Drugs in the Therapy of Angina

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Drugs in the Therapy of Angina
Dr. Thomas Abraham PHAR417 Fall 2004
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Regulation of vascular smooth muscle
contractility by Nitric oxide

•    Acetylcholine (via M2/M3 receptors) and
  bradykinin (via B1/B2 receptors) causes
  endothelial cells on arteries and veins to
  release nitric oxide (NO).
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• Released NO travels through the wall of the
  blood vessel to reach the smooth muscle cells to
  initiate biological response.
•     NO binds and activates cytosolic guanylate
  cyclase, which converts GTP to cGMP.

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Role of Nitric Oxide In Vascular smooth muscle
relaxation.

•    The overall effect of the cGMP-PKG system is
  to cause smooth muscle relaxation by decreasing
  intracellular calcium levels to decrease
  actin-myosin interactions
• -         phosphorylates and inactivate PLC and
  the IP3 channel.
•   decreased production of IP3 and decreased
  effectiveness of IP3 to release calcium from SR
  stores.
•   -         activate the SR Ca2-ATPase.
•   increased rate of removal of calcium from the
  cytoplasm.
•    Organic nitrates mimic the effects of NO to
  cause smooth muscle relaxation.

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Pathophysiology of Angina

•     Angina pectoris is caused by accumulation of
  metabolic byproducts in myocardial tissue and
  results because oxygen demand by the myocardium
  far exceeds the oxygen (blood) supply.
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•      Oxygen supply and demand mismatch are
  primarily due to atherosclerotic occlusion of
  coronary arteries (exertional, stable angina).
  Angiospasms (variant angina) is also responsible
  for cardiac ischemia.
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•       Theoretically the supply to demand mismatch
  can be corrected by
• -         improving blood flow to the myocardium
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• -         decreasing myocardial oxygen demand

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Nitrate vasodilators in Angina Therapy

•       Are polyol organic esters of nitric acid
• - the nitrate esters (R-- CONO2)
• - the nitrite esters (RCONO)
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•       Amyl nitrite is volatile administered as
  a gas.

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Nitrate vasodilators in Angina Therapy

•      Fully nitrated polyols are non-polar and
  lipid soluble allows rapid absorption from
  inhalational, dermal and sublingual sites.
• -         NTG sublingual, transdermal (patch and
  ointment), spray
• -         Amyl nitrite inhalational
• -         Isosorbide dinitrate sublingual,
  chewable
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•      Degradation of the nitrates in the presence
  of glutathione generates the NO free radical,
  which causes vasodilation.

• Greater potency of erythrityl tetranitrate and
  nitroglyerin relative to other organic nitrates
  may be due to more rapid bioactivation.

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Nitrate vasodilators in Angina Therapy

•     Rapid onset of action after sublingual admin.
  due to by-pass of liver first time through.
  Sublingual administration in acute attacks and
  prophylaxis of acute attacks.
•     Oral administration of nitrates has longer
  onset time but longer duration of action.
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•     Transdermal delivery (NTG patch) onset time
  of 1hour and duration of 4-8 hours.
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•      Tolerance to all nitrate compounds develops
  after prolonged use and treatment has to be
  interrupted every 8 hours.
• Tolerance may be due to decreased production
  of NO from nitrate drugs or due to the production
  of oxygen free radicals (O2-) which react with
  NO to form peroxynitrates that are not
  vasodilators.

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Nitrate vasodilators in Angina Therapy

•     Nitrates dilate veins preferentially over
  arteries leading to decreased left and right
  heart end-diastolic pressure (decreased preload)
  with small change in TPR.
• -          heart rate unchanged or slightly
  increased due baroreceptor reflex mechanism.
• -          Cardiac output decreases due to lower
  ventricular end-diastolic pressure.
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•      Lower doses dilate arterial vessels of skin,
  meninges flushing, headache
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•       Higher doses (1) decrease systolic and
  diastolic pressure decrease TPR
• (2) decrease C.O. (3) cause venous blood
  pooling (4) reflex sympathetic nerve activity.

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Nitrate vasodilators in Angina Therapy

•    Appear to alleviate anginal pain by restoring
  myocardial oxygen supply/demand via
• -          decreasing myocardial work due to
  decreased afterload and preload.
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• -          Ischemic regions of heart may have
  improved blood flow to subendocardial regions
  due to decreased preload that decreases
  ventricular wall tension.
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•     Adverse effects (cardiovascular) headache,
  dizziness, weakness, postural hypotension,
  flushed skin, tachycardia, rash.

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Nitrate vasodilators in Angina Therapy
Drug Interactions Nitrates are contraindicated in
patients on sildenafil (Viagra) due to increased
potential for hypotensive episode via PDE5
inhibition. Therapeutic Use Used in exertional
and variant angina to restore myocardial oxygen
supply/demand. Nitrates are used in congestive
heart failure Improve coronary blood flow after
MI
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Other agents in Angina Therapy
b-blockers metoprolol, timolol, atenolol have
been shown effective in reducing anginal attacks
by decreasing myocardial oxygen
demand. Calcium-channel blockers amlodipine,
bepridil, nicardipine improve coronary blood flow
to increase myocardial oxygen supply