Inotropic drugs Flashcards
Inotropic drugs: broad categories
B agonists
Digitalis compound
PDEi
Ca2+ sensitizers
B agonist MOA
- Sympathomimetic drug: bind B-R in cardiac nodal, conducting system and myocytes
o ↑Ca2+ availability via cAMP - Limited efficacy in B-R downregulation: 24-72h
Natural B-R ligands
NE from ∑ nerves or in systemic circulation
B-R types
o B1-R = heart muscle
o B2-R = vascular and bronchial SM
o B3-R = endothelial
B1-R effects
Heart: positive inotrope, dromotrope, chronotrope and lusitrope
Kidneys: renin release → Ang II + aldosterone release
B2-R effects
Bronchodilation
↑ blood glucose
* Hepatic glycogenolysis
* Pancreatic release of glucagon
B agonist drugs
Epinephrine
NE
Dopamine
Dobutamine
Isoproterenol
Epinephrine: which R action
o Beta selective: B1 = B2 > α1 = α2
Epinephrine: effect depend on
dose
Low dose → cardiac stimulation and vasodilation
High dose → vasoconstriction
* α = β selectivity
Epinephrine: indication
anaphylactic, cardiogenic shock, cardiac arrest
NE: which R action
o R-1 selective: B1 = α1 > β2 = α2
NE: side effects
o Reflex bradycardia → mask direct effects on SA node
NE: indications
septic shock, severe hypotension
Dopamine: dose
2-8mcg/kg/min
Dopamine: which R action
o Beta selective: B1 = B2 > α1
Dopamine: MOA
o Biosynthetic precursor of NE → stimulate NE release
Dopamine: effect depend on
o Effect depend on dose
Low dose (<5mcg/kg/min): ↑ contractility and ↓ SVR
* Selective vasodilation from peripheral dopamine R: renal (D1-R), mesenteric, coronary, cerebral vascular beds → improve blood flow
High dose: vasoconstriction
* Will bind to lower affinity α-R
Dopamine: indications
acute CHF, cardiogenic shock
Dobutamine: dose
5-15mcg/kg/min
Dobutamine: which R action
o B-1 selective: B1 > B2 > α1
Dobutamine: net effect
cardiac stimulation, modest vasodilation, little change in HR or afterload
Dobutamine: indications
CHF, cardiogenic shock
Isoproterenol: net effect
cardiac stimulation, vasodilation with little change in pressure
Isoproterenol: indications
bradycardia, AVB
PharmacoK B agonists
- Dobutamine/dopamine: synthetic catecholamines
o Short ½ life → short term IV use
Digitalis compound MOA
- Inhibit Na+/K+ ATPase on sarcolemma of myocytes
o Bind site where K+ attach
o Activate Na+/Ca2+ exchanger → ↑ intracell [Ca2+] + ↑ Ca2+ release from SR
↑ Ca2+ available to bind Troponin C → ↑ contractility
o Depolarization → SM contraction → vasoconstriction
- ↑ vagal afferent activity = p∑ activation:
o ↓ SA node firing rate → negative chronotrope
o ↓ AV node conduction velocity and prolong refractoriness → negative dromotrope
Normal action of Na+/K+ ATPase
normally move K+ in, Na+ out → maintain resting membrane potential
* Inhibition leads to ↑[Na+] intracell
Normal action of Na+/Ca2+ exch
normally move Ca2+ out and Na+ in
* Intracell [Na+] compete for intracell [Ca2+]
* As [Na+] ↑ → ↓ concentration gradient driving Na+ into cell
o ↓ activity of exchanger → ↑[Ca2+]
Inotrope effect of digitalis vs B agonist
- Positive inotrope effect is 1/3 of effect seen w B agonists
1/2 life digitalis
Long → necessitate constant dosing to reach therapeutic plasma levels
o Digoxin: 40h
o Digitoxin: 160h
o Ouabain: 20h
o Digitalization: loading doses to ↑ plasma levels rapidly
Digitalis: toxicity dose
- Toxicity >2.0ng/ml
o Narrow therapeutic safety window: 0.5-1.5ng/ml
o Can take days for levels to ↓
Digitalis: what can potentiate toxicity
o HypoK+: potentiate toxicity
Compete for binding sites
↑ # of sites available
C/s digitalis
GI dysfunction: anorexia, vomiting
* Effects on chemoR in area postrema in medulla
Neurologic signs: depression, disorientation, delirium
Myocardial toxicity: arrhythmias
* Slow conduction + alter refractory period of myocardial cells
o ↑ risk for re-entrant arrhythmias
* High doses → ↑∑ activity to heart → ↑ normal automaticity
* Promote abnormal automaticity in myocardial cells
* DADs from Ca2+ overload
o Especially in myocardium w structural changes (stretch)
o HypoK+ environment
* Bradyarrhythmias: AVB, sinus brady, sinus arrest
Treatment digitalis tox
Digibind (Immune Fab): ↓ plasma digoxin levels
K+ supplementation: reverse toxic effects related to hypoK+
Oral bioavailability digitalis
Digoxin:75%, 27% bound to albumin
Digitoxin: >90%
Ouabain: 0%
Elimination digitalis
Digoxin: renal
Digitoxin: hepatic
Ouabain: renal
Drug interactions digitalis
- Class IA anti arrhythmic: Quinidine
o Compete w digoxin binding site - ↓ Renal clearance → can lead to toxicity (↓ dose by 50%)
- Ca2+ channel blockers = similar mechanism
- NSAIDs = similar mechanism
- Amiodarone
- Beta blockers
- Diuretics: indirect interaction
o Potential to ↓ K+ levels → ↑ digoxin binding to Na+/K+ ATPase pump
o ↑ therapeutic/toxic effects - Hyper Ca2+ → ↑ intracell Ca2+ → Ca2+ overload → ↑ susceptibility to arrhythmias
PDE3i: drugs
Pimobendan, milrinone, amrinone
PDE3i MOA and effect
inhibit PDE3 enzyme
o Responsible for breaking down cAMP
o Effect: ↑ cAMP levels
↑ inotropy, chronotropy, dromotropy
Vasodilation
PDE5i drugs
Sildenafil, tadalafil
PDE5i: MOA and effect
- Mechanism: inhibit PDE5 enzyme
o Responsible for breaking down cGMP
o Effect: ↑ cGMP levels → ↑ NO and ↓[Ca2+]
SM relaxation → vasodilation
Ca2+ sensitizers drugs
Pimobendan, levosimendan
Ca2+ sensitizers effect
- ↑ sensitivity of Troponin-C to Ca2+ → ↑ contractility
