Drugs for ischemia & angina

Question 1

• causes vasodilation of coronary arteries by NO release
• opens potassium channels to maintain resting membrane potential
• nicotinamide nitrate ester

Answer 1

Nicorandil (Europe and Japan)

Question 2

• nonselectively blocks L-type calcium channels of the vessels and the heart
• binding to receptor is better when channel is open but then drug decreases frequency of opening, decreasing the calcium current-> smooth muscle relaxation
• reduces vascular resistance, HR (AV node and SA node effects), force of contraction-> decreases myocardial demand
• high first pass effect, high protein binding, extensive metabolism
• binding to its receptors allosterically affects binding of dihydropyridine
• caution with digoxin -> interaction raises its level
• short-term formulations contraindicated in unstable angina -> increased risk of cardiac events

Answer 2

verapamil
diltiazem

• verapamil and diltiazem uses include:
  1. supraventricular reentry tachycardia
  2. afib
  3. aflutter

Use long-acting calcium channel blockers as second line treatment for angina. Do not use short-acting calcium channel blockers for angina as can cause rapid changes in bp

Question 3

• dihydropyridine that selectively blocks vascular L-type calcium channels more than cardiac channels (less cardiac effect)
• orthostatic hypotension is not a significant effect

Answer 3

nifedipine

*does not affect conduction, so is safer for use in blocks

Question 4

Why is skeletal muscle contraction not depressed by calcium channel blockers?

Answer 4

it uses intracellular pools of calcium for EC coupling and does not require as much transmembrane calcium influx

Question 5

Why is verapamil inhibition of release of insulin not typically a concern?

Answer 5

the dosage required to produce this effect is greater than the dosage used to manage angina & other cardiac conditions
-this is referring to the stimulus-secretion coupling in glands and nerve endings

Question 6

Toxicities of calcium channel blockers are?

Answer 6

serious cardiac depression: bradycardia, AV block, cardiac arrest, heart failure
-minor tox: flushing, dizziness, nausea, constipation (verapamil), peripheral edema

Question 7

What are the undesirable effects of beta blockers in treatment of angina?

Answer 7

increased end diastolic volume and increased ejection time, both of which increase myocardial O2 demand
Give nitrates to balance this effect
Note: beta blockers are contraindicated in asthma, severe bradycardia, AV block, bradycardia-tachycardia syndrome, severe LV failure

Question 8

Side effects of beta blockers?

Answer 8

fatigue
impaired exercise tolerance
insomnia
unpleasant dreams
worsened claudication
erectile dysfunction

Question 9

reduces late sodium current that facilitates calcium entry via sodium-calcium exchanger -> reduces intracellular calcium overload which is thought to impair diastolic relaxation and cause contractile inefficiency

• does not reduce HR, bp or myocardial work or oxygen demand
• inhibits fatty acid oxidation
• used to treat angina pectoris to decrease the frequency of attacks and need for nitroglycerin

Answer 9

Ranolazine

Question 10

inhibits smooth muscle Rho kinase, which is an inhibitor of vascular relaxation
-used to reduce coronary vasospasm

Answer 10

Fasudil

Question 11

Why is treatment of claudication in skeletal muscles needed?
Why do you not treat it with a vasodilator?

Answer 11

Peripheral artery disease is associated with increased mortality, can limit exercise tolerance & may be associated with ischemic ulcers/susceptibility to infection.
Intermittent claudication results from obstruction of blood flow by atheromas in large and medium arteries. The vessel distal to the occlusion is usually already dilated at rest, therefore vasodilators do not help.
Treat peripheral artery disease with pentoxifylline (decreases blood viscosity) and cilostazol (PDE3 inhibitor).

Question 12

What is thought to cause the pain associated with angina?

Answer 12

Ischemia causes inadequate myocardial oxygenation and accumulation of waste products from anaerobic glycolysis. Lactate, serotonin and adenosine collect locally and activate peripheral pain receptors in C7-T4

Question 13

how is variant angina different from stable angina?

Answer 13

caused by intense coronary artery vasospasm and is thought to be from dysfunctional endothelium
-happens at rest, unlike stable angina