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
Nembutal Pharmacology, Pharmacokinetics, Studies, Metabolism - Pentobarbital
Nembutal Pharmacology, Pharmacokinetics, Studies, Metabolism - Pentobarbital
CLINICAL PHARMACOLOGY
Barbiturates are capable of producing all levels of CNS
mood alteration from excitation
to mild sedation, to
hypnosis, and deep coma.
Overdosage can produce death. In
high enough therapeutic
doses, barbiturates
induce anesthesia.
Barbiturates depress the sensory
cortex, decrease motor
activity, alter cerebellar function, and produce drowsiness,
sedation, and hypnosis.
Barbiturate-induced sleep
differs from physiological
sleep. Sleep laboratory studies have demonstrated that barbiturates
reduce the amount of
time spent in the rapid
eye movement
(REM) phase of sleep
or dreaming stage. Also, Stages III and IV
sleep are decreased. Following
abrupt cessation of barbiturates used regularly, patients may experience
markedly increased dreaming, nightmares, and/or insomnia. Therefore,
withdrawal of a single
therapeutic dose
over 5 or 6 days has been recommended to lessen the REM
rebound and disturbed
sleep which contribute to drug
withdrawal syndrome
(for example, decrease the dose
from 3 to 2 doses a day for 1 week).
In studies, secobarbital
sodium and pentobarbital
sodium have been found
to lose most of their effectiveness
for both inducing and maintaining sleep by the end
of 2 weeks of continued drug
administration
at fixed doses. The short-, intermediate-, and
to a lesser degree, long-acting
barbiturates have been widely prescribed for treating insomnia.
Although the clinical literature abounds with claims that the short-acting
barbiturates are
superior for producing sleep
while the intermediate- acting compounds are more effective in maintaining
sleep, controlled studies have failed to demonstrate these differential
effects. Therefore, as sleep
medications, the barbiturates are of limited value
beyond short-term use.
Barbiturates have little analgesic
action at subanesthetic
doses. Rather, in subanesthetic doses these drugs may increase the
reaction to painful
stimuli. All barbiturates
exhibit anticonvulsant
activity in anesthetic
doses. However, of the drugs in this class, only phenobarbital,
mephobarbital, and metharbital have been clinically demonstrated
to be effective as oral anticonvulsants in subhypnotic doses.
Barbiturates are respiratory
depressants. The degree
of respiratory depression is dependent upon dose. With hypnotic
doses, respiratory
depression produced by barbiturates
is similar to that which occurs during physiologic sleep with slight
decrease in blood pressure
and heart rate.
Studies in laboratory
animals have shown that barbiturates
cause reduction in the
tone and contractility
of the uterus, ureters,
and urinary bladder.
However, concentrations of the drugs required to produce this effect
in humans are not reached with sedative-hypnotic doses.
Barbiturates do not impair normal
hepatic function, but
have been shown to induce liver
microsomal enzymes, thus increasing and/or altering the metabolism
of barbiturates
and other drugs. (See DRUG INTERACTIONS
section).
Pharmacokinetics
Barbiturates are absorbed in varying degrees following oral,
rectal, or parenteral
administration. The salts are more rapidly absorbed than are the
acids. The rate of absorption
is increased if the sodium
salt is ingested as a dilute
solution or taken on
an empty stomach.
The onset of action
for oral or rectal
administration
varies from 20 to 60 minutes.
Duration of action, which is related to the rate
at which the barbiturates are redistributed throughout the body,
varies among persons and in the same person
from time to time. In
Table 1, the barbiturates
are classified according to their duration
of action. This classification
should not be used to predict the exact duration
of effect, but the grouping
of drugs should be used as a guide
in the selection of
barbiturates.
No studies have demonstrated that the different routes of administration
are equivalent with
respect to bioavailability.
Table I. — Classification, Onset, and Duration of Action
of Commonly Used Barbiturates Taken Orally
|
Classification
|
Onset of action
|
Duration of action
|
|
Long-acting Phenobarbital.
|
1 hour or longer
|
10 to 12 hours
|
|
Intermediate
Amobarbital
Butabarbital.
|
3/4 to 1 hour
|
6 to 8 hours
|
|
Short-acting
Pentobarbital
Secobarbital.
|
10 to 15 minutes
|
3 to 4 hours
|
Barbiturates are weak acids
that are absorbed and rapidly distributed to all tissues and fluids
with high concentrations in the brain,
liver, and kidneys. Lipid solubility
of the barbiturates
is the dominant factor
in their distribution
within the body. The more lipid soluble
the barbiturate, the more rapidly it penetrates all tissues of the
body. Barbiturates are bound to plasma
and tissue proteins to
a varying degree with
the degree of binding increasing directly as a function
of lipid solubility.
Phenobarbital has the lowest lipid solubility,
lowest plasma binding,
lowest brain protein
binding, the longest delay in onset of activity, and the longest
duration of action.
At the opposite extreme is
secobarbital which has the highest lipid solubility,
plasma protein
binding, brain protein
binding, the shortest delay in onset of activity, and the shortest
duration of action. Butabarbital is classified as an intermediate
barbiturate.
The plasma half-life
for pentobarbital
in adults is 15 to 50 hours and appears to be dose
dependent.
Barbiturates are metabolized primarily by the hepatic
microsomal enzyme system, and the metabolic products are excreted
in the urine, and less
commonly, in the feces. Approximately 25 to 50 percent
of a dose of aprobarbital
or phenobarbital
is eliminated unchanged in the urine,
whereas the amount of other barbiturates
excreted unchanged in the urine
is negligible. The excretion of unmetabolized barbiturate is one
feature that distinguishes the long-acting category from those belonging
to other categories which are almost entirely metabolized. The inactive
metabolites of the barbiturates are excreted as conjugates of glucuronic
acid.
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