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