Pharmacokinetics and Barbiturates: Introduction and
Barbiturates: Although barbituric acid
was the first barbiturate synthesized over hundred years ago,
thiopental (Pentothal) has been clinical use for about 70 years in
its use mark the beginning of IV anesthesia. Barbiturate acid is
composed of urea and melonic acid (cyclic ureide of malonic acid)
Particularly advantageous characteristics of thiopental (Pentothal)
(and methohexital (Brevital)) include rapid onset but
short duration of action due to redistribution.
Furthermore, these agents appear relatively safe to use
As noted above the primary mechanism for termination of action
of thiopental (Pentothal) and methohexital (Brevital) is
redistribution from the brain to other compartments, as a result
of equilibration. This mechanism is distinct from
metabolism as a means of terminating anesthetic effect.
Also, rapid onset is a characteristic of these agents and can
be understood in terms of their chemical properties
To understand this aspect we need to consider the molecular
characteristics of these drugs.
Barbiturates exists in two molecular forms, and enol and keto
Enol forms for barbiturates are water-soluble at pH
10-11at 6% sodium carbonate. Therefore, in the
injected form the drug is not initially lipid-soluble and
would not be expected to enter the brain readily.
Here's the structure of enol form for
Once in circulation, the enol form undergoes a
structural change called "tautomerization" to a keto
form which is more lipid soluble:
Specific pharmacological characteristics of different
barbiturates are mainly due to chemical substitutions at the
"5" position in the molecule. Hypnotic
properties are influenced by the nature of side chains at
position 5. Duration of action and potency are also
affected by the length of site chains at position 5.
Here are some examples
Rapidity of onset and duration of action (that is more rapid
onset with a shorter duration) is significantly affected by a
substitution at position 2: Thiopental (Pentothal) and
thioamylal exhibit a shorter duration of action and a rapid
onset compared to secobarbital (Seconal) and pentobarbital
Side Chain Differences between Barbituric
Major factors that determine to the characteristic uptake
for thiopental (Pentothal) include not only its intrinsic
lipid solubility but also the concentration gradient between
blood and tissue and importantly the extent of perfusion.
For example, the brain received a significant percentage
of cardiac output and is also relatively lipophilic.
As a result, there is a rapid rise in thiopental (Pentothal)
brain concentration and as a result a short time to onset of
On the other hand, there will also be a relatively rapid
decrease in brain thiopental (Pentothal) concentration as a
thiopental (Pentothal) equilibrates with other compartments,
such as muscle initially and ultimately with other large but
increasingly poorly perfused compartments.
An understanding of thiopental (Pentothal) pharmacology
begins with the recognition that the rapid time to onset is
largely due to the lipophilic characteristic of the drug and
the significant percentage of cardiac output that goes to
the brain. The second important aspect is the
recognition that the short duration is due not to metabolism
but to redistribution from the brain to other compartments.
pharmacology-- a summary of organ system and other effects:
Barbiturates may increase the patient's sensitivity to
pain. Administration of barbiturates the patient
in pain may result in agitation as opposed to
sedation. This observation suggests that other
drugs, for example opioids, might be appropriate to
manage pain and then subsequently an assessment made
concerning the need to sedate.
Cerebral metabolism is depressed by barbiturates and
barbiturate administration is associated with decreased
cerebral blood flow and intracranial pressure. Changes
in these parameters are of sufficient size to be
important in neurosurgical cases.
Slight myocardial depression is associated with some
tachycardia (increased myocardial oxygen consumption)
Peripheral vasodilation (venodilation) is a principal
effect that, because of reduced preload, results in
reduced cardiac output.
These cardiovascular effects should be considered as
important for the subgroup of patients who may be
particularly sensitive to these hemodynamic
effects. For instance patients with ischemic heart
disease might be adversely affected by the increased
myocardial oxygen requirement secondary to tachycardia.
Similarly, a hypovolemic patient may be more sensitive
to reduced preload due to increase peripheral
capacitance. The peripheral vasodilation results
in a hypotensive state which appears more pronounced in
patients who were initially hypertensive compared to
those who were normotensive.
Barbiturates are respiratory depressants; Depressed
respiration can lead to apnea during induction
Also, respiratory system responses to hypoxia and
hypercarbia will be diminished following barbiturate
Laryngospasm may still occur because laryngeal
reflexes are relatively less affected by the drug.
Reduced urine output may occur secondary to reduced
renal blood flow (presumably due to depressed cardiac
Vasodilation may increase heat loss to an extent that
postoperative shivering may be worsened.
As discussed earlier, barbiturate are absolutely
contraindicated in patients who have abnormalities in
porphyrin metabolism. Episodes of acute
intermittent porphyria may be induced by barbiturates
because of their effect in increasing aminolevulinic
acid synthetase, which is the enzyme that catalyzes the
rate-determining step in the porphyrin biosynthetic
Although barbiturate are properly classified as
sedative-hypnotic agents, they lack certain characteristics
which are important for anesthesia -- including analgesia
and amnesia. Other drug groups, such as the opioids,
represent effective approaches to analgesia, whereas
certain benzodiazepines are very effective amnestic and
Thiopental (Pentothal), however, is an effective
anesthetic induction drug although other agents, such as
propofol (Diprivan) are increasingly commonly used.
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