Disposition of Toxic Drugs and Chemicals in Man

Occurrence and Usage. Cocaine is the most potent of the naturally occurring central nervous system stimulants. The compound is found in the leaves of Erythroxylon coca, a South American shrub, in amounts of up to 2% by weight. It was first isolated in pure form in 1855, and has been widely utilized in medicine as a local anesthetic and increasingly by drug abusers for its stimulant properties. For anesthetic uses cocaine is administered topically as the hydrochloride in 1%-4% solutions for ophthalmological procedures and in 10%-20% solutions for the membranes of the nose and throat. When self-administered it is commonly taken as the hydrochloride by nasal insufflation or intravenous injection or as the free base by smoking, in doses of 10-120 mg.

Blood Concentrations. The chewing of powdered coca leaves containing 17-48 mg of cocaine produced peak plasma concentrations of 0.011-0.149 mg/L within 0.4-2 hours in 6 volunteers (Holmstedt et al., 1979). A 2 mg/kg (140 mg/ 70 kg) intranasal application of

Occurrence and Usage. Pentobarbital (pentobarbitone, Nembutal) is a very popular short-acting barbiturate derivative first prepared in 1930. The drug is available alone and in combination with other agents in amounts of 15-200 mg for oral, intramuscular, or rectal administration. It is supplied as the racemic mixture in the form of both the free acid and the sodium salt, the latter being strongly alkaline in aqueous solution.

Blood Concentrations. After a 5-minute intravenous infusion of 50 mg, plasma concentrations in 5 subjects averaged 1.18 mg/L (range, 1.05-1.33) at 0.08 hours, declining to 0.54 mg/L by 1 hour and 0.27 mg/L by 24 hours (Smith et al., 1973). Plasma concentrations averaged 3 mg/L at 6 minutes after intravenous injection of 100 mg of pentobarbital to 7 volunteers and fell to 1.6 mg/L by 1 hour, when they began to decline with a half-life of 22 hours (Ehrnebo, 1974). A single oral dose of 100 mg produced Occurrence and Usage. Pentobarbital (pentobarbitone, Nembutal) is a very popular short-acting barbiturate derivative first prepared in 1930. The drug is available alone and in combination with other agents in amounts of 15-200 mg for oral, intramuscular, or rectal administration. It is supplied as the racemic mixture in the form of both the free acid and the sodium salt, the latter being strongly alkaline in aqueous solution.

Blood Concentrations. After a 5-minute intravenous infusion of 50 mg, plasma concentrations in 5 subjects averaged 1.18 mg/L (range, 1.05-1.33) at 0.08 hours, declining to 0.54 mg/L by 1 hour and 0.27 mg/L by 24 hours (Smith et al., 1973). Plasma concentrations averaged 3 mg/L at 6 minutes after intravenous injection of 100 mg of pentobarbital to 7 volunteers and fell to 1.6 mg/L by 1 hour, when they began to decline with a half-life of 22 hours (Ehrnebo, 1974). A single oral dose of 100 mg produced...

Occurrence and Usage. Phenobarbital is a barbiturate derivative that has been used as a daytime sedative and very extensively as an anticonvulsant since 1912. Phenobarbital is an excellent inducer of drug-metabolizing microsomal enzymes and its use often results in the lowering of plasma levels of other drugs. Its low oil/water partition coefficient relative to other barbiturates is the basis for its slow accumulation in brain tissue and its limited metabolism. The drug is available as either the free acid or the sodium salt in an elixir or as tablets of 15-65 mg for oral use or in a 65-130 mg/mL solution for intramuscular or intravenous injection. It is often found in combination with bronchodilators, vasodilators, analgesics, and anticholinergic agents. It is generally administered to epileptic patients in oral doses of 60-200 mg daily, often in combination with other anticonvulsant drugs.

Blood Concentrations. A single 30 mg oral dose given to 3 volunteers produced an average peak serum concentration of

Occurrence and Usage. Primidone (Mysoline), a desoxy derivative of phenobarbital, was synthesized in 1949 and first evaluated as an anticonvulsant in 1952. It is used frequently for the treatment of grand mal and temporal lobe seizures, in daily oral doses of 250-1500 mg. The drug is supplied as the free acid in tablets of 50 and 250 mg and as a 250 mg/5 mL suspension for oral administration.

Blood Concentrations. A single 250 mg oral dose of primidone given to 10 patients who were not receiving other anticonvulsants produced an average peak serum primidone concentration of 4.9 mg/L at 4 hours. Primidone concentrations declined with an average half-life of 15 hours (range, 9-22) in these patients, but patients receiving other anticonvulsant drugs exhibited primidone half-lives averaging 8 hours. The metabolites phenylethylmalonamide and phenobarbital were present at detectable levels within 24 or 48 hours, respectively, of the single primidone dose (Cloyd et al., 1981). After a 500 mg oral dose, one subject achieved a peak...

Chapter. 11. Movement Disorders and Neurologic Aspects of Psychotropic Drugs

OVERVIEW

1. Acute dystonic reactions are common when starting antipsychotic chemotherapy - diphentydramine (Benadryl) 50 mg IV provides most rapid and safe relief within minutes. Alternatively, diphenhydramine may be given IM or benztropine may be given IV or IM ( 1-2 mg).

2. Parkinsonism is commonly seen, especially in the first few weeks of antipsychotic chemotherapy. There may be stiffness, reduced arm movement when walking, tremors, and sialorrhea. Prophylactic administration of an antiparkinsonian drug in low dosage 2 to 4 times daily may reduce the incidence and severity of acute extrapyramidal symptoms. These drugs should not be used prophylactically in the elderly or in patients with OBS. More potent antipsychotic agents with less anticholinergic potency are more likely to produce acute extrapyramidal (parkinsonian) effects. There is no evidence that neuroleptics with lower potential for producing acute EPS are less likely to produce the late-occurring neurologic syndrome known as tardive dyskinesia.

3. Akathisia is the most common acute EPS, and responds...