General anesthesia began with inhaled agents but now can be induced and maintained with drugs that enter the patient through a wide range of routes. Drug administration can be oral, rectal, transder-mal, transmucosal, intramuscular, or intravenous for the purpose of producing or enhancing an anes-thetic state. Preoperative sedation of adults is usu-ally accomplished by way of oral or intravenous routes. Induction of general anesthesia in adults usually includes intravenous drug administration. Effective topical anesthesia with EMLA (eutectic mixture of local anesthetic) cream, LMX (plain lidocaine cream 4% and 5%), or 2% lidocaine jelly has increased the ease of intravenous inductions in children. Maintenance of general anesthesia is feasible with a total intravenous anesthesia (TIVA) technique.
Barbiturates depress the reticular activating sys-tem in the brainstem, which controls multiple vital functions, including consciousness. In clinical con-centrations, barbiturates more potently affect the function of nerve synapses than axons. Their primary mechanism of action is believed to be through bind-ing to the γ-aminobutyric acid type A (GABAA) receptor. Barbiturates potentiate the action of GABA in increasing the duration of openings of a chloride-specific ion channel.
Barbiturates are derived from barbituric acid (Figure 9–1). Substitution at carbon C5 determines hypnotic potency and anticonvulsant activity. A long-branched chain conveys more potency than does a short straight chain. Likewise, the phenyl group in phenobarbital is anticonvulsive, whereas the methylgroup in methohexital is not. Replacing the oxygen at C2 (oxybarbiturates) with a sulfur atom (thio-barbiturates) increases lipid solubility. As a result, thiopental and thiamylal have a greater potency, more rapid onset of action, and shorter durations of action (after a single “sleep dose”) than pentobar-bital. The sodium salts of the barbiturates are water soluble but markedly alkaline (pH of 2.5% thiopen-tal >10) and relatively unstable (2-week shelf-life for 2.5% thiopental solution). Concentrations greater than recommended cause an unacceptable incidence of pain on injection and venous thrombosis.
In clinical anesthesiology, thiopental, thiamylal, and methohexital were frequently administered intrave-nously for induction of general anesthesia in adults and children (prior to the introduction of propofol). Rectal thiopental or, more often, methohexital has been used for induction in children, and intramus-cular (or oral) pentobarbital was often used in the past for premedication of all age groups.
The duration of sleep doses of the highly lipid-solu-ble barbiturates (thiopental, thiamylal, and metho-hexital) is determined by redistribution, not by metabolism or elimination. For example, although thiopental is highly protein bound (80%), its great lipid solubility and high nonionized fraction (60%)
account for rapid brain uptake (within 30 s). If the central compartment is contracted (eg, hypovolemic shock), if the serum albumin is low (eg, severe liver disease or malnutrition), or if the nonionized frac-tion is increased (eg, acidosis), larger brain and heart concentrations will be achieved for a given dose. Redistribution to the peripheral compartment— specifically, the muscle group—lowers plasma and brain concentration to 10% of peak levels within 20–30 min (Figure 9–2). This pharmacokinetic profile correlates with clinical experience—patients typically lose consciousness within 30 s and awaken within 20 min.
The minimal induction dose of thiopental will depend on body weight and age. Reduced induction doses are required for elderly patients primarily due to slower redistribution. In contrast to the rapid initial distribution half-life of a few minutes, elimination of thiopental is prolonged (elimination half-life ranges of 10–12 h). Thiamylal and methohexital have similar distribution patterns, whereas less lipid-soluble barbi-turates have much longer distribution half-lives and durations of action after a sleep dose. Repetitive administration of barbiturates (eg, infusion of thiopental for “barbiturate coma” and brain protection) saturates the peripheral compartments,minimizing any effect of redistribution, and render-ing the duration of action more dependent on elimi-nation. This is an example of context sensitivity.
Barbiturates are principally biotransformed via hepatic oxidation to inactive water-soluble metabo-lites. Because of greater hepatic extraction, metho-hexital is cleared by the liver more rapidly than thiopental. Although redistribution is responsible for the awakening from a single sleep dose of any of these lipid-soluble barbiturates, full recovery of psy-chomotor function is more rapid following metho-hexital due to its enhanced metabolism.
Increased protein binding decreases barbiturate glo-merular filtration, whereas increased lipid solubility tends to increase renal tubular reabsorption. Except for the less protein-bound and less lipid-soluble agents such as phenobarbital, renal excretion is lim-ited to water-soluble end products of hepatic bio-transformation. Methohexital is excreted in the feces.
Intravenous bolus induction doses of barbiturates cause a decrease in blood pressure and an increase in heart rate. Hemodynamic responses to barbiturates are reduced by slower rates of induction. Depression of the medullary vasomotor center produces vaso-dilation of peripheral capacitance vessels, which increases peripheral pooling of blood, mimicking a reduced blood volume. Tachycardia following administration is probably due to a central vagolytic effect and reflex responses to decreases in blood pressure. Cardiac output is often maintained by an increased heart rate and increased myocardial con-tractility from compensatory baroreceptor reflexes. Sympathetically induced vasoconstriction of resis-tance vessels (particularly with intubation under light planes of general anesthesia) may actually increase peripheral vascular resistance. However, in situations where the baroreceptor response will be blunted or absent (eg, hypovolemia, congestive heart failure, β-adrenergic blockade), cardiac output and arterial blood pressure may fall dramatically due to uncompensated peripheral pooling of blood and direct myocardial depression. Patients with poorly controlled hypertension are particularly prone to wide swings in blood pressure during anesthesia induction. The cardiovascular effects of barbiturates therefore vary markedly, depending on rate of administration, dose, volume status, baseline autonomic tone, and preexisting cardiovascular dis-ease. A slow rate of injection and adequate preopera-tive hydration attenuates or eliminates these changes in most patients.
Barbiturates depress the medullary ventilatory cen-ter, decreasing the ventilatory response to hypercap-nia and hypoxia. Deep barbiturate sedation often leads to upper airway obstruction; apnea often fol-lows an induction dose. During awakening, tidal volume and respiratory rate are decreased follow-ing barbiturate induction. Barbiturates incompletely depress airway reflex responses to laryngoscopy and intubation, and airway instrumentation may lead to bronchospasm (in asthmatic patients) or laryngo-spasm in lightly anesthetized patients.
Barbiturates constrict the cerebral vascula-ture, causing a decrease in cerebral bloodflow, cerebral blood volume, and intracranial pres-sure. Intracranial pressure decreases to a greater extent than arterial blood pressure, so cerebral perfusion pressure (CPP) usually increases. (CPP equals cerebral artery pressure minus the greater of jugular venous pressure or intracranial pressure.) Barbiturates induce a greater decline in cerebral oxygen consumption (up to 50% of normal) than in cerebral blood flow; therefore the decline in cerebral blood flow is not detrimental. Barbiturate-induced reductions in oxygen requirements and cerebral metabolic activity are mirrored by changes in the electroencephalogram (EEG), which progress from low-voltage fast activity with small doses to high-voltage slow activity, burst suppression, and electrical silence with larger doses. Barbiturates may protect the brain from transient episodes of focal ischemia (eg, cerebral embolism) but probably do not protect from global ischemia (eg, cardiac arrest). Abundant animal data document these effects but the clinical data are sparse and inconsistent. Furthermore, thio-pental doses required to maintain EEG suppression (most often burst suppression or flat line) are associ-ated with prolonged awakening, delayed extubation, and the need for inotropic support.
The degree of central nervous system depres-sion induced by barbiturates ranges from mild seda-tion to unconsciousness, depending on the dose administered (Table 9–1). Some patients relate a taste sensation of garlic, onions, or pizza dur-ing induction with thiopental. Barbiturates do not impair the perception of pain. In fact, they some-times appear to lower the pain threshold. Small doses occasionally cause a state of excitement and disorientation that can be disconcerting when seda-tion is the objective. Barbiturates do not produce
muscle relaxation, and some induce involuntary skeletal muscle contractions (eg, methohexital). Relatively small doses of thiopental (50–100 mg intravenously) rapidly (but temporarily) control most grand mal seizures. Unfortunately, acute toler-ance and physiological dependence on the sedative effect of barbiturates develop quickly.
Barbiturates reduce renal blood flow and glomeru-lar filtration rate in proportion to the fall in blood pressure.
Hepatic blood flow is decreased. Chronic expo-sure to barbiturates has opposing effects on drug biotransformation. Induction of hepatic enzymes increases the rate of metabolism of some drugs, whereas binding of barbiturates to the cytochrome P-450 enzyme system interferes with the biotrans-formation of other drugs (eg, tricyclic antidepres-sants). Barbiturates promote aminolevulinic acid synthetase, which stimulates the formation of porphyrin (an intermediary in heme synthesis).This may precipitate acute intermittent porphyria or variegate porphyria in susceptible individuals.
Anaphylactic or anaphylactoid allergic reactions are rare. Sulfur-containing thiobarbiturates evoke mast cell histamine release in vitro, whereas oxyba-rbiturates do not. For this reason, some anesthesiol-ogists prefer induction agents other than thiopental or thiamylal in asthmatic or atopic patients, but the evidence for this choice is sparse. There is no question that airway instrumentation with light anesthesia is troublesome in patients with reactive airways.
Contrast media, sulfonamides, and other drugs that occupy the same protein-binding sites as thiopental may displace the barbiturate, increasing the amount of free drug available and potentiating the organ sys-tem effects of a given dose. Ethanol, opioids, antihistamines, and other central nervous system depressants potentiate the sedative effects of barbiturates. The common clinical impression that chronic alcohol abuse is associ-ated with increased thiopental requirements during induction lacks scientific proof.
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