08 - 29.8 Barbiturates and Similarly Acting Drugs

29.8 Barbiturates and Similarly Acting Drugs

Hydroxyzine is most commonly used as a short-term anxiolytic. Hydroxyzine should not be given IV because it is irritating to the blood vessels. Dosages of 50 to 100 mg given orally four times a day for long-term treatment or 50 to 100 mg IM every 4 to 6 hours for short-term treatment are usually effective. SSRI-induced anorgasmia may sometimes be reversed with 4 to 16 mg a day of cyproheptadine taken by mouth 1 or 2 hours before anticipated sexual activity. A number of case reports and small studies have also reported that cyproheptadine may be of some use in the treatment of eating disorders, such as anorexia nervosa. Cyproheptadine is available in 4 mg tablets and a 2 mg/5 mL solution. Children and elderly patients are more sensitive to the effects of antihistamines than are young adults. REFERENCES Armstrong SC, Cozza KL. Antihistamines. Psychosomatics. 2003;44(5):430. Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol. 2001;63(6):637. Camelo-Nunes IC. New antihistamines: A critical view. J Pediatr (Rio J). 2006;82[5 Suppl]:S173. Davies AJ, Harindra V, McEwan A. Cardiotoxic effect with convulsions in terfenadine overdose. BMJ. 1989;298(6669):325. Haas H, Panula P. The role of histamine and the tuberomammillary nucleus in the nervous system. Nat Rev Neurosci. 2003;4(2):121. Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol. 2008;18(3):157. McIntyre RS. Antihistamines. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2009:3033. Montoro J, Sastre J, Bartra J, del Cuvillo A, Davila I. Effect of H1 antihistamines upon the central nervous system. J Investig Allergol Clin Immunol. 2006;16[Suppl 1]:24. Shapiro BJ, Lynch KL, Toochinda T, Lutnick A, Cheng HY, Kral AH. Promethazine misuse among methadone maintenance patients and community-based injection drug users. J Addict Med. 2013;7(2):96–101. Simons FE. Advances in H1-antihistamines. N Engl J Med. 2004;351(21):2203. Theunissen EL, Vermeeren A, Vuurman EF, Ramaekers JG. Stimulating effects of H1-antagonists. Curr Pharm Des. 2006;12(20):2501. Welch MJ, Meltzer EO, Simons FE. H1-antihistamines and the central nervous system. Clin Allergy Immunol. 2002;17:337. Yanai K, Tashiro M. The physiological and pathophysiological roles of neuronal histamine: An insight from human positron emission tomography studies. Pharmacol Ther. 2007;113(1):1. 29.8 Barbiturates and Similarly Acting Drugs The first barbiturate to be used in medicine was barbital (Veronal), which was introduced in 1903. It was followed by phenobarbital (Luminal), amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), and thiopental (Pentothal). Many others have been synthesized, but only a handful has been used clinically (Table 29.8-1). Many problems are associated with these drugs, including high abuse and addiction

potential, a narrow therapeutic range with low therapeutic index, and unfavorable side effects. The use of barbiturates and similar compounds such as meprobamate (Miltown) has practically been eliminated by the benzodiazepines and hypnotics, such as zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata), which have a lower abuse potential and a higher therapeutic index than the barbiturates. Nevertheless, the barbiturates still have an important role in the treatment of certain mental and convulsive disorders. Table 29.8-1 Barbiturate Dosages (Adult) PHARMACOLOGICAL ACTIONS The barbiturates are well absorbed after oral administration. The binding of barbiturates to plasma proteins is high, but lipid solubility varies. The individual barbiturates are metabolized by the liver and excreted by the kidneys. The half-lives of specific barbiturates range from 1 to 120 hours. The barbiturates may also induce hepatic enzymes (cytochrome P450, CYP), thereby reducing the levels of both the barbiturate and any other concurrently administered drugs metabolized by the liver. The mechanism of action of barbiturates involves the γ-aminobutyric acid (GABA) receptor– benzodiazepine receptor–chloride ion channel complex. THERAPEUTIC INDICATIONS Electroconvulsive Therapy Methohexital (Brevital) is commonly used as an anesthetic agent for electroconvulsive therapy (ECT). It has lower cardiac risks than other barbiturate anesthetics. Used intravenously (IV), methohexital produces rapid unconsciousness, and because of its rapid redistribution, it has a brief duration of action (5 to 7 minutes). Typical dosing for ECT is 0.7 to 1.2 mg/kg. Methohexital can also be used to abort prolonged seizures in

ECT or to limit postictal agitation. Seizures Phenobarbital (Solfoton, Luminal), the most commonly used barbiturate for treatment of seizures, has indications for the treatment of generalized tonic–clonic and simple partial seizures. Parenteral barbiturates are used in the emergency management of seizures independent of cause. Intravenous phenobarbital should be administered slowly at 10 to 20 mg/kg for status epilepticus. Narcoanalysis Amobarbital (Amytal) has been used historically as a diagnostic aid in a number of clinical conditions, including conversion reactions, catatonia, hysterical stupor, and unexplained muteness, and to differentiate stupor of depression, schizophrenia, and structural brain lesions. The Amytal interview is performed by placing the patient in a reclining position and administering amobarbital IV at 50 mg a minute. Infusion is continued until lateral nystagmus is sustained or drowsiness is noted, usually at 75 to 150 mg. After this, 25 to 50 mg can be administered every 5 minutes to maintain narcosis. The patient should be allowed to rest for 15 to 30 minutes after the interview before attempting to walk. Because of the risk of laryngospasm with IV amobarbital, diazepam has become the drug of choice for narcoanalysis. Sleep The barbiturates reduce sleep latency and the number of awakenings during sleep, although tolerance to these effects generally develops within 2 weeks. Discontinuation of barbiturates often leads to rebound increases on electroencephalographic measures of sleep and a worsening of the insomnia.

WITHDRAWAL FROM SEDATIVE-HYPNOTICS Barbiturates are sometimes used to determine the extent of tolerance to barbiturates or other hypnotics to guide detoxification. After intoxication has resolved, a test dose of pentobarbital (200 mg) is given orally. One hour later, the patient is examined. Tolerance and dose requirements are determined by the degree to which the patient is affected. If the patient is not sedated, another 100 mg of pentobarbital can be administered every 2 hours, up to three times (maximum, 500 mg over 6 hours). The amount needed for mild intoxication corresponds to the approximate daily dose of barbiturate used. Phenobarbital (30 mg) may then be substituted for each 100 mg of pentobarbital. This daily dose requirement can be administered in divided doses and gradually tapered by 10 percent a day, with adjustments made according to withdrawal signs. PRECAUTIONS AND ADVERSE REACTIONS Some adverse effects of barbiturates are similar to those of benzodiazepines, including paradoxical dysphoria, hyperactivity, and cognitive disorganization. Rare adverse effects associated with barbiturate use include the development of Stevens–Johnson syndrome, megaloblastic anemia, and neutropenia. Prior to the advent of benzodiazepines, the widespread use of barbiturates as hypnotics and anxiolytics made them the most common cause of acute porphyria reactions. Severe attacks of porphyria have decreased largely because barbiturates are now seldom used and are contraindicated in patients with the disease. A major difference between the barbiturates and the benzodiazepines is the low therapeutic index of the barbiturates. An overdose of barbiturates can easily prove fatal. In addition to narrow therapeutic indexes, the barbiturates are associated with a significant risk of abuse potential and the development of tolerance and dependence. Barbiturate intoxication is manifested by confusion, drowsiness, irritability, hyporeflexia or areflexia, ataxia, and nystagmus. The symptoms of barbiturate withdrawal are similar to, but more marked than, those of benzodiazepine withdrawal. Ten times the daily dose or 1 g of most barbiturates causes severe toxicity; 2–10 g generally proves fatal. Manifestations of barbiturate intoxication may include delirium, confusion, excitement, headache, and central nervous system (CNS) and respiratory depression, ranging from somnolence to coma. Other adverse reactions include Cheyne– Stokes respiration, shock, miosis, oliguria, tachycardia, hypotension, hypothermia, irritability, hyporeflexia or areflexia, ataxia, and nystagmus. Treatment of overdose includes induction of emesis or lavage, activated charcoal, and saline cathartics; supportive treatment, including maintaining airway and respiration and treating shock as needed; maintaining vital signs and fluid balance; alkalinizing the urine, which increases excretion; forced diuresis if renal function is normal, or hemodialysis in severe cases. Because of some evidence of teratogenicity, barbiturates should not be used by

pregnant women or women who are breastfeeding. Barbiturates should be used with caution by patients with a history of substance abuse, depression, diabetes, hepatic impairment, renal disease, severe anemia, pain, hyperthyroidism, or hypoadrenalism. Barbiturates are also contraindicated in patients with acute intermittent porphyria, impaired respiratory drive, or limited respiratory reserve. DRUG INTERACTIONS The primary area for concern about drug interactions is the potentially dangerous effects of respiratory depression. Barbiturates should be used with great caution with other prescribed CNS drugs (including antipsychotic and antidepressant drugs) and nonprescribed CNS agents (e.g., alcohol). In addition, caution must be exercised when prescribing barbiturates to patients who are taking other drugs that are metabolized in the liver, especially cardiac drugs and anticonvulsants. Because individual patients have a wide range of sensitivities to barbiturate-induced enzyme induction, it is not possible to predict the degree to which the metabolism of concurrently administered medications may be affected. Drugs that have their metabolism enhanced by barbiturate administration include opioids, antiarrhythmic agents, antibiotics, anticoagulants, anticonvulsants, antidepressants, β-adrenergic receptor antagonists, dopamine receptor antagonists, contraceptives, and immunosuppressants. LABORATORY INTERFERENCES No known laboratory interferences are associated with the administration of barbiturates. DOSE AND CLINICAL GUIDELINES Barbiturates and other drugs described later begin to act within 1 to 2 hours of administration. The doses of barbiturates vary, and treatment should begin with low doses that are increased to achieve a clinical effect. Children and older people are more sensitive to the effects of the barbiturates than are young adults. The most commonly used barbiturates are available in a variety of dose forms. Barbiturates with half-lives in the 15- to 40-hour range are preferable, because long-acting drugs tend to accumulate in the body. Clinicians should instruct patients clearly about the adverse effects and the potential for dependence associated with barbiturates. Although determining plasma concentrations of barbiturates is rarely necessary in psychiatry, monitoring of phenobarbital concentrations is standard practice when the drug is used as an anticonvulsant. The therapeutic blood concentrations for phenobarbital in this indication range from 15 to 40 mg/L, although some patients may experience significant adverse effects in that range. Barbiturates are contained in combination products with which the clinician should be familiar.

OTHER SIMILARLY ACTING DRUGS A number of agents that act similarly to the barbiturates have been used in the treatment of anxiety and insomnia. Three such available drugs are paraldehyde (Paral), meprobamate, and chloral hydrate (Noctec). These drugs are rarely used because of their abuse potential and potential toxic effects. Paraldehyde Paraldehyde is a cyclic ether and was first used in 1882 as a hypnotic. It has also been used to treat epilepsy, alcohol withdrawal symptoms, and delirium tremens. Because of its low therapeutic index, it has been supplanted by the benzodiazepines and other anticonvulsants. Pharmacologic Actions. Paraldehyde is rapidly absorbed from the gastrointestinal (GI) tract and from intramuscular (IM) injections. It is primarily metabolized to acetaldehyde by the liver, and unmetabolized drug is expired by the lungs. Reported half-lives range from 3.4 to 9.8 hours. The onset of action is 15 to 30 minutes. Therapeutic Indications. Paraldehyde is not indicated as an anxiolytic or a hypnotic and has little place in current psychopharmacology. Precautions and Adverse Reactions. Paraldehyde frequently causes foul breath because of expired unmetabolized drug. It can inflame pulmonary capillaries and cause coughing. It can also cause local thrombophlebitis with IV use. Patients may experience nausea and vomiting with oral use. Overdose leads to metabolic acidosis and decreased renal output. There is risk of abuse among drug addicts. Drug Interactions. Disulfiram (Antabuse) inhibits acetaldehyde dehydrogenase and reduces metabolism of paraldehyde, leading to possible toxic concentration of paraldehyde. Paraldehyde has addictive sedating effects in combination with other CNS depressants such as alcohol or benzodiazepines. Laboratory Interferences. Paraldehyde can interfere with the metyrapone, phentolamine, and urinary 17-hydroxycorticosteroid tests. Dosing and Clinical Guidelines. Paraldehyde is available in 30-mL vials for oral, IV, or rectal use. For seizures in adults, up to 12 mL (diluted to a 10% solution) can be administered by gastric tube every 4 hours. For children, the oral dose is 0.3 mg/kg. Meprobamate Meprobamate, a carbamate, was introduced shortly before the benzodiazepines,

specifically to treat anxiety. It is also used for muscle relaxant effects. Pharmacologic Actions. Meprobamate is rapidly absorbed from the GI tract and from IM injections. It is metabolized primarily by the liver, and a small portion is excreted unchanged in urine. The plasma half-life is approximately 10 hours. Therapeutic Indications. Meprobamate is indicated for short-term treatment of anxiety disorders. It has also been used as a hypnotic and is prescribed as a muscle relaxant. Precautions and Adverse Reactions. Meprobamate can cause CNS depression and death in overdose and carries the risk of abuse by patients with drug or alcohol dependence. Abrupt cessation after long-term use can lead to withdrawal syndrome, including seizures and hallucinations. Meprobamate can exacerbate acute intermittent porphyria. Other rare side effects include hypersensitivity reactions, wheezing, hives, paradoxical excitement, and leukopenia. It should not be used in patients with hepatic compromise. Drug Interactions. Meprobamate has additive sedating effects in combination with other CNS depressants, such as alcohol, barbiturates, or benzodiazepines. Laboratory Interferences. Meprobamate can interfere with the metyrapone, phentolamine, and urinary 17-hydroxycorticosteroid tests. Dosing and Clinical Guidelines. Meprobamate is available in 200, 400, and 600 mg tablets; 200 and 400 mg extended-release capsules; and various combinations, for example, aspirin, 325 mg and 200 mg of meprobamate (Equagesic) for oral use. For adults, the usual dose is 400 to 800 mg twice daily. Elderly patients and children aged 6 to 12 years require half the adult dose. Chloral Hydrate Chloral hydrate is a hypnotic agent rarely used in psychiatry because numerous safer options, such as benzodiazepines, are available. Pharmacological Actions. Chloral hydrate is well absorbed from the GI tract. The parent compound is metabolized within minutes by the liver to the active metabolite trichloroethanol, which has a half-life of 8 to 11 hours. A dose of chloral hydrate induces sleep in about 30 to 60 minutes and maintains sleep for 4 to 8 hours. It probably potentiates GABAergic neurotransmission, which suppresses neuronal excitability. Therapeutic Indications. The major indication for chloral hydrate is to induce

sleep. It should be used for no more than 2 or 3 days because longer-term treatment is associated with an increased incidence and severity of adverse effects. Tolerance develops to the hypnotic effects of chloral hydrate after 2 weeks of treatment. The benzodiazepines are superior to chloral hydrate for all psychiatric uses. Precautions and Adverse Reactions. Chloral hydrate has adverse effects on the CNS, GI system, and skin. High doses (>4 g) may be associated with stupor, confusion, ataxia, falls, or coma. The GI effects include nonspecific irritation, nausea, vomiting, flatulence, and an unpleasant taste. With long-term use and overdose, gastritis and gastric ulceration can develop. In addition to the development of tolerance, dependence on chloral hydrate can occur, with symptoms similar to those of alcohol dependence. With a lethal dose between 5,000 and 10,000 mg, chloral hydrate is a particularly poor choice for potentially suicidal persons. Drug Interactions. Because of metabolic interference, chloral hydrate should be strictly avoided with alcohol, a notorious concoction known as a Mickey Finn. Chloral hydrate may displace warfarin (Coumadin) from plasma proteins and enhance anticoagulant activity; this combination should be avoided. Laboratory Interferences. Chloral hydrate administration can lead to falsepositive results for urine glucose determinations that use cupric sulfate (e.g., Clinitest) but not in tests that use glucose oxidase (e.g., Clinistix and Tes-Tape). Chloral hydrate can also interfere with the determination of urinary catecholamines in 17hydroxycorticosteroids. Dosing and Clinical Guidelines. Chloral hydrate is available in 500 mg capsules; 500 mg/5 mL solution; and 324, 500, and 648 mg rectal suppositories. The standard dose of chloral hydrate is 500 to 2,000 mg at bedtime. Because the drug is a GI irritant, it should be administered with excess water, milk, other liquids, or antacids to decrease gastric irritation. Propofol Propofol (Diprivan) is a GABAA agonist that is used as an anesthetic. It induces presynaptic release of GABA and dopamine (the latter possibility through an action on GABAB receptors) and is a partial agonist at dopamine D2 and N-methyl-d-aspartate (NMDA) receptors. Because it is very lipid soluble, it crosses the blood–brain barrier readily and induces anesthesia in less than 1 minute. Rapid redistribution from the CNS results in offset of action within 3 to 8 minutes after the infusion is discontinued. It is well tolerated when used for conscious sedation, but it has a potential for acute adverse effects, including respiratory depression, apnea, and bradyarrhythmias, and prolonged infusion can cause acidosis and mitochondrial myopathies. The carrier used for the infusion is a soybean emulsion that can be a culture medium for various organisms. In