Intravenous Anesthesia - Barbiturates

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 (2,4,6-trioxyhexahydropyrimidine):

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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:
NaOH

Hypnotically active barbiturates:


secobarbital	thiamylal


pentobarbital	thiopental


methohexital

Na salts + 6% by weight NaCO₃ + H₂O or NS
= 2.5% thiopental,
2% thiamylal,
1% methohexital
Buffering action of NaCO₃ plus atmospheric CO₂ 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 d-isomers, barbiturates are marketed as racemic mixtures. Methohexital has two asymmetric carbon atoms, so exists as 4 stereoisomers (alpha,beta-d,l-methohexital). 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_A.
Effects on GABA_A 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 ligand-gated chloride ion channel
- activation (e.g. 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_A receptor 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)	V_dss(L)	Cl_E(ml/min/kg)	t_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_C is the central volume of distribution (that includes the brain), V_dss is the volume of distribution at steady state, Cl_E is elimination clearance, t_1/2beta 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_E 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!

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
- upper chest, neck, face
- fades in a few minutes
- probably due to histamine
anaphylactoid reactions are occasionally seen
- hives, facial edema, bronchospasm, shock
- absence of reaction to oral barbiturates does NOT ensure lack of sensitivity to IV barbiturates
- 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
- methohexital -> mild discomfort, no sequelae
- thiopental extravasation
  pain edema, erythema -> sequelae ranging from slight soreness to extensive tissue necrosis depending on concentration and total amount injected
- 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 CMRO₂ to 55% with flat EEG reflecting a decrease in neuronal but not metabolic need for O₂. (Hypothermia is the only way to decrease the metabolic O₂ 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 dose-dependent 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)