CHF drugs

Question 1

Continuing with CHF drugs, is Inotropic Drugs. Cardiac Glycosides, Digoxin, is next. What is the clinical application of this drug?

Answer 1

Decreases the symptoms of HF
–does not increase survival
Used in patients with HF and SVT or A-fib
–controls ventricular response rate
Needs to be used in combo with standard HF therapies

Question 2

What is the MOA of Digoxin?

Answer 2

Positive inotropic effect on failing myocardium
Efficacy in controlling the ventricular rate response
Autonomic nervous system activity is modulated
Digoxin is both positively inotropic (increased contractility) and negatively chronotropic (decreases heart rate)

Question 3

What is the MOA of the positive inotropic effect of digoxin?

Answer 3

Inhibits Na/K ATPase
–increase in intracellular calcium is required for cardiac muscle cells to contract (occurs by Ca entering myocyte via Ca channels during depolarization)
–intracellular calcium has to decline for muscle to relax. (occurs during repolarization by intracellular Ca being re-sequestered by the SR together with removal form the cell via the Na-Ca exchanger)
Digoxin causes a rise in cytosolic Na therefore Ca accumulates in the myocyte
–increased Ca causes more Ca to be release during Ca induced Ca release = increase contractility
Inhibition of Na/K ATPase causes vascular smooth muscle to depolarize which then contracts and vasoconstricts

Question 4

What is the electrophysiological actions of digoxin?

Answer 4

Decreases automaticity
Increases Maximal Diastolic Resting Membrane Potential in Atrial and AV nodal Tissues
–all due to an increase in vagal tone and decrease in SNS activity

Question 5

Digoxin has been shown to cause baroreceptor sensitization what does this cause?

Answer 5

Offsets baroreceptor desensitization that is present in HF

–sustained elevation in norepinephrine

Question 6

Explain the pharmacokinetics of digoxin

Answer 6

Narrow Therapeutic Window

• -half life is 36-40 hours
• -large Vd
• -excreted in kidneys therefore used in caution in patients with renal failure

Question 7

What are the adverse effects in a patient given digoxin?

Answer 7

Digoxin toxicity is very common

1. cardiac effects: arrhythmias (Atrial tachy or AV block)
2. GI effects
3. CNS effects: alteration of color perception: seeing yellow and halo on dark objects

Question 8

Potassium decreases the affinity of the Na/K- ATPase for digoxin, therefore hypokalemia results in what?

Answer 8

Increased digoxin binding and thereby enhances therapeutic and toxic effects
–Hyperkalemia has the opposite effects

Question 9

Hypercalcemia enhances digoxin-induced increases in intracellular Ca, which can lead to what?

Answer 9

Overloading of Ca stores and increased susceptibility to digoxin induced arrhythmias

Question 10

Hypomagnesemia sensitizes the heart to?

Answer 10

Digoxin induced arrhythmias

Question 11

What drugs compete with digoxin for binding sites and depress renal clearance of digoxin?

Answer 11

Quinidine
Amiodarone
Verapamil
NSAIDs

Question 12

Diuretics can indirectly interact with digoxin because?

Answer 12

Because of their potential for decreasing plasma potassium levels

Question 13

Explain hypothyroidism, hyperthyroidism and renal failure interactions with digoxin

Answer 13

Hypothyroidism: use with caution as higher digoxin concentrations may result
Hyperthyroidism: due to decreased absorption digoxin concentrations may be lower
Renal failure: digoxin levels need to be monitored

Question 14

What are the contraindications for digoxin?

Answer 14

Diastolic or Right sided HF: leads to outflow obstruction 
Uncontrolled HTN
Bradyarrhythmias
Intolerance or non responders 
Hypokalemic

Question 15

In case of digoxin toxicity what should be done??

Answer 15

1. Withdraw drug or lower dose
2. Adjust electrolyte status
3. Treat ventricular tachyarrhythmia’s with lidocaine and/or Mg
4. If toxicity is severe treat with digitalis antibodies which bind and inactivate the drug

Question 16

Moving on to drugs used in Acute HF. First are the Inotropic Agents including Phosphodiesterase (PDE) III inhibitors. These drugs are Inamrinone and Milrinone. What is the clinical application, MAO, Pharmacokinetics and Adverse Effects of these drugs?

Answer 16

Clinical:
– Short term therapy for intractable heart failure
MOA:
–inhibit myocardial PDE activity — cAMP levels increased — intropic and arterial/venous vasodilating effects
Pharmacokinetics:
–IV: Again short term therapy
Adverse Effects:
–Arrhythmias, Hypotension, Thrombocytopenia

Question 17

The next Phosphoidesterase (PDE) III inhibitor is Dopamine, what is the clinical application of this drug?

Answer 17

Clinical:
–treatment of shock (raises BP by stimulating the heart and increasing blood flow to the kidneys) that persists after adequate fluid volume replacement

Question 18

What is the MOA for Dopamine?

Answer 18

Dopaminergic (D1) and Adrenergic Agonist (alpha1,beta1 and beta 2)

• -low doses: D1 vasodilation occurs (also is a diuretic)
• -Intermediate doses: B1 receptors mediated so positive inotropic effects
• -High Doses: Chronotropic and Alpha 1 vasoconstricting dominates

Question 19

What are adverse effects of Dopamine?

Answer 19

Cardiac Arrhythmias
At high Doses: increase myocardial oxygen demand and decrease myocardial blood flow, worsening ischemia in some patients with CAD

Question 20

The next Phosphoidesterase (PDE) III inhibitor is Dobutamine, what is the clinical application?

Answer 20

Increase cardiac output in acute management of heart failure

Question 21

What is the MOA for Dobutamine?

Answer 21

Racemic Mixture:

• at therapeutic levels the stimulation of B1 receptors predominant, leading to a potent inotropic effect (With little change in the HR). Net vascular effect is usually vasodilation (B2)
• -increases cardiac output without elevating the O2 demands of the myocardium

Question 22

What are the side effects of Dobutamine?

Answer 22

Less arrhythmogenic than dopamine

Question 23

Finally the last drug in the Acute HF section is another Phosphoidesterase (PDE) III inhibitor called Glucagon. What is the clinical application and MOA of this drug?

Answer 23

Cardiac stimulant in management of severe cases of beta blocker overdosage
MOA:
–stimulates adenylyl cyclase — increase in cAMP levels — positive inotropic and chronotropic effects
Produce same effects as Beta Agonist without activating the beta receptors thus is useful for beta blocker overdosing