A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Proamatine Pharmacology, Pharmacokinetics, Studies, Metabolism - Midodrine
Proamatine Pharmacology, Pharmacokinetics, Studies, Metabolism - Midodrine
CLINICAL PHARMACOLOGY
Mechanism of Action
ProAmatine® forms an active metabolite, desglymidodrine, that
is an alpha1-agonist, and exerts its actions via
activation of the
alpha-adrenergic receptors of the arteriolar and venous
vasculature, producing an increase in vascular
tone and elevation
of blood pressure. Desglymidodrine
does not stimulate
cardiac beta-adrenergic
receptors. Desglymidodrine diffuses poorly across the blood-brain
barrier, and is therefore not associated with effects on the central
nervous system. Administration
of ProAmatine® results in a rise in standing, sitting, and supine
systolic and diastolic
blood pressure in patients
with orthostatic
hypotension of various
etiologies. Standing systolic
blood pressure
is elevated by approximately 15 to 30 mmHg at 1 hour after a 10-mg
dose of midodrine, with
some effect persisting
for 2 to 3 hours. ProAmatine® has no clinically significant
effect on standing or supine
pulse rates in patients
with autonomic failure.
Pharmacokinetics
ProArnatine® is a prodrug, i.e., the therapeutic
effect of orally administered
midodrine is due to the major metabolite
desglymidodrine formed by deglycination of midodrine. After oral
administration, ProAmatine® is rapidly absorbed. The plasma
levels of the prodrug
peak after about half an hour, and decline
with a half- life of approximately
25 minutes, while the metabolite
reaches peak blood concentrations
about 1 to 2 hours after a dose
of midodrine and has a half-life
of about 3 to 4 hours. The absolute bioavailability of midodrine
(measured as desglymidodrine) is 93%. The bioavailability of desglymidodrine
is not affected by food. Approximately the same amount of desglymidodrine
is formed after intravenous
and oral administration of midodrine. Neither midodrine nor desglymidodrine
is bound to plasma proteins
to any significant
extent.
Metabolism and Excretion
Thorough metabolic studies have not been conducted, but it appears
that deglycination of midodrine to desglymidodrine takes place in
many tissues, and both compounds are metabolized in party
by the liver. Neither midodrine nor desglymidodrine is a substrate
for monoamine oxidase.
Renal elimination of midodrine is insignificant. The renal
clearance of desglymidodrine
is of the order of 385
mL/minute, most, about 80%, by active renal
secretion. The actual
mechanism of active
secretion has not
been studied, but it is possible that it occurs by the base-secreting
pathway responsible for the secretion of several other drugs that
are bases (see also DRUG INTERACTIONS).
Clinical Studies
Midodrine has been studied in 3 principal
controlled trials, one of 3-weeks duration
and two of 1 to 2 days duration. All studies were randomized, double-blind
and parallel-designed trials in patients with orthostatic hypotension
of any etiology and supine-to-standing fall
of systolic blood pressure
of at least 15 mmHg accompanied by at least moderate dlizziness/lightheadedness.
Patients with pre-existing sustained supine
hypertension above
180/110 mmHg were routinely excluded. In
a 3-week study in 170 patients, most previously untreated with midodrine,
the midodrine-treated patients (10 mg
t. i. d., with the last dose
not later than 6 P.M.) had significantly higher (by about 20 mmHg)
1-minute standing systolic
pressure 1 hour after
dosing (blood pressures were not measured at other times) for all
3 weeks. After week 1, midodrine-treated patients had small improvements
of dizziness/light headedness/unsteadiness scores and global evaluations,
but these effects were made difficult to interpret by an early drop-out
rate (about 25% vs. 5%
on placebo). Supine and sitting blood
pressure rose 16/8
and 20/10 mmHg, respectively, on average.
In a 2-day study, after open-label midodrine known midodrine responders
received midodrine 10 mg
or placebo at 0, 3 and
6 hours. One-minute standing systolic blood
pressures were increased 1 hour after each dose
by about 15 mmHg and 3 hours after each dose
by about 12 mmHg; 3-minute standing pressures were increased also
at 1, but not 3, hours after dosing. There were increases in standing
time seen intermittently
1 hour after dosing, but not at 3 hours.
In a 1-day, dose-response trial, single doses of 0, 2.5, 10, and
20 mg of midodrine were given to 25 patients. The 10- and 20- mg
doses produced increases in standing 1-minute systolic
pressure of about 30
mmHg at 1 hour; the increase was sustained in party
for 2 hours after 10 mg and
4 hours after 20 mg. Supine systolic
pressure was ³
200 mmHg in 22% of patients on 10 mg
and 45% of patients on 20 mg; elevated pressures often lasted 6
hours or more.
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