myocardial ischemia (IHD)
imbalance between myocardial O2 supply and demand
IHD contributing factors
- increased sympathetic outflow-> incr HR, ventricular wall tension & ventricular contractility-> incr myocardial demand
- decreased coronary blood flow due to coronary vasospasm &/or coronary atherosclerosis (CAD)-> decreased myocardial O2 supply
coronary artery disease
a condition in which coronary arteries are narrowed by the formation of atherosclerotic plaques
main symproms of myocardial ischemia
- angina
2. decreased exercise tolerance
myocardial ischemia generally preceds
MI
2 distinct characteristics of MI
- sudden interruption of blood supply to the myocardium by rupture of a plaque resulting in thrombosis
- myocardial function is compromised & tissue can become necrotic
IHD short term goal of therapy
prevent/reduce symptoms of angina that limits exercise capability & quality of life
IHD long term goals of therapy
prevent events of myocardial ischemia (MI, arrhythmias, HF) & reduce mortality (extend life)
IHD treatment
- risk factor modification
- nonpharm therapy: revascularization, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty
pharmacological agents used
- nitrates
- beta blcokers
- CCB
- anticoagulants
- antiplatelet agents
- thrombolytic agents
- statins
- ACEI
- pure antianginal drugs
- morphine
pharmacological treatments improved the balance between O2 supply & demand by:
- dilating the coronary vasculature (increase O2 supply)
- reducing cardiac workload (decrease demand)
organic nitrates MOA
- prodrugs
- upon metabolism release NO
- NO is also biosynthesized in different tissues by NOS
- Potent vasodilator
- NO stimulates guanylyl cyclase-> incr cGMP-> dec intracellular Ca & MLC dephosphorylation-> SM relaxation
hemodynamic effects of low dose nitrates
- preferentially dilate veins compared to arterioles-> decreased venous return & preload & decreased left & right ventricular chamber size
- (slight decr. in BP)
hemodynamic effects of high dose nitrates
- cause further venous pooling & decrease arteriol resistance
- activation of compensatory sympathetic reflexes (tachycardia)
- cronary blood flow may increase transiently, but it will decrease again if cardiac output & BP are decreased significantly
total & regional coronary blood flow (low to moderate doses of nitrates)
- vasodilate & restore the flow in epicardial vessels
- do not impair autoregulation in smaller vessels
- decrease intracavitary systolic & diastolic pressures-> incr blood flow to the subendocardium
- dilate cardiac veins (may improve cardiac microcirculation)
nitrate effects on myocardial O2 requirements
- incr ventous capacitance-> decr venous return-> decr preload-> reduced O2 demand & incr blood flow to subendocardium
antianginal effects of nitrates
- reduction of venous return & myocardial O2 demand- primary effect*
- dilation of epicardial coronary arteries-> improved blood flow & O2 supply
- NO in plts-> antiplt effect (modest, but important)
tolerance to nitrates
repeated/continuous use of (high) doses of nitrates may lead to marked attenuation of their pharmacological effects (tachyphylaxis)
nitrate side effects
- HA
- transient dizziness & weakness
- postural/orthostatic hypotension
- drug rash
caution using nitrates with
PDE5 inhibitors-> severe hypotension!
PDE5I inhibit the conversion of cGMP to GMP-> incr cGMP-> vasodilation
PDE5 inhibitors
sildenafil (viagra)
tadalafil (cialis)
vardenafi (levitra)
nitrate drugs
nitroglycerin isosorbide dinitrate isosorbide mononitrate nitroglycerin IV nitroglycerin patch
nitrates
- all have a large first pass effects
- all but isosorbine mono have short T1/2 & high clearance rates
- large interindiviual variations in plasma conc.
nitroglycerin concentrations are effected by
- route of admin
- IV: highest
- oral: lowerst
