DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 27–1
Organic Nitrates Available for Clinical Use
NONPROPRIETARY NAMES
PREPARATIONS, USUAL DOSES, AND ROUTES
AND TRADE NAMES CHEMICAL STRUCTURE OF ADMINISTRATION a
Nitroglycerin
T: 0.3-0.6 mg as needed
(glyceryl trinitrate;
S: 0.4 mg per spray as needed
NITRO-BID, NITROSTAT,
C: 2.5-9 mg 2-4 times daily
NITROL, NITRO-DUR,
B: 1 mg every 3-5 h
others)
O: 2.5-5 cm, topically to skin every 4-8 h
D: 1 disc (2.5-15 mg) for 12-16 h per day
IV: 10-20 μg/min; increments of 10 μg/min to
a maximum of 400 μg/min
Isosorbide dinitrate
T: 2.5-10 mg every 2-3 h
(ISORDIL, SORBITRATE,
T(C): 5-10 mg every 2-3 h
DILATRATE-SR, others)
T(O): 5-40 mg every 8 h
C: 40-80 mg every 12 h
Isosorbide-5-mononitrate
(IMDUR, ISMO, others)
T: 10-40 mg twice daily
C: 60-120 mg daily
a
B, buccal (transmucosal) tablet; C, sustained-release capsule or tablet; D, transdermal disc or patch; IV, intravenous injection;
O, ointment; S, lingual spray; T, tablet for sublingual use; T(C), chewable tablet; T(O), oral tablet or capsule.
consequence of the NO-mediated increase in intracellular
cyclic GMP is the activation of PKG, which catalyzes
the phosphorylation of various proteins in
smooth muscle. Another important target of this
kinase is the myosin light-chain phosphatase, which
is activated on binding PKG and leads to dephosphorylation
of the myosin light chain and thereby promotes
vasorelaxation and smooth muscle relaxation in
many other tissues.
The pharmacological and biochemical effects of
the nitrovasodilators appear to be identical to those of
an endothelium-derived relaxing factor now known to
be NO. Although the soluble isoform of guanylyl
cyclase remains the most extensively characterized
molecular “receptor” for NO, it is increasingly clear that
NO also forms specific adducts with thiol groups in proteins
and with reduced glutathione to form nitrosothiol
compounds with distinctive biological properties
(Stamler et al., 2001). Mitochondrial aldehyde dehydrogenase
has been shown to catalyze the reduction of
nitroglycerin to yield bioactive NO metabolites (Chen
et al., 2002), providing a potentially important clue to
the biotransformation of organic nitrates in intact tissues.
The regulation and pharmacology of eNOS have
been reviewed (Dudzinski et al., 2006).
Cardiovascular Effects Hemodynamic Effects. The nitrovasodilators
promote relaxation of vascular smooth muscle.
Low concentrations of nitroglycerin preferentially dilate
veins more than arterioles. This venodilation decreases
venous return, leading to a fall in left and right ventricular
chamber size and end-diastolic pressures, but usually
results in little change in systemic vascular resistance.
Systemic arterial pressure may fall slightly, and heart rate
is unchanged or may increase slightly in response to a