Block 3: positive inotropic drugs
Terms
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- what is the term for any of the steroid and steroid glycoside compounds that exert typical positive inotropic and electrophysiologic effects on the heart
- digitalis
- what is the primary agent used clinically
- digoxin
- during what condition are the digitalis glycosides used to enhance cardiac output
-
congestive heart failure
have no effect on cardiac output in normal patient - these drugs are used to treat what type of arrhythmias even if toxic doses may cause cardiac arrhythmias
- supraventricular arrhythmias
- Where do digitalis compounds come from and what is their common structure
-
foxglove plant
steroid nucleus with a lactone ring at position 17 - what has higher oral availability, digoxin or digitoxin
- digitoxin - 90-100%, compared to 70-80%
- what has higher oral absorption of digoxin- an encapsulated gel or a tablet
- encapsulated gel
- name three things that retard absorption
-
food
antacids
steroid binding resins - there is a close correlation between ___ ___ and plasma digoxin concentration
- creatinine clearance
- what is the consequence of the 10% of patients who metabolize digoxin to inactive products in the gut lumen by bacteria
- higher doses are needed
- what is a loading dose of digoxin called
- digitalizing dose
- name three ways drugs interact with digoxin
-
1. inhibit absorption (cholestyramine)
2. antibiotics eradicate gut bacteria causing increased plasma concentrations
3. increase digoxin blood levels (antiarrhythmic agents like quinidine, verapamil) - what is meant by positive inotropic action
- increased force and velocity of contraction by direct action on the heart, not mediated by catecholamines or by activation of adenylyl cyclase
- digitalis binds to the external portion of and inhibits which enzyme
- membrane bound Na-K-ATPase
- is digitalis binding to Na-K-ATPase enhanced or inhibited by hypokalemia
- enhanced
- What is the net effect of inhibition of the Na-K-ATPase enzyme
- increase in availability of Ca to myocardial contractile proteins
- digoxin increases the __ and __ of myocardial contraction by increasing intracellular __
-
force
velocity
Ca - how does digoxin help CHF
- direct positive inotropic action -> inc CO -> increased ejection fraction -> decreases cardiac filling pressure -> reflex reduction in heart rate and peripheral resistance
- digoxin causes improved renal perfusion, what does this result in
- inhanced sodium excretion and reduction in edema
- digoxin reduces venous pressure and left ventricular end diastolic volume, what does this allow?
- the distended heart to return to a smaller, more normal size, and relieves edema
- What is meant by "digitalis increases the efficency of the failing heart"
- CO and O2 consumption
- why does the hemodynamic outcome of digitalis administration differ between patients with CHF and those without CHF
- the DIRECT VASOCONSTRICTOR ACTION of digitalis
- What does digitalis do in patients without CHF
- it increases peripheral resistance and therefore afterload; no increased CO because of the increased afterload
- Why doesn't digitalis increase afterload in patients with CHF
- because the peripheral resistance is already very high due to compensatory vasoconstriction
- ___ is a complex of signs and symptoms which comprise a recognizable clinical syndrome of pulmonary and peripheral tissue congestion with or without the effects of decreased cardiac output at rest
- CHF
- digoxin is used to treat CHF resulting from ___, which generally results from MI, myocarditis, toxins, or chronic mechanical overload
- left ventricular systolic dysfunction (dilated cardiomyopathy)
- does digoxin reduce the overall mortality of HF? does it reduce the rate of hospitalization?
-
no
yes - how does digoxin act as an anti-arrhythmic action
-
enhances vagal tone- due to sensitized arterial baroreceptors, increased efferent vagal fiber excitability and increased sensitivity of heart to ACh
slows AV nodal conduction and sinus rate - Name three anti-arrhythmic uses of digoxin
-
a-fib
a-flutter
Paroxysmal supraventricular tachycardia (PSVT) - what is the most frequent antiarrhythmic use of digoxin
- atrial fibrillation
- can digoxin achieve and maintain sinus rhythm during a-fib?
- no- other antiarrhythmic drugs or DC cardioversion are often needed
- name 8 predisposing factors for digtalis toxicity
-
1. ionic imbalance
2. DECREASED K
3. increased Ca
4. heart disease
5. RENAL DYSFUNCTION - DIGOXIN
6. LIVER DYSFUNCTION- DIGITALIS
7. hypothyroidism
8. drug interactions - name four manifestations of digitalis toxicity
-
1. arrhythmias
2. stimulate "trigger zone"- anorexia, nausea, vomitting
3. visual changes
4. neurologic changes: HA, fatigue, insomnia, confusion, depression - What particular arrhythmia is specific to digoxin toxicity?
- none- it can cause most any type of arrhythmia or conduction block
- what nerves to the heart are effected by digoxin
- both sympathetic and parasympathetic nerves are activated
- at toxic doses, the direct toxic effect of digoxin on the ventricle, combined with the enhanced sympathetic input to the ventricle can cause
- synergy- AV dissociation, premature ventricular beats, v-tach, and fibrillation
- name five steps to treat digoxin toxicity
-
1. stop digoxin and monitor cardiac rhythm
2. correct electrolytes
3. KCl- unless AV block present
4. atropine or pacing for bradyarrhythmias
5. digoxin-immune Fab or lidocaine for ventricular arrhythmias - except for ___, oral agents for chronic positive inotropic therapy have been show to increase mortality due to increased arrhythmias
- digoxin
- name two sympathomimetic amines parenterally administered primarily in cardiogenic shock, low output states which follow open heart surgery, and severe refractory CHF
-
dopamine- i.v.
dobutamine- i.v. - name two phophodiesterase inhibitors whose inotropic action is due to inhibition of cyclic nucleotide phophodiseterase isoenzyme III which leads to inc intracellular calcium
-
inamrinone
milrinone - what else do inamrinone and milrinone do
- vasodilators
- how are inamrinone and milrinone given
- parenterally
- toxicity of which, inamrinone or milrinone, includes reversible thrombocytopenia
- inamrinone
- which, inamrinone or milrinone, is the agent of choice for short term i.v therapy for severe CHF
- milrinone