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Flashcards in Drugs affecting cyclic AMP Deck (11):

What are cyclic nucleotides?

Nucleotides in which a phosphate group is bonded to two of the sugar's OH residues
Formed from ATP and GTP by action of specific cyclases- adenylate cyclase/ guanylate cyclase


Major cardiovascular actions of cyclic nucleotides

Increases vascular smooth muscle relaxation
Decreases platelet aggregation
Increases myocardial contractility
Increases heart rate


Action of cAMP in cardiac muscle, vascular smooth muscle and platelets

In cardiac muscle, cAMP/PKA promotes contraction by increasing intracellular calcium concentration and calcium sensitivity (increase in calcium influx through L-type calcium channels and increase in calcium sequestration by SR >>> CICR)


Anti-platelet action of low dose aspirin

Irreversible serine acetylation and inhibition of COX-1
Relatively selective effect of low-dose aspirin on platelets:
Endothelial cells can resynthesise COX-1, platelets can not
Aspirin absorbed from gut into portal circulation
A concentration is achieved that is high enough to inhibit COX-1 in platelets passing through portal circulation
Endothelial cells in general circulation are only exposed to low concentration of aspirin (and can regenerate COX-1)


Why is low dose aspirin not pro-aggregatory through inhibition of endothelial COX-1?

Low dose aspirin produces major reduction in pro-aggregatory platelet TXA2 synthesis while having little effect on endothelial PG12 synthesis which is anti-aggregatory


What are the actions of prostanoids and what are they being developed for?
Give some examples

Cause pulmonary vasodilation, inhibition of platelet aggregation and inhibition of smooth muscle cell hyperplasia
Prostanoids are particularly being developed for severe idiopathic pulmonary arterial hypertension (PAH)
e.g. epoprostenol, iloprost, treprostinol and bereprost
Inhaled NO gas also used for some forms of PAH and respiratory distress syndrome in premature infants


Phosphodiesterase -III selective inhibitors

PDE-III inhibitors are used as inotropes in short-term management of heart failure (acute decompensation)
Short term IV use
Chronic treatment worsens survival, probably by promoting arrhythmia development


What is the role of cAMP?
How is cAMP affected by prostanoids?

cAMP is a secondary messenger for many physiological mediators, regulated by enzyme pathways
Prostanoids elevate cAMP concentration


How does low dose aspirin spare endothelial COX-1/ prevent platelet adhesion and activation?

By targeting COX-1 in platelets preferentially, low dose aspirin spares endothelial COX-1 and prevents platelet activation and adhesion


What are the evolving uses of prostanoids?

Vasodilators in PAH


What are the effects of PDE-III inhibitors?

PDE-III inhibitors prevent breakdown of cAMP, inotropic, enhancing sympathetic action on cardiac contractility but are only used for short term management of CHF