Treatment for Ischemic Heart Disease

Question 1

What is angina pectoris?

Answer 1

• characteristic chest pain caused by insufficient coronary blood flow to meet the oxygen demands of the myocardium
• Stable angina : most common and caused by demand>perfusion like atherosclerotic plaque so relieved by rest and vasodilator
• Prinzmetal angina : uncommon form that is due to arterial spasm with unknown cause and is not related to physical activity, HR or BP but responds to vasodilator.
  -Unstable angina : increasingly frequent pain of prolonged duration and longer rest time needed to alleviate symptoms and is associated with disruption of atherosclerotic plaque complicated by partially occlusive thrombosis and vasoconstriction

Question 2

What are the determinants of cardiac oxygen requirement?

Answer 2

• preload (diastolic filling pressure that depends on blood volume and venous tone)
• afterload (resistance to ejection of stroke volume determined by peripheral vascular resistance)
• heart rate
• cardiac contractility

Question 3

What are the drugs used to treat angina?

Answer 3

Either increase oxygen supply by increasing blood flow or decrease oxygen demand by making tissues more relaxed.
1. Beta Blockers (cardiac depressant and vasodilators)
2. DHP and non-DHP Calcium Channel Blockers (cardiac depressant and vasodilators)
3. Ivabradine (cardiac pacemaker retardant)
4. Glyceryl trinitrate and Isosorbide mononitrate (nitrates are vasodilators)
*antiplatelets and cholesterol lowering drugs can also be used to treat angina

Question 4

What is the MOA of Glyceryl Trinitrate?

Answer 4

• glyceryl trinitrate, glyceryl dinitrate and glyceryl mononitrate are all nitric oxide donors
• glyceryl trinitrate and glyceryl dinitrate are more significant vasodilators as they have more than one nitric oxide group
• nitric oxide stimulates guanylyl cyclase which causes cGMP formation from GTP. cGMP causes deactivation of myosin light chain so this leads to muscle relaxation and hence vasodilation. venodilation leads to decreased preload as more blood pools in the veins and arteriolar dilation leads to decreased peripheral resistance so decreased afterload. therefore there is decreased oxygen demand and this should relieve angina

Question 5

What is the pharmacodynamics of Glyceryl Trinitrate?

Answer 5

• in acute angina, GTN can be placed under tongue for sublingual absorption which has a fast onset of 1 to 5 minutes but also a fast duration of action of 10 to 30 minutes
• in non acute situations, GTN can be delivered transdermally and this has slow onset of 30-60 mins and a long duration of action of 7-10 hours
• with chronic use of GTN, tolerance builds up so chronic angina patients need to increase their dosage to achieve the same therapeutic effect

Question 6

What is the MOA of Isosorbide mononitrate?

Answer 6

• used as angina pectoris prophylaxis
• derived from Isosorbide dinitrate but this is not used in angina
• nitric oxide group donors as well
• at low plasma concentration, only causes venous dilation but at high plasma concentration, also causes arterial dilation
• has direct dilatory effect on coronary arteries arteries so there is improvement in subendocardial blood flow

Question 7

What is the pharmacodynamics of Isosorbide mononitrate?

Answer 7

• oral onset is 30-45 minutes
• duration of action is 6 hours for immediate release tablet or 12-24 hours for sustained release

Question 8

What are the side effect of all nitrates?

Answer 8

• vasodilation can cause drop in BP and this activates the baroreceptor reflex leading to reflex tachycardia which is transient as the tachycardia will be dampened after the body realises it is not in a fight or flight mode
• too much venodilation can also cause hypotension
• meningeal artery vasodilation will also lead to headache
• tolerance can develop in long term so will need to increase dosage

Question 9

Compare the effects of nitrate administered alone vs effects of nitrate administered with either beta-blockers or calcium channel blockers.

Answer 9

(just need to memorise, no understood mechanism)

Nitrates alone :
- reflex tachycardia
- decreased arterial pressure
- decreased end diastolic pressure due to venodilation
- reflex increase in heart contractility
- reflex decrease in ejection time

Nitrates + beta-blockers/calcium channel blockers :
- decreased heart rate
- decreased arterial pressure
- little to no decrease in end diastolic pressure
- no change to contractility
- no change to ejection time

Question 10

What is the MOA of beta-blockers for angina?

Answer 10

• beta blockers block receptors in cardiac myocytes so there is decreased contractility and decreased heart rate
• this reduces cardiac oxygen requirements
• beta blockers used : propranolol, carvedilol, atenolol, bisoprolol, metoprolol, nebivolol

Question 11

What is the MOA of calcium channel blockers for angina?

Answer 11

Dihydropyridines :
- act more on blood vessels and less effect on heart
- vasodilation leads to decreased preload and afterload so there is decreased oxygen demand by myocytes
- nifedipine, amlodipine, nicardipine
- side effects include low blood pressure, headache, dizziness and facial flushing. ankle swelling due to vasodilation. there can also be sympathetic reflex leading to palpitations.

Non-dihydropyridine :
- act more on heart and less effect on blood vessels
- causes reduced heart contractility and decreased conduction speed in heart so this decreases oxygen demand by myocytes
- verapamil, diltiazem (used in anti-arrhythmias)
- side effects include constipation, worsening cardiac output, and bradycardia

For lowering BP :
verapamil = diltiazem = nifedipine

For vasodilation :
nifedipine > diltiazem > verapamil

For cardiac depressant :
verapamil > diltiazem > nifedipine