Disorders of the Nervous System Caused by Drugs, Toxins, and Chemical Agents: Introduction
Subsumed under this title is a diverse group of disorders of the nervous system that result from drugs and other injurious or poisonous substances. The neurologist must be concerned with the myriad of chemical agents that have no therapeutic utility but may adversely affect the nervous system; they abound in the environment as household products, insecticides, industrial solvents and other poisons, as well as substances that may have therapeutic value but are used for their “recreational” psychotropic effects, or are conventional medications with known toxic effects and may be accidentally ingested. These constitute the field of neurotoxicology. Also among the neurotoxins are those generated by bacteria and other infectious organisms, as well as toxins several found in nature, such as marine toxins.
It would hardly be possible within one chapter to discuss the innumerable drugs and toxins that affect the nervous system. The interested reader is referred to a number of comprehensive monographs and references listed at the end of this chapter. In addition, a current handbook of pharmacology and toxicology is a useful part of the library of every physician.
The scope of this chapter is also limited because the therapeutic and adverse effects of many drugs are considered elsewhere in this volume in relation to particular symptoms and diseases. Thus, the toxic effects of ethyl, methyl, amyl, and isopropyl alcohol, as well as ethylene and diethylene glycol, are discussed in Chap. 42. The adverse effects of antibiotics on cochlear and vestibular function and on neuromuscular transmission are discussed in Chaps. 15 and 49, respectively. Many of the undesirable side effects of the common drugs used in the treatment of extrapyramidal motor symptoms, pain, headache, seizure and sleep disorders, psychiatric illnesses, and so forth are also considered in the chapters dealing with each of these disorders and in the chapters that cover psychiatric diseases. Cyanide and carbon monoxide poisoning are discussed in relation to anoxic encephalopathy (see Chap. 40). A number of therapeutic agents that predictably damage the peripheral nerves (e.g., cisplatin, disulfiram, vincristine) are mentioned in this chapter but are discussed further in Chap. 46, and those that affect muscle are included in Chap. 48, “Diseases of Muscle.”
The presentation of this subject is introduced by some general remarks on the action of drugs on the nervous system and is followed by discussion of the main classes of agents that affect nervous function. The references at the end of the chapter are listed in relation to each of these categories:
General Principles of Neurotoxicology
The rational use of any drug requires knowledge of the best route of administration, the drug’s absorption characteristics, its distribution in the nervous system and other organs, and its biotransformations and excretion (pharmacokinetics). Because every drug, if given in excess, has some adverse effects, therapeutics and toxicology are inseparable.
All systems of neurons are not identical; each has its own vulnerabilities to particular drugs and toxic agents. This principle, originally enunciated by Oskar and Ceclie Vogt in their theory termed pathoclisis is now embodied as “selective vulnerability.” For example, selective vulnerability explains the production of parkinsonism by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in which a synthetic toxin affects a progressive loss of melanin-bearing dopaminergic nigral neurons (see Chap. 39). Another example is the preferential effects of anesthetics on the neurons of the upper brainstem reticular formation. Not only may certain groups of nerve cells be selectively destroyed by a particular agent but particular parts of their structure may be altered. Drugs may be targeted even to the terminal axons, dendrites, neurofilaments, or receptors on pre- and postsynaptic surfaces of neurons or to certain of their metabolic activities, whereby they synthesize and release neurotransmitters or maintain their cellular integrity by the synthesis of RNA, DNA, and other proteins. An intriguing but not yet fully established extension of this theme relates to the manner in which certain drugs or toxins affect individuals differently with a genetic disposition by way of single nucleotide polymorphisms; this is the emerging field of pharmacogenetics.
The same mechanisms by which drugs and toxins act on particular steps in the formation, storage, release, uptake, catabolism, and resynthesis of neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine, and other catecholamines cannot be separated from their toxic effects. Johnston and Gross have summarized views of how these transmitters and modulating agents, by attaching to receptors at neuronal synapses, are able to increase or decrease the permeability of ion channels and stimulate or inhibit second cytoplasmic messengers (cyclic adenosine monophosphate [cAMP] and G-proteins). For example, drugs such as L-dopa, tryptophan, and choline enhance the synthesis of dopamine, serotonin, and acetylcholine, respectively, and may impart toxic effects through these same mechanisms. Baclofen modulates the release of gamma-aminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system (CNS). Botulinum toxin prevents the release of acetylcholine in the neuromuscular junction and tetanus toxin does the same on GABA in Renshaw cells of the spinal cord. Benzodiazepines, bromocriptine, and methylphenidate are viewed as receptor agonists; the phenothiazines and anticholinergics act as receptor antagonists. Certain drugs enhance the activity of neurotransmitters by inhibiting their reuptake as, for example, the class of antidepressant drugs that has a relatively selective influence on the reuptake of serotonin. Others deplete existing neurotransmitters, as reserpine does for norepinephrine and another class of drugs promotes the release of preformed synaptic transmitters; amphetamines and modafinil are examples in this class. Amantadine, an antiviral agent, may promote the release of dopamine. One must not assume that these are the exclusive modes of action of each of these drugs; for example, cocaine acts as a direct stimulant and through the inhibition of reuptake of catecholamines.
A majority of drugs that act on the nervous system are ingested; factors that govern their intestinal absorption must therefore be taken into account. Small molecules usually enter the plasma by diffusion, larger ones by pinocytosis. The substances with which the drugs are mixed; the presence of food, other drugs, or intestinal diseases; and the age of the patient all influence the rate of absorption and blood concentrations. Different calculations are necessary for intramuscular, subcutaneous, and intrathecal routes of administration. To some extent, the solubilities of drugs (in lipid or water) determine the routes by which they can be given; some drugs, such as morphine, can be administered by numerous routes. Carried in the blood, the drug (or toxin) reaches many tissues, including the nervous system; protein binding in the plasma has an important influence on distribution. Many drugs and toxic substances bind to serum albumin and other serum proteins, limiting the availability of the ionized form. The common drug and toxin transformations involve hydroxylation, deamination, oxidation, and dealkylation, which enhance their solubility and elimination mainly by the kidney. Most of these catalytic processes occur in liver cells and utilize multiple enzymes.
To enter the extracellular compartment of the nervous system, a drug or toxic agent must transgress the tight capillary–endothelial barrier (blood–brain barrier) and the barrier between the blood and cerebrospinal fluid (blood–CSF barrier). Intrathecal injection circumvents these barriers, but then the agent tends to concentrate in the immediate subpial and subependymal regions. The process of movement from plasma to brain is by diffusion through capillaries or by facilitated transport. The solubility characteristics of the drug determine its rate of diffusion.
In the following discussion on neurotoxins, the reader will appreciate a number of phenomena: tolerance (lessening effect of increasing dose), dependence and addiction (insatiable need), habituation, drug-seeking behaviors, and abstinence with its associated withdrawal effects. These were described in Chap. 42 regarding alcoholism and are further elaborated in sections below. Particularly difficult in reference to drugs such as nicotine is the separation of habituation from addiction, i.e., of psychologic dependence from physical dependence (see further on).
The few examples given earlier are intended to provide a glimpse of the complex interactions between chemical agents and the cells of the nervous system. For more specific information, the reader is referred to The Biochemical Basis of Neuropharmacology by Cooper, Bloom, and Roth, a text that we have consulted through its many editions and to Goodman and Gilman’s The Pharmacological Basis of Therapeutics.
Opiates and Synthetic Analgesic Drugs
The opiates, or opioids, strictly speaking, include all the naturally occurring alkaloids in opium, which is prepared from the seed capsules of the poppy Papaver somniferum. For clinical purposes, the term opiate refers only to the alkaloids that have a high degree of analgesic activity, i.e., morphine. The terms opioid and narcotic-analgesic designate drugs with actions similar to those of morphine. Compounds that are chemical modifications of morphine include diacetylmorphine, or heroin, hydromorphone (Dilaudid), codeine, hydrocodone, oxycodone (OxyContin), and from the Victorian era and later, laudanum and paregoric. A second class of opioids comprises the purely synthetic analgesics: meperidine (Demerol) and its congeners, notably fentanyl, methadone, levorphanol, propoxyphene (Darvon), loperamide (the active ingredient in Imodium), and diphenoxylate (the main component of Lomotil). The synthetic analgesics are similar to the opiates in both their pharmacologic effects and patterns of abuse, the differences being mainly quantitative.
Opioids activate G-coupled transmembrane receptors, meaning they influence neuronal activity through the intermediate of cAMP; the receptor types are denominated as mu, delta, and kappa. An understanding of the clinical effects of opioids is clarified by the knowledge that these receptors are concentrated in the thalamus and dorsal root ganglia (mu receptors, pain), amygdala (affect) and brainstem raphe (alertness), and Edinger-Westphal nuclei (pupillary miosis). Receptors in the brainstem, also of the mu type, are involved in modulating respiratory responses to hypoxia and hypercarbia (respiratory suppression). Receptors are also widely distributed in neural components of other organs, particularly the gastrointestinal tract, accounting for the constipation that is an effect of the administration of this class of drugs.
The clinical effects of the opioids are considered from two points of view: acute poisoning and addiction.
Because of the common, and particularly the illicit, use of opioids, poisoning is a frequent occurrence. This happens also as a result of ingestion or injection accidentally or with suicidal intent, errors in the calculation of dosage, the use of a substitute or contaminated street product, or unusual sensitivity. Children exhibit an increased susceptibility to opioids, so that relatively small doses may prove toxic. This is true also of adults with myxedema, Addison disease, chronic liver disease, and pneumonia. Acute poisoning may also occur in persons who are unaware that opioids available from illicit sources vary greatly in potency and that tolerance for opioids declines quickly after the withdrawal of the drug; upon resumption of the habit, a formerly well-tolerated dose can be fatal.
Unresponsiveness, shallow respirations, slow respiratory rate (e.g., 2 to 8 per min) or periodic breathing, pinpoint pupils, bradycardia, and hypothermia are the well-recognized clinical manifestations of acute opioid poisoning. In the most advanced stage, the pupils dilate, the skin and mucous membranes become cyanotic, and the circulation fails. Later in the course, pulmonary edema may arise, or aspiration pneumonia may become evident as summarized the review of opioid overdose by Boyer. The immediate cause of death is usually respiratory depression with consequent asphyxia. Patients who suffer a cardiorespiratory arrest are sometimes left with all the known residua of anoxic encephalopathy (see Chap. 40). Mild degrees of intoxication are reflected by anorexia, nausea, vomiting, constipation, and loss of sexual interest. Toxicology screens for opiates may be useful but action must be taken before the results of these tests are completed.
This consists of the support of ventilation and administration of naloxone (Narcan), or the longer-acting nalmefene, both specific antidotes to the opiates and also to the synthetic analgesics. The dose of naloxone in adults is usually 0.05 mg and repeated in larger increments (the second dose is typically 2 mg) every 2 min to a dose of 15 mg intravenously as outlined by Boyer. For children, a higher initial dose of 0.1 mg/kg is recommended. The improvements in circulation and respiration and reversal of miosis are usually dramatic. Failure of naloxone to produce such a response should cast doubt on the diagnosis of opioid intoxication. If an adequate respiratory and pupillary response to naloxone is obtained, the patient should nonetheless be observed for up to 24 h and further doses of naloxone (50 percent higher than the ones previously found effective) can be given intramuscularly as often as necessary. An intravenous infusion of naloxone has been recommended if a long-acting narcotic is the cause of overdose. (It is well to inspect the patient for the presence of unnoticed fentanyl patches and establish if a long-acting drug has been available for abuse.)
Naloxone has less direct effect on consciousness, however, and the patient may remain drowsy for many hours. This is not harmful provided respiration is well maintained. Although nalmefene has a plasma half-life of 11 h, compared to 60 to 90 min for naloxone, it has no clear advantage in emergency practice. Gastric lavage is a useful measure if the drug was taken orally. This procedure may be efficacious many hours after ingestion, as one of the toxic effects of opioids is ileus, which causes some of the drug to be retained in the stomach. Concerns of precipitating opioid withdrawal by giving naloxone are generally unfounded.
Once the patient regains consciousness, complaints such as pruritus, sneezing, tearing, piloerection, diffuse body pains, yawning, and diarrhea may appear. These are the recognizable symptoms of the opioid abstinence, or withdrawal, syndrome described later. Consequently, an antidote must be used with great caution in an addict who has taken an overdose of opioid, because in this circumstance, it may precipitate withdrawal phenomena. Nausea and severe abdominal pain, presumably because of pancreatitis (from spasm of the sphincter of Oddi), are other troublesome symptoms of opiate use or withdrawal. Seizures are rare.
Just 50 years ago there were an estimated 60,000 persons addicted to narcotic drugs in the United States, exclusive of those who were receiving drugs because of incurable painful diseases. This represented a relatively small public health problem in comparison with the abuse of alcohol and barbiturates. Moreover, opioid addiction was of serious proportions in only a few cities—New York, Chicago, Los Angeles, Washington, DC, and Detroit. Since the late 1960s, a remarkable increase in opioid (mainly heroin) addiction has taken place. The precise number of opioid addicts is unknown but is currently estimated by the Drug Enforcement Administration to be well more than 500,000 (a disproportionate number in large cities). The problem assumes enormous importance when one recognizes that one-quarter of addicts are seropositive for HIV and are the chief source of transmission of AIDS to newborns and to the heterosexual nonaddicted population.
A number of factors—socioeconomic, psychologic, and pharmacologic—contribute to the genesis of opioid addiction. The most susceptible subjects are young men living in the economically depressed areas of large cities but significant numbers are found in suburbs and in small cities. The onset of opioid use is usually in adolescence, with a peak at 17 to 18 years; fully two-thirds of addicts start using the drugs before the age of 21. Almost 90 percent engage in criminal activity to obtain their daily ration of drugs but most of them have a history of arrests or convictions predating their addiction. Also, many of them have psychiatric disturbances, conduct disorder and sociopathy being the most common (“dual-diagnosis,” in psychiatric jargon). Monroe and colleagues, using the Lexington Personality Inventory, examined a group of 837 opioid addicts and found evidence of antisocial personality in 42 percent, emotional disturbance in 29 percent, and thought disorder in 22 percent; only 7 percent were free of such disorders. Vulnerability to addiction was not confined to one personality type.
Association with addicts is the apparent explanation for becoming addicted. In this sense, opioid addiction is contagious, and partly as a result of this pattern, opioid addiction has attained epidemic proportions. A small, almost insignificant proportion of addicts are introduced to drugs by physicians in the course of an illness. Thus there has been a regrettable tendency not to prescribe opiates to patients with acute or chronic pain (e.g., cancer pain) because of the risk of addiction.
Opioid addiction consists of three recognizable phases: (1) intoxication, or “euphoria,” (2) pharmacogenic dependence or drug-seeking behavior (addiction), and (3) the propensity to relapse after a period of abstinence. Some of the symptoms of opioid intoxication have already been considered. In patients with severe pain or pain-anticipatory anxiety, the administration of opioids produces a sense of unusual well-being, a state that has traditionally been referred to as morphine euphoria. It should be emphasized that only a negligible proportion of such persons continue to use opioids habitually after their pain has subsided. The vast majority of potential addicts are not suffering from painful illnesses at the time they initiate opioid use, and the term euphoria is probably not an apt description of the initial effects. These persons, after several repetitions, recognize a “high,” despite the subsequent recurrence of unpleasant, or dysphoric, symptoms (nausea, vomiting, and faintness as the drug effect wanes).
The repeated self-administration of the drug is the most important factor in the genesis of addiction. Regardless of how one characterizes the state of mind that is produced by episodic injection of the drug, the individual quickly discovers the need to increase the dose in order to obtain the original effects (tolerance). Although the initial effects may not be fully recaptured, the progressively increasing dose of the drug does relieve the discomfort that arises as the effects of each injection wear off. In this way a new pharmacogenically induced need is developed, and the use of opioids becomes self-perpetuating. At the same time a marked degree of tolerance is produced, so that enormous amounts of drugs, e.g., 5,000 mg of morphine daily, can eventually be administered without the development of toxic symptoms.
The pharmacologic (in contrast to psychologic) criteria of addiction, as indicated in Chap. 42 in regards to alcoholism, are tolerance and physical dependence. The latter refers to the symptoms and signs that become manifest when the drug is withdrawn following a period of continued use. These symptoms and signs constitute a specific clinical state, termed the abstinence or withdrawal syndrome (see later). The mechanisms that underlie the development of tolerance and physical dependence are not fully understood. However, it is known that opioids activate an opioid antinociceptive system (enkephalins, dynorphins, endorphins), which are opioid receptors and are located at many different levels of the nervous system (these were referred to earlier and are described in Chap. 8; see also the review of Fields). The desensitization of opioid receptors, probably mainly the mu type, accounts for tolerance through a mechanism of uncoupling of the receptor from the G-protein complex.
The intensity of the abstinence or withdrawal syndrome depends on the dose of the drug and the duration of addiction. The onset of abstinence symptoms in relation to the last exposure to the drug, however, is related to the pharmacologic half-life of the agent. With morphine, the majority of individuals receiving 240 mg daily for 30 days or more will show moderately severe abstinence symptoms following withdrawal. Mild signs of opiate abstinence can be precipitated by narcotic antagonists in persons who have taken as little as 15 mg of morphine or an equivalent dose of methadone or heroin tid for 3 days.
The abstinence syndrome that occurs in the morphine addict may be taken as the prototype. The first 8 to 16 h of abstinence usually pass asymptomatically. At the end of this period, yawning, rhinorrhea, sweating, piloerection, and lacrimation are manifest. Mild at first, these symptoms increase in severity over a period of several hours and then remain constant for several days. The patient may be able to sleep during the early abstinence period but is restless, and thereafter insomnia remains a prominent feature. Dilatation of the pupils, recurring waves of “gooseflesh,” and twitching of the muscles appear. The patient complains of aching in the back, abdomen, and legs and of “hot and cold flashes”; he frequently asks for blankets. At about 36 h the restlessness becomes more severe, and nausea, vomiting, and diarrhea usually develop. Temperature, respiratory rate, and blood pressure are slightly elevated. All these symptoms reach their peak intensity 48 to 72 h after withdrawal and then gradually subside. The opioid abstinence syndrome is rarely fatal (it is life-threatening only in infants). After 7 to 10 days, the clinical signs of abstinence are no longer evident, although the patient may complain of insomnia, nervousness, weakness, and muscle aches for several more weeks, and small deviations of a number of physiologic variables can be detected with refined techniques for up to 10 months (protracted abstinence).
Habituation, the equivalent of emotional or psychologic dependence, refers to the substitution of drug-seeking activities for all other aims and objectives in life. It is this feature that fosters relapse to the use of the drug long after the physiologic (“nonpurposive”) abstinence changes seem to have disappeared. The cause for relapse is not fully understood. Theoretically, fragments of the abstinence syndrome may remain as a conditioned response, and these abstinence signs may be evoked by the appropriate environmental stimuli. Thus, when a “cured” addict returns to a situation where narcotic drugs are readily available or in a setting that was associated with the initial use of drugs, the incompletely extinguished drug-seeking behavior may reassert itself.
The characteristics of addiction and of abstinence are qualitatively similar with all drugs of the opiate group as well as the related synthetic analgesics. The differences are quantitative and are related to the differences in dosage, potency, and length of action. Heroin is 2 to 3 times more potent than morphine but the heroin withdrawal syndrome encountered in hospital practice is usually mild in degree because of the low dosage of the drug in the street product. Dilaudid (hydromorphone) is more potent than morphine and has a shorter duration of action; hence the addict requires more doses per day, and the abstinence syndrome comes on and subsides more rapidly. Abstinence symptoms from codeine, while definite, are less severe than those from morphine. The addiction liabilities of propoxyphene, a weak opioid, are negligible. Abstinence symptoms from methadone are less intense than those from morphine and do not become evident until 3 or 4 days after withdrawal; for these reasons methadone can be used in the treatment of morphine and heroin dependency (see further on). Meperidine addiction is of particular importance because of its high incidence among physicians and nurses. Tolerance to the drug’s toxic effects is not complete, so that the addict may show tremors, twitching of muscles, confusion, hallucinations, and sometimes convulsions. Signs of abstinence appear 3 to 4 h after the last dose and reach their maximum intensity in 8 to 12 h, at which time they may be worse than those of morphine abstinence.
As to the biologic basis of addiction and physical dependence, our understanding is still very limited. Experiments in animals have provided insights into the neurotransmitter and neuronal systems involved. As a result of microdialyzing opiates and their antagonists into the central brain structures of animals, it has been tentatively concluded that mesolimbic structures, particularly the nucleus accumbens, ventral tegmentum of the midbrain, and locus ceruleus are activated or depressed under conditions of repeated opiate exposure. Thus, chronic opiate usage increases the levels of intracellular messengers (G-proteins) as noted earlier that drive cAMP activity in the locus ceruleus and in the nucleus accumbens; blocking the expression of these proteins markedly increases the self-administration of opiates by addicted rats. As in alcoholism, certain subtypes of the serotonin and dopamine receptors in limbic structures have been implicated in the psychic aspects of addiction and habituation. These same structures are conceived as a common pathway for the impulse to human drives such as sex, hunger, and psychic fulfillment. Camí and Farré reviewed the neurochemical mechanism of addiction.
The diagnosis of addiction is usually made when the patient admits to using and needing drugs. Should the patient conceal this fact, one relies on collateral evidence such as miosis, needle marks, emaciation, abscess scars, or chemical analyses. Meperidine addicts are likely to have dilated pupils and twitching of muscles. The finding of morphine or opiate derivatives (heroin is excreted as morphine) in the urine is confirmatory evidence that the patient has taken or has been given a dose of such drugs within 24 h of the test. The diagnosis of opiate addiction is also at once apparent when the treatment of acute opiate intoxication precipitates a characteristic abstinence syndrome.
Views on the nature of drug addiction and appropriate methods of treatment are as much national and sociologic as they are biologic. Berridge has reviewed some of these historically based factors in reference overall “harm reduction” by using heroin itself to treat heroin addiction. One approach that has achieved some degree of success over the past 40 years has been the substitution of methadone for opioid, in the ratio of 1 mg methadone for 3 mg morphine, 1 mg heroin, or 20 mg meperidine. Because methadone is long acting and effective orally, it needs to be given only twice daily by mouth—10 to 20 mg per dose being sufficient to suppress abstinence symptoms. After a stabilization period of 3 to 5 days, this dosage of methadone is reduced and the drug is withdrawn over a similar period. An alternative but probably less effective method has been the use of clonidine (0.2 to 0.6 mg bid for a week), a drug that counteracts most of the noradrenergic withdrawal symptoms; however, the hypotension that is induced by this drug may be a problem (Jasinski et al).
In Europe, addicts who could not be detoxified and kept free of drugs by any other means have been given diacetylmorphine, the active ingredient in heroin, with some success when compared in clinical trials to methadone (see Oviedo-Joekes et al). Special settings that are capable of medical reversal of overdose are required but the notion of overall reduction in personal and societal harm seems to be attained by even this seemingly extreme measure.
A rapid detoxification regimen that is conducted under general anesthesia was popular in a number of centers as a means of treating opiate addiction has now been largely abandoned for reasons of safety but it could be resurrected if other more conventional approaches continue to be futile. The technique consisted of administering increasing doses of opioid receptor antagonists (naloxone or naltrexone) over several hours while the autonomic and other features of the withdrawal syndrome were suppressed by the infusion of propofol or a similar anesthetic, supplemented by intravenous fluids. Medications such as clonidine and sedatives were also given in the immediate postanesthetic period. There are substantial risks involved in this procedure and several deaths have occurred for which reason it has been all but abandoned. Furthermore, a number of patients continue to manifest signs of withdrawal after the procedure and require continued hospitalization.
This is in some ways far more demanding than the treatment of opioid withdrawal and can be best accomplished in special facilities and programs that are devoted wholly to the problem. These are available in most communities. The most effective ones have been the ambulatory methadone maintenance clinics, where more than 100,000 former heroin addicts are participating in rehabilitation programs approved by the FDA. Methadone, in a dosage of 60 to 100 mg daily (sufficient to suppress the craving for heroin), is given under supervision day by day (less often with long-acting methadone) for months or years. Various forms of psychotherapy and social service counseling often administered by former heroin addicts are integral parts of the program.
The results of methadone treatment are difficult to assess and vary considerably from one program to another. Even the most successful programs suffer an attrition rate of approximately 25 percent when they are evaluated after several years. Of the patients who remain, the majority achieves a degree of social rehabilitation, i.e., they are gainfully employed and no longer engage in criminal behavior or prostitution.
The usual practice of methadone programs is to accept only addicts older than age 16 years with a history of heroin addiction for at least 1 year. This leaves many adolescent addicts untreated. The number of addicts who can fully withdraw from methadone and maintain a drug-free existence is very small. This means that the large majority of addicts now enrolled in methadone programs are committed to an indefinite period of methadone maintenance and the effects of such a regimen are uncertain.
An alternative method of ambulatory treatment of the opiate addict involves the use of narcotic antagonists, of which naloxone and naltrexone are the best known. The physical effects of abusing narcotics are thereby partially blocked, and there may be some degree of aversive conditioning if withdrawal symptoms are produced. Naltrexone is favored because it has a longer effect than naloxone, is almost free of agonist effects, and can be administered orally. Similar results have also been achieved with cyclazocine in a small number of highly motivated patients; this drug is administered orally in increasing amounts until a dosage of 2 mg/70 kg body weight is attained. The drug is taken bid (for 2 to 6 weeks) and is then withdrawn slowly.
More recently, interest has centered on the use of sublingual buprenorphine for the treatment of heroin (and cocaine) abuse; this drug has both opioid agonist and antagonist properties; it mutes the effect of withdrawal, also serves as an aversive agent, and its abuse potential is relatively low. A randomized trial conducted by Fudala and colleagues has demonstrated the superiority over methadone of a combination of buprenorphine and naloxone combined with brief counseling in keeping opioid addicts in treatment and abstinent of abused drugs. This approach has been available in Europe for many years and has been adopted in the United States under a Department of Health–supervised program for primary care offices. In addition, there is evidence, based on animal experiments and experience with small numbers of addicts, that it may be useful for the treatment of dual dependence on cocaine and opiates (see Mello and Mendelson), but this has not been confirmed in other clinical trials.
In addition to the toxic effects of the opioid itself, the addict may suffer a variety of neurologic and infectious complications resulting from the injection of contaminated adulterants (quinine, talc, lactose, powdered milk, and fruit sugars) and of various infectious agents (injections administered by unsterile methods). The most important of these is HIV infection, but septicemia, endocarditis, and viral hepatitis may also occur. Particulate matter that is injected with heroin or a vasculitis that is induced by chronic heroin abuse may cause stroke by an incompletely understood occlusion of cerebral arteries, with hemiplegia or other focal cerebral signs. Amblyopia, probably as a result of the toxic effects of quinine in the heroin mixtures, has been reported, as well as transverse myelopathy and several types of peripheral neuropathy. The spinal cord disorder expresses itself clinically by the abrupt onset of paraplegia with a level on the trunk below which motor function and sensation are lost or impaired and by urinary retention. Pathologically, there is an acute necrotizing lesion involving both gray and white matter over a considerable vertical extent of the thoracic and occasionally the cervical cord. In some cases, a myelopathy has followed the first intravenous injection of heroin after a prolonged period of abstinence. We have also seen two cases of cervical myelopathy from heroin-induced stupor and a prolonged period of immobility with the neck hyperextended over the back of a chair or sofa.
In addition, we have observed several instances of a subacute progressive cerebral leukoencephalopathy after heroin use, similar to ones that occurred in Amsterdam in the 1980s, the result of inhalation of heroin or an adulterant (Wolters et al; Tan et al). Most instances of this leukoencephalopathy are the result of inhalation of heated heroin vapor in a practice known as “chasing the dragon.” The clinical presentation has varied but generally includes stupor, coma, and death, after a latent period of hours or days. In one of our patients, the white matter changes were concentrated in the posterior regions of the hemispheres and in the internal capsules and, in one striking case, in the cerebellar white matter. The MRI is fairly characteristic and the white matter is vacuolated, sparing U-fibers, as indicated by Ryan and colleagues, with an appearance that some authors have indicated simulates the spongiform change of prion disease. The pathophysiology is unknown but adulterants or mitochondrial damage has been suggested.
A similar leukoencephalopathy has also been reported in cocaine users, although a hypertensive encephalopathy or an adrenergic-induced vasculopathy may have played a role in these cases.
Damage to single peripheral nerves at the site of injection of heroin and from compression is a relatively common occurrence. However, bilateral compression of the sciatic nerves, the result of sitting or lying for a prolonged period in a stuporous state or in the lotus position, has occurred in several of our patients. In sciatic compression of this type, the peroneal branch has been more affected than the tibial, causing foot-drop with less weakness of plantar flexion. More difficult to understand in heroin abusers is the involvement of other individual nerves, particularly the radial nerve, and painful affection of the brachial plexus, apparently unrelated to compression and remote from the sites of injection. Possibly in some instances there was a vasculitis affecting peripheral nerves.
An acute generalized myonecrosis with myoglobinuria and renal failure has been ascribed to the intravenous injection of adulterated heroin. Brawny edema and fibrosing myopathy (Volkmann contracture) are the sequelae of venous thrombosis resulting from the administration of heroin and its adulterants by the intramuscular and subcutaneous routes. Occasionally, there may be massive swelling of an extremity into which heroin had been injected subcutaneously or intramuscularly; infection and venous thrombosis appears to be involved in its causation.
The diagnosis of drug addiction always raises the possibility of an assortment of infectious complications: AIDS, syphilis, abscesses and cellulitis at injection sites, septic thrombophlebitis, hepatitis, and periarteritis from circulating immune complexes. Tetanus, endocarditis (mainly caused by Staphylococcus aureus), spinal epidural abscess, meningitis, brain abscess, and tuberculosis have occurred less frequently.
Sedative-Hypnotic Drugs
This class of drugs consists of two main groups. The first includes the barbiturates, meprobamate, and chloral hydrate. These drugs are now little used, having been largely replaced by a second group, the benzodiazepines, the most important of which are chlordiazepoxide (Librium), lorazepam (Ativan), alprazolam (Xanax), clonazepam (Klonopin), and diazepam (Valium). Closely related are the nonbenzodiazepine hypnotics, typified by zolpidem. The advantages of the benzodiazepine drugs are their relatively low toxicity and addictive potential and their minimal interactions with other drugs.
In the past, about 50 barbiturates were marketed for clinical use, but now only a few are encountered with any regularity: pentobarbital (Nembutal), secobarbital (Seconal), amobarbital (Amytal), thiopental (Pentothal), and phenobarbital. The first three were the ones most commonly abused. Barbiturates are also a component of combination preparations for the treatment of migraine (e.g., butalbital in Fiorinal).
All the common barbiturates are derived from barbituric acid; the differences among them depend on variations in the side chains of the parent molecule. The potency of each drug is a function of the ionization constant and lipid solubility. The higher its lipid solubility, the greater the drug’s central nervous system potency and the quicker and briefer its action. The lowering of plasma pH increases the rate of entry of the ionized form into the brain. The action of barbiturates is to suppress neuronal transmission, presumably by enhancing GABA inhibition at pre- and postsynaptic receptor sites, and to reduce excitatory postsynaptic potentials. The major points of action in the CNS are similar to those of alcohol and other coma-producing drugs; impaired consciousness or coma relates to inactivation of neurons in the reticular formation of the upper brainstem. The liver is the main locus of drug metabolism and the kidney is the method of elimination of the metabolites. The clinical problems posed by the barbiturates are different depending on whether the intoxication is acute or chronic.
The symptoms and signs vary with the type and amount of drug as well as with the length of time that has elapsed since it was ingested. Pentobarbital and secobarbital produce their effects quickly and recovery is relatively rapid. Phenobarbital induces coma more slowly and its effects tend to be prolonged. In the case of long-acting barbiturates, such as phenobarbital and barbital, the hypnotic-sedative effect lasts 6 h or more after an average oral dose; with the intermediate-acting drugs such as amobarbital, 3 to 6 h; and with the short-acting drugs, secobarbital and pentobarbital, less than 3 h. Most fatalities follow the ingestion of secobarbital, amobarbital, or pentobarbital. The ingestion by adults of more than 3 g of these drugs at one time will prove fatal unless intensive treatment is applied promptly. The potentially fatal dose of phenobarbital is 6 to 10 g. The lowest plasma concentration associated with lethal overdosage of phenobarbital or barbital has been approximately 60 mg/mL and that of amobarbital and pentobarbital, 10 mg/mL.
Severe intoxication occurs with the ingestion of 10 to 20 times the oral hypnotic dose. The patient cannot be roused by any means, i.e., the patient is comatose. Respiration is slow and shallow or irregular, and pulmonary edema and cyanosis may be present. The tendon reflexes are usually, but not invariably, absent. Most patients show no response to plantar stimulation, but in those who do, the responses are extensor. With deep coma, the corneal and gag reflexes may also be abolished. Ordinarily the pupillary light reflex is retained in severe intoxication and is lost only if the patient is asphyxiated; but in advanced cases, the pupils become miotic and poorly reactive, simulating opiate intoxication. At this point respiration is greatly depressed and oculocephalic and oculovestibular reflex responses are usually abolished. In the early hours of coma, there may be a phase of flexor or extensor posturing or rigidity of the limbs, hyperactive reflexes, ankle clonus, and extensor plantar signs; persistence of these signs indicates that anoxic damage has been added. The temperature may be subnormal, the pulse is faint and rapid, and the blood pressure is greatly reduced. Failure of respiration to quicken on painful stimulation is an ominous sign.
There are few conditions other than barbiturate intoxication that cause a flaccid coma with small reactive pupils, hypothermia, and hypotension. A pontine hemorrhage may do so, but a hysterical trance or catatonic stupor does not present a problem in differential diagnosis. The use of gas and high-pressure liquid chromatography provides a reliable means of identifying the type and amount of barbiturate in the blood. A patient who has also ingested alcohol may be comatose with relatively low blood barbiturate concentrations. Contrariwise, the barbiturate addict may show only mild signs of intoxication with very high blood barbiturate concentrations.
In mild or moderate intoxication, recovery is the rule and special treatment is not required except to prevent aspiration. If the patient is unresponsive, special measures must be taken to maintain respiration and prevent infection. An endotracheal tube should be inserted, with suctioning as necessary. Any risk of respiratory depression or underventilation requires the use of a positive-pressure respirator.
Hemodialysis or hemofiltration with charcoal may be used in comatose patients who have ingested long-acting barbiturates and these treatments are particularly advisable if anuria or uremia has developed. Occasionally, in the case of a barbiturate addict who has taken an overdose of the drug, recovery from coma is followed by the development of abstinence symptoms, as described later.
Immediately following withdrawal, the patient seemingly improves over a period of 8 to 12 h, as the symptoms of intoxication diminish. Then a new group of symptoms develops, consisting of nervousness, tremor, insomnia, postural hypotension, and weakness. With chronic phenobarbital or barbital intoxication, withdrawal symptoms may not become apparent until 48 to 72 h after the final dose or it does not occur at all because of the slow metabolism and long half-life of these drugs. Generalized seizures with loss of consciousness may occur, usually between the second and fourth days of abstinence, but occasionally as long as 6 or 7 days after withdrawal. There may be a single seizure, several seizures, or, rarely, status epilepticus. Characteristically, in the withdrawal period, there is a greatly heightened sensitivity to photic stimulation, to which the patient responds with myoclonus or a seizure accompanied by paroxysmal changes in the EEG. The convulsive phase may be followed directly by a delusional-hallucinatory state or, as occurred in one of our cases (Romero et al), a full-blown delirium indistinguishable from delirium tremens. Death has been reported under these circumstances. The abstinence syndrome may occur in varying degrees of completeness; some patients have seizures and recover without developing delirium, and others have a delirium without preceding seizures.
This is the oldest and one of the safest, most effective, and most inexpensive of the sedative-hypnotic drugs. After oral administration, chloral hydrate is reduced rapidly to trichloroethanol, which is responsible for the depressant effects on the CNS. A significant portion of the trichloroethanol is excreted in the urine as the glucuronide, which may give a false-positive test for glucose.
Tolerance and addiction to chloral hydrate develop only rarely; for this reason, it was in the past commonly used for insomnia. Poisoning with chloral hydrate is a rare occurrence and resembles acute barbiturate intoxication except for the finding of miosis, which is said to characterize the former. Treatment follows along the same lines as for barbiturate poisoning. Death from poisoning is because of respiratory depression and hypotension; patients who survive may show signs of liver and kidney disease. Combining alcohol and chloral hydrate, the popular “Mickey-Finn” of detective stories in the mid-last century, produced severe intoxication and amnesia.
Paraldehyde, another member of this group of sedative drugs, is no longer being manufactured in the United States, and chloral hydrate is now available mainly as an elixir for pediatric use.
With the introduction of chlordiazepoxide in 1960 and the benzodiazepine drugs that followed (particularly diazepam), the older sedative drugs (barbiturates, paraldehyde, chloral hydrate) have become virtually obsolete. Indeed, the benzodiazepines are among the most commonly prescribed drugs in the world today. According to Hollister (1990), 15 percent of all adults in the United States use a benzodiazepine at least once yearly and about half this number use the drug for a month or longer.
The benzodiazepines have been prescribed frequently for the treatment of anxiety and insomnia, and they are especially effective when the anxiety symptoms are severe. Also, they have been used to control overactivity and destructive behavior in children and the symptoms of alcohol withdrawal in adults. Diazepam is particularly useful in the treatment of delirious patients who require parenteral medication. The benzodiazepines possess anticonvulsant properties, and the intravenous use of diazepam, lorazepam, and midazolam is an effective means of controlling status epilepticus, as described in Chap. 16. Diazepam in massive doses has been used with considerable success in the management of muscle spasm in tetanus and in the “stiff man” syndrome (see Chap. 50). Alprazolam has a central place in the treatment of panic attacks and other anxiety states, and as an adjunct in some depressive illnesses. It seems, however, to create more dependence than some of the others in its class.
Other important benzodiazepine drugs are lorazepam (Ativan), flurazepam (Dalmane), triazolam (Halcion), clorazepate (Tranxene), temazepam (Restoril), oxazepam (Serax), alprazolam (Xanax) and other newer varieties, all widely used in the treatment of insomnia (see Chap. 19), and clonazepam (Klonopin), which is useful in the treatment of myoclonic seizures (see Chap. 16) and intention myoclonus (see Chaps. 6 and 40). Midazolam (Versed), a short-acting parenteral agent, is given frequently to achieve the brief sedation required for procedures such as MRI or endoscopy and is useful in the treatment of status epilepticus. Many other benzodiazepine compounds have appeared in recent years, but a clear advantage over the original ones remains to be demonstrated (Hollister, 1990).
The benzodiazepine drugs, like barbiturates, have a depressant action on the CNS by binding to specific receptors on GABA inhibitory systems. The newer nonbenzodiazepine sleeping medication differs from the benzodiazepines structurally but is pharmacologically similar in binding to similar gabaergic receptors. The benzodiazepines act in concert with GABA to open chloride ion channels and hyperpolarize postsynaptic neurons and reduce their firing rate. The primary sites of their action are the cerebral cortex and limbic system, which accounts for their anticonvulsant and anxiolytic effects.
While quite safe in the recommended dosages, they are far from ideal. They frequently cause unsteadiness of gait and drowsiness and at times syncope, confusion, and impairment of memory, especially in the elderly. If taken in large doses, the benzodiazepines can depress the state of consciousness, resembling that of other sedative-hypnotic drugs, but with less respiratory suppression and hypotension.
Flumazenil, a specific pharmacologic antagonist of the CNS effects of benzodiazepines, rapidly but briefly reverses most of the symptoms and signs of benzodiazepine overdose. It acts by binding to CNS diazepine receptors and thereby blocking the activation of inhibitory gabanergic synapses. Flumazenil also may be diagnostically useful in cases of coma of unknown etiology and in hepatic encephalopathy.
Signs of physical dependence and true addiction, although relatively rare, undoubtedly occur in chronic benzodiazepine users, even in those taking therapeutic doses. The withdrawal symptoms are much the same as those that follow the chronic use of other sedative drugs (anxiety, jitteriness, insomnia, seizures) but may not appear until the third day after the cessation of the drug and may not reach their peak of severity until the fifth day (Hollister, 1990). In chronic benzodiazepine users, the gradual tapering of dosage over a period of 1 to 2 weeks minimizes the withdrawal effects. However, we have observed numerous cases over the years in which the cessation of moderate doses of chronically used diazepines has resulted in one or more seizures. This is likely to happen when the patient is hospitalized for other reasons and the accustomed sleeping or anxiolytic medication is omitted.
A class of antianxiety agents, exemplified by the selective 5-HT1A receptor serotonergic agonist buspirone, is chemically and pharmacologically different from the benzodiazepines, barbiturates, and other sedatives. Its distinctive nature is confirmed by the observation that it does not block the withdrawal syndrome of other sedative-hypnotic drugs. Because of its apparently reduced potential for abuse and tolerance, it is not included in the list of controlled pharmaceutical substances in the United States but adverse interactions with monoamine oxidase (MAO) inhibitors are known. Its use with other psychotropic drugs is still under investigation (see Chap. 52).
Antipsychosis Drugs
In the mid-1950s, a large series of pharmacologic agents, originally referred to as tranquilizers (later, as psychotropic or neuroleptic drugs), came into prominent use, mainly for the control of schizophrenia, psychotic states associated with “organic brain syndromes,” and affective disorders (depression and bipolar disease). The mechanisms by which these drugs ameliorate disturbances of thought and affect in psychotic states are not fully understood, but presumably they act by blocking the postsynaptic mesolimbic dopamine receptors of which there are four subtypes, termed D1 through D4 on neuronal membranes (see Table 4-2, and discussion of dopamine receptor subtypes). The D2 receptors are located mainly in the frontal cortex, hippocampus, and limbic cortex, and the D1 receptors are in the striatum, as discussed in Chap. 4. The blockade of dopamine receptors in the striatum is probably responsible for the parkinsonian side effects of this entire class of drugs, and the blockade of another dopaminergic (tuberoinfundibular) system, for the increased prolactin secretion by the pituitary. These drugs also produce some adrenergic blocking effect. The newer “atypical” antipsychotic drugs, exemplified by clozapine, apparently achieve the same degree of D2 and D3 blockade in the temporal and limbic lobes while exhibiting substantially less antagonistic activity in the striatum—accounting also for their lesser parkinsonian side effects. These drugs also block subsets of serotonin receptors.
Since the introduction in the 1950s of the phenothiazine chlorpromazine as an anesthetic agent and the serendipitous discovery of its antipsychotic effect on schizophrenia, a large number of antipsychotic drugs have been marketed for clinical use. No attempt is made here to describe or even list all of them. Some have had only an evanescent popularity and others have yet to prove their value. Chemically, these compounds form a heterogeneous group. Eight classes of them are of particular clinical importance: (1) the phenothiazines; (2) the thioxanthenes; (3) the butyrophenones; (4) the rauwolfias alkaloids; (5) an indole derivative, loxapine, and a unique dihydroindolone, molindone; (6) a diphenylbutylpiperidine, pimozide; (7) dibenzodiazepines, typified by clozapine and olanzapine; and (8) a benzisoxazole derivative, risperidone. Molindone and loxapine are about as effective as the phenothiazines in the management of schizophrenia and their side effects are similar, although claims have been made that they are less likely to induce tardive dyskinesias and seizures. Their main use is in patients who are not responsive to the older drugs or who suffer intolerable side effects from them.
The antipsychotic agents in the class of clozapine (which is less used than other agents in the class because of cases of aplastic anemia) have attracted great interest, because—as already mentioned—they are associated with relatively fewer extrapyramidal side effects. For this reason, they are particularly favored in controlling the confusion and psychosis of parkinsonian patients. The other new class of drugs, of which risperidone is the main example, also has fewer extrapyramidal side effects than the phenothiazines and a more rapid onset of action than the traditional antipsychotic medications. All of these newer medications produce the “metabolic syndrome” of weight gain, adverse lipid changes, and glucose intolerance. Pimozide may be useful in the treatment of haloperidol-refractory cases of Gilles de la Tourette syndrome (see Chap. 6); its main danger is its tendency to produce cardiac arrhythmias.
This group comprises chlorpromazine (Thorazine), promazine (Sparine), triflupromazine (Vesprin), prochlorperazine (Compazine), perphenazine (Trilafon), fluphenazine (Permitil, Prolixin), thioridazine (Mellaril), mesoridazine (Serentil), and trifluoperazine (Stelazine). In addition to their psychotherapeutic effects, these drugs have a number of other actions, so that certain members of this group are used as antiemetics (prochlorperazine) and antihistaminics (promethazine).
The phenothiazines have had their widest application in the treatment of the major psychoses, namely schizophrenia and, to a lesser extent, bipolar psychosis. Under the influence of these drugs, many patients who would otherwise have been hospitalized were able to live at home and even work productively. In the hospital, the use of these drugs has facilitated the care of hyperactive, delirious, and combative patients (see Chaps. 52 and 53 for details of this clinical use).
Side effects of the phenothiazines are frequent and often serious. All of them may cause a cholestatic type of jaundice, agranulocytosis, seizures, orthostatic hypotension, skin sensitivity reactions, mental depression, and, most importantly, immediate or delayed extrapyramidal motor disorders. The neuroleptic malignant syndrome is the most extreme complication and is discussed separately further on and in Chap. 53. The following types of extrapyramidal symptoms, also discussed in Chap. 6, have been noted in association with all of the phenothiazines as well as the butyrophenones, and to a lesser extent with metoclopramide and pimozide, which block dopaminergic receptors. These are summarized in Table 53-1.
A parkinsonian syndrome is the most common complication—masked facies, slight symmetric tremor, reduced blinking, generalized rigidity, shuffling gait, and slowness of movement. These symptoms may appear after several days of drug therapy but more often after several weeks. Suppression of dopamine in the striatum (similar to the effect of loss of dopaminergic nigral cells that project to the striatum) is presumably the basis of the parkinsonian signs.
Acute dyskinetic and dystonic reactions, taking the form of involuntary movements of lower facial muscles (mainly around the mouth) and protrusion of the tongue (buccolingual or oral-masticatory syndrome), dysphagia, torticollis and retrocollis, oculogyric crises, and tonic spasms of a limb. These complications usually occur early in the course of administration of the drug, sometimes after the initial dose, in which case they recede dramatically upon immediate discontinuation of the drug and the intravenous administration of diphenhydramine hydrochloride or benztropine.
Akathisia, which is an inner restlessness reflected by a persistent shifting of the body and feet and an inability to sit still, such that the patient paces the floor or jiggles the legs constantly (see Chap. 6). Of all the phenothiazines, molindone has a tendency to cause akathisia. This disorder often responds to oral propranolol.
Tardive dyskinesias are a group of late and persistent complications of neuroleptic therapy, which may continue after removal of the offending drug, that comprises lingual-facial-buccal-cervical dyskinesias, choreoathetotic and dystonic movements of the trunk and limbs, diffuse myoclonus (rare), perioral tremor (“rabbit” syndrome), and dysarthria or anarthria. Snyder postulated that the movements are because of hypersensitivity of dopamine receptors in the basal ganglia, secondary to prolonged blockade of the receptors by antipsychotic medication. Baldessarini estimates that as many as 40 percent of patients receiving long-term antipsychotic medication develop tardive dyskinesia of some degree. The effect is likely a result of subcellular pathophysiologic alterations in the basal ganglia. Treatment is discussed later.
The neuroleptic malignant syndrome is discussed separately later because of its gravity and requirement for specific treatment.
Haloperidol (Haldol) is the only member of this group approved for use as an antipsychotic in the United States. It has much the same therapeutic effects as the phenothiazines in the management of acute psychoses and shares the same side effects as the phenothiazines, but exhibits little or no adrenergic blocking action. It is an effective substitute for the phenothiazines in patients who are intolerant of the latter drugs, particularly of their autonomic effects. It is also one of the main drugs for the treatment of Gilles de la Tourette syndrome (the other being pimozide; see Chap. 6) and the movement disorder of Huntington chorea.
As indicated earlier, acute dystonic spasms usually respond to cessation of the offending drug and to the administration of diphenhydramine. Administration of antiparkinsonian drugs of the anticholinergic type (trihexyphenidyl, procyclidine, and benztropine) may hasten recovery from some of the acute symptoms. The purely parkinsonian syndrome usually improves as well, but the tardive dyskinesias stand apart because they may persist for months or years and may be permanent.
Oral, lingual, and laryngeal dyskinesias of the tardive type are affected relatively little by any antiparkinsonian drugs. Amantadine in doses of 50 to 100 mg tid has been useful in a few of the cases of postphenothiazine dyskinesia. Other drugs such as benztropine have been tried in the treatment of regional and more generalized tardive dyskinesia with uncertain results. Nevertheless, there is a tendency for most of the obstinate forms to subside slowly even after several years of unsuccessful therapy. Once a tardive syndrome has been identified, several authoritative clinicians recommend a gradual reduction in the dose of the antipsychosis medication to the minimum necessary for the control of psychotic symptoms. Some reports favor the substitution of one of the newer “atypical” antipsychotic medications but no systematic study of their effectiveness has been undertaken.
For severe and recalcitrant cases, particularly those involving axial dystonias and similar disabling features, Fahn recommends administration of the dopamine-depleting drug tetrabenazine (similar but faster in action and less toxic than reserpine). This medication is given in doses of 75 to 300 mg/d. Jankovic and Beach report an 83 percent success rate using this approach for tardive dyskinesias. The medication is not easily available in the United States.
This is the most dreaded complication of phenothiazine and haloperidol use; rare instances have been reported after the institution or the withdrawal of L-dopa and similar dopaminergic agents, as well as a few instances reported with the newer antipsychosis drugs. Its incidence has been calculated to be only 0.2 percent of all patients receiving neuroleptics (Caroff and Mann) but its seriousness is underscored by a mortality rate of 15 to 30 percent if not recognized and treated promptly. It may occur days, weeks, or months after neuroleptic treatment is begun.
The syndrome consists of hyperthermia, rigidity, stupor, unstable blood pressure, diaphoresis, and other signs of sympathetic overactivity, high serum creatine kinase (CK) values (up to 60,000 units), and, in some cases, renal failure because of myoglobinuria. The syndrome was first observed in patients treated with haloperidol, but since then other neuroleptic drugs have been incriminated, particularly the highly potent thioxanthene derivatives and the phenothiazines—chlorpromazine, fluphenazine, and thioridazine—but also, on rare occasions, the less potent drugs that are used to control nausea, such as promethazine. It has become evident that the newer antipsychotic drugs, and specifically olanzapine, are also capable of inducing the syndrome but the risk in comparison to the first generation of antipsychotic drugs has not been established.
If treatment of the neuroleptic malignant syndrome is started early, when consciousness is first altered and the temperature is rising, bromocriptine in oral doses of 5 mg tid (up to 20 mg tid) will terminate the condition in a few hours. If oral medication can no longer be taken because of the patient’s condition, dantrolene, 0.25 to 3.0 mg intravenously, may be lifesaving. Once coma has supervened, shock and anuria may prove fatal or leave the patient in a vegetative state. The rigors during high fever may cause muscle damage and myoglobinuria, and shock may lead to hypoxic-ischemic brain injury.
One pitfall is to mistake neuroleptic malignant syndrome for worsening of the psychosis and inadvisably administer more antipsychosis medication. Meningitis, heat stroke, lithium intoxication, catatonia, malignant hyperthermia, and acute dystonic reactions figure in the differential diagnosis. Of course, neuroleptic medication must be discontinued as soon as any of the severe extrapyramidal reactions are recognized. It has been common practice to avoid future administration of the offending neuroleptic but the risk of using another class of antipsychotic agents has not been fully addressed.
The neuroleptic malignant syndrome bears an uncertain relationship to malignant hyperthermia by way of its clinical aspects but also in its response to bromocriptine and dantrolene (see later). Malignant hyperthermia in susceptible individuals is triggered by inhalation anesthetics and skeletal muscle relaxants (see Chap. 53). This disorder was described before the introduction of neuroleptic drugs, and in a small proportion of cases, has been related to a mutation of the ryanodine receptor gene. A genetic factor may underlie a small number of cases of the neuroleptic malignant syndrome (a polymorphism in the D2 receptor gene; see Suzuki et al) possibly provoked by fatigue and dehydration. There is no evidence that the occurrence of one of these syndromes confers a susceptibility to the other.
Antidepression Medications
Four classes of drugs—the MAO inhibitors, the tricyclic compounds, the serotonergic drugs, and lithium—are particularly useful in the treatment of depressive illnesses. The adjective antidepressant refers to their therapeutic effect and is employed here in deference to common clinical practice. Antidepressive or antidepression drugs would be preferable, as the term depressant still has a pharmacologic connotation that does not necessarily equate with the therapeutic effect.
The observation that iproniazid, an inhibitor of MAO, had a mood-elevating effect in tuberculous patients initiated a great deal of interest in compounds of this type and led quickly to their exploitation in the treatment of depression. Iproniazid proved exceedingly toxic to the liver, as were several subsequently developed MAO inhibitors; but other drugs in this class, much better tolerated, are still available. These include isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate), the latter two being the more frequently used. Tranylcypromine, which bears a close chemical resemblance to dextroamphetamine, may produce unwanted stimulation, but the most common adverse effect of all the MAO inhibitors is postural hypotension. Also, interactions with a wide array of other drugs and ingested substances may induce severe hypertension.
Monoamine oxidase is located on the outer surface of the mitochondria in neurons and is used in the catabolism of catecholamines (Coyle). In the gut and liver, the isoenzyme MAO-A normally serves to deaminate phenethylamine, tyramine, and tryptamine—all of which are products of protein catabolism. Inhibition of MAO-A allows these dietary amines, which have an amphetamine-like action, to enter the systemic circulation in increased quantities, thus releasing norepinephrine from sympathetic nerve endings and increasing heart rate and blood pressure. Most antidepressant medications are of this class. Medications used in Parkinson disease (see Chap. 39) inhibit the MAO-B isoenzyme, which deaminates phenylethylamine and trace amines, with a correspondingly lower risk of causing hypertension.
More relevant to their action as antidepressants, the MAO inhibitors have in common the ability to block the intraneuronal oxidative deamination of naturally occurring amines (norepinephrine, epinephrine, dopamine, and serotonin) and it has been suggested that the accumulation of these substances is responsible for the antidepressant effect. However, many enzymes other than monoamine oxidase are inhibited by MAO inhibitors, and the latter drugs have numerous actions unrelated to enzyme inhibition. Furthermore, many agents with antidepressant effects like those of the MAO inhibitors do not inhibit MAO. Therefore, one cannot assume that the therapeutic effect of these drugs has a direct relation to MAO inhibition in the brain.
The MAO inhibitors must be dispensed with caution and awareness of their potentially serious side effects. They may at times cause excitement, restlessness, agitation, insomnia, and anxiety, occasionally with the usual dose but more often with an overdose. Mania and convulsions may occur (especially in epileptic patients). Other side effects are muscle twitching and involuntary movements, urinary retention, skin rashes, tachycardia, jaundice, visual impairment, enhancement of glaucoma, impotence, sweating, muscle spasms, paresthesias, and a serious degree of orthostatic hypotension.
Patients taking MAO-A inhibitors must be warned against the use of phenothiazines, CNS stimulants, and tricyclic and serotoninergic antidepressants (see later), as well as sympathomimetic amines and tyramine-containing foods. The combination of an MAO inhibitor and any of these drugs or amines may induce hypertension, atrial and ventricular arrhythmia, pulmonary edema, stroke, or death. Sympathomimetic amines are contained in some commonly used cold remedies, nasal sprays, nose drops, and certain foods—aged cheese, beer, red wine, pickled herring, sardines, sausages, and certain preserved meat or fish. Exaggerated responses to the usual dose of meperidine (Demerol) and other narcotic drugs have also been observed sporadically; in these cases, respiratory function may be depressed to a serious degree, and hyperpyrexia, agitation, and pronounced hypotension may occur as well, sometimes with fatal issue. Unpredictable side effects may also accompany the simultaneous administration of barbiturates and MAO inhibitors. The abrupt occurrence of severe occipital headache, nausea, vomiting, pupillary dilatation, or visual blurring should suggest a hypertensive crisis. Treatment is with intravenous phentolamine 5 mg, nitroprusside, labetalol, or a calcium channel blocker administered slowly to prevent hypotension. Overdosage of MAO inhibitors may lead to coma, for which there is no treatment other than supportive care.
The therapeutic use of MAO inhibitors for depression is discussed in Chaps. 51 and 52, and for Parkinson disease, in Chap. 39.
Soon after the first successes with MAO inhibitors, another class of tricyclic compounds appeared. The mode of action of these agents is not fully understood, but there is evidence that they block the reuptake of amine neurotransmitters, both norepinephrine and serotonin. Blocking this amine pump mechanism (called the presynaptic plasma transporter), which ordinarily terminates synaptic transmission, permits the persistence of neurotransmitter substances in the synaptic cleft and does no more than support the hypothesis that endogenous depression is associated with a deficiency of noradrenergic or serotonergic transmission.
These medications have been divided into classes of tertiary amines (imipramine, amitriptyline and doxepin, trimipramine), which have activity as reuptake inhibitors of norepinephrine and serotonin, and the secondary amines (desipramine, amoxapine, maprotiline, nortriptyline, protriptyline), which have a preferential effect on reuptake of norepinephrine. Subsequently, a number of additional antidepressant drugs were introduced. A full account of these drugs, which will not be attempted here, can be found in the chapters by Baldessarini listed in the references.
The tricyclic antidepressants and the serotonergic drugs discussed in the next section, are presently the most effective drugs for the treatment of patients with depressive illnesses, the former being particularly useful for those with anergic depressions, early morning awakening, and decreased appetite and libido. The side effects of the tricyclic drugs are less frequent and far less serious than those of the MAO inhibitors.
The tricyclic compounds are also potent anticholinergic agents, which accounts for their most prominent and bothersome side effects—orthostatic hypotension, urinary bladder weakness, drowsiness, confusion, blurred vision, and dry mouth. They may also occasionally produce CNS excitation—leading to insomnia, agitation, and restlessness—but usually these effects are readily controlled by small doses of benzodiazepines given concurrently or in the evenings.
As indicated earlier, the tricyclic drugs should not be given with an MAO inhibitor; serious reactions have occurred when small doses of imipramine were given to patients who had discontinued the MAO in the previous days or week. Both the MAO inhibitors and the tricyclic antidepressants are dangerous drugs when taken in excess.
Related posts:
Disorders of the Special Senses
Chapter 20. Delirium and Other Acute Confusional States
Chapter 24. Fatigue, Asthenia, Anxiety, and Depression
Chapter 28. Normal Development and Deviations in Development of the Nervous System
Chapter 39. Degenerative Diseases of the Nervous System
Chapter 38. Developmental Diseases of the Nervous System
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