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IV Anesthesia - Barbiturates
Thiopental , the flagship of the barbiturate anesthetic group, has been for
more than 60 years a standard anesthetic induction agent to which all others are
compared.
Barbiturate Development
In 1864 von Baeyer synthesized the first barbiturate,barbituric acid . The
first hypnotic barbiturate, diethylbarbituric acid , was synthesized by Fischer and
Mering in 1903. A number of other hypnotic-sedative barbiturates were developed
and tested, but all had too slow onset and too long duration of action. In 1932
Weese and Schapff synthesized the first rapid onset, short duration barbiturate,
the methylated oxybarbiturate hexobarbital .Unfortunately, hexobarbital caused
undesirable excitatory side effects. Thiopental was first administered by Waters
(Wisconsin) and Lundy (Mayo Clinic) in 1934. Thiopental proved to be fast and brief
acting and devoid of excitatory side effects. When hexobarbital and thiopental
were used to anesthetize the wounded at Pearl Harbor in 1941, there were so many
deaths that intravenous anesthesia with these agents was later described as "an
ideal method of euthanasia." (probably Halford FJ, 1943) A responding anonymous
editorial correctly suggested that the cause of death might be the method of
administration rather than any inherent barbiturate toxicity. In 1950 Brodie et al
demonstrated that barbiturate hypnotic-sedative activity was terminated not by
metabolism, but by redistribution from central neural sites of action to other body
tissues. It was later shown (Price, 1960) that during prolonged infusions,
redistribution becomes less effective because redistribution sites approach
equilibrium.
Basic Barbiturate Pharmacology
Chemistry and Formulation

Barbiturates are derivatives of barbituric acid (2,4,6trioxyhexahydropyrimidine):

<-->
keto-enol tautomerism of barbituric acid,
devoid of hypnotic activity
Clinically important hypnotic-sedative barbiturates have substitutions at sites 1, 2
and, especially, 5 of barbituric acid.
Barbituric acid may be described as a "cyclic ureide of malonic acid:"

+
urea

->

malonic acid

->

barbituric acid

Keto-enol tautomerization allows formation of water-soluble barbiturate salts:

+

->

Hypnotically active barbiturates:

secobarbital

thiamylal

pentobarbital

thiopental

methohexital
Na salts + 6% by weight NaCO

+H

O or NS

= 2.5% thiopental,
2% thiamylal,
1% methohexital
Buffering action of NaCO 3 plus atmospheric CO 2 maintains pH at 10 to 11. In less
alkaline solutions, these barbiturates may precipitate as the free acids; so

do not reconstitute with NS or LR; and do not mix with acidic solutions of other
drugs. Properly reconstituted, refrigerated solutions of thiobarbiturates are
stable for 1 week, while similar solutions of methohexital are stable for 6 weeks.
Structure-Activity Relationships
Hypnotic activity: side chains at position 5 (especially if one of them is branched)
Potency and duration of action: length of side chain at position 5 (so, secobarbital
and thiamylal are slightly more potent than pentobarbital and thiopental,
respectively)
More rapid onset and shorter duration of action: sulfur instead of oxygen atom at
position 2 (so thiamylal and thiopental have more rapid onset and shorter duration
of action than secobarbital and pentobarbital, respectively)
Increased incidence of excitatory side effects: methylation at position 1
(methohexital)
Increased potency, rate of onset and short action: increased lipophilicity
Stereoisomerism Though their l-isomers are nearly twice as potent as their disomers, barbiturates are marketed as racemic mixtures. Methohexital has two
asymmetric carbon atoms, so exists as 4 stereoisomers (alpha,beta-d,lmethohexital). The beta isomers are associated with extensive motor activity, so
methohexital is marketed as racemic alpha-d,l-methohexital . Different
activities among different stereoisomers (enantiomers or enantiomorphs) is
consistent with a site of action at a chiral center of a receptor or enzyme.
Mechanism of Action
Most likely site of action: gamma-aminobutyric acid (GABA) receptor complex,
GABA

Effects on GABA

occur at clinical drug concentrations, correlate with anesthetic

potency and are stereospecific.

GABA is the principal inhibitory neurotransmitter in the mammalian CNS
GABA A complex:
- oligomeric complex of 4 to 6 glycoprotein subunits assembled to form a ligandgated chloride ion channel
- activation (eg by GABA) leads to increased chloride conductance causing
hyperpolarization, hence inhibition or decreased excitability, of the postsynaptic

neuron
Barbiturates enhance and mimic the action of GABA at the GABA Areceptor
complex. Barbiturate binding to this receptor decreases the rate of GABA
dissociation and increases the duration of GABA-activated chloride channel
opening. At slightly higher concentrations, barbiturates directly activate chloride
channel opening even in the absence of GABA, leading to "barbiturate anesthesia."
Pharmacokinetics
An intravenous barbiturate bolus distributes first into a "central blood pool"
chiefly perfusing relatively low-volume, high blood flow organs such as the
brain. (Despite high affinity, adipose tissue takes up drug slowly due to relatively
low perfusion.) Elimination clearance contributes almost nothing to termination of
induction effect. Drug effect is terminated in large part by uptake into lean
tissues such as muscle. First-pass pulmonary uptake of thiopental is about 14%.
Mean data from compartmental models
V

C (L/kg)

Cl

dss (L)

E (ml/min/kg)

1/2beta (hrs)

Hepatic ER

thiopental

0.38

2.5

3.4

11.6

0.15

methohexital

0.35

2.3

10.9

3.9

0.50

Where, in the above table, V

the brain), V
clearance, t

dss

is the central volume of distribution (that includes

is the volume of distribution at steady state, Cl

1/2beta

is elimination

is elimination half-time, and Hepatic ER is the hepatic extraction

ratio. Note that the slower elimination clearance of thiopental may relflect it's
lower hepatic extraction ratio. Cl

becomes the dominant factor controlling drug

concentration only after the rapid decline during initial drug redistribution. After
large or multiple doses or a continuous infusion of barbiturate, termination of drug
activity depends increasingly on adipose tissue uptake and Cl E . After about 3 days
of thiopental administration for cerebral resuscitation, recovery took almost 4
days!
Pharmacodynamics
Pharmacodynamics may be most easily elucidated by studying a continuous
noninvasive measure of drug effect: for thipental, the electroencephalogram
(EEG). Thiopental causes a biphasic EEG response with activation at low
concentrations followed by inhibition at higher concentrations. However, a unique

relationship between thiopental's EEG effect and anesthetic depth (measured by

response to noxious stimuli) could not be established.
Clinical Pharmacology and Uses
Altered responses to induction doses of barbiturates are due altered
pharmacodynamics or early distribution pharmacokinetics.The classic example is
the markedly reduced dose required in the presence of hypovolemic shock. In this
situation, the brain receives a higher fraction of the induction dose and removal is
quite slow because of decreased blood flow to other organs. The decreasing dose
requirement with age is probably related to the relative decrease in lean body mass
with age and the relative increase in adipose tissue. For similar reasons, induction
dose is decreased in females and in the obese.
It has been suggested that thiopental dose(mg) = 350 + wt - 2(age) - 50(if female)
Induction of General Anesthesia
Barbiturates induce general anesthesia rapidly and pleasantly (painlessly). They act
in one arm-to-brain circulation time with maximum effect in about 1 minute and
duration about 5-8 minutes.Induction doses produce the highest blood
concentration, the greatest effects on body systems and the most side effects.
Usual, recommended induction doses of thiopental:
adults
2.5-4.5 mg/kg
children 5-6 mg/kg
infants 7-8 mg/kg
Since, some individuals seem "particularly sensitive" to thiopental, a conservative
technic might be to inject 1/4 of the calculated (above) dose and observe patient
response. If this smaller dose has great effect, reduce calculated subsequent
dose.
Premedication and ASA Physical Status influence induction dose (mg/kg):
Premed
ASA I ASA II ASA III & IV
none

4.0

3.7

3.2

benzodiazepine

3.4

3.3

3.1

light opioid

3.4

3.1

3.0

heavy opioid

3.1

2.8

2.7

Premedicated geriatric patients require a 30-40% reduction in dose.Concomittant

midazolam administration shifts dose response curve to the left. In hypothermia
and circulatory failure a much lower dose is needed and the effect is greater. In
acute EtOH intoxication a lower barbiturate dose will suffice; but increased doses
may be needed in chronic alcohol drinkers.
Methohexital is about 2.7 times more potent than thiopental.Methohexital 1.5
mg/kg is approximately equivalent to 4.0 mg/kg thiopental.
Thiamylal is not significantly different from thiopental in potency, incidence of
laryngospasm, respiratory depression, cardiotoxicity or recovery time.
Injection complications

urticarial rash
o upper chest, neck, face
o fades in a few minutes
o probably due to histamine
anaphylactoid reactions are occasionally seen
o hives, facial edema, bronchospasm, shock
o absence of reaction to oral barbiturates does NOT ensure
lack of sensitivity to IV barbiturates
o treatment symptomatic: may include epinephrine in 100 mcg
increments, IV fluids, bronchodilators
pain on intravenous injection - uncommon: thiopental 1-2% and
methohexital <5% when injected into small veins
intra-arterial injection or subcutaneous extravasation
o methohexital -> mild discomfort, no sequelae

o thiopental extravasation
pain edema, erythema -> sequelae ranging from slight soreness
to extensive tissue necrosis depending on concentration and
total amount injected
o thiopental intra-arterial
may cause intense arterial spasm with possibly severe pain at
and distal to the injection site which may persist for hours
and be associated with anesthesia or hyperesthesia of the
distal extremity, edema or motor weakness
sequelae range from mild discomfort to gangrene and loss of
distal tissue
Treatment is aimed at preventing permanent sequelae and
consists of
diluting the drug and relieving spasm: papaverine 40-80
mg in 10-20 ml NS intra-arterial or
lidocaine 1% 5-10 ml intra-arterial , and
consider sympathetic block ( stellate ganglion block or
brachial plexus block) to relieve spasm, and
heparin IV to prevent thrombosis
Specific Organ Function Effects
CNS Effects

Barbiturates may be hyperalgesic in subanesthetic doses.

Thiopental produces dose-related depression of the EEG:
1. delta and theta waves (increasing amplitude and decreasing
frequency)
2. burst supression

3. flat line
Thiopental 4 mg/kg/hr maintains flat EEG (as may pentobarbital
infusion that maintains a plasma concentration of 3-6 mg%).
Thiopental causes a dose-related decrease in CMRO 2 to 55% with
flat EEG reflecting a decrease in neuronal but not metabolic need
for O 2 . (Hypothermia is the only way to decrease the metabolic
O 2 requirement.)
Thiopental decreases CBF and ICP. CPP is maintained because ICP
decreases more than arterial pressure.
Methohexital is associated with seizures after high doses; and 33%
incidence of postoperative seizures when given by continuous
infusion.
SSEP's remain even after doses of thiopental that flatten the EEG,
but median nerve SSEP and BSAEP responses change in a dosedependent fashion.
Intraocular Pressure
IOP decreases 40% after an induction dose of thiopental or methohexital. If
succinylcholine is given immediately after thiopental, IOP returns to preinduction
value. (Delay in giving succinylcholine leads to more elevated IOP.)
Respiratory Effects

central respiratory depression

both rate and depth of breathing are decreased
respiration apparently returns toward normal in a few minutes, but
responses to hypercarbia and hypoxia remain depressed for a longer
time

 low incidence of hypersalivation

rare bronchospasm
laryngeal reflexes are more active (intact) after thiopental than
after propofol
mucociliary clearance depressed (to same degree as with the
volatile agents)
Cardiovascular Effects

predominant one: venodilation leading to peripheral blood pooling

myocardial contractility is depressed to a lesser extent than with
volatile agents
baroreflex mechanism only slightly depressed
SVR usually unchanged (decreases 21% in patients with preloadindependent artificial hearts and constant cardiac output)
thiopental also dilates pulmonary vessels
methohexital: heart rate increases more than with thiopental
no arrhythmias occur (unless hypercarbia or hypoxia occur)
decreased sympathetic output from the CNS
do not sensitize the heart to catecholamines
use with caution whenever increase in heart rate (especially
methohexital) or decrease in preload may be detrimental to the
patient (eg: pericardial tamponade, hypovolemia, CHF, ischemic
heart disease, heart block)