CHF drugs Flashcards
Continuing with CHF drugs, is Inotropic Drugs. Cardiac Glycosides, Digoxin, is next. What is the clinical application of this drug?
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
What is the MOA of Digoxin?
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)
What is the MOA of the positive inotropic effect of digoxin?
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
What is the electrophysiological actions of digoxin?
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
Digoxin has been shown to cause baroreceptor sensitization what does this cause?
Offsets baroreceptor desensitization that is present in HF
–sustained elevation in norepinephrine
Explain the pharmacokinetics of digoxin
Narrow Therapeutic Window
- -half life is 36-40 hours
- -large Vd
- -excreted in kidneys therefore used in caution in patients with renal failure
What are the adverse effects in a patient given digoxin?
Digoxin toxicity is very common
- cardiac effects: arrhythmias (Atrial tachy or AV block)
- GI effects
- CNS effects: alteration of color perception: seeing yellow and halo on dark objects
Potassium decreases the affinity of the Na/K- ATPase for digoxin, therefore hypokalemia results in what?
Increased digoxin binding and thereby enhances therapeutic and toxic effects
–Hyperkalemia has the opposite effects
Hypercalcemia enhances digoxin-induced increases in intracellular Ca, which can lead to what?
Overloading of Ca stores and increased susceptibility to digoxin induced arrhythmias
Hypomagnesemia sensitizes the heart to?
Digoxin induced arrhythmias
What drugs compete with digoxin for binding sites and depress renal clearance of digoxin?
Quinidine
Amiodarone
Verapamil
NSAIDs
Diuretics can indirectly interact with digoxin because?
Because of their potential for decreasing plasma potassium levels
Explain hypothyroidism, hyperthyroidism and renal failure interactions with digoxin
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
What are the contraindications for digoxin?
Diastolic or Right sided HF: leads to outflow obstruction Uncontrolled HTN Bradyarrhythmias Intolerance or non responders Hypokalemic
In case of digoxin toxicity what should be done??
- Withdraw drug or lower dose
- Adjust electrolyte status
- Treat ventricular tachyarrhythmia’s with lidocaine and/or Mg
- If toxicity is severe treat with digitalis antibodies which bind and inactivate the drug
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?
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
The next Phosphoidesterase (PDE) III inhibitor is Dopamine, what is the clinical application of this drug?
Clinical:
–treatment of shock (raises BP by stimulating the heart and increasing blood flow to the kidneys) that persists after adequate fluid volume replacement
What is the MOA for Dopamine?
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
What are adverse effects of Dopamine?
Cardiac Arrhythmias
At high Doses: increase myocardial oxygen demand and decrease myocardial blood flow, worsening ischemia in some patients with CAD
The next Phosphoidesterase (PDE) III inhibitor is Dobutamine, what is the clinical application?
Increase cardiac output in acute management of heart failure
What is the MOA for Dobutamine?
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
What are the side effects of Dobutamine?
Less arrhythmogenic than dopamine
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?
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
