Week 2: Pharmacology of Angina Pectoris

Question 1

What are the major physiologic mechanisms behind the treatment of angina? Show via Frank Starling law.

Answer 1

• As stroke volume increases, oxygen consumption increases. Angina results when oxygen supply is inadequate
• in EDV vs. SV graph, to reduce pain from angina, must decrease oxygen demand of heart muscle by decreasing preload or EDV
• can also decrease afterload (aortic resistance), but not as effect in reducing SV as decreasing preload

Question 2

What is the mechanism of organic nitrates in the treatment of angina pectoris?

Answer 2

• nitrates converted to NO
• NO activates guanylyl cyclase, converting GTP to cGMP, leads to dephospho rylation of myosin light chain, leading to blood vessel relaxation
• mainly venous relaxation–>blood pools in veins, less blood to heart, less EDV
• NO also activates Ca2+ dependent K+ channels, moving K+ out of the cell and hyperpolarizing muscle cell. Leading to relaxation.
• also act on coronary arteries and relieve coronary vessel spasm, won’t dilate vessels with plaque but will dilate collateral circulation

Question 3

What are the pharmacokinetics of nitrate drugs?

Answer 3

1. sublingual has rapid onset. onset 2 mins, duration 25 minutes. Isosorbide dinitrate in sublingual has onset 5 mints, duration 1 hr.
2. oral, sustained release nitroglycerine: isosorbide dinitrate and isosorbide mononitrate (onset 30-35 mins, duration 8-12 hrs.) –good for chronic pain
3. transdermal nitroglycerine: 30 min onset, duration 8-14 hrs.
   - -Tolerance
   - rapid tolerance by SM, need to have 10-12 hour drug free periods without drugs to allow or resensitization

Question 4

What are side effects of nitrate drugs?

Answer 4

• Headache is most common. due to dilation of meningeal vessels.
• postural hypotension
• tachycardia
• activity of nitrates potentiated by phosphodiesterase V inhibitors (Viagra), leads to severe hypotension and even death

Question 5

What is the mechanism of action of beta blockers (adrenergic blockers)?

Answer 5

• b1 selective: lower rate and force of contraction o heart, decreasing workload and reducing oxygen demand. Also increase EDV because bradycardia allows longer filling time during diastole and less blood ejected during systole because of decreased force of contraction.
• propanolol: beta1 and beta2 blocker. beta2 effect is unwanted-vasoconstriction and bronchoconstriction. increases bp and preload and after load.
• beta1 selective drugs: Metoprolol and atenolol
• Carvedilol: b1,b2,a1 blocker. a1 blocking activity counters b2 blocking activity by vasodilating and decreasing atrial filling.

Question 6

What are the side effects of adrenergic blockers?

Answer 6

• ones that cross BBB may cause depression. e.g. propanolol and metaprolol. Atenolol doesn’t.
• results in up regulation of beta receptors, if drug stopped quickly, beta stimulation is greatly increased due to more receptors. can cause angina and/or MI.
• insulin sensitive changes. Insulin drops blood glucose, stimulates epinephrine to stimulate glycogen breakdown and glucose release. However prevented by beta blockers.

Question 7

What is the mechanism of calcium channel blockers?

Answer 7

ACTION
-decrease O2 demand on heart by decreasing after load by arteriole dilation
-depressing SA node and slowing heart rate
-slow conduction of AV node
-cause negative inotropic effect on atria and ventricles
-dilation of coronary arteries, increase O2 to myocardium
MECHANISM
-Normally , Ca2+binds to calmodulin in SM, activates myosin light chain cleavage kinase which phosphorylates myosin light chains, combines with actin and contracts SM
-ca channel blockers stop Ca from entering SM. Get vasodilation instead.

Question 8

Describe the types of Ca2+ channel blockers.

Answer 8

1. Dihydropyridines: amlopidine, nicardipine, nifedipine
   - good vasodilators
   - little suppression of cardiac contractility, SA, AV nodes
2. Diltiazem
   - less vasodilation but good suppression of contractility and SA and AV nodes
3. Verapamil
   - best overall activity in all categories

Question 9

Side effects of Calcium channel blockers?

Answer 9

• hypotension, but not postural hypotension because doesn’t affect veins.
• also can have headache and constipation with verapamil.

Question 10

What is ranolazine?

Answer 10

• newer drug used to treat angina
• reduce late Na current that is coupled to Ca entry into myocardial cell. Reduces intracellular Ca, decreases contractility and therefore O2 demand