Cardiotonic Drugs Flashcards
What are cardiotonic drugs/cardiovascular stimulants?
Agents that act on the heart and/or vascular tone (BP).
What are the predominant adrenergic receptors of the heart? What do they cause when stimulated?
β1’s; they increase the HR and contractility of the heart
What are the adrenergic receptors in the vasculature? How do they affect the vascular tone when activated?
- α’s; they cause vasoconstriction (VSM contraction)
2. β2’s are only in skeletal muscle vessels, where they cause vasodilation
What happens to the tone of skel m vessels during a fight/flight sympathetic response, given the opposing effects of α1’s and β2’s located there?
The increased local demand for O2 in skel m tissue during fight/flight causes the α1-mediated vasoconstriction to be lost and the β2-mediated vasodilatory action predominates.
What causes this loss of α1-mediated vasoconstriction in skel m blood vessels during fight/flight response?
Localized control via the release of NO or PG’s, which modulate the effects of α1-R’s and reduce α1-mediated vasoconstriction, leading to the emergence of the β2-vasodilatory effect.
What are the 7 cardiovascular stimulant/cardiotonic drugs?
- Epinephrine (E)
- NE
- Dopamine (DA)
- Dobutamine
- Isoproterenol
- Phenylephrine
- Ephedrine
What is the mechanism of downstream signaling of α1 and α2 metabotropic receptors?
α1→Gq→PLC→DAG and IP3→increase intracellular Ca2+
α2→Gi→inhibits AC→decreased cAMP
What is the mechanism of downstream signaling of the β receptors?
β→Gs→stimulation of AC→increased cAMP
occasionaly β2 stimulates cardiac Gi under some conditions
What is the downstream signaling mechanism of D1 and D5 receptors? What about D2?
D1/5→Gs→stimulation of AC→increased cAMP
D2→Gi→inhibition of AC→reduced cAMP
What are the three classifications of sympathomimetic drugs based on their mechanisms of action?
- Direct-acting drugs→stimulate the postsynaptic receptor
- Indirect-acting drugs→act presynaptically to increase the availability of NE or E
- Mixed-acting drugs→direct activation and indirect release of NE
What are three mechanisms thru which indirect-acting drugs act presynaptically to increase the availability of NE or E?
- Releasing or displacing NE from sympathetic nerve terminals
- Blocking reuptake/transport of NE into presynaptic sympathetic nerve terminals (e.g. cocaine)
- Blocking metabolizing enzymes of catecholamines such as MAO or COMT.
How does reserpine work? What effect does it have on the presynaptic availability of nt?
Reserpine prevents the packaging of the nt in the presynaptic nerve terminal. So, it depletes NE from sympathetic neurons, so there is no presynaptic NE available.
How would pre-treatment with Reserpine affect the action of a direct-acting drug at the level of the synapse? Why?
The response/action of the direct-acting drug is NOT reduced, as this type of drug act directly on the postsynaptic receptors. It may actually increase response, b/c lack of endogenous nt (NE) stimulating the receptor induces compensatory changes that upregulate receptors or enhance the signaling pathway. (this is why you have to taper off BBs)
How would pre-treatment with Reserpine affect the action of a indirect-acting drug at the level of the synapse?
The response would be ABOLISHED by pre-treatment of reserpine, because there is no presynaptic NE for it to indirectly increase the release of.
How would pre-treatment with Reserpine affect the action of a mixed-acting drug at the level of the synapse? What is this called?
The effects are blunted/reduced but not abolished by reserpine, b/c you still get the direct action, but you’ve lost the indirect action. This is a form of TACHYPHYLAXIS.
What is tachyphylaxis?
A fairly rapid loss/reduction of pharmacologic effect. It is progressive, so you’d get less and less effect as you keep repeating the dose. (In contrast, desensitization via endocytosis of GPCRs is a more long-term effect)
Both E and NE are __________?
pro-arrhythmogenic
How do the cardiac effects of E on HR, SV, CO, arrhythmia, and coronary blood flow compare with effects of NE?
They are both pro-arrhythrmogenic, and increase SV and coronary blood flow the same.
However, E increases the HR and CO, while NE either has no affect on or decreases these.
Why can E produce this increase in HR, while NE doesn’t?
This is b/c of the reflexive relationship b/t BP and SNS stimulation of the heart. NE is predominantly α1-mediated vasoconstriction which increases the BP. Immediately, the vagus (PS) fires off and tries to calm the heart down, so you don’t get the dramatic increase in HR, that you would with E. This is b/c E causes β2-mediated vasodilation of skel m vascular beds.
How do the effects of E and NE on systolic arterial P and diastolic arterial P compare?
Both NE and E increase systolic arterial P.
However, E has pretty much no effect on the diastolic arterial P (due to β2 involvement; increases Pulse pressure), while NE produces an increase diastolic P.
What are the effects of intravenous infusion of NE on PVR, HR, and BP?
a) You get potent vasoconstriction (increased PVR), so you get a rise in both systolic and diastolic BP, so the MAP increases, but pulse pressure is not significantly effected.
b) Increased MAP results in results in a reflexive decrease in HR (pulse rate) due to vagal stimulation
What are the effects of IV infusion of E on PVR, HR, and BP?
E stimulates the β2’s which vasodilate skel m vessels, so you don’t get the increase in PVR or in diastolic P, and it may even decrease. B/c of that, you dont get the compensatory suppression of the heart function, so HR increases.
What are the effects of IV infusion of isoproterenol on
Isoproterenol has no alpha-mediated action at all, only β-mediated. PVR decreases. Pulse pressure increases due to an increase in SBP but a decrease in DBP, and the MAP actually decreases slightly. There is not reflexive inhibition of the heart, so HR increases dramatically, even more so than it would be with E.
What are the two major factors involved in CV BP regulation?
- The wide-spread distribution of alpha and beta receptors in the heart, and blood vessels
- The neural and hormonal systems involved in BP regulations.
The net effect of a given sympathomimetic drug depends on what two things?
- Its relative receptor selectivity
2. Compensatory baroreceptor reflex mechanisms aimed at restoring BP homeostasis.
What are the effects of IV E on the BP?
- Direct vasoconstriction, esp in precapillary resistance vessels of skin, mucosa, and kidney, along with constriction of veins.
- Increase in SBP is greater than increase in DBP, so PP increases.
- Cardiostimulatory: direct myocardial inotropic and chronotropic effects (increased contractility and HR). This increased HR may be slowed by compensatory vagal stimulation.
- However, small doses may decrease BP
