Title: Pharmacology CVS Final / Drugs for HF 1

Q: What is heart failure? (3)
A: • Heart is unable to provide adequate perfusion of peripheral organs to meet their metabolic requirements
• Usually characterized by decreased CO and increased TPR
• Progression to congestive heart failure (CHF) is accompanied by peripheral and pulmonary edema.

Q: Causes of congestive heart failure: (3)
A: 1. Mechanical causes
2. Impaired cardiac filling
3. Myocardial failure

Q: Mechanical causes of congestive heart failure: (6)
A: Either pressure overload or volume overload
1. Hypertension
2. Aortic valve stenosis
3. Pulmonary hypertension
4. Valvular regurgitation
5. Shunts
6. Increased blood volume

Q: Impaired cardiac filling: (4)
A: 1. Pericardial disease (constriction or tamponade)
2. Restrictive heart disease (endo- or myocardial)
3. Ventricular hypertrophy
4. Ventricular aneurysm

Q: Myocardial failure: (6)
A: Can be primary or secondary:
1. Loss of functioning muscle (myocardial infarction)
2. Cardiomyopathy
3. Myocarditis
4. Dysdynamic heart failure (response to chronic overload)
5. Drug induced
6. Involvement in systemic disease (hypothyyrodism)

Q: Factors affecting cardiac output: (4)
A: 1. Contractility
2. Heart rate
3. Afterload (ejection tension)
4. Preload (EDV)

Q: Mechanisms of heart failure: (5)
A: Reduction in the intrinsic myocardial contractility
1. Depletion of NE in the heart muscle
2. Decreased myosine ATPase activity
3. Decreased ATP and other high energy phosphate compounds
4. Decreased beta receptor density (due to down regulation after chronic exposure to high circulating catecholamines)
5. Abnormal Ca++ binding

Q: Abnormal Ca++ binding can be caused by: (5)
A: 1. Less stored in the SR
2. More stored in the mitochondria
3. Less Ca++ released
4. Lesser reuptake into the SR
5. Slow reuptake into mitochondria leading to slow relaxation

Q: Compensatory mechanisms in heart failure: (3)
A: 1. Frank straling mechanism
2. Increased activity of SNS
3. Myocardial hypertrophy leading to increased wall tension

Q: Increased activity of SNS: (4)
A: 1. Tachycardia  and increased CO.
2. Increased myocardial contractility
3. Vasoconstriction leading to   redistribution of blood to important   viscera.
4. Renin release leading to increased plasma volume.

Q: Compensatory SNS mechanisms in HF: (2+2)
A: • In a failing heart, the loss of contractile function leads to a decline in CO and a decrease in BP.
• Baroreceptors sense the hemodynamic changes and initiate countermeasures to maintain support of the circulatory system. This is achieved by activation of the SNS.
• This helps maintain adequate cardiac output by:
1. Increasing myocardial contractility and heart rate (β1-adrenergic receptors)
2. Increasing peripheral vasomotor tone (α1-adrenergic receptors) to maintain systemic blood pressure

Q: Consequences of hyperadrenergic state: (5)
A: • Enhancement of RAAS leading to increased Angio II.
• Irreversible myocyte damage, cell death, and fibrosis.
• Increased peripheral vasomotor tone leading to increased LV afterload.
• This places an added stress upon the left ventricle and an increase in myocardial O2 demand and ventricular remodeling.
• The frequency and severity of cardiac arrhythmias are enhanced in the failing heart

Q: Signs and symptoms of HF: (4)
A: • Tachycardia, sweating
• Decreased exercise tolerance & SOB
• Peripheral and pulmonary edema
• Cardiomegaly(with or without Hypertrophy)

Q: Objectives of long term management of chronic cardiac failure: (5)
A: • Improve cardiac performance (hemodynamics) at rest and during exercise.
• Relieve symptoms.
• Improve myocardial efficiency(myocardial oxygen consumption).
• Improve quality of life(particularly symptom-free and effort tolerance).
• Improve patient survival.

Q: Cardiac vs
Noncardiac
Therapeutic Targets: (4)
A: • Conventional belief that the primary defect in HF is in the heart.
• Reality is that HF involves many other processes and organs.
• Research has shown that therapy directed at noncardiac targets is more valuable than cardiac targets.
• CHF should be viewed as a complex, interrelated sequence of events involving hemodynamic, and neurohormonal events.

Q: The "problems" that occur due to heart failure: (9)
A: • Reduced force of contraction
• Decreased cardiac output
• Increased total peripheral resistance
• Inadequate organ perfusion
• Edema
• Decreased exercise tolerance
• Ischemic heart disease
• Sudden death
• Ventricular remodeling, dilatation, hypertrophy, and decreased function

Q: Nonpharmacologic treatment of heart failure: (4)
A: 1. Salt restriction
2. Treat the cause
3. Moderate excercise
4. Heart transplantation

Q: Diuretics in the treatment of heart failure: (6)
A: 1. Only for congestive symptoms
2. Do not increase cardiac, and may decrease it
3. Can be used alone initially and is given intravenously
4. May be used in combination with Digitalis or others
5. Cause K+ loss and decreased blood pressure
6. Can be reduced or withdrawn

Q: Causes of Diuretic resistance in heart failure: (6)
A: 1. Noncompliance with medical regimen; excess dietary Na+ intake.
2. Reduced or impaired diuretic absorption due to gut wall edema and reduced splanchnic blood flow
3. Decreased renal perfusion and glomerular filtration rate
4. Selective reduction in glomerular perfusion pressure following initiation (or dose increase) of ACE inhibitor therapy
5. Nonsteroidal anti-inflammatory drugs
6. Primary renal pathology

Q: Drugs used chronic heart failure: (7)
A: 1. Diuretics
2. Aldosterone recetor antagonists
3. Angiotensin-converting enzyme inhibitors
4. Angiotensin receptor blockers
5. Beta blockers
6. Cardiac glycosides
7. Vasodilators

Q: Drugs used in acute heart failure: (5)
A: 1. Diuretics
2. Vasodilators
3. Beta agonists
4. Bipyridines
5. Natriuretic peptide

Q: Mechanisms (roles) of aldosterone: (6)
A: 1. Increased Na+ and water retention
2. K+ and Mg++ loss
3. Reduced myocardial norepinephrine uptake
4. Reduced baroreceptor sensitivity
5. Myocardial fibrosis, fibroblast proliferation
6. Alterations in Na+ channel expression

Q: The pathophysiological effect of Increased Na+ and water retention: (2)
A: 1. Edema
2. Elevated cardiac filling

Q: The pathophysiological effect of K+ and Mg++ loss: (2)
A: 1. Arrythmogenesis
2. Risk of sudden cardiac death

Q: The pathophysiological effect of reduced myocardial Ne uptake:
A: Potentiation of norepinephrine effects: myocardial remodeling and arrythmogenesis

Q: The pathophysiological effect of reduced baroreceptor sensivity: (2)
A: 1. Reduced parasympathetic activity
2. Risk of sudden cardiac death

Q: The pathophysiological effect of myocardial fibrosis, fibroblast proliferation:
A: Remodelling and ventricular dysfunction

Q: The pathophysiological effect of alteration in Na+ channel expression:
A: Increased excitability and contractility of cardiac myocytes

Q: Effects of angiotensin II: (12)
A: 1. Sympathetic activation
2. Aldosterone release
3. Myocyte hypertrophy
4. Myocardial fibrosis
5. Myocyte apoptosis
6. Endothelial dysfunction
7. Altered gene expression
8. Vasoconstriction
9. Sodium retention
10. Myocardial and vascular fibrosis
11. Endothelin synthesis
12. Cytokine release

Q: Therapeutic values of ACEI: (5)
A: •  Nowadays drugs of choice.
•  No tolerance.
•  Retard progression of HF.
•  Decrease arrhythmias.
•  Proved to decrease mortality, but only when the highest tolerated doses are used.

Q: Preparations of ACEI: (5)
A: • Captopril
• Enalapril
• Lisinopril
• Quinapril
• Fosinopril
  All are similarly effective
  Might differ in toxicity

Q: Toxicity of ACEI: (4)
A: 1. Hypotension (first does phenomenon)
2. Renal impairment (proteinurea)
3. K+ retention
4. Cough 10%

Q: Angiotensin II Receptor Blockers
(AT-1):
A: • Losartan.
• Valsartan.
• Candesartan.
• Irbesartan.
• Eprosartan
• Telmisartan ( Also increases peroxisome proliferator- activated receptor “PPR “-γ  activity).

Q: Effects of Angiotensin
II Receptor Blockers (AT-1): (4)
A: • Result in more complete inhibition of angiotensin II actions with no effects on bradykinins.
• May be only indicated when ACEI are intolerable.
• Most expensive, but fastest growing class of antihypertensive drugs.
• Free of side effects, especially cough.

Q: Beta blockers: (6)
A: • Traditionally, they should have negative inotropic effects.
• However, nowadays there is overwhelming evidence to support the use of β-blockers in CHF.
• Not useful in refractory HF.
• Mechanism involved remains unclear.
• Suggested mechanisms also include reduced remodeling of the heart muscle.
• Contraindicated in sever, refractory, unstable cases.

Q: Beneficial effects of beta blockers: (5)
A: • Slowing of heart rate
• Decreased cardiac work and consequently decreased myocardial O2 consumption and enhanced efficiency.
• This would lessen the frequency of ischemic events and arrhythmias.
• β-Blockers may be beneficial through resensitization of the down-regulated beta receptors, thus improving myocardial contractility.
• Should be started with low doses and gradually increased.

Q: Types of beta blockers: (4)
A: 1. Metoprolol
2. Carvedilol
3. Bucindolol
4. Bisoprolol