortic coarctation, or secondary to drugs (drug-induced hypertension) such as:
-

Vasoconstrictors, e.g. phenylephrine or flu medicine Volume expanders, e.g. glucocorticoids, NSAIDs and oral contraceptives.

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Target Blood Pressure <140/90 <130/85 in low-risk group in high-risk group

Lifestyle Modification
(Nonpharmacological Management of Hypertension)

Beneficial in reducing high blood pressure and its complications. Reduces the dose requirement of antihypertensive drugs. Recommended in all hypertensives initially and with drug therapy.

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Lifestyle modification includes :-

(1). Reduced dietary intake of Na+ and fat, increased Ca2+ and K+ intake, together with diet rich in fruits and vegetables and low-fat dairy products. (2). Weight reduction for overweight patients. (3). Regular physical exercise. (4). Stopping smoking and reducing alcohol intake
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I. Diuretics
Mechanism of Action

Initially, they act by reducing plasma volume and COP, followed by vasodilation and reduction in peripheral vascular resistance.

Advantages

Reduce mortality, stroke and cardiovascular complications of hypertension. 5/24/12

Indications
1st choice in uncomplicated hypertension. Specially indicated in: 1. Systolic hypertension. 2. Hypertension in elderly, black and obese patients (salt-sensitive). 3. Hypertension complicated with heart failure.

Combined with other antihypertensives to potentiate their effect: 1. Control edema of vasodilators. 2. Reduce plasma volume increase renin and potentiate the hypotensive action of ACEIs and b blockers, especially in black old patients.

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Thiazides are the preferred diuretics for hypertension because in single daily dose they cause persistent volume depletion which is required to lower BP; whereas once daily dose of frusemide is inadequate as it causes temporary Na+ loss. Thiazides tend to retain Ca2+ risk of bone fracture in the elderly.

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Side Effects-:
1. Metabolic Side Effects

Hyperuricemia - hyperglycemia -hyperlipidemia.

2. Electrolyte Disturbances

Hypokalemia - hyponatremia -hypomagnesemia.

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These side effects can be minimized by:a. Low-sodium and high-potassium diet.

b. Using low dose of thiazide especially when combined with b blockers to avoid unfavorable additive metabolic effects. c. Combination with spironolactone in cardiac patients to avoid the dangerous effects of hypokalemia and hypomagnesemia. d.5/24/12 Combination with ACEIs which may

3. Impotence (common). 4. Sulfonamide hypersensitivity reactions (rare) as jaundice, pancreatitis and blood disorders.

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II. B-Adrenergic Blockers

Mechanism of Action-:

Initially, they decrease COP without effective drop in BP due to reflex vasospasm with early increase in TPR. Later, they decrease TPR and BP through: a. Renin release.

b. NA release by central and peripheral effects. c. Prostaglandins causing vasodilation.

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Advantages

Decrease cardiovascular mortality & morbidity and protect against coronary heart disease. Relatively not expensive.

Indications

Alternative to diuretics as 1st line treatment of uncomplicated hypertension.

Used in young hypertensives where COP is high.

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Side Effects (Less with B1-selective): 1. Bronchospasm, cold extremities. 2. Metabolic: glucose intolerance, dyslipidemia. 3. Bradycardia, heart block. 4. CNS depression, sense of fatigue. 5. Impotence.

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There are two main types of voltagedependent Ca2+ channels:-

III. Calcium Channel Blockers

1. L-type (Long-lasting) with slow inactivation and high conductivity. 2. T-type (Transient) with fast inactivation and low conductivity.

Ca2+ channel blockers act on 1 subunit of L-type channel that is located in conductive tissues (SAN & AVN) cardiac myocytes and vascular smooth muscle 5/24/12

Classification, Actions, Uses and Adverse Reactions of Calcium Channel Class Actions Uses Adverse Reactions Blockers
I. Dihydropyridine (DHP) A. Short-acting Nifedipine B. Long-acting Amlodipine (5-10 mg once daily)
Vessels > Myocardium > SAN,1. Hypertension. AVN 2. Peripheral DHP induce strong coronary & peripheral vasodilation with vascular disease less cardiac effect. (e.g., Raynaud's Lower BP with reflex phenomenon). sympathetic activation: - Marked with nifedipine HR. - Less with amlodipine minimal HR change Marked tachycardia & acute myocardial ischemia in coronary disease (nifedipine). 2. Hypotension. 3. Headache, flushing, lower limb edema.
1.

II. Non-DHP A. Phenylalkylamines Verapamil (240 mg SR once daily) B. Benzothiazepines Diltiazem

(Heart-Rate Lowering) SAN, AVN > Myocardium = Vessels Inhibition of SAN & AVN HR. -ve inotropic effect. Less VD effect lower BP with mild reflex sympathetic activation, partially offsetting the direct cardiac effect (especially verapamil).

1. SV arrhythmia: 1. Bradycardia & - Prophylaxis of PSVT ( heart block. nodal reentry). 2. HF (especially with - HR control in chronic diltiazem). AF. 3. Constipation (only 2. HOCM ( outflow obstruction). with verapamil). 3. Angina pectoris (effort or vasospastic). 4. Hypertension.

Mechanism of Action

Calcium Channel Blockers for Hypertension

Peripheral VD and TPR. Diuretic action secondary to renal blood flow. Aldosterone secretion. No metabolic side effects (no changes in glucose, lipid or uric acid levels). No affection of sexual activity.
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Advantages

Indications : 2nd Choice after diuretics in elderly hypertensives or in isolated systolic hypertension. 2nd Choice after b blockers in hypertensives with coronary heart disease. Hypertension with peripheral vascular disease (PVD). Hypertension with renal impairment. Preparations and Dosage: 5/24/12 Amlodipine 5 mg once daily.