Angina Pectoris Drugs

Question 1

Amyl nitrite

Answer 1

• organic nitrite
• NO donor - generates nitric oxide
• inhaled
• fast onset, short (15 min) acting
• bad odor; limited use
• used by drug abusers for enhancement of sexual perception and pleasure as well as vasodilation of cerebral blood vessels along with warm sensations and facial flushing –> contribute to the users perception of a rush or high

Question 2

Nitroglycerin

Answer 2

• organic nitrate
• sublingual: fast onset, short (30 min) acting
• intravenous: immediate onset, transient short acting
• buccal (transmucosal): fast onset, long (6 hrs) acting
• oral: slow onset, long (8 hrs) acting
• transdermal: slow onset, long (24 hrs) acting
  Nitroglycerin is adsorbed on lactose, colloidal silicone dioxide and silicone medical fluid
  A layer of silicone adhesive ensures attachment to skin

Mechanism of action of nitrates:
Vasodilatory effect on different vessels: veins > larger arteries > arterioles. Nitroglycerin is denitrated in the tissues by mitochondrial aldehyde DH, and NO is liberated. Nitroglycerin is also denitrated in the liver by glutathione-S-transferase and nitrite ion is liberated, which is then reduced to NO by enzymes. Amount of nitric oxide (NO) liberated depends on different blood vessels. Venodilation causes pooling of blood in the large veins, less venous blood returns to the heart and there is decrease in the ventricular end‐diastolic volume and
pressure
Thus, pre‐load on the heart is decreased
NO stimulates soluble guanylate cyclase which increases intracellular cyclic guanosine monophosphate (cGMP) –> increase in cGMP results in relaxation of smooth muscle by dephosphorylation of phosphorylated myosin light chain.

Vasodilatory effect of nitrates on the arterioles decreases systemic blood pressure causing decrease in the after‐load on the heart
Decrease in pre‐load (due to venous pooling of blood) and after‐load (due to arteriolar
vasodilation and fall in BP) result in decrease in myocardial oxygen demand.
Decrease in myocardial oxygen demand is the most important mechanism by which nitrates relieve anginal pain

Nitroglycerin increases blood to cardiac ischemic areas whereas other vasodilator drugs like dipyridamole and hydrazine elicit the coronary steal phenomenon (both normal and ischemic vessels are dilated) and are not effective in relieving anginal pain

• cross run with Sildenafil (Viagra) - both cause increased cGMP so potentiation of cGMP induced hypotension may be dangerous in these patients
• side effects: because of venous pooling of blood postural hypotension associated with dizziness and weakness, dilation of meningeal blood vessels may cause headache, dilation of cutaneous vessels may cause flushing of the face

Question 3

Isosorbide dinitrate

Answer 3

• organic nitrate
• sublingual: slow onset, long *2 hrs) acting
• oral: slow onset, long (10 hrs) acting
• NO donor - generates nitric oxide

Question 4

Isosorbide mononitrate

Answer 4

• organic nitrate
• oral: slow onset, long (12 hrs) acting
• NO donor - generates nitric oxide

Question 5

Erithrityl tetranitrate

Answer 5

• organic nitrate
• sublingual: slow onset, long (3 hrs) acting
• oral: slow onset, long (6 hrs) acting
• NO donor - generates nitric oxide

Question 6

Pentaerythritol tetranitrate

Answer 6

• organic nitrate
• oral: slow onset, long (12 hrs) acting
• explosive
• NO donor - generates nitric oxide

Question 7

Sodium nitroprusside

Answer 7

• inorganic nitroso compound
• NO donor - generates nitric oxide - unknown mech
• used for treatment of hypertensive emergencies and heart failure when short term reduction of cardiac pre-load and after-load is needed
• liberates CN ion (not good but should not be a problem in normal doses); mitochondrial enzyme rhodanase converts CN to less toxic thiocyanate in the presence of a sulfur donor
  to prevent excessive CN formation, the drug must be prepared just before use and placed in an opaque container

Question 8

Fatty acid oxidation inhibitors

Answer 8

mechanism of action
• Inhibitors of long‐chain 3‐ketoacylcoenzyme
A thiolase shift myocardial
metabolism toward greater use of
glucose as a substrate resulting in
reduced oxygen demand which is
helpful in patients with angina pectoris.
• Trimetazidine (a fatty acid oxidation
inhibitor) is not available in USA

Ranolazine: high concentrations of the drug are needed to serve as an inhibitor of fatty acid oxidation.

Question 9

Ranolazine

Answer 9

• at high concentrations serves as an inhibitor of FA oxidation
  Ranolazine has been shown to inhibit late
  sodium current (INa+) in the myocardial
  ventricular muscle during ischemia.
  • Increase in intracellular Na+ concentration, via
  increase in INa+, in ischemic cardiac cells is
  reduced.
  • Consequently, intracellular Ca++ concentration
  is reduced in ischemic cardiac cells due to
  lesser Na+/Ca++ exchange.
  • Increase in diastolic ventricular muscle tension
  during ischemia is reduced.
  • Ventricular muscle MVO2 is reduced which is
  useful in the treatment of angina pectoris.

Question 10

Clopidogrel (Plavix)

Answer 10

• reduce platelet aggregation by blocking the adenosine diphosphate (ADP) receptor on platelets
• for unstable angina

Question 11

Abciximab (ReoPro)

Tirofiban (Aggrastat)

Answer 11

• prevent platelet aggregation by inhibiting platelet glycoprotein IIb/IIIa receptor complex
• for unstable angina

Question 12

beta blockers

calcium channel blockers

Answer 12

also anti-angina drugs