Extracorporeal Treatment for Barbiturate Poisoning
Extracorporeal Treatment for Barbiturate Poisoning
All barbiturates are derivatives of barbituric acid and are classified according to their pharmacokinetic properties into long-acting and short-acting agents (consisting of ultrashort-, short-, and intermediate-acting agents). Each barbiturate has a unique structure that relates to its effective duration of action. Short-acting barbiturates are more protein bound and lipid soluble than their long-acting counterparts; have a more rapid onset, higher pKa (logarithmic acid dissociation constant), and shorter duration of action; and are metabolized nearly exclusively in the liver. Conversely, long-acting barbiturates accumulate less extensively in tissue (ie, their volume of distribution is smaller), are less lipid soluble, and are excreted as active drugs by the kidneys more readily. For example, the long-acting agent phenobarbital is a weak acid and approximately 20%-25% is excreted unchanged in urine, whereas <5% of pentobarbital is excreted unchanged. Consequently, long-acting agents are more amenable to enhanced removal using urinary alkalinization; historically, forced alkaline diuresis was used in cases of moderate phenobarbital poisoning. Table 1 summarizes physicochemical and pharmacokinetic data for barbiturates.
Hepatic metabolism is the main route of endogenous clearance of all barbiturates. They are well-known inducers of the hepatic cytochrome P450 (CYP) enzyme system and thus increase the metabolic clearance of medications that are CYP substrates. Barbiturates undergo CYP-mediated metabolism and exhibit autoinduction, which leads long-term users to develop tolerance. Although tolerance to the sedative-hypnotic effects of barbiturates develops, tolerance to the serum drug concentration associated with lethal toxicity (ie, respiratory failure) does not appear to develop. Thus, long-term users tolerate a higher dose but not a higher serum concentration before being at risk of lethal toxicity and will be at greater risk of drug withdrawal if concentrations are reduced rapidly using ECTR. When barbiturates are combined with other central nervous system (CNS) depressants, such as alcohol, opiates, or benzodiazepines, overdose is even more dangerous due to additive depressant effects on the CNS and respiratory system.
Pharmacokinetics of Barbiturates
All barbiturates are derivatives of barbituric acid and are classified according to their pharmacokinetic properties into long-acting and short-acting agents (consisting of ultrashort-, short-, and intermediate-acting agents). Each barbiturate has a unique structure that relates to its effective duration of action. Short-acting barbiturates are more protein bound and lipid soluble than their long-acting counterparts; have a more rapid onset, higher pKa (logarithmic acid dissociation constant), and shorter duration of action; and are metabolized nearly exclusively in the liver. Conversely, long-acting barbiturates accumulate less extensively in tissue (ie, their volume of distribution is smaller), are less lipid soluble, and are excreted as active drugs by the kidneys more readily. For example, the long-acting agent phenobarbital is a weak acid and approximately 20%-25% is excreted unchanged in urine, whereas <5% of pentobarbital is excreted unchanged. Consequently, long-acting agents are more amenable to enhanced removal using urinary alkalinization; historically, forced alkaline diuresis was used in cases of moderate phenobarbital poisoning. Table 1 summarizes physicochemical and pharmacokinetic data for barbiturates.
Hepatic metabolism is the main route of endogenous clearance of all barbiturates. They are well-known inducers of the hepatic cytochrome P450 (CYP) enzyme system and thus increase the metabolic clearance of medications that are CYP substrates. Barbiturates undergo CYP-mediated metabolism and exhibit autoinduction, which leads long-term users to develop tolerance. Although tolerance to the sedative-hypnotic effects of barbiturates develops, tolerance to the serum drug concentration associated with lethal toxicity (ie, respiratory failure) does not appear to develop. Thus, long-term users tolerate a higher dose but not a higher serum concentration before being at risk of lethal toxicity and will be at greater risk of drug withdrawal if concentrations are reduced rapidly using ECTR. When barbiturates are combined with other central nervous system (CNS) depressants, such as alcohol, opiates, or benzodiazepines, overdose is even more dangerous due to additive depressant effects on the CNS and respiratory system.
