CLINICAL PHARMACOLOGY
Metoclopramide stimulates motility of the upper gastrointestinal
tract without stimulating gastric, biliary, or pancreatic secretions.
Its mode of action is unclear. It seems to sensitize tissues to the
action of acetylcholine. The effect of metoclopramide on motility is not
dependent on intact vagal innervation, but it can be abolished by
anticholinergic drugs.
Metoclopramide increases the tone and amplitude of gastric
(especially antral) contractions, relaxes the pyloric sphincter and the
duodenal bulb, and increases peristalsis of the duodenum and jejunum
resulting in accelerated gastric emptying and intestinal transit. It
increases the resting tone of the lower esophageal sphincter. It has
little, if any, effect on the motility of the colon or
gallbladder.
In patients with gastroesophageal reflux and low LESP (lower
esophageal sphincter pressure), single oral doses of metoclopramide
produce dose-related increases in LESP. Effects begin at about 5 mg and
increase through 20 mg (the largest dose tested). The increase in LESP
from a 5 mg dose lasts about 45 minutes and that of 20 mg lasts between
2 and 3 hours. Increased rate of stomach emptying has been observed with
single oral doses of 10 mg.
The antiemetic properties of metoclopramide appear to be a result
of its antagonism of central and peripheral dopamine receptors. Dopamine
produces nausea and vomiting by stimulation of the medullary
chemoreceptor trigger zone (CTZ), and metoclopramide blocks stimulation
of the CTZ by agents like l-dopa or apomorphine which are known to
increase dopamine levels or to possess dopamine-like effects.
Metoclopramide also abolishes the slowing of gastric emptying caused by
apomorphine.
Like the phenothiazines and related drugs, which are also
dopamine antagonists, metoclopramide produces sedation and may produce
extrapyramidal reactions, although these are comparatively rare (see
WARNINGS). Metoclopramide inhibits the
central and peripheral effects of apomorphine, induces release of
prolactin and causes a transient increase in circulating aldosterone
levels, which may be associated with transient fluid
retention.
The onset of pharmacological action of metoclopramide is 1 to 3
minutes following an intravenous dose, 10 to 15 minutes following
intramuscular administration, and 30 to 60 minutes following an oral
dose; pharmacological effects persist for 1 to 2 hours.
Pharmacokinetics
Metoclopramide is rapidly and well absorbed. Relative to
an intravenous dose of 20 mg, the absolute oral bioavailability
of metoclopramide is 80% ± 15.5% as demonstrated in a crossover
study of 18 subjects. Peak plasma concentrations occur at about
1-2 hr after a single oral dose. Similar time to peak is
observed after individual doses at steady state.
In a single dose study of 12 subjects, the area under the
drug concentration-time curve increases linearly with doses from
20 to 100 mg. Peak concentrations increase linearly with dose;
time to peak concentrations remains the same; whole body
clearance is unchanged; and the elimination rate remains the
same. The average elimination half-life in individuals with
normal renal function is 5‑6 hr. Linear kinetic processes
adequately describe the absorption and elimination of
metoclopramide.
Approximately 85% of the radioactivity of an orally
administered dose appears in the urine within 72 hr. Of the 85%
eliminated in the urine, about half is present as free or
conjugated metoclopramide.
The drug is not extensively bound to plasma proteins
(about 30%). The whole body volume of distribution is high
(about 3.5 L/kg) which suggests extensive distribution of drug
to the tissues.
Renal impairment affects the clearance of metoclopramide.
In a study with patients with varying degrees of renal
impairment, a reduction in creatinine clearance was correlated
with a reduction in plasma clearance, renal clearance, non-renal
clearance, and increase in elimination half-life. The kinetics
of metoclopramide in the presence of renal impairment remained
linear however. The reduction in clearance as a result of renal
impairment suggests that adjustment downward of maintenance
dosage should be done to avoid drug accumulation.
Adult
Pharmacokinetic Data
|
Parameter
|
Value
|
| Vd (L/kg) |
~ 3.5
|
| Plasma Protein Binding |
~ 30%
|
| t1/2 (hr) |
5-6
|
| Oral Bioavailability |
80%±15.5% |
In pediatric patients, the pharmacodynamics of
metoclopramide following oral and intravenous administration are
highly variable and a concentration-effect relationship has not
been established.
There are insufficient reliable data to conclude whether
the pharmacokinetics of metoclopramide in adults and the
pediatric population are similar. Although there are
insufficient data to support the efficacy of metoclopramide in
pediatric patients with symptomatic gastroesophageal reflux
(GER) or cancer chemotherapy-related nausea and vomiting, its
pharmacokinetics have been studied in these patient
populations.
In an open-label study, six pediatric patients (age
range, 3.5 weeks to 5.4 months) with GER received a
metoclopramide 0.15 mg/kg oral solution every 6 hours for 10
doses. The mean peak plasma concentration of metoclopramide
after the tenth dose was 2‑fold (56.8 μg/L) higher compared to
that observed after the first dose (29 μg/L) indicating drug
accumulation with repeated dosing. After the tenth dose, the
mean time to reach peak concentrations (2.2 hr), half-life
(4.1 hr), clearance (0.67 L/h/kg), and volume of distribution
(4.4 L/kg) of metoclopramide were similar to those observed
after the first dose. In the youngest patient (age, 3.5 weeks),
metoclopramide half-life after the first and the tenth dose
(23.1 and 10.3 hr, respectively) was significantly longer
compared to other infants due to reduced clearance. This may be
attributed to immature hepatic and renal systems at
birth.
Single intravenous doses of metoclopramide 0.22 to
0.46 mg/kg (mean, 0.35 mg/kg) were administered over 5 minutes
to 9 pediatric cancer patients receiving chemotherapy (mean age,
11.7 years; range, 7 to 14 yr) for prophylaxis of
cytotoxic-induced vomiting. The metoclopramide plasma
concentrations extrapolated to time zero ranged from 65 to
395 μg/L (mean, 152 μg/L). The mean elimination half-life,
clearance, and volume of distribution of metoclopramide were
4.4 hr (range, 1.7 to 8.3 hr), 0.56 L/h/kg (range, 0.12 to
1.20 L/h/kg), and 3.0 L/kg (range, 1.0 to 4.8 L/kg),
respectively.
In another study, nine pediatric cancer patients (age
range, 1 to 9 yr) received 4 to 5 intravenous infusions (over 30
minutes) of metoclopramide at a dose of 2 mg/kg to control
emesis. After the last dose, the peak serum concentrations of
metoclopramide ranged from 1060 to 5680 μg/L. The mean
elimination half-life, clearance, and volume of distribution of
metoclopramide were 4.5 hr (range, 2.0 to 12.5 hr), 0.37 L/h/kg
(range, 0.10 to 1.24 L/h/kg), and 1.93 L/kg (range, 0.95 to
5.50 L/kg), respectively.
Pediatric
Pharmacokinetic Studies
|
|
|
Reference
|
Dose, Route
|
t1/2
(hr)
|
Cl
(L/hr/kg)
|
Vd
(L/kg)
|
Cmax
(µg/L)
|
1 0.35 mg/kg,
IV over 5 min |
4.4±0.56 |
0.56±0.10 |
3.0±0.38 (Dose/Cp0) |
152±31 |
| 2 |
2 mg/kg 30 min IV infusion 4-5 times within 9.5
hours |
4.5a
|
0.37a
|
1.93a
|
1060 to 5680a
|
|
a. SEM not available |
- Bateman, DN, et al. Br J Clin
Pharmac 15:557-559, 1983.
- Ford, C. Clin
Pharmac Ther 43:196, 1988.
|
