Question 7

Classify the commonly used inotropic agents and describe their mechanism of action.

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College Answer

This question required a classification based on chemical structure and class action.
Sympathomimetics, phosphodiesterase inhibitors, calcium sensitizers and cardiac
glycosides should have been mentioned. Additional detail was expected,
subdividing Sympathomimetics into catecholamines (naturally occurring and
synthetic), and non-catecholamines (direct and indirect acting). Further classification
based on peripheral vasomotor action demonstrated greater understanding

Better answers included diagrams illustrating the mechanism and point of action on
the cardiac myocyte. Discussion of receptors, second messengers, and the role of
calcium was essential.
The question was aimed at “commonly used” agents, although some marks were
awarded for discussion of calcium, glucagon and other rarely used drugs.
Insufficient detail regarding mechanisms of action was a common observation.
Syllabus: C2d 2
References: Pharmacology and Physiology in Anaesthetic Practice, Stoelting 4th Ed
p293-320. Basic and Clinical Pharmacology Katzung 10th Ed p121-198.
Pharmacology Rang & Dale 6th Ed p168-187, 290-291

Discussion

Judging by the college answer, they wanted something like this:

Classification of inotropes
Class	Mechanism
Direct sympathomimetics
Endogenous Adrenaline Noradrenaline Dopamine Synthetic Dobutamine	Bind to beta-1 receptors Activate G-protein coupled adenylyl cyclase Increase cAMP production This leads to increased calcium availability inside the cardiac myocytes, and therefore increased contractility and pacemaker automaticity
Indirect sympathomimetics
Ephedrine	Act as "false neurotransmitters"; displace catecholamines from presynaptic storage vesicles The resulting catecholamine release produces direct catecholamine effects
Phosphodiesterase inhibitors
Milrinone Inamrinone Enoximone	Inhibit phosphodiesterase 3, which is responsible for cAMP catabolism. Thus, increases cyclic AMP Thus, increases calcium availability by increased voltage Selective for vascular smooth muscle and cardiac muscle.
Calcium sensitisers
Levosimendan Pimobendan	Bind to troponin C and stabilise its open state This allows muscle contraction. Thus increased trop C / calcium complex stability increases contractility.
Cardiac glycosides
Digoxin	Inhibits Na+/K+ ATPase Thus, increases intracellular sodium This increases sodium-calcium exchange by the Na+/Ca2+ exchanger (INCX) during Phase 1 of the cardiac action potential. The resulting increase in intracellular calcium promotes inotropy.

References

Palmer, Kenneth, and Stephen H. Pennefather. "Inotropes." Anaesthesia & Intensive Care Medicine 10.8 (2009): 362-366.

Feldman, Arthur M. "Classification of positive inotropic agents." Journal of the American College of Cardiology 22.4 (1993): 1223-1227.

Jentzer, Jacob C., et al. "Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit." Journal of cardiovascular pharmacology and therapeutics 20.3 (2015): 249-260.

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