Cardiac Ischemia Flashcards
Angina pectoris is the result of
the build up of metabolites in the heart as a result of inadequate coronary blood flow
The goal of antianginal therapy is
to re-establish adequate blood supply to the myocardium (heart muscle)
Myocardial oxygen demand is related to
heart rate, contractility, and wall tension
Double Product (Estimate):
heart rate X systolic BP
conditions that compromise blood flow through the coronary arteries can cause
angina
What can exacerbate angina?
factors that increase the work load of the myocardium
Factor affecting blood flow to the myocardium
pre-load, after-load, heart rate
Pre-load
left ventricular end-diastolic pressure
After-load
force distributed in ventricular wall during systole
What is pre-load decreased by?
decreased by dilation of the veins
A decrease in pre-load leads to
decrease in oxygen consumption and an increase in myocardial perfusion
What is after-load decreased by?
decreased by dilation of the arteries
A decrease in after-load leads to
decrease in oxygen consumption
What is the blood flow through the coronary arteries during systole?
little or no flow through coronaries during systole
Stable or classic angina (angina of effort)
Chronic obstruction of coronary arteries - usually atherosclerotic; perfusion is inadequate to meet increased oxygen demand
When does stable angina occur
occurs with increased physical exertion - predictable
Variant (Vasospastic, Prinzmetal’s) angina
caused by sudden, transient constriction of large coronary arteries; occurs at rest, often at night; not predictable
Unstable (pre-infarct, crescendo) angina
new or sudden worsening of angina at rest; caused by thrombosis (clot formation) usually secondary to atherosclerotic rupture; often first warning of MI
Therapy for unstable angina is based on
inhibiting platelet function and dissolving clot
goal of treatment for stable and variant angina
goal is to dilate coronary arteries and increase perfusion and/or decrease myocardial oxygen demand
Agents used in treating stable and variant angina
organic nitrates
calcium channel blockers
beta-adrenergic receptor antagonists (beta blockers)
Mechanism of organic nitrates
NO donating compounds; activators of guanylate cyclase
Activity of organic nitrates
marked dilation of veins; some dilation of arteries (esp. coronaries); some inhibition of platelet aggregation
When/how are organic nitrates given?
given sublingually in treatment of acute attacks of angina
given orally or transdermally for prolonged prophylaxis
What happens with continuous administration of organic nitrates?
tolerance develops; mechanism involves inhibition of ALDH2
How do you avoid tolerance with organic nitrates
avoided by brief periods (several hours) without the drug
Mechanism of calcium channel blockers in angina
decrease influx of Ca2+, the trigger for contraction
Which calcium channel blocker has high vascular selectivity?
DHPs
Activity calcium channel blockers in angina?
dilation of arteries: decrease in afterload
no dilation of veins: no effect on preload
Mechanism of beta blockers in angina
block of epinephrine stimulation of myocardium; negative inotropic and chronotropic effect; lower heart rate increases coronary perfusion
Activity of beta blockers in angina
decreases oxygen demand by depressing myocardium, especially during exertion
Automaticity is caused by
HCN2/4 channels - depolarizing Na+ current activated at “resting” membrane potential
SA and AV node rate is increased by
hypokalemia; beta-adrenergic stimulation; fiber stretch; acidosis; depolarized resting potential (injury)
beta1-adrenergic antagonists inhibit
the HCN conductance mediated by endogenous epinephrine and norepinephrine
Ivabradine (Procoralan)
selective blocker of the HCN channel; reduces HR; approved for symptomatic treatment of angina in Europe and Asia for patients who can’t take beta-blockers
PKA phosphorylation of Cav1.2 does what?
increases Ca2+ influx; increases contractility/force of contraction; increased AV nodal action potential conduction rate
Combination therapies for angina:
- organic nitrates and beta-blockers
- calcium channel blockers and beta-blockers
- calcium channel blockers and organic nitrates
- calcium channel blockers, organic nitrates, and beta blockers
combination therapy particularly effect in stable angina
organic nitrates and beta-blockers
combination therapy effective in stable angina refractory to organic nitrate/beta-blocker combination
calcium channel blockers and beta-blockers
combination therapy contraindicated in angina associated with heart failure
calcium channel blockers and organic nitrates
combination therapy effective in the treatment of severe vasospastic or stable angina
calcium channel blockers and organic nitrates
combination therapy that may be effective when double therapy is not
calcium channel blockers, organic nitrates, beta-blockers
Side effects of Diltiazem
low incidence of intolerance
Side effects of Verapamil
constipating
Side effects of beta-blockers
exacerbate bronchoconstriction
Side effects of DHPs
have no antiarrhythmic activty
Ranolazine inhibits
late sodium current
Ranolazine (Ranexa) is used to prevent
angin
Ranolazine is not effective in
terminating angina attacks
Ranolazine is metabolized by
CYP3A (major) and CYP2D6 (minor)
Ranolazine is a substrate for
P-glycoprotein transporter
Side effects of Ranolazine
dizziness; may cause lengthening of the QT interval
Factors that lead to plaque instability
large lipid pool, thin fibrous cap, inflammation
Strategies to stabilize plaques and prevent rupture
Reduce LDL
Increase HDL
Inhibit Lp-PLA2
Inhibit MMPs
Inhibition of inflammation (esp. IL-1, IL-6)
Inhibition of cholesterol crystallization
Paclitaxel
binds microtubules and stabilizes polymerization
Sirolimus
macrolide that binds FKBP12 and inhibits mTOR to prevent cell cycle progression
How do paclitaxel and sirolimus prevent restenosis
by inhibiting smooth muscle cell proliferation
