Human aspects of cardiovascular and renal pharmacology: Angina Flashcards
Angiogenesis
Individuals with ischaemic heart disease develop collateral blood vessels as a response to the poor perfusion.
Collaterals also develop in normal individuals who take regular, sustained, aerobic exercise
Nitrovasodilators- mechanism of action
Side effects?
‘Nitrovasodilators’ is a misnomer- are organic nitro derivatives.
Are converted into NO in vascular smooth muscle cells (modulated by endothelial cell Ca sensitive NO synthase [ecNOS] )
Vasodilatory action, mediated by cGMP.
Main action in angina through
- venous dilation (decreases right atrial filling pressure)
- action on collateral blood vessels (seem to produce vasodilation in ischaemic > well oxygenated areas)
Secondary response to use of nitrates to treat angina may be severe headache (NB changes in cerebral blood flow implicated in migrane)
Nitrovasodilators- examples
Glyceryl trinitrate, isosorbide dinitrate, amyl nitrate
Glyceryl trinitrate
Uses? Administration?
Nitrovasodilator
Used to treat angina, esp acute attacks
Poorly absorbed from the stomach, taken sublingually.
Actually nitroglycerin, the main component of dynamite
Isosorbide dinitrate
Nitrovasodilator
Used in treatment of angina
Prodrug: metabolised in liver -> isosorbide mononitrate
Amyl nitrate
Nitrovasodilator
Dipyridamole
Vasodilator
Stimulates adenosine receptors
Effects on all vessels- in ischaemic & well oxygenated tissues - ‘coronary steal’
Dihydropyridines
Mechanism?
Selectivity?
Ca2+ channel antagonists
Blocks Ca2+ entry into vascular smooth muscle cells
Vasodilation, reduces BP and afterload
Binds to inactivated form of channel- so work preferentially on smooth muscle > cardiac channels. Low resting potential (-50 to -60) of smooth muscle- more channels inactivated.
Nifedipine
A dihydropyridine
Ivabradine
Side effects?
Targets HCN channels. Acts on If current, highly expressed in SAN.
Reduces cardiac pacemaker activity, slows HR & allows more time for blood to flow to myocardium
Effects selective for sinus node, no effects on intra-cardiac conduction, myocardial contractility or ventricular repolarization.
Ischaemic preconditioning
Phenomenon by which several short periods of ischaemia increase the ability of the heart to withstand longer periods.
Mechanism is unclear, may involve opening of mitoK[ATP] channels. NO dependent pathway implicated
Can be blocked by adenosine R antagonists, mimicked by agonists
Nicorandil
Opens K[ATP] channels
Seems to stimulate ischaemic preconditioning
May act via opening of a mitochondrial KATP channel- acts to preserve mitochondrial ATP levels during ischaemia.
Also a NO donor.
Vascular endothelial growth factor (VEGF)
Possible future gene therapy for angina in stimulating angiogenesis
Causes development of new blood vessels at site of expression
Neo-vascularisation can be achieved with single injection of gene transfer vector, but limited duration required to avoid abnormal angiogenesis (plasmid & adenoviral vectors are promising)
Hypoxia-inducible factor 1 α (HIF-1 α)
Possible future gene therapy for angina in stimulating angiogenesis
Regulates expression of multiple angiogenic genes incl VEGF.
Sirolimus
Eluted by antiproliferative drug-eluting stents
Targets mTOR
Reduce incidence of restenosis by inhibiting development of neointimal proliferation.
