B.4 Flashcards
Positive inotropic drugs
Digoxin,
Digitoxin,
Milrinone,
Levosimendan,
Dobutamine
Digoxin
MOA: inhibits Na+/K+ ATPase
(reduced ability of myocytes to pump Na+ outside→ results in small but important increase in free Ca2+→ increased cardiac contractility), strong cardioselective vagus stimulation and inhibition of AV-conduction;
IND: A.fib and A.flutter in heart failure (HFrEF, treatment of pulse deficit), chronic congestive heart failure, ;
Extra: Ca2+ channel blockers and adenosine significantly replaced its use;
Kinetics: p.o or i.v adm., ↓protein binding, accumulates in muscle, long T1/2- 36-40h, eliminated by kidney (dose adjustment in renal failure);
SEs: at low serum cc- well tolerated. has a NARROW therapeutic index, anorexia, nausea, vomiting, blurred vision or yellowish vision, increased risk of arrhythmias; Contra-IND: hypokalemia (predisposes to digoxin toxicity, b/c digoxin normally competes with K+ for the same binding site on the Na+/K+-pump)
Digitoxin
Extra: Cardiac glycoside, digitalis derivative, one of the oldest drugs/toxins, DOES NOT decrease HF mortality!; MOA: Na+/K+-ATPase inhibitor (→IC[Na+]↑→ Na+/Ca2+ exchange↓→ IC[Ca2+]↑→ more Ca2+ stored in SR→ AP initiates a larger Ca2+ release→ positive inotropic effect);
-Cardiac effects:
->Positive inotropy (→IC[Ca2+]↑),
->Negative chrono- and dromotropy (↓HR and AV conduction→ Central vagal stimulation + increased sensitivity of baroreceptors. ↑PSY tone and ↓SY tone in the heart→ slower SA and AV node function→ bradycardia),
->Proarrhythmic effect (in case of toxicity! Ca2+ overload in cardiac muscle→IC[Ca2+] fluctuation→ heterotropic impulse generation→ ventricular extrasystole→ ventricular tachycardia, ventricular fibrillation), Frequent ECG alterations (bradycardia/AV-block + ventricular ES, bigeminy, curved ST segment depression, T-wave decrease/inversion);
Extracardiac effects:
-Kidney (inhibited Na+/K+-ATPase→ ↓renin production), -Smooth muscle- arterioles (IC[Ca2+]↑→increased afterload),
-GI tract (CTZ sensitization→ nausea, vomiting, diarrhea),
-CNS (disorientation, seizures, color vision disturbances, hallucinations, agitation),
-Endocrine system (gynecomastia);
Pharmacokinetics: NARROW THERAPEUTIC INDEX!, >90% p.o abs., ↑protein binding, 3-6h onset of effects, T1/2- 5-7 days, Metabolized and Eliminated by the liver; IND: chronic congestive heart failure (if 1st line therapies are not effective/contra-IND), Chronic congestive heart failure + A.fib with rapid ventricular rhythm, Hypertrophic cardiomyopathy, WPW-syndrome, AV-block, suspected digitalis intoxication; Contra-IND: Acute coronary syndrome (e.g. AMI→ increased O2 consumtion), Renal failure (electrolyte disturbances), sinus bradycardia and sick sinus syndrome, Combination with drugs leading to bradycardia (e.g. Verapamil, Amiodarone, BBL),
States with increased digitalis sensitivity (e.g. hypokalemia), HF with preserved EF (diastolic HF); Intoxication and its treatment:
-Cardiac symptoms (Extreme bradycardia, AV-block; Bigeminy, ventricular tachy., V.fib;
ECG disturbances: curved ST-depression, T-inversion),
-Extracardiac symptoms (Vision disturbances: color vision, blurred vision, photosensitivity;
-CNS symptoms: headache, hallucinations, anxiety); GI symptoms (nausea, vomiting, GI pain),
Treatment: Treatment of electrolyte imbalance, Antiarrhythmic agents in the I/B group (phenytoin, lidocain), Digitalis-binding antibody/plasmapharesis, Atropin (if bradycardia dominates);
Important interactions:
-Hypokalemia (increased toxicity→ the inhibitory effect on Na+/K+-ATPase increases),
-Hyperkalemia (effect and toxicity decreases→ Cardiac glycosides are antagonists of K+ anatagonists),
-Other conditions enhancing toxicity (Hypercalcemia and hypomagnesemia;
mechanism: function of Na+/K+-ATPase is Mg2+-dependent, if there’s less Mg2+ or more Ca2+, the function of Na+/K+-ATPase will decrease and the toxicity of cardiac glycosides increase)
Levosimendan
MOA:
-heart: binds troponin-C in Ca2+-dependent manner (in systole) and stabilizes it in a conformation required for contraction (→positive inotropic effect without affecting IC[Ca2+]),
-vessels: activates ATP-dependent K+-channels (→vasodilator effect), its effect is partly mediated by PDE-inhibition;
Effect: improves hemodynamics without increasing the O2 need of the heart;
IND: acute decompensation of chronic HF (with signs of hypotension/hypoperfusion);
Pharmacokinetics: adm. via infusion pump (24h), with close observation!, active metabolite is found in circulation for at least 7 days
Milrinone
MOA: PDE inhibitor (→↑IC [cAPM]→ in the heart: ↑[Ca2+] IC→ ↑contractility;
in the vessels: vasodilating effect →decreased afterload);
Kinetics: NARROW THERAPEUTIC INDEX, i.v adm., short term treatment;
IND: acute HF (in case of Dobutamine resistance);
SEs: chronically it can lead to severe arrhythmias and increased mortality of HF
Dobutamin
MOA: β1-R agonist (↑HR, CO), minor β2-R ago (vasodilation);
IND: acute HF, inotropic support aftercardiac surgery; SEs: Tolerance(Tachyphylaxia), HTN, tachycardia, Incresed O2 consumption of the heart;
Kinetics: i.v perfusion adm., short T1/2, short term treatment
