Treating Angina Flashcards
What is the principle type of heart disease?
CAD
What are the primary risk factors for CAD? How common are these risk factors?
half of Americans have at least one:
- hypertension
- high LDL
- smoking
What is angina? What is the underlying event that elicits it?
- it is chest pain or discomfort
- occurs when the amount of blood delivered to the heart by the coronaries isn’t sufficient
What is the primary symptom of heart disease?
angina pectoris
What is angina pectoris?
- the primary symptom of heart disease
- it refers to chest pain result from myocardial ischemia
What drug class is used for immediate relief of angina? What about for prophylaxis?
- organic nitrates for immediate relief
- calcium channel blockers and beta blockers for prophylaxis
How is angina often described by patients?
as a strangling, vise-like, constricting, or crushing chest pain
- retrosternal, often radiating down the left arm
- usually relieved within minutes of rest or administration of nitroglycerin
Where do most patients localize their angina to?
retrosternal, often radiating down the left arm
What are the two general types of angina? How do they differ in etiology?
- classic (aka atherosclerotic): atheromatous obstruction of large coronaries, often presenting during exercise
- variant (aka angiospastic): spasm or constriction of atherosclerotic coronary vessels, often not in the setting of exercise
How does the treatment of classic angina differ from that of variant angina?
- variant is relieved by nitrates or calcium channel blockers
- classic may be uncontrolled by drugs and require coronary bypass or angioplasty
The oxygen demand of cardiac tissue depends on what?
cardiac workload as determined by inotropy, heart rate, and wall stress
Why does angina often present during times of stress or during physical activity?
because both increase sympathetic tone and increase the workload of the heart
What is the main energy source in cardiac myocytes? How does this affect it’s oxygen demand?
these cells use primarily fatty acid oxidation, which requires more oxygen than glycolysis
How is trimetazidine used in the treatment of angina?
it is a pFOX inhibitor which partially inhibits fatty acid oxidation and shifts the heart’s metabolism toward more glycolysis, reducing it’s oxygen demand
What are pFOX inhibitors?
drugs that reduce the hearts oxygen demand by inhibiting fatty acid oxidation and shifting the hearts metabolism towards glycolysis
Coronary blood flow is directly related to what two factors?
- perfusion pressure
- duration of diastole
Through what second messenger does NO induce vasodilation?
it stimulates GC to produce more cGMP
Through what mechanism does Ranolazine treat angina?
its reduces intracellular calcium concentration to reduce cardiac contractility and oxygen demand
Through what mechanism does allopurinol treat angina?
it preserves coronary blood flow by inhibiting xanthine oxidase, thereby reducing oxidative stress and endothelial dysfunction
List the short acting nitrates used for treating angina.
- amyl nitrite
- nitroglycerin
- isosorbide dinitrate
What are the beneficial effects of nitrates?
- pronounced dilation of large veins, reducing preload
- reduced ventricular diastolic pressure, improving subendocardial perfusion
- redistribution of regional coronary blood flow from normal to ischemic areas
- mild arteriolar dilation, reducing afterload
Are nitrates balanced vasodilators or not?
no, they preferentially dilate large veins
What is sildenafil?
an inhibitor of PDE-5, an enzyme that normally metabolizes cGMP, and serves to potentiate the effects of nitrate therapy
When using a nitrate with sildenafil, what must you be careful of?
sildenafil will potentiate the effects of nitric oxide and could induce severe hypotension leading to myocardial ischemia and infarction
How does cGMP affect platelets?
it inhibits aggregation
Nitrates
- a class of drugs used in the treatment of angina
- function to increase NO release and the downstream effects of cGMP
- benefits arise from pronounced dilation of large veins reducing preload, redistribution of regional coronary blood flow to ischemic areas, and mild arteriolar dilation which reduces afterload
- adverse effects include reflex tachycardia and increased inotropy, which increase O2 demand while shortening diastole and cardiac blood supply
- acute nitrate toxicity can cause strong vasodilation leading to orthostatic hypotension, tachycardia, and throbbing headaches (“Monday disease”)
- often given sublingual for rapid administration without first pass effect
- fastest preparations are inhaled amyl nitrite and IV sodium nitroprusside
- subject to a strong first pass effect by hepatic reductase
- minimize tolerance, which builds quickly, in those receiving chronic treatment by using the lowest effective dose with nitrate-free intervals of 10-12 hours daily
What is the preferred route of administration for nitroglycerin and isosorbide dinitrate? Why?
they are given sublingual, which allows for rapid absorption and avoiding hepatic destruction
Which oral route of administration isn’t subject to first pass effect?
sublingual
Oral nitrates are subject to a strong first pass effect by which enzyme?
hepatic reductase
What is unique about sodium nitroprusside compared to the other nitrates?
it dilates arteries and veins equally
What are the two fastest acting preparations of nitrate therapy?
- inhaled amyl nitrite
- IV sodium nitroprusside
Describe the pharmacokinetics of sublingual nitroglycerin.
- used for immediate anginal relief
- rapid onset
- short duration although they avoid first pass effect
How is tolerance minimized in those receiving nitrate therapy?
in those receiving chronic treatment, the lowest effective dose is administered in addition to nitrate-free intervals of 10-12 hours daily
What is “Monday disease”?
headache and dizziness experienced by explosives manufactures on Mondays as their tolerance diminishes over weekends
What are the two major types of calcium channels in the heart?
L-channel (long lasting) and T-channel (transient)
What are the two important cardiovascular actions of calcium current?
- triggers contraction of myocardium and vascular smooth muscles
- required for pacemaker activity of the SA node and conduction through the AV node
Calcium channel blockers typically block which specific channel type?
L-type channels in the myocardium and vascular smooth muscles
Do CCBs induce a balanced vasodilation or not?
no, arterioles are more sensitive to the effects than veins
Which smooth muscles in the body are most sensitive to the effects of CCBs?
- vascular smooth muscles are most sensitive (arterioles > veins)
- followed by bronchiolar, GI, and uterine smooth muscle
What are 1A, 1B, and 1C CCBs?
refer to CCBs that act on different binding sites on the L-type calcium channel
What controls the tissue selectivity of calcium channel blockers?
the binding site (1A, 1B, or 1C) to which they bind on the L-type calcium channels
CCBs work on which calcium channel?
L-type
What are the three classes of CCBs? How do they differ in action and tissue selectivity?
- dihydropyridines (nifedipine): binds 1A and has vascular selectivity
- benzothiazepines (diltiazem): binds 1B and has balanced action between the vasculature and heart
- phenylalkylamine (verapamil): binds 1C and preferentially acts in the myocardium
What are the major cardiac effects of CCBs like verapamil?
- decrease contractility
- reduce SA node impulse generation
- slow AV node conduction
A balanced CCB like diltiazem has what effects?
- preferential dilation of arterioles
- decreased inotropy
- slowed SA node impulse generation (low HR)
- slowed AV node conduction
How does the CCB nifedipine affect the heart?
- it has vascular selectivity and causes arteriolar dilation
- because it doesn’t also inhibit calcium channels in the heart, there is a reflex tachycardia
Which CCB is most and least likely to elicit reflex tachycardia?
- nifedipine is has vascular selectivity and therefore is most likely
- verapamil has a strong myocardial depressive effect and is least likely
Dihydropyridine CCBs
- 1A CCBs with vascular selectivity
- act by blocking L-type calcium channels
- induce coronary and systemic vasodilation, thereby increasing myocardial oxygen delivery and reducing afterload
- risk of MI due to reflex tachycardia
- side effects include flushing, edema, dizziness, nausea, and constipation (smooth muscle outside the CV system)
- also interfere with platelet aggregation and insulin secretion
Non-dihydropyridine CCBs
- 1B and 1C CCBs that act on L-type calcium channels
- 1B are balanced while 1C have more cardiac effects than vascular
- function to reduce SA automaticity, AV conduction, and inotropy
- both inhibit reflex tachycardia, in contrast to the dihydropyridines
- but serious cardiac depression could cause cardiac arrest, CHF, or AV heart block
- side effects include flushing, edema, dizziness, nausea, and constipation (smooth muscle outside the CV system)
- also interfere with insulin secretion and platelet aggregation
- may reduce renal clearance of digoxin and enhance toxicity
- contraindicated in patients with SA or AV node disturbances
What are the side effects of calcium channel blockers?
- inhibition of insulin secretion
- interference with platelet aggregation
- flushing, edema
- dizziness
- nausea
- constipation
Beta-Blockers in the treatment of angina
- atenolol, metoprolol, and propranolol are the most commonly used for angina
- act by decreasing sympathetic tone, reducing inotropy, heart rate (prolonged diastole), and afterload (inhibit constriction and some directly induce dilation), without dilating coronary arteries
- produce better outcomes and symptomatic relief than CCBs, improve mortality in patients with MI, reduce incidence of stroke in patients with HTN, effective in those with silent/ambulatory ischemia
- most useful for management of angina associated with effort
- may induce or worsen CHF in patients with acute MI or decompensated heart failure and reduce exercise tolerance in these patients
- potentially harmful in variant angina
- may increase plasma triglycerides and decrease HDL, promoting atherogenesis; inhibit the hyperglycemic response of epinephrine, delaying normoglycemia
- use with caution in patients with reduced myocardial reserve, asthma, peripheral vascular insufficiency, or diabetes
- minor SE: GI or CNS disturbance
How does the efficacy of beta blockers compare to CCBs?
beta blockers are associated with better outcomes and greater symptomatic relief than CCBs
Beta blockers are especially useful for what kind of angina?
that associated with exercise
Beta blockers have been shown to have what beneficial long-term outcomes?
- reduced mortality in patients with MI
- improved survival and prevention of stroke in patients with hypertension
- better outcomes and symptomatic relief than CCB in those with angina
- reduce ischemic time per day in those with ambulatory or silent myocardial ischemia
What is ambulatory ischemia? How is it best treated?
- myocardial ischemia which is only detected by the appearance of ECG signs
- beta blockers are particularly useful in treating these cases because they reduce total amount of ischemic time per day
Through what mechanism do beta blockers reduce afterload?
some inhibit vasoconstriction and some also induce vasodilation directly
What are the adverse effects associated with beta blocker use in angina?
- may induce or worsen CHF and reduce exercise tolerance in these patients
- may promote atherogenesis by increasing plasma triglycerides and decreasing HDL
- may be harmful in those with variant angina
- inhibits hyperglycemic responses mediated by epinephrine and delays recovery of normoglycemia
Why are beta blockers harmful for patients with variant angina?
- because beta blockers slow heart rate and prolong ejection time
- this increases LV EDV and increases the myocardial oxygen requirement
Why is it beneficial to combine nitrates with a beta blocker or non-dihydropyridine CCB?
because beta blockers and these CCBs will inhibit the reflex tachycardia that accompanies nitrate use
Effective anti-anginal therapy will achieve what two goals?
- increase exercise tolerance
- decrease frequency and duration of myocardial ischemia
What are the preferred drugs for variant angina? Why?
nitrates and CCBs which both dilate spastic coronary blood vessels
What is first-line therapy for angina?
- modify risk factors
- add an anti-platelet drug like aspirin
- recommend a statin plus weight loss
- treat the underlying cause of atherosclerosis
What are the two most effective drug combinations for the treatment of angina?
- beta blocker + CCB
- a dihydropyridine CCB and verapamil
What mono therapy for angina is recommended in patients hypertension? Normotensive?
- hypertensive patients: slow release CCB or beta blocker
- normotensive: long-acting nitrate
