B4.050 Treatment of Angina Flashcards
etiology of CAD
mainly due to obstruction of coronaries by atheromatous plaques
leading cause of death in US
heart disease
both women and men
CAD is principle type of heart disease
three major risk factors of CAD
high BP
high LDL cholesterol
smoking
49% of americans have one of the three at least
other risk factors of CAD
diabetes overweight/ obesity poor diet physical inactivity excessive alcohol use
what is angina pectoris
primary symptom of heart disease, refers to chest pain resulting from myocardial ischemia
characterize angina pectoris
chest pain when amount of blood delivered to heart by coronary arteries cannot supply enough O2 to satisfy myocardial requirement
oxygen need exceeds oxygen supply
for immediate relief of angina
organic nitrates (nitroglycerin)
for prophylaxis for angina
CCBs and B blockers
describe pain associated with angina
severe chest pain described as: strangling, constricting, suffocating, crushing, heavy, or squeezing
chest discomfort may be vague (esp in women) and accompanied by numbing, nausea, sweating, SOB
usually retrosternal; often radiating down left arm though may involve both arms
typically relieved within minutes by rest or w nitro
2 types of angina
classic/ atherosclerotic
variant/ angiospastic / prinzmetals
etiology of classic angina
atheromatous obstruction of large coronaries
especially present w exercise
treatment of classic angina
if uncontrolled by drugs, may require coronary bypass or angioplasty
etiology of variant angina
spasm or constriction of in atherosclerotic coronary vessels
treatment of variant angina
relieved by nitrates or CCBs
what determines oxygen demand of myocardium
cardiac workload:
- contractility (major determinant)
- HR
- wall stress (IV pressure, ventricular volume, wall thickness)
what drugs help with myocardial ischemia?
drugs that reduce cardiac size, rate, or force and therefore reduce cardiac oxygen demand
CCBs, B-blockers
what is the main energy source in the heart and why is it significant
fatty acid oxidation
required more oxygen than glycolysis
mechanism of trimetazidine
shift myocardial metabolism towards greater use of glucose
has potential to reduce O2 demand without affecting hemodynamics
called pFOX inhibitors: partially inhibit fatty acid oxidation
what determines O2 supply
O2 delivery
extraction (better when blood speed is slower moving through vessels)
how might additional O2 be supplied to the myocardium
ONLY by increasing O2 delivery through coronary blood flow
what are the determinants of O2 delivery through coronary blood flow
directly related to perfusion pressure and duration of diastole
inversely proportional to coronary vascular resistance, determined by: metabolic products, autonomic activity, various drugs
damage to endothelium of coronary vessels increases vascular resistance
what are some mechanical interventions that can increase O2 supply
stent
angioplasty
coronary bypass surgery
how do CCBs impact vascular tone
decrease intracellular Ca2+
Ca2+ needed in pathway to myosin/actin contraction
why does increasing cAMP relax vascular smooth muscle
cAMP phosphorylates MLCK which prevents it from phosphorylating myosin light chains allowing them to contract
what drugs increase cAMP
B2 agonists
not used in angina
what is the mechanism of action of nicorandil
K+ channel opener
prevents depolarization
how does increasing cGMP relax vascular smooth muscle?
cGMP dephosphorylates myosin light chains preventing them from relaxing
how does NO work to relax muscle?
activator of soluble guanylyl cyclase
guanylyl cyclase is involved in converting GTP to cGMP
how does sildenafil work
inhibits PDE5, which normally breaks down cGMP
if you inhibit the breakdown, you have more free cGMP, thus more relaxation
how do organic nitrates, CCBs, and B blockers decrease myocardial O2 demand?
decrease
- HR
- ventricular volume
- BP
- contractility
what is 4th drug group used in angina?
recently approved
ranolazine
mechanism of action of ranolazine
reduces intracellular calcium concentration and thus reduces contractility and work
mechanism of action of allopurinol
inhibits xanthine oxidase (which contributes to oxidative stress and endothelial dysfunction)
high doses prolong exercise time in patients w angina
direct bradycardic agent
ivabradine
mechanism of action of ivabradine
inhibit hyperpolarization activated sodium channel in the SA node
rho-kinase inhibitor
fasudil
mechanism of action of fasudil
reduce coronary vasospasm in experimental animals
where do nitrates primarily work and why
venous side
this is where enzymes are primarily found
why does sodium nitroprusside act on both veins and arteries
doesn’t require enzymes to work
what can endogenously release NO
endothelial cells
what is the mechanism of action of NO
activate guanylyl cyclase
GC can then convert GTP to cGMP
CGMP dephosphorylates myosin light chains
relaxation
2 types of nitrates
short acting 3-60 min
long acting 2-10 hours
routes of administration of short acting nitrates
inhalant
sublingual
routes of administration of long acting nitrates
oral ointment buccal transdermal chewable
4 primary nitrates
amyl nitrite (short only) nitroglycerin (short or long) isosorbide dinitrate (short or long) isosobide mononitrate (long only)
other effects of NO
erection via relaxation of corpora cavernosa
increased cGMP in platelets decreases aggregation
nitrite ion reaction with hemoglobin can cause methemoglobinemia
3 primary mechanisms by which nitrate therapy is beneficial
- pronounced dilation of large veins to reduce preload, myocardial O2 demand, and cardiac work
- redistribution of regional coronary blood flow from normal to ischemic areas due to preferential dilation of large epicardial arteries
- mild arteriolar dilation to reduce afterload and myocardial O2 demand
harmful effects of nitrates
reflex tachycardia and contractility
- increased myocardial O2 demand
- reduced perfusion due to shortened diastole
how to prevent harmful effects of nitrates
add B-blocker of CCB to nitrate administration
issue with oral nitrates
rapidly metabolized by hepatic reductase
fast acting drugs bypass the liver
fastest acting nitrate preparations
inhaled amyl nitrite
IV sodium nitroprusside
sublingual nitroglycerin pharmacokinetics
used for immediate angina relief rapid action (onset 1-3 min), short (duration 10-30 min), but not suitable for maintenance or chronic therapy
how do you minimize tolerance from nitrates?
during chronic treatment use lowest effective dose with nitrate free intervals of 10-12 hrs daily
acute nitrate toxicity
strong vasodilation resulting in orthostatic hypotension, tachycardia, and throbbing headaches
“Monday disease”
manufacturers that are chronically exposed to high nitrate levels become tolerant
after a weekend away from nitrates, get headache and dizziness on Mondays bc tolerance diminishes
2 important cardio actions of intracellular calcium
triggers contraction in myocardium and vascular smooth muscle
required for pacemaker activity of SA node and for conduction through AV node
how are Ca2+ channels regulated in heart and vascular smooth muscle
opened by stimulation of B receptors to enhance calcium entry
closed by CCBs to inhibit calcium entry
which muscles are most sensitive to CCBs
vascular smooth muscles, bronchiolar, GI, and uterine
arterioles more sensitive than veins
how is CCB tissue selectivity established
L-type Ca channel has 3 different binding sites (1A, 1B, 1C)
1A = vascular
1B = combo
1C = myocardial
what happens on the molecular level with a CCB binds to a calcium channel?
pores close on calcium channel
decrease of transmembrane Ca currents
major cardiac effects of CCBs
decreased contractility
decreased SA node impulse generation
decreased AV node conduction
discuss differences in tissue selectivity and how they impact HR
nifedipine (dihydropyridines) strongest vasodilator, verapamil strongest cardiac effects, diltiazem in between
HR increased by nifedipine bc of reflex tachy after vasodilation, HR decreased by verapamil due to SA and AV depression
beneficial effects of dihydropyridines
coronary vasodilation > increased myocardial O2 supply
vasodilation of systemic arteries > decreased afterload
harmful effect of dihydropyridines
increased risk of MI
pronounced hypotension > reflex tachy > increased cardiac workload
short acting CCB should be avoided in patients with HTN
beneficial effects of verapamil/diltiazem
reduced SA automaticity and AV conduction
decreased myocardial contractility and bradycardia > reduced cardiac workload
harmful effect of verapamil and diltiazem
the potential for serious cardiac depression that could result in
-cardiac arrest
-AV block
-CHF
don’t use in pts with ventricular dysfunction of SA-AV node disturbances
other CCB effects
inhibition of insulin secretion
interference with platelet aggregation
flushing, edema, dizziness, nausea, constipation
how do verapamil and diltiazem enhance digoxin toxicity
reduce digoxin renal clearance to increase plasma digoxin
B blockers used in angina
atenolol
metoprolol
sometimes propranolol, nadolol
when are B blockers especially useful
management of angina associated with effort
reduce myocardial O2 requirements at rest and during exercise
which is better for angina, B blockers or CCBs?
B blockers produce better outcomes and symptomatic treatment
what have B blockers been shown to do in patents with heart disease
reduce mortality in patients with MI
improve survival and prevent stroke in hypertensive pts
beneficial effects of B blockers in angina
decreased sympathetic activity > decreased contractility, HR, and vasoconstriction > decreased cardiac workload > decreased O2 demand
direct vasodilation by some B blockers
bradycardia prolongs diastole and increases perfusion time
harmful effect of B blockers
may induce or worsen CHF whenever sympathetic activity is critical to support cardiac performance
goals of effective antianginal therapy
increase exercise tolerance
decrease frequency and duration or myocardial ischemia
which drugs are more effective for variant angina
nitrates and CCBs
B-blockers do not dilate spastic coronary blood vessels
angina therapy for hypertensive patient
monotherapy w slow release CCB or B blocker
angina therapy for normotensive patient
long acting nitrates
most effective drug combos
B blocker + CCB 2 CCBs (vera and nife)
how can harmful effects of CCBs or B blockers be avoided?
combined treatment w nitrates
