ORGANIC NITRATES


I. Preparations used:

  1. Nitroglycerin (IV, SL, TDP, Buccal)
  2. Isosorbide dinitrate (PO, PO-SR, TDP, SL)
  3. Isosorbide mononitrate--longer acting (PO, PO-SR)

II. Effects, in decreasing order of importance:

  1. Dilate coronary aa.
  2. Venodilation
  3. Arteriodilation
  4. Decrease LVEDP; helps in CHF this way

III. Mechanism: Stimulates guanylate cyclase, enhancing production of cGMP, decreases Ca release from sarcoplasmic reticulum in vasc. SM, producing vasodilation

IV. Tolerance:

  1. Develops early, in all preparations tested, us. in 1st 12h, to both hemodynamic f/x (HR, BP, CHF improvement) & antianginal/coronary dilatory f/x; Apparently due to bona fide tolerance, rather than accelerated catabolism of drug--plasma conc. in nl range
  2. Many small studies w/conflicting results with R-T-C NTG TDP
  1. FDA Transdermal NTG Coop. Study (Am.J.Cardiol. 64:931, 89)
    1. Tested 562 pts w/NTG TDP 15-105mg/d; showed walking time before anginal pain @4h but not @24h; @8wk, still walking time but no diff. from placebo
    2. Showed tol. developing in 1st 24h w/NTG TDP
  1. However, sig. improvement in treadmill walking time, acutely & chronically, compared with placebo in pts. with stable angina with intermittent NTG TDP 15-20mg/d (Transderm Nitro Trial Study; J.Am.Coll.Cardiol. 13:786, 89)
  1. Often tol. develops in only a portion, e.g. 50% of pts given IV NTG; no known predictors for tolerance
  2. Unclear whether development of tol. is dose-dependent
  3. There apparently is cross-tolerance among diff. forms of org. nitrates; overcomable with large doses, however.
  4. Mech. of tol:
  1. Reduced guanylate cyclase activity
  2. Enhanced activity of cGMP-phosphodiesterase
  3. Depletion of sulfhydryl groups in vasc. sm cells by thiol groups on drug
  1. Only thiol-containing nitrates (NTG, Isosorbide di- & mono-nitrate) produce tolerance
  2. Thiol-free nitrates nitroprusside & molsidomine cause only negligible tolerance, but can't give nitroprusside IV long-term; causes much hypotn
  1. Activation of reflex vasoconstriction & other neurohormonal compensatory responses--probably limited role
  1. Prevention/reversal of nitrate tolerance:
  1. Sulfhydryl donors, e.g. n-acetylcysteine (mucormyst), methionine (may be better--better-tasting; fewer GI side f/x), captopril (some preliminary pos. evidence as of 1995), vit. C (scant evidence; Circ. 97:886, 1998--JW)
  1. Potentiates f/x of nitrates; prevents & reverses nitrate tol. to some degree; some studies show no effect, however
  1. Intermittent dosing--prevents tol. to antianginal & hemodynamic f/x--overnight "nitrate washout period"
  1. NTG TDP, 10-12h/d washout req'd
  2. 7% get increase in rest angina during nitrate-free intervals; also, pts have less exercise tol. during nitrate-free intervals than pts on placebo (withdrawal effect)
  3. NTG IV--12-48h continuous then 8h off
  4. Isosorbide mononitrate--tol. develops even with Q12h dosing; need > washout time
  5. Isosorbide mononitrate PO-SR is bad--tol. develops even with QD dosing!
  6. For Isosorbide dinitrate, 12h is insufficient, 14 is ok, 17 is better

(Ann Int. Med. 114:667, 4/91--rvw)

V. Adverse effects of NTG

  1. Methemoglobinemia because metabolized to nitrite (NO3)
  1. Higher risk if critically ill (oxidant stress predisposes to sig. methemoglobinemia)
  2. Prob. dose-related but unclear what dose needed
  1. Can increase bleeding time due to increase in prostacyclin production
  2. Can decrease O2 sat. by interfering with ventilation-perfusion balance in lung through pulmonary vasodilation
  3. Can increase ICP by cerebral vasodilation
  4. Effects from ethanol vehicle (comes in EtOH 5-70%)-intoxication, gout, Wenicke's, interaction with disulfiram
  5. Effects from propylene glycol vehicle
  1. Hemolysis, acidosis, coma, hyperosmolarity
  2. Esp. in neonates and pts with renal failure

(Source: Crit. Care Clin. 7:555, 1991)