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studies show that these drugs also fail to stimulate dopamine release, further supporting the idea that only drugs that activate the mesolimbic dopamine system are addictive. Instead, hallucinogens increase glutamate release in the cortex, presumably by enhancing excitatory afferent input via presynaptic serotonin receptors (eg, 5-HT2A) from the thalamus.

LSD is an ergot alkaloid. After synthesis, blotter paper or sugar cubes are sprinkled with the liquid and allowed to dry. When LSD is swallowed, psychoactive effects typically appear after 30 minutes and last 6–12 hours. During this time, subjects have impaired ability to make rational judgments and understand common dangers, which puts them at risk for accidents and personal injury.

In an adult, a typical dose is 20–30 mcg. LSD is not considered neurotoxic, but like most ergot alkaloids, it may lead to strong contractions of the uterus that can induce abortion (see Chapter 16).

The main molecular target of LSD and other hallucinogens is the 5-HT2A receptor. This receptor couples to G proteins of the

Gq type and generates inositol trisphosphate (IP3), leading to a release of intracellular calcium. Although hallucinogens, and LSD in particular, have been proposed for several therapeutic indications, efficacy has never been demonstrated.

DRUGS THAT MEDIATE THEIR EFFECTS VIA IONOTROPIC RECEPTORS

NICOTINE

In terms of numbers affected, addiction to nicotine exceeds all other forms of addiction, affecting more than 50% of all adults in some countries. Nicotine exposure occurs primarily through smoking of tobacco, which causes associated diseases that are responsible for many preventable deaths. The chronic use of chewing tobacco and snuff tobacco is also addictive.

Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine (see Chapters 6 and 7). Based on nicotine’s enhancement of cognitive performance and the association of Alzheimer’s dementia with a loss of ACh-releasing neurons from the nucleus basalis of Meynert, nAChRs are believed to play an important role in many cognitive processes. The rewarding effect of nicotine requires involvement of the VTA, in which nAChRs are expressed on dopamine neurons. When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs. Recent work has identified α4β2-containing channels in the VTA as the nAChRs that are required for the rewarding effects of nicotine. This statement is based on the observation that knockout mice deficient for the β2 subunit lose interest in self-administering nicotine, and that in these mice, this behavior can be restored through an in vivo transfection of the β2 subunit in neurons of the VTA. Electrophysiologic evidence suggests that homomeric nAChRs made exclusively of α7 subunits also contribute to the reinforcing effects of nicotine. These receptors are mainly expressed on synaptic terminals of excitatory afferents projecting onto the dopamine neurons. They also contribute to nicotine-evoked dopamine release and the long-term changes induced by the drugs related to addiction (eg, long-term synaptic potentiation of excitatory inputs).

Nicotine withdrawal is mild compared with opioid withdrawal and involves irritability and sleep problems. However, nicotine is among the most addictive drugs (relative risk 4), and relapse after attempted cessation is very common.

Treatment

Treatments for nicotine addiction include nicotine itself in forms that are slowly absorbed and several other drugs. Nicotine that is chewed, inhaled, or transdermally delivered can be substituted for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke. Recently, two partial agonists of α4β2-containing nAChRs have been characterized: the plant-extract cytisine and its synthetic derivative varenicline. Both work by occupying nAChRs on dopamine neurons of the VTA, thus preventing nicotine from exerting its action. Varenicline may impair the capacity to drive and has been associated with suicidal ideation. The antidepressant bupropion is approved for nicotine cessation therapy. It is most effective when combined with behavioral therapies.

Many countries have banned smoking in public places to create smoke-free environments. This important step not only reduces passive smoking and the hazards of secondhand smoke, but also the risk that ex-smokers will be exposed to smoke, which as a contextual cue, may trigger relapse.

benzodiazepines for their euphoriant effects, but most often abuse occurs concomitant with other drugs, eg, to attenuate anxiety during withdrawal from opioids.

Benzodiazepine dependence is very common, and diagnosis of addiction is probably often missed. Withdrawal from benzodiazepines occurs within days of stopping the medication and varies as a function of the half-life of elimination. Symptoms include irritability, insomnia, phonophobia and photophobia, depression, muscle cramps, and even seizures. Typically, these symptoms taper off within 1–2 weeks.

Benzodiazepines are positive modulators of the GABAA receptor, increasing both single-channel conductance and open-channel probability. GABAA receptors are pentameric structures consisting of α, β, and γ subunits (see Chapter 22). GABA receptors on dopamine neurons of the VTA lack α1, a subunit isoform that is present in GABA neurons nearby (ie, interneurons). Because of this difference, unitary synaptic currents in interneurons are larger than those in dopamine neurons, and when this difference is amplified by benzodiazepines, interneurons fall silent. GABA is no longer released, and benzodiazepines lose their effect on dopamine neurons, ultimately leading to disinhibition of the dopamine neurons. The rewarding effects of benzodiazepines are, therefore, mediated by α1-containing GABAA receptors expressed on VTA neurons. Receptors containing α5 subunits seem to be required for tolerance to the sedative effects of benzodiazepines, and studies in humans link α2β3-containing receptors to alcohol dependence (the GABAA receptor is also a target of alcohol, see following text). Taken together, a picture is emerging linking GABAA receptors that contain the α1 subunit isoform to their addiction liability. By extension, α1-sparing compounds, which at present remain experimental and are not approved for human use, may eventually be preferred to treat anxiety disorders because of their reduced risk of induced addiction.

Barbiturates, which preceded benzodiazepines as the most commonly abused sedative-hypnotics (after ethanol), are now rarely prescribed to outpatients and therefore constitute a less common prescription drug problem than they did in the past. Street sales of barbiturates, however, continue. Management of barbiturate withdrawal and addiction is similar to that of benzodiazepines.

ALCOHOL

Alcohol (ethanol, see Chapter 23) is regularly used by a majority of the population in many Western countries. Although only a minority becomes dependent and addicted, abuse is a very serious public health problem because of the social costs and many diseases associated with alcoholism.

BENZODIAZEPINES

Benzodiazepines are commonly prescribed as anxiolytics and sleep medications. They represent a definite risk for abuse, which has to be weighed against their beneficial effects. Some persons abuse

Pharmacology

The pharmacology of alcohol is complex, and no single receptor mediates all of its effects. On the contrary, alcohol alters the function of several receptors and cellular functions, including GABAA receptors, Kir3/GIRK channels, adenosine reuptake (through

the equilibrative nucleoside transporter, ENT1), glycine receptor, NMDA receptor, and 5-HT3 receptor. They are all, with the exception of ENT1, either ionotropic receptors or ion channels. It is not clear which of these targets is responsible for the increase of dopamine release from the mesolimbic reward system. The inhibition of ENT1 is probably not responsible for the rewarding effects (ENT1 knockout mice drink more than controls) but seems to be involved in alcohol dependence through an accumulation of adenosine, stimulation of adenosine A2 receptors, and ensuing enhanced CREB signaling.

Dependence becomes apparent 6–12 hours after cessation of heavy drinking as a withdrawal syndrome that may include tremor (mainly of the hands), nausea and vomiting, excessive sweating, agitation, and anxiety. In some individuals, this is followed by visual, tactile, and auditory hallucinations 12–24 hours after cessation. Generalized seizures may manifest after 24–48 hours. Finally, 48–72 hours after cessation, an alcohol withdrawal delirium (delirium tremens) may become apparent in which the person hallucinates, is disoriented, and shows evidence of autonomic instability. Delirium tremens is associated with 5–15% mortality.

Treatment

Treatment of ethanol withdrawal is supportive and relies on benzodiazepines, taking care to use compounds such as oxazepam and lorazepam, which are not as dependent on oxidative hepatic metabolism as most other benzodiazepines. In patients in whom monitoring is not reliable and liver function is adequate, a longeracting benzodiazepine such as chlordiazepoxide is preferred.

As in the treatment of all chronic drug abuse problems, heavy reliance is placed on psychosocial approaches to alcohol addiction. This is perhaps even more important for the alcoholic patient because of the ubiquitous presence of alcohol in many social contexts.

The pharmacologic treatment of alcohol addiction is limited, although several compounds, with different goals, have been used. Therapy is discussed in Chapter 23.

KETAMINE & PHENCYCLIDINE PCP

Ketamine and PCP were developed as general anesthetics (see Chapter 25), but only ketamine is still used for this application. Both drugs, along with others, are now classified as “club drugs” and sold under names such as “angel dust,” “Hog,” and “Special K.” They owe their effects to their use-dependent, noncompetitive antagonism of the NMDA receptor. The effects of these substances became apparent when patients undergoing surgery reported unpleasant vivid dreams and hallucinations after anesthesia. Ketamine and PCP are white crystalline powders in their pure forms, but on the street they are also sold as liquids, capsules, or pills, which can be snorted, ingested, injected, or smoked. Psychedelic effects last for about 1 hour and also include increased blood pressure, impaired memory function, and visual alterations. At high doses, unpleasant out-of-body and near-death

experiences have been reported. Although ketamine and phencyclidine do not cause dependence and addiction (relative risk = 1), chronic exposure, particularly to PCP, may lead to long-lasting psychosis closely resembling schizophrenia, which may persist beyond drug exposure. Surprisingly, intravenous administration of ketamine can eliminate episodes of depression within hours (see Chapter 30), which is in strong contrast to selective serotonin reuptake inhibitors and other antidepressants, which usually take weeks to act. The antidepressive mechanism is believed to involve the antagonism of NMDA receptors, thus favoring the mTOR pathway downstream of other glutamate receptors. Recent evidence suggests an alternate explanation. Hydroxynorketamine, a metabolite of ketamine, may actually target AMPA receptors to exert the antidepressant effect. Regardless, a limitation is the transient nature of the effect, which wears off within days even with repetitive administration.

INHALANTS

Inhalant abuse is defined as recreational exposure to chemical vapors, such as nitrites, ketones, and aliphatic and aromatic hydrocarbons. These substances are present in a variety of household and industrial products that are inhaled by “sniffing,” “huffing,” or “bagging.” Sniffing refers to inhalation from an open container, huffing to the soaking of a cloth in the volatile substance before inhalation, and bagging to breathing in and out of a paper or plastic bag filled with fumes. It is common for novices to start with sniffing and progress to huffing and bagging as addiction develops. Inhalant abuse is particularly prevalent in children and young adults.

The exact mechanism of action of most volatile substances remains unknown. Altered function of ionotropic receptors and ion channels throughout the central nervous system has been demonstrated for a few. Nitrous oxide, for example, binds to NMDA receptors, and fuel additives enhance GABAA receptor function. Most inhalants produce euphoria; increased excitability of the VTA has been documented for toluene and may underlie its addiction risk. Other substances, such as amyl nitrite (“poppers”), primarily produce smooth muscle relaxation and enhance erection but are not addictive. With chronic exposure to the aromatic hydrocarbons (eg, benzene, toluene), toxic effects can be observed in many organs, including white matter lesions in the central nervous system. Management of overdose remains supportive.

DRUGS THAT BIND TO TRANSPORTERS OF BIOGENIC AMINES

Cocaine

The prevalence of cocaine abuse has increased greatly over the last decade and now represents a major public health problem worldwide. Cocaine is highly addictive (relative risk = 5), and its use is associated with a number of complications.

Cocaine is an alkaloid found in the leaves of Erythroxylum coca, a shrub indigenous to the Andes. For more than 100 years, it has been extracted and used in clinical medicine, mainly as a local anesthetic and to dilate pupils in ophthalmology. Sigmund Freud famously proposed its use to treat depression and alcohol dependence, but addiction quickly brought an end to this idea.

Cocaine hydrochloride is a water-soluble salt that can be injected or absorbed by any mucosal membrane (eg, nasal snorting). When heated in an alkaline solution, it is transformed into the free base, “crack cocaine,” which can then be smoked. Inhaled crack cocaine is rapidly absorbed in the lungs and penetrates swiftly into the brain, producing an almost instantaneous “rush.”

In the peripheral nervous system, cocaine inhibits voltagegated sodium channels, thus blocking initiation and conduction of action potentials (see Chapter 26). This mechanism, underlying its effect as a local anesthetic, seems responsible for neither the acute rewarding nor the addictive effects. In the central nervous system, cocaine blocks the uptake of dopamine, noradrenaline, and serotonin through their respective transporters. The block of the dopamine transporter (DAT), by increasing dopamine concentrations in the nucleus accumbens, has been implicated in the rewarding effects of cocaine (Figure 32–4). In fact, the rewarding effects of cocaine are abolished in mutant mice with a cocaine-insensitive DAT. The activation of the sympathetic nervous system results mainly from blockage of the norepinephrine transporter (NET) and leads to an acute increase in arterial pressure, tachycardia, and often, ventricular arrhythmias. Users typically lose their appetite, are hyperactive, and sleep little. Cocaine exposure increases the risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures. Cocaine overdose may lead to hyperthermia, coma, and death. In the 1970s, when crack-cocaine appeared in the USA, it was suggested that the drug is particularly harmful to the fetus in addicted pregnant women. The term “crack-baby” was used to describe a specific syndrome

of the newborn, and the mothers faced harsh legal consequences. The follow-up of the children, now adults, does not confirm a drug-specific handicap in cognitive performance. Moreover, in this population, the percentage of drug-users is comparable to controls matched for socioeconomic environment.

Susceptible individuals may become dependent and addicted after only a few exposures to cocaine. Although a withdrawal syndrome is reported, it is not as strong as that observed with opioids. Tolerance may develop, but in some users, a reverse tolerance is observed; that is, they become sensitized to small doses of cocaine. This behavioral sensitization is in part contextdependent. Cravings are very strong and underlie the very high addiction liability of cocaine. To date, no specific antagonist is available, and the management of intoxication remains supportive. Developing a pharmacologic treatment for cocaine addiction is a top priority.

AMPHETAMINES

Amphetamines are a group of synthetic, indirect-acting sympathomimetic drugs that cause the release of endogenous biogenic amines, such as dopamine and noradrenaline (see Chapters 6 and 9). Amphetamine, methamphetamine, and their many derivatives exert their effects by reversing the action of biogenic amine transporters at the plasma membrane. Amphetamines are substrates of these transporters and are taken up into the cell (Figure 32–4). Once in the cell, amphetamines interfere with the vesicular monoamine transporter (VMAT; see Figure 6–4), depleting synaptic vesicles of their neurotransmitter content. As a consequence, levels of dopamine (or other transmitter amine) in the cytoplasm increase and quickly become sufficient to cause release into the synapse by reversal of the plasma membrane DAT. Normal vesicular release of dopamine consequently decreases (because synaptic

vesicles contain less transmitter), whereas nonvesicular release increases. Similar mechanisms apply for other biogenic amines (serotonin and norepinephrine).

Together with GHB and ecstasy, amphetamines are often referred to as “club drugs” because they are increasingly popular in the club scene. They are often produced in small clandestine laboratories, which makes their precise chemical identification difficult. They differ from ecstasy chiefly in the context of use: intravenous administration and “hard-core” addiction are far more common with amphetamines, especially methamphetamine. In general, amphetamines lead to elevated catecholamine levels that increase arousal and reduce sleep, whereas the effects on the dopamine system mediate euphoria but may also cause abnormal movements and precipitate psychotic episodes. Effects on serotonin transmission may play a role in the hallucinogenic and anorexigenic functions as well as in the hyperthermia often caused by amphetamines.

Unlike many other abused drugs, amphetamines are neurotoxic. The exact mechanism is not known, but neurotoxicity depends on the NMDA receptor and affects mainly serotonin and dopamine neurons.

Amphetamines are typically taken initially in pill form by abusers, but can also be smoked or injected. Heavy users often progress rapidly to intravenous administration. Within hours after oral ingestion, amphetamines increase alertness and cause euphoria, agitation, and confusion. Bruxism (tooth grinding) and skin flushing may occur. Effects on heart rate may be minimal with some compounds (eg, methamphetamine), but with increasing dosage these agents often lead to tachycardia and dysrhythmias. Hypertensive crisis and vasoconstriction may lead to stroke. Spread of HIV and hepatitis infection in inner cities has been closely associated with needle sharing by intravenous users of methamphetamine.

With chronic use, amphetamine tolerance may develop, leading to dose escalation. Withdrawal consists of dysphoria, drowsiness (in some cases, insomnia), and general irritability.

ECSTASY MDMA

Ecstasy is the name of a class of drugs that includes a large variety of derivatives of the amphetamine-related compound methylenedioxymethamphetamine (MDMA). MDMA was originally used in some forms of psychotherapy, but no medically useful effects were documented. This is perhaps not surprising, because the main effect of ecstasy appears to be to foster feelings of intimacy and empathy without impairing intellectual capacities. Today, MDMA and its many derivatives are often produced in small quantities in ad hoc laboratories and distributed at parties or “raves,” where it is taken orally. Ecstasy therefore is the prototypic designer drug and, as such, is increasingly popular.

Similar to the amphetamines, MDMA causes release of biogenic amines by reversing the action of their respective transporters. It has a preferential affinity for the serotonin transporter (SERT) and therefore most strongly increases the extracellular concentration of serotonin. This release is so profound that there

is a marked intracellular depletion for 24 hours after a single dose. With repetitive administration, serotonin depletion may become permanent, which has triggered a debate on its neurotoxicity. Although direct proof from animal models for neurotoxicity remains weak, several studies report long-term cognitive impairment in heavy users of MDMA.

In contrast, there is a wide consensus that MDMA has several acute toxic effects, in particular hyperthermia, which along with dehydration (eg, caused by an all-night dance party) may be fatal. Other complications include serotonin syndrome (mental status change, autonomic hyperactivity, and neuromuscular abnormalities; see Chapter 16) and seizures. Following warnings about the dangers of MDMA, some users have attempted to compensate for hyperthermia by drinking excessive amounts of water, causing water intoxication involving severe hyponatremia, seizures, and even death.

Withdrawal is marked by a mood “offset” characterized by depression lasting up to several weeks. There have also been reports of increased aggression during periods of abstinence in chronic MDMA users.

Taken together, the evidence for irreversible damage to the brain, although not completely convincing, implies that even occasional recreational use of MDMA cannot be considered safe.

■ CLINICAL PHARMACOLOGY OF DEPENDENCE & ADDICTION

To date no single pharmacologic treatment (even in combination with behavioral interventions) efficiently eliminates addiction. This is not to say that addiction is irreversible. Pharmacologic interventions may in fact be useful at all stages of the disease. This is particularly true in the case of a massive overdose, in which reversal of drug action may be a life-saving measure. However, FDA-approved antagonists are available only for opioids and benzodiazepines.

Pharmacologic interventions may also aim to alleviate the withdrawal syndrome, particularly after opioid exposure. On the assumption that withdrawal reflects—at least in part—a hyperactivity of central adrenergic systems, the α2-adrenoceptor agonist clonidine (also used as a centrally active antihypertensive drug, see Chapter 11) has been used with some success to attenuate withdrawal. Today, most clinicians prefer to manage opioid withdrawal by very slowly tapering the administration of long-acting opioids.

Another widely accepted treatment is substitution of a legally available agonist that acts at the same receptor as the abused drug. This approach has been approved for opioids and nicotine. For example, heroin addicts may receive methadone to replace heroin; smoking addicts may receive nicotine continuously via a transdermal patch system to replace smoking. In general, a rapidacting substance is replaced with one that acts or is absorbed more slowly. Substitution treatments are largely justified by the benefits of reducing associated health risks, the reduction of drugassociated crime, and better social integration. Although dependence persists, it may be possible, with the support of behavioral

interventions, to motivate drug users to gradually reduce the dose and become abstinent.

The biggest challenge is the treatment of addiction itself. Several approaches have been proposed, but all remain experimental. One approach is to pharmacologically reduce cravings. The µ-opioid receptor antagonist and partial agonist naltrexone is FDA-approved for this indication in opioid and alcohol addiction. Its effect is modest and may involve a modulation of endogenous opioid systems.

Clinical trials are currently being conducted with a number of drugs, including the high-affinity GABAB-receptor agonist baclofen, and initial results have shown a significant reduction of craving. This effect may be mediated by the inhibition of the dopamine neurons of the VTA, which is possible at baclofen concentrations obtained by oral administration because of its very high affinity for the GABAB receptor.

Rimonabant is an inverse agonist of the CB1 receptor that behaves like an antagonist of cannabinoids. It was developed for smoking cessation and to facilitate weight loss. Because of frequent adverse effects—most notably severe depression carrying

a substantial risk of suicide—this drug is no longer used clinically. It was initially used in conjunction with diet and exercise for patients with a body mass index above 30 kg/m2 (27 kg/m2 if associated risk factors, such as type 2 diabetes or dyslipidemia, are present). Although a recent large-scale study confirmed that rimonabant is effective for smoking cessation and the prevention of weight gain in smokers who quit, this indication has never been approved. While the cellular mechanism of rimonabant remains to be elucidated, data in rodents convincingly demonstrate that this compound can reduce self-administration in naive as well as drug-experienced animals.

While still experimental, the emergence of a circuit model for addiction has prompted interest in neuromodulatory interventions, such as deep brain stimulation (DBS) or transcranial magnetic stimulation (TMS). Inspired by optogenetic “treatments” in rodent models of addiction, novel protocols have been proposed for DBS in the nucleus accumbens or TMS of the prefrontal cortex. Case studies seem to confirm the potential of such approaches, but controlled clinical studies are lacking.

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Everitt BJ, Robbins TW: Drug addiction: Updating actions to habits to compulsions ten years on. Annu Rev Psychol 2016;67:23.

Goldman D, Oroszi G, Ducci F: The genetics of addictions: Uncovering the genes. Nat Rev Genet 2005;6:521.

Lüscher C: Emergence of circuit model for addiction. Annu Rev Neurosci 2016;39:257-76.

Redish AD, Jensen S, Johnson A: A unified framework for addiction: Vulnerabilities in the decision process. Behav Brain Sci 2008;31:461.

Walker DM, Cates HM, Heller EA, Nestler EJ: Regulation of chromatin states by drugs of abuse. Curr Opin Neurobiol 2015;30:112.

Pharmacologyof Drugs of Abuse

Benowitz NL: Nicotine addiction. N Engl J Med 2010;362:2295.

Maskos U et al: Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 2005;436:103.

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Pascoli V, Terrier J, Hiver A, Lüscher C: Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction. Neuron 2015;88:1054.

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C A S E S T U D Y A N S W E R

When found by his parents, the patient was having visual hallucinations of colorful insects. Hallucinations are often caused by a cannabis overdose, especially when hashish is ingested. The slower kinetics of oral cannabis are more difficult to control compared to smoking marijuana. The poor learning performance may be due to the interference of

exogenous cannabis with endocannabinoids that fine-tune synaptic transmission and plasticity. While probably not fulfilling the criteria for addiction at present, the patient is at risk as epidemiologic studies show that drug abuse typically begins in late adolescence. The fact that he is not yet using other drugs is a positive sign.

C A S E S T U D Y

A 25-year-old woman who has been on a strict vegan diet for the past 2 years presents with increasing numbness and paresthesias in her extremities, generalized weakness, a sore tongue, and gastrointestinal discomfort. Physical examination reveals a pale woman with diminished vibration sensation, diminished spinal reflexes, and extensor plantar reflexes (Babinski sign). Examination of her oral cavity reveals atrophic glossitis, in which the tongue appears deep red in color and abnormally smooth and shiny due to atrophy of the lingual papillae. Laboratory testing reveals a macrocytic anemia based on a hematocrit of 30% (normal for

Hematopoiesis, the production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes, is a remarkable process that produces more than 200 billion new

The author acknowledges contributions of the previous author of this chapter, Susan B. Masters, PhD.

women, 37–48%), a hemoglobin concentration of 9.4 g/dL, an erythrocyte mean cell volume (MCV) of 123 fL (normal, 84–99 fL), an erythrocyte mean cell hemoglobin concentration (MCHC) of 34% (normal, 31–36%), and a low reticulocyte count. Further laboratory testing reveals a normal serum folate concentration and a serum vitamin B12 (cobalamin) concentration of 98 pg/mL (normal, 250–1100 pg/mL). Once megaloblastic anemia was identified, why was it important to measure serum concentrations of both folic acid and cobalamin? Should this patient be treated with oral or parenteral vitamin B12?

blood cells per day in the normal person and even greater numbers of cells in persons with conditions that cause loss or destruction of blood cells. The hematopoietic machinery resides primarily in the bone marrow in adults and requires a constant supply of three essential nutrients—iron, vitamin B12, and folic acid—as well as the presence of hematopoietic growth factors, proteins

that regulate the proliferation and differentiation of hematopoietic cells. Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells. Anemia, a deficiency in oxygen-carrying erythrocytes, is the most common deficiency and several forms are easily treated. Sickle cell anemia, a condition resulting from a genetic alteration in the hemoglobin molecule, is common but is not easily treated. It is discussed in the Box: Sickle Cell Disease and Hydroxyurea.

Thrombocytopenia and neutropenia are not rare, and some forms are amenable to drug therapy. In this chapter, we first consider treatment of anemia due to deficiency of iron, vitamin B12, or folic acid and then turn to the medical use of hematopoietic growth factors to combat anemia, thrombocytopenia, and neutropenia, and to support stem cell transplantation.

■ AGENTS USED IN ANEMIAS

IRON

Basic Pharmacology

Iron deficiency is the most common cause of chronic anemia. Like other forms of chronic anemia, iron deficiency anemia leads to pallor, fatigue, dizziness, exertional dyspnea, and other generalized symptoms of tissue hypoxia. The cardiovascular adaptations to chronic anemia—tachycardia, increased cardiac output,

vasodilation—can worsen the condition of patients with underlying cardiovascular disease.

Iron forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin. Hemoglobin reversibly binds oxygen and provides the critical mechanism for oxygen delivery from the lungs to other tissues. In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to microcytic hypochromic anemia. Ironcontaining heme is also an essential component of myoglobin, cytochromes, and other proteins with diverse biologic functions.

Pharmacokinetics

Free inorganic iron is extremely toxic, but iron is required for essential proteins such as hemoglobin; therefore, evolution has provided an elaborate system for regulating iron absorption, transport, and storage (Figure 33–1). The system uses specialized transport, storage, ferrireductase, and ferroxidase proteins whose concentrations are controlled by the body’s demand for hemoglobin synthesis and adequate iron stores (Table 33–1). A peptide called hepcidin, produced primarily by liver cells, serves as a key central regulator of the system. Nearly all of the iron used to support hematopoiesis is reclaimed from catalysis of the hemoglobin in senescent or damaged erythrocytes. Normally, only a small amount of iron is lost from the body each day, so dietary requirements are small and easily fulfilled by the iron available in a wide variety of foods. However, in special populations with

Sickle Cell Disease and Hydroxyurea

Sickle cell disease is an important genetic cause of hemolytic anemia, a form of anemia due to increased erythrocyte destruction, instead of the reduced mature erythrocyte production seen with iron, folic acid, and vitamin B12 deficiency. Patients with sickle cell disease are homozygous for the aberrant β-hemoglobin S (HbS) allele (substitution of valine for glutamic acid at amino acid 6 of β-globin) or heterozygous for HbS and a second mutated β-hemoglobin gene such as hemoglobin C (HbC) or β-thalassemia. Sickle cell disease has an increased prevalence in individuals of African descent because the heterozygous trait confers resistance to malaria.

In the majority of patients with sickle cell disease, anemia is not the major problem; the anemia is generally well compensated even though such individuals have a chronically low hematocrit (20–30%), a low serum hemoglobin level (7–10 g/dL), and an elevated reticulocyte count. Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization. Abnormal erythrocytes aggregate in the microvasculature—where oxygen tension is low and hemoglobin is deoxygenated—and cause veno-occlusive damage. In the musculoskeletal system, this results in characteristic,

extremely severe bone and joint pain. In the cerebral vascular system, it causes ischemic stroke. Damage to the spleen increases the risk of infection, particularly by encapsulated bacteria such as Streptococcus pneumoniae. In the pulmonary system, there is an increased risk of infection and, in adults, an increase in embolism and pulmonary hypertension. Supportive treatment includes analgesics, antibiotics, pneumococcal vaccination, and blood transfusions. In addition, the cancer chemotherapeutic drug hydroxyurea (hydroxycarbamide) reduces veno-occlusive events. It is approved in the United States for treatment of adults with recurrent sickle cell crises and approved in Europe in adults and children with recurrent vaso-occlusive events. As an anticancer drug used in the treatment of chronic and acute myelogenous leukemia, hydroxyurea inhibits ribonucleotide reductase and thereby depletes deoxynucleoside triphosphate and arrests cells in the S phase of the cell cycle (see Chapter 54). In the treatment of sickle cell disease, hydroxyurea acts through poorly defined pathways to increase the production of fetal hemoglobin γ (HbF), which interferes with the polymerization of HbS. Clinical trials have shown that hydroxyurea decreases painful crises in adults and children with severe sickle cell disease. Its adverse effects include hematopoietic depression, gastrointestinal effects, and teratogenicity in pregnant women.