Barbiturates

Mechanism of action of IV
agents
1-inotropic

Glutamate receptor w
is Ecxitatory NT
A-NMDA sodium and Potasium
cation(learning,memeory,disociat
ed)
B-non NMDA

2-Ligand

gated ion channel :like

GABAA,5HT3,glycin ,nicotinic Acl
GABA A is clorid,Bicarb anion
For all sedative and anesthetics
exept Ketamin

The

classification of barbiturates
as long-, intermediate-, short-,
and ultrashort-acting is not
recommended, because it
incorrectly suggests that the
action of these drugs ends
abruptly after specified time
intervals

COMMERCIAL PREPARATIONS
as

sodium salts that are readily

soluble in water or saline from
highly alkaline solutions (pH of a
2.5% solution of thiopental is
10.5). These highly alkaline
solutions are incompatible for
mixture with drugs such as
opioids, catecholamines, and
neuromuscular-blocking drugs

Barbituric

acid is formed by the

combination of urea and malonic
acid.
Replacement of this oxygen atom
with a sulfur atom results in
thiobarbiturates, which are more
lipid
soluble(potency,onset,recovery)
than oxybarbiturates.
solutions of the thiobarbiturates

When

barbiturates are added to

Ringer lactate or an acidic solution
containing other water-soluble drugs,
precipitation will occur and can
occlude the IV catheter.
When high doses of thiopental are
administered, a desulfuration reaction
can occur with the production of
pentobarbital, which has long-lasting
CNS-depressant activity

MECHANISM OF ACTION
produce

their sedative-hypnotic effects through

an interaction with the inhibitory
neurotransmitter -aminobutyric acid (GABA) in
the CNS. When GABAA receptors are activated,
transmembrane chloride conductance increases,
resulting in hyperpolarization of the postsynaptic
cell membranes and functional inhibition of
postsynaptic neurons. The ability of barbiturates
to uniquely depress the reticular activating
system, which is presumed to be important in the
maintenance of wakefulness, may reflect the
ability of barbiturates to decrease the rate of
dissociation of GABA from its receptors.

PHARMACOKINETICS
Prompt

awakening reflects the

redistribution of these drugs from
the brain to inactive tissues
Distribution of barbiturates in the
body is determined by their lipid
solubility (most important),
protein binding, and degree of
ionization.

Brain
brain

receives about 10% of the

total dose of thiopental in the
first 30 to 40 seconds. This
maximal brain concentration is
followed by a decrease over the
next 5 minutes to one-half the
initial peak concentration,n
uptake within 30 seconds

Skeletal Muscles
are

the most prominent sites for

the initial redistribution of highly
lipid-soluble barbiturates such as
thiopental

Fat
only

compartment in which
thiopental content continues to
increase 30 minutes after
injection
Large or repeated doses of lipidsoluble barbiturates produce a
cumulative effect because of the
storage capacity of fat

Cardiopulmonary Bypass
results

in an abrupt 50%
decrease in the plasma
concentration, followed by a
gradual increase to 70% of the
prebypass concentration.

Ionization
pK

of thiopental (7.6) is near

blood pH acidosis will favor the
nonionized fraction of drug
The nonionized form of drug has
greater access to the CNS
because of its higher lipid
solubility. Acidosis will thus
increase and alkalosis will
decrease the intensity of the
barbiturate effect

Metabolism
Oxybarbiturates

are metabolized
only in hepatocytes, whereas
thiobarbiturates also break down
to a small extent in extrahepatic
sites, such as the kidneys and
possibly the CNS

Metabolism

of thiopental occurs
at a slow rate, with 10% to 24%
being metabolized by the liver
each hour

Renal Excretion
All

barbiturates are filtered by

the renal glomeruli, but the high
degree of protein binding limits
the magnitude of filtration,
whereas high lipid solubility
favors reabsorption of any filtered
drug back into the circulation
(<1% of administered thiopental,
thiamylal, or methohexital is
excreted unchanged in urine).

Elimination Half-Time
is

prolonged in obese patients

Increasing age is associated with
a slower passage of thiopental
from the central compartment to
peripheral compartments

CLINICAL USES
(a)

induction of anesthesia and

(b) treatment of increased
intracranial pressure (ICP).
The use of phenobarbital to treat
hyperbilirubinemia and
kernicterus reflects barbiturateinduced increases in hepatic
glucuronyl transferase enzyme
activity

Other

clinical uses of barbiturates

are declining in frequency because
these drugs (a) lack specificity of
effect in the CNS, (b) have a lower
therapeutic index than do
benzodiazepines, (c) result in
tolerance more often than do
benzodiazepines, (d) have a greater
liability for abuse, and (e) have a
high risk for drug interactions

The

dose of barbiturates necessary to

induce anesthesia is reduced in
premedicated patients, patients in early
pregnancy (7 to 13 weeks' gestation), and
those of more advanced American Society
of Anesthesiologists physical status (III or
IV). Geriatric patients require a 30 to 40%
reduction in the usual adult dose because
of a decrease of the volume of the central
compartment and slowed redistribution of
thiopental from the vessel-rich tissues to
lean muscle

Plasma

thiopental levels
necessary to maintain a hypnotic
state range between 10 and 20
mg/mL.
A typical infusion rate necessary
to treat intracranial hypertension
or intractable convulsions is 2 to
4 mg/kg/hr.

SIDE EFFECTS
Cardiovascular

System
The mild and transient decrease in
systemic blood pressure that
accompanies the induction of anesthesia
with barbiturates is principally due to
peripheral vasodilation, reflecting
depression of the medullary vasomotor
center and decreased sympathetic
nervous system outflow from the CNS.
increases in heart rate(Baroreceptor)
More with HTN,IHD,Valve,shocked pt

Ventilation
produce

dose-dependent
depression of medullary and
pontine ventilatory centers
Laryngeal reflexes and the cough
reflex are not depressed until
large doses of barbiturates have
been administered

Electroencephalogram
A

continuous infusion of thiopental, 4

mg/kg, produces an isoelectric EEG that is
consistent with near-maximal decreases in
cerebral metabolic oxygen requirements.
Barbiturate-induced depression of cerebral
metabolic oxygen requirements when the
EEG is isoelectric is about 55%, reflecting a
decrease in neuronal needs for oxygen.
Hypothermia is the only reliable method for
decreasing the basal cellular metabolic
requirements for oxygen

Somatosensory

Evoked

Responses
thiopental is an acceptable drug
to administer when the ability to
monitor somatosensory evoked
potentials is desirable

Liver
modest

decreases in hepatic
blood flow. Induction doses of
thiopental do not alter
postoperative liver function tests
enzyme induction) after 2 to 7
days of sustained drug
administration

Barbiturates

also stimulate the

activity of a mitochondrial
enzyme (in contrast to a
microsomal enzyme) known as Daminolevulinic acid synthetase.
As a result, the production of
heme is accelerated, and acute
intermittent porphyria may be
exacerbated in susceptible
patients who receive
barbiturates.

Kidneys
modest

decreases in renal blood

flow and glomerular filtration
rate.

Placental

Transfer
Barbiturates used for the intravenous
induction of anesthesia readily cross the
placenta, but fetal plasma
concentrations of barbiturates are
substantially less than those in maternal
plasma. Clearance by the fetal liver and
dilution by blood from the fetal viscera and
extremities result in the fetal brain being
exposed to lower barbiturate concentrations
than those measured in the umbilical vein.
8mg/kg is harmful for fetus

Tolerance and Physical

Dependence
Abrupt

discontinuation of
phenobarbital in patients being
treated for epilepsy may result in
status epilepticus.

Intraarterial

Injection
vasoconstriction and excruciating
pain that radiates along the
distribution of the artery.
Vasoconstriction may obscure
distal arterial pulses, and
blanching of the extremity is
followed by cyanosis. Gangrene
and permanent nerve damage
may occur.

the

precipitation of thiopental
crystals in the arterial vessels,
leading to an inflammatory
response and arteritis, which,
coupled with the
microembolization that follows,
eventually results in occlusion of
the distal circulation

Dilution

of the barbiturate is best

accomplished by the injection of saline
through the needle or catheter that still
remains in the artery. At the same
time, an injection of lidocaine,
papaverine, or phenoxybenzamine
may be administered to produce
vasodilation. Sympathectomy of the
upper extremity produced by a stellate
ganglion block or brachial plexus block
may relieve vasoconstriction

Venous

Thrombosis reflects
deposition of barbiturate crystals
in the vein
Allergic Reactions

Immunosuppression
The

long-term administration of high doses

of thiopental is associated with an
increased incidence of nosocomial
infections and associated mortality. Bone
marrow suppression and leukopenia may
accompany the long-term administration
of thiopental to treat increased ICP. It is
possible that thiopental could exert its
permissive effect on nosocomial infections
in part by inhibiting the function of
immune cells.