Pharmacology_Katzung

Pharmacology_Katzung. Many of the recent advances in addiction research have been made possible by the use of animal models. Since drugs of abuse are not only rewarding but also reinforcing, an animal will learn a behavior (eg, press a lever) when paired with drug administra-tion. In such a self-administration paradigm, the number of times an animal is willing to press the lever in order to obtain a single dose reflects the strength of reinforcement and is therefore a measure of the rewarding properties of a drug. Observing with-drawal signs specific for rodents (eg, escape jumps or “wet-dog” shakes after abrupt termination of chronic morphine administra-tion) allows the quantification of dependence. Behavioral tests for addiction in the rodent do not fully capture the complexity of the disease. However, it is possible to model core components of addiction; for example, by monitoring behavioral sensitization and conditioned place preference. In the first test, an increase in locomotor activity is observed


Pharmacology_Katzung

Pharmacology_Katzung. possible to model core components of addiction; for example, by monitoring behavioral sensitization and conditioned place preference. In the first test, an increase in locomotor activity is observed with intermittent drug exposure. The latter tests for the preference of a particular environment associated with drug exposure by measuring the time an animal spends in the compartment where a drug was received com-pared with the compartment where only saline was injected (conditioned place preference). Both tests have in common that they are sensitive to cue-conditioned effects of addictive drugs. Subsequent exposures to the environment without the drug lead to extinction of the place preference, which can be reinstated with a low dose of the drug or the presentation of a conditioned stimulus. These persistent changes serve as a model of relapse and have been linked to synaptic plasticity of excitatory trans-mission in the ventral tegmental area, nucleus accumbens, and prefrontal cortex


Pharmacology_Katzung

Pharmacology_Katzung. These persistent changes serve as a model of relapse and have been linked to synaptic plasticity of excitatory trans-mission in the ventral tegmental area, nucleus accumbens, and prefrontal cortex (see also Box: The Dopamine Hypothesis of Addiction). More sophisticated tests rely on self-administration of the drug, in which a rat or a mouse has to press a lever in order to obtain an injection of, for example, cocaine. Once the animal has learned the association with a conditioned stimulus (eg, light or brief sound), the simple presentation of the cue elicits drug seeking. Prolonged self-administration of addictive drugs over months leads to behaviors in rats that more closely resemble human addiction. Such “addicted” rodents are very strongly motivated to seek cocaine, continue looking for the drug even when no longer available, and self-administer cocaine despite negative consequences, such as punishment in the form of an electric foot shock. While there is little evidence for


Pharmacology_Katzung

Pharmacology_Katzung. for the drug even when no longer available, and self-administer cocaine despite negative consequences, such as punishment in the form of an electric foot shock. While there is little evidence for addicted animals in the wild, these findings suggest that addiction is a disease that does not respect species boundaries once drugs become available.


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Pharmacology_Katzung. receptors (δ, κ). Although activation of the μ-opioid receptor initially strongly inhibits adenylyl cyclase, this inhibition becomes weaker after several days of repeated exposure. The reduction of the inhibition of adenylyl cyclase is due to a counteradaptation of the enzyme system during exposure to the drug, which results in overproduction of cAMP during subsequent withdrawal. Several mechanisms exist for this adenylyl cyclase compensatory response, including up-regulation of transcription of the enzyme. Increased cAMP concentrations in turn strongly activate the transcription factor cyclic AMP response element binding protein (CREB), leading to the regulation of downstream genes. Of the few such genes identified to date, one of the most interesting is the gene for the endogenous κ-opioid ligand dynorphin. The main targets of dynorphin are the presynaptic κ-opioid receptors that regulate the release of dopamine in the nucleus accumbens. More recently, an input from the thalamus to


Pharmacology_Katzung

Pharmacology_Katzung. ligand dynorphin. The main targets of dynorphin are the presynaptic κ-opioid receptors that regulate the release of dopamine in the nucleus accumbens. More recently, an input from the thalamus to the nucleus accumbens conveying an aversive state during withdrawal has been implicated, further elucidating the circuits underlying opioid dependence.


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Pharmacology_Katzung. ADDICTION: A DISEASE OF MALADAPTIVE LEARNING Addiction is characterized by a high motivation to obtain and use a drug despite negative consequences. With time, drug use becomes compulsive (“wanting without liking”). Addiction is a recalcitrant, chronic, and stubbornly relapsing disease that is very difficult to treat.


Pharmacology_Katzung

Pharmacology_Katzung. The central problem is that even after successful withdrawal and prolonged drug-free periods, addicted individuals have a high risk of relapsing. Relapse is typically triggered by one of the following three conditions: re-exposure to the addictive drug, stress, or a context that recalls prior drug use. It appears that when paired with drug use, a neutral stimulus may undergo a switch and motivate (“trigger”) addiction-related behavior. This phenomenon may involve synaptic plasticity in the target nuclei of the mesolimbic projection (eg, projections from the medial prefrontal cortex to the neurons of the nucleus accumbens that express the D1 receptors). Several recent studies suggest that the recruitment of the dorsal striatum is responsible for the compulsion. This switch may depend on synaptic plasticity in the nucleus accumbens of the ventral striatum, where mesolimbic dopamine afferents converge with glutamatergic afferents to modulate their function. If dopamine release codes for


Pharmacology_Katzung

Pharmacology_Katzung. plasticity in the nucleus accumbens of the ventral striatum, where mesolimbic dopamine afferents converge with glutamatergic afferents to modulate their function. If dopamine release codes for the prediction error of reward (see Box: The Dopamine Hypothesis of Addiction), pharmacologic stimulation of the mesolimbic dopamine system will generate an unusually strong learning signal. Unlike natural rewards, addictive drugs continue to increase dopamine even when reward is expected. Such overriding of the prediction error signal may eventually be responsible for the usurping of memory processes by addictive drugs.


Pharmacology_Katzung

Pharmacology_Katzung. The involvement of learning and memory systems in addiction is also suggested by clinical studies. For example, the role of context in relapse is supported by the report that soldiers who became addicted to heroin during the Vietnam War had significantly better outcomes when treated after their return home, compared with addicts who remained in the environment where they had taken the drug. In other words, cravings may recur at the presentation of contextual cues (eg, people, places, or drug paraphernalia). Current research therefore focuses on the effects of drugs on associative forms of synaptic plasticity, such as long-term potentiation (LTP), which underlie learning and memory (see Box: Synaptic Plasticity, Altered Circuit Function, & Addiction). CHAPTER 32 Drugs of Abuse 579


Pharmacology_Katzung

Pharmacology_Katzung. In the earliest version of the hypothesis described in this chapter, mesolimbic dopamine was believed to be the neurochemical correlate of pleasure and reward. However, during the past decade, experimental evidence has led to several revisions. Pha-sic dopamine release may actually code for the prediction error of reward rather than the reward itself. This distinction is based on pioneering observations in monkeys that dopamine neurons in the ventral tegmental area (VTA) are most efficiently activated by a reward (eg, a few drops of fruit juice) that is not anticipated. When the animal learns to predict the occurrence of a reward (eg, by pairing it with a stimulus such as a sound), dopamine neurons stop responding to the reward itself (juice), but increase their firing rate when the conditioned stimulus (sound) occurs. Finally, if reward is predicted but not delivered (sound but no juice), dopamine neurons are inhibited below their baseline activity and become silent. In other words,


Pharmacology_Katzung

Pharmacology_Katzung. stimulus (sound) occurs. Finally, if reward is predicted but not delivered (sound but no juice), dopamine neurons are inhibited below their baseline activity and become silent. In other words, the mesolimbic system continuously scans the reward situation. It increases its activity when reward is larger than expected and shuts down in the opposite case, thus coding for the prediction error of reward. Under physiologic conditions the mesolimbic dopamine signal could represent a learning signal responsible for reinforc-ing constructive behavioral adaptation (eg, learning to press a lever for food). Addictive drugs, by directly increasing dopamine, would generate a strong but inappropriate learning signal, thus hijacking the reward system and leading to pathologic reinforce-ment. As a consequence, behavior becomes compulsive; that is, decisions are no longer planned and under control, but auto-matic, which is the hallmark of addiction. This appealing hypothesis has been challenged based


Pharmacology_Katzung

Pharmacology_Katzung. behavior becomes compulsive; that is, decisions are no longer planned and under control, but auto-matic, which is the hallmark of addiction. This appealing hypothesis has been challenged based on the observation that some reward and drug-related learning is still possible in the absence of dopamine. Another intriguing observation is that mice genetically modified to lack the primary molecular target of cocaine, the dopamine transporter DAT, still self-administer the drug. Only when transporters of other biogenic amines are also knocked out does cocaine completely lose its rewarding properties. However, in DAT –/– mice, in which basal synaptic dopamine levels are high, cocaine still leads to increased dopamine release, presumably because other cocaine-sensitive monoamine transporters (NET, SERT) are able to clear some dopamine. When cocaine is given, these transporters are also inhibited and dopamine is again increased. As a conse-quence of this substitution among monoamine


Pharmacology_Katzung

Pharmacology_Katzung. (NET, SERT) are able to clear some dopamine. When cocaine is given, these transporters are also inhibited and dopamine is again increased. As a conse-quence of this substitution among monoamine transporters, fluoxetine (a selective serotonin reuptake inhibitor, see Chapter 30) becomes addictive in DAT –/– mice. This concept is supported by newer evidence showing that deletion of the cocaine-binding site on DAT leaves basal dopamine levels unchanged but abol-ishes the rewarding effect of cocaine. The dopamine hypothesis of addiction has also been chal-lenged by the observation that salient stimuli that are not rewarding (they may actually even be aversive and therefore nega-tive reinforcers) also activate a subpopulation of dopamine neu-rons in the VTA. The neurons that are activated by aversive stimuli preferentially project to the prefrontal cortex, while the dopamine neurons inhibited by aversive stimuli are those that mostly tar-get the nucleus accumbens. These recent findings


Pharmacology_Katzung

Pharmacology_Katzung. aversive stimuli preferentially project to the prefrontal cortex, while the dopamine neurons inhibited by aversive stimuli are those that mostly tar-get the nucleus accumbens. These recent findings suggest that in parallel to the reward system, a system for aversion-learning originates in the VTA, which may be at the origin of the negative affective state seen during drug withdrawal. Regardless of the many roles of dopamine under physi-ologic conditions, all addictive drugs significantly increase its concentration in target structures of the mesolimbic projection. This suggests that high levels of dopamine may actually be at the origin of the adaptive changes that underlie dependence and addiction, a concept that is now supported by novel tech-niques that allow controlling the activity of dopamine neurons in vivo. In fact manipulations that drive sustained activity of VTA dopamine neurons cause the same cellular adaptations and behavioral changes typically observed with addictive drug


Pharmacology_Katzung

Pharmacology_Katzung. dopamine neurons in vivo. In fact manipulations that drive sustained activity of VTA dopamine neurons cause the same cellular adaptations and behavioral changes typically observed with addictive drug exposure, including late-stage symptoms such as persistence of self-stimulation during punishment.


Pharmacology_Katzung

Pharmacology_Katzung. Non-substance-dependent disorders, such as pathologic gambling and compulsive shopping, share many clinical features of addiction. Several lines of arguments suggest that they also share the underlying neurobiologic mechanisms. This conclusion is supported by the clinical observation that, as an adverse effect of dopamine agonist medication, patients with Parkinson’s disease may become pathologic gamblers. Other patients may develop a habit for recreational activities, such as shopping, eating compulsively, or hypersexuality. Although large-scale studies are not yet available, an estimated one in seven parkinsonian patients develops an addiction-like behavior when receiving dopamine agonists (see chapter 28).


Pharmacology_Katzung

Pharmacology_Katzung. Large individual differences exist also in vulnerability to substance-related addiction. Whereas one person may become “hooked” after a few doses, others may be able to use a drug occasionally during their entire lives without ever having difficulty in stopping. Even when dependence is induced with chronic exposure, only a small percentage of dependent users progress to addiction. For example, a retrospective analysis shows that after several decades of cocaine abuse, only 20% become addicted. With cannabis, the fraction is only 10%. A similar percentage for cocaine is also observed in rats and mice that have extended access to the drug. Surprisingly, with dopamine neuron self-stimulation, the fraction of mice that resist punishment is > 50%. Recent studies in rats suggest that impulsivity or excessive anxiety may be crucial traits that represent a risk for addiction. The transition to addiction is determined by a combination of environmental and genetic factors. Heritability of


Pharmacology_Katzung

Pharmacology_Katzung. or excessive anxiety may be crucial traits that represent a risk for addiction. The transition to addiction is determined by a combination of environmental and genetic factors. Heritability of addiction, as determined by comparing monozygotic with dizygotic twins, is relatively modest for cannabinoids but very high for cocaine. It is of interest that the relative risk for addiction (addiction liability) of a drug (Table 32–1) correlates with its heritability, suggesting that the neurobiologic basis of addiction common to all drugs is what is being inherited. Further genomic analysis indicates that numerous, perhaps even hundreds of alleles need to function in combination to produce the phenotype. However, identification of the genes involved remains elusive. Although some substance-specific candidate genes have been identified (eg, alcohol dehydrogenase, nicotinic acetylcholine receptor subunits), future research will also focus on genes implicated in the neurobiologic mechanisms


Pharmacology_Katzung

Pharmacology_Katzung. candidate genes have been identified (eg, alcohol dehydrogenase, nicotinic acetylcholine receptor subunits), future research will also focus on genes implicated in the neurobiologic mechanisms common to all addictive drugs. An appealing idea, now supported by experimental evidence, is the contribution of epigenetics as a determinant of addiction vulnerability. Cocaine regulates posttranslational modifications of histones, DNA methylation, and signaling via non-coding RNAs, which eventually may have an impact on behavior. The cellular mechanism involved and the relationship to synaptic plasticity are currently under investigation.


Pharmacology_Katzung

Pharmacology_Katzung. Synaptic Plasticity, Altered Circuit Function, & Addiction


Pharmacology_Katzung

Pharmacology_Katzung. Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity that is induced by activating glutamate receptors of the N-methyl-D-aspartate (NMDA) type. Since NMDA receptors are blocked by magnesium at negative potentials, their activation requires the concomitant release of glutamate (presynaptic activity) onto a receiving neuron that is depolarized (postsynaptic activity). Correlated preand postsynaptic activity durably enhances synaptic efficacy and triggers the formation of new connections. Because asso-ciativity is a critical component, LTP has become a leading candidate mechanism underlying learning and memory. LTP can be elicited at glutamatergic synapses of the mesolimbic reward system and is modulated by dopamine. Drugs of abuse could therefore interfere with LTP at sites of convergence of dopamine and glutamate projections (eg, ventral tegmental area [VTA], nucleus accumbens, or prefrontal cortex). Interest-ingly, exposure to an addictive drug triggers a


Pharmacology_Katzung

Pharmacology_Katzung. LTP at sites of convergence of dopamine and glutamate projections (eg, ventral tegmental area [VTA], nucleus accumbens, or prefrontal cortex). Interest-ingly, exposure to an addictive drug triggers a specific form of synaptic plasticity at excitatory afferents (drug-evoked synaptic plasticity) and potentiates GABAA receptor-mediated inhibi-tion of the GABA neurons in the VTA and the ventral pallidum (VP), both primary targets of the medium spiny neurons of the nucleus accumbens. As a consequence, the excitability of dopa-mine neurons is increased, the synaptic calcium sources altered, and the rules for subsequent LTP inverted. In the nucleus accumbens, drug-evoked synaptic plasticity appears with some delay and mostly involves the D1 receptor-expressing neurons, which are the ones projecting back to the VTA to control the activity of the GABA neurons as well as to the VP. Manipula-tions in mice that prevent or reverse drug-evoked plasticity in vivo also have effects on persistent


Pharmacology_Katzung

Pharmacology_Katzung. back to the VTA to control the activity of the GABA neurons as well as to the VP. Manipula-tions in mice that prevent or reverse drug-evoked plasticity in vivo also have effects on persistent changes of drug-associated behavioral sensitization or cue-induced drug seeking, provid-ing more direct evidence for a causal role of synaptic plasticity in drug-adaptive behavior. Together, a circuit model of staged drug-evoked synaptic plasticity is emerging, whereby various symptoms are caused by changes in specific projections, even-tually combining into addiction.


Pharmacology_Katzung

Pharmacology_Katzung. Some drugs of abuse do not lead to addiction. This is the case for substances that alter perception without causing sensations of reward and euphoria, such as the hallucinogens and the dissociative anesthetics (Table 32–1). Unlike addictive drugs, which primarily target the mesolimbic dopamine system, these agents primarily target cortical and thalamic circuits. Lysergic acid diethylamide (LSD), for example, activates the serotonin 5-HT2A receptor in the prefrontal cortex, enhancing glutamatergic transmission onto pyramidal neurons. These excitatory afferents mainly come from the thalamus and carry sensory information of varied modalities, which may constitute a link to enhanced perception. Phencyclidine (PCP) and ketamine produce a feeling of separation of mind and body (which is why they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibition of glutamate receptors of the NMDA type. High doses of


Pharmacology_Katzung

Pharmacology_Katzung. they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibition of glutamate receptors of the NMDA type. High doses of dextromethorphan, an over-the-counter cough suppressant, can also elicit a dissociative state. This effect is mediated by a rather nonselective action on serotonin reuptake, and opioid, acetylcholine, and NMDA receptors.


Pharmacology_Katzung

Pharmacology_Katzung. The classification of NMDA antagonists as nonaddictive drugs was based on early assessments, which, in the case of PCP, have recently been questioned. In fact, animal research shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents. Concurrent effects on both thalamocortical and mesolimbic systems also exist for other addictive drugs. Psychosis-like symptoms can be observed with cannabinoids, amphetamines, and cocaine, which may reflect their effects on thalamocortical structures. For example, cannabinoids, in addition to their documented effects on the mesolimbic dopamine system, also enhance excitation in cortical circuits through presynaptic inhibition of GABA release. Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects.


Pharmacology_Katzung

Pharmacology_Katzung. Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects. Flashbacks of altered perception can occur years after LSD use. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.


Pharmacology_Katzung

Pharmacology_Katzung. Flashbacks of altered perception can occur years after LSD use. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis. Since all addictive drugs increase dopamine concentrations in target structures of the mesolimbic projections, we classify them on the basis of their molecular targets and the underlying mechanisms (Table 32–1 and Figure 32–2). The first group contains the opioids, cannabinoids, f-hydroxybutyric acid (GHB), and the hallucinogens, which all exert their action through Gio protein-coupled receptors. The second group includes nicotine, alcohol, the benzodiazepines, dissociative anesthetics, and some inhalants, which interact with ionotropic receptors or ion channels. The last group comprises cocaine, amphetamines, and ecstasy, which all bind to monoamine transporters. The nonaddictive drugs are classified using the same criteria.


Pharmacology_Katzung

Pharmacology_Katzung. Opioids may have been the first drugs to be abused (preceding stimulants) and are still among the most commonly used for nonmedical purposes. As described in Chapter 31, opioids comprise a large family of endogenous and exogenous agonists at three G protein-coupled receptors: the μ-, κ-, and δ-opioid receptors. Although all three receptors couple to inhibitory G proteins (ie, they all inhibit adenylyl cyclase), they have distinct, sometimes even opposing effects, mainly because of the cell type-specific expression throughout the brain. In the VTA, for example, μ-opioid receptors are selectively expressed on GABA neurons (which they inhibit), whereas κ-opioid receptors are expressed on and inhibit dopamine neurons. This may explain why μ-opioid agonists cause euphoria, whereas κ agonists induce dysphoria.


Pharmacology_Katzung

Pharmacology_Katzung. In line with the latter observations, the rewarding effects of morphine are absent in knockout mice lacking μ receptors but persist when either of the other opioid receptors are ablated. In the VTA, μ opioids cause an inhibition of GABAergic inhibitory interneurons, which leads eventually to a disinhibition of dopamine neurons. The most commonly abused μ opioids include morphine, heroin (diacetylmorphine, which is rapidly metabolized to morphine), codeine, and oxycodone. Meperidine abuse is common among health professionals. All of these drugs induce strong


Pharmacology_Katzung

Pharmacology_Katzung. CHAPTER 32 Drugs of Abuse 581 tolerance and dependence. The withdrawal syndrome may be very severe (except for codeine) and includes intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, and fever. Beyond the withdrawal syndrome, which usually lasts no longer than a few days, individuals who have received opioids as analgesics only rarely develop addiction. In contrast, when taken for recreational purposes, opioids are highly addictive. The relative risk of addiction is 4 out of 5 on a scale of 1 (nonaddictive) to 5 (highly addictive). The opioid antagonist naloxone reverses the effects of a dose of morphine or heroin within minutes. This may be life-saving in the case of a massive overdose (see Chapters 31 and 58). Naloxone administration also provokes an acute withdrawal (precipitated abstinence) syndrome in a dependent person who has recently taken an opioid.


Pharmacology_Katzung

Pharmacology_Katzung. In the treatment of opioid addiction, a long-acting opioid (eg, methadone, buprenorphine, morphine sulphate) is often substituted for the shorter-acting, more rewarding, opioid (eg, heroin). For substitution therapy, methadone is given orally once daily, facilitating supervised intake. Using a partial agonist (buprenorphine) and the much longer half-life (methadone, morphine sulphate, and buprenorphine) may also have some beneficial effects (eg, weaker drug sensitization, which typically requires intermittent exposures), but it is important to realize that abrupt termination of methadone administration invariably precipitates a withdrawal syndrome; that is, the subject on substitution therapy remains dependent. Levomethadone, a preparation containing only the active enantiomer, has similar kinetics and effects as methadone, but lower side effects, particularly when cardiac repolarization is perturbed (long QT interval in the electrocardiogram). Some countries (eg, Canada, Denmark,


Pharmacology_Katzung

Pharmacology_Katzung. kinetics and effects as methadone, but lower side effects, particularly when cardiac repolarization is perturbed (long QT interval in the electrocardiogram). Some countries (eg, Canada, Denmark, Netherlands, United Kingdom, Switzerland) even allow substitution of medical heroin for street heroin. A follow-up of a cohort of addicts who received heroin injections in a controlled setting and had access to counseling indicates that addicts under heroin substitution have an improved health status and are better integrated in society. Abuse of prescription opioids has soared in the USA over the last 10 years, and the National Institute on Drug Abuse (NIDA) estimates that more than 2 million individuals are dependent on these substances, some of whom may become heroin addicts.


Pharmacology_Katzung

Pharmacology_Katzung. Endogenous cannabinoids that act as neurotransmitters include 2-arachidonyl glycerol (2-AG) and anandamide, both of which bind to CB1 receptors. These very lipid-soluble compounds are released at the postsynaptic somatodendritic membrane, and diffuse through the extracellular space to bind at presynaptic CB1 receptors, where they inhibit the release of either glutamate or GABA. Because of such backward signaling, endocannabinoids are called retrograde messengers. In the hippocampus, release of endocannabinoids from pyramidal neurons selectively affects inhibitory transmission and may contribute to the induction of synaptic plasticity during learning and memory formation.


Pharmacology_Katzung

Pharmacology_Katzung. Exogenous cannabinoids, eg, in marijuana, which when smoked contains thousands of organic and inorganic chemical compounds, exert their pharmacologic effects through active substances including Δ9-tetra-hydrocannabinol (THC), a powerful psychoactive substance. Like opioids, THC causes disinhibition of dopamine neurons, mainly by presynaptic inhibition of GABA neurons in the VTA. The half-life of THC is about 4 hours. The onset of effects of THC after smoking marijuana occurs within minutes and reaches a maximum after 1–2 hours. The most prominent effects are euphoria and relaxation. Users also report feelings of well-being, grandiosity, and altered perception of passage of time. Dose-dependent perceptual changes (eg, visual distortions), drowsiness, diminished coordination, and memory impairment may occur. Cannabinoids can also create a dysphoric state and, in rare cases following the use of very high doses, eg, in hashish, result in visual hallucinations, depersonalization, and frank


Pharmacology_Katzung

Pharmacology_Katzung. may occur. Cannabinoids can also create a dysphoric state and, in rare cases following the use of very high doses, eg, in hashish, result in visual hallucinations, depersonalization, and frank psychotic episodes. Additional effects of THC, eg, increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain, have led to the use of cannabinoids in medical therapeutics. The justification of medicinal use of marijuana was comprehensively examined by the Institute of Medicine (IOM) of the National Academy of Sciences in its 1999 report, Marijuana & Medicine. Today, medical use of botanical marijuana has been legalized in 25 states and the District of Columbia. Nevertheless this continues to be a controversial issue, mainly because of the fear that cannabinoids may serve as a gateway to the consumption of “hard” drugs or cause schizophrenia in individuals with a predisposition.


Pharmacology_Katzung

Pharmacology_Katzung. Chronic exposure to marijuana leads to dependence, which is revealed by a distinctive, but mild and short-lived, withdrawal syndrome that includes restlessness, irritability, mild agitation, insomnia, nausea, and cramping. The relative risk for addiction is 2.


Pharmacology_Katzung

Pharmacology_Katzung. The synthetic Δ9-THC analog dronabinol is a US Food and Drug Administration (FDA) -approved cannabinoid agonist currently marketed in the USA and some European countries. Nabilone, an older commercial Δ9-THC analog, was recently reintroduced in the USA for treatment of chemotherapy-induced emesis. Nabiximols is a botanical drug obtained by standard extraction. Its active principles are Δ9-THC and cannabidiol. Initially only marketed in the United Kingdom, it is now widely available to treat symptoms of multiple sclerosis. In the USA, nabiximols is in phase III testing for cancer pain. The cannabinoid system is likely to emerge as an important drug target in the future because of its apparent involvement in several therapeutically desirable effects.


Pharmacology_Katzung

Pharmacology_Katzung. Gamma-hydroxybutyric acid (GHB, or sodium oxybate for its salt form) is produced during the metabolism of GABA, but the function of this endogenous agent is unknown at present. The pharmacology of GHB is complex because there are two distinct binding sites. The protein that contains a high-affinity binding site (1 μM) for GHB has been cloned, but its involvement in the cellular effects of GHB at pharmacologic concentrations remains unclear. The low-affinity binding site (1 mM) has been identified as the GABAB receptor. In mice that lack GABAB receptors, even very high doses of GHB have no effect; this suggests that GABAB receptors are the sole mediators of GHB’s pharmacologic action.


Pharmacology_Katzung

Pharmacology_Katzung. GHB was first synthesized in 1960 and introduced as a general anesthetic. Because of its narrow safety margin and its addictive potential, it is not available in the USA for this purpose. Sodium oxybate can, however, be prescribed (under restricted access rules) to treat narcolepsy, because GHB decreases daytime sleepiness and episodes of cataplexy through a mechanism unrelated to the reward system. Before causing sedation and coma, GHB causes euphoria, enhanced sensory perceptions, a feeling of social closeness, and amnesia. These properties have made it a popular “club drug” that goes by colorful street names such as “liquid ecstasy,” “grievous bodily harm,” or “date rape drug.” As the latter name suggests, GHB has been used in date rapes because it is odorless and can be readily dissolved in beverages. It is rapidly absorbed after ingestion and reaches a maximal plasma concentration 20–30 minutes after ingestion of a 10–20 mg/kg dose. The elimination half-life is about 30 minutes.


Pharmacology_Katzung

Pharmacology_Katzung. Although GABAB receptors are expressed on all neurons of the VTA, GABA neurons are much more sensitive to GHB than are dopamine neurons (Figure 32–3). This is reflected by the EC50s, which differ by about one order of magnitude, and indicates the difference in coupling efficiency of the GABAB receptor and the potassium channels responsible for the hyperpolarization. Because GHB is a weak agonist, only GABA neurons are inhibited at the concentrations typically obtained with recreational use. This feature may underlie the reinforcing effects of GHB and the basis for addiction to the drug. At higher doses, however, GHB also hyperpolarizes dopamine neurons, eventually completely inhibiting dopamine release. Such an inhibition of the VTA may in turn preclude its activation by other addictive drugs and may explain why GHB might have some usefulness as an “anticraving” compound. LSD, MESCALINE, & PSILOCYBIN


Pharmacology_Katzung

Pharmacology_Katzung. LSD, MESCALINE, & PSILOCYBIN LSD, mescaline, and psilocybin are commonly called hallucinogens because of their ability to alter consciousness such that the individual senses things that are not present. They induce, often in an unpredictable way, perceptual symptoms, including shape and color distortion. Psychosis-like manifestations (depersonalization, hallucinations, distorted time perception) have led some to classify these drugs as psychotomimetics. They also produce somatic symptoms (dizziness, nausea, paresthesias, and blurred vision). Some users have reported intense reexperiencing of perceptual effects (flashbacks) up to several years after the last drug exposure.


Pharmacology_Katzung

Pharmacology_Katzung. Hallucinogens differ from most other drugs described in this chapter in that they induce neither dependence nor addiction. However, repetitive exposure still leads to rapid tolerance (also called tachyphylaxis). Animals do not self-administer hallucinogens, suggesting that they are not rewarding to them. Additional


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 32–3 Disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA) through drugs that act via Gio-coupled receptors. Top: Opioids target μ-opioid receptors (MORs) that in the VTA are located exclusively on γ-aminobutyric acid (GABA) neurons. MORs are expressed on the presynaptic terminal of these cells and the somatodendritic compartment of the postsynaptic cells. Each compartment has distinct effectors (insets). G protein-βγ-mediated inhibition of voltage-gated calcium channels (VGCC) is the major mechanism in the presynaptic terminal. Conversely, in dendrites MORs activate K channels. Together the preand postsynaptic mechanisms reduce transmitter release and suppress activity, ultimately taking away the inhibition by the GABA neurons. Middle: Δ9-tetrahydrocannabinol (THC) and other cannabinoids mainly act through presynaptic inhibition. Bottom: Gamma-hydroxybutyric acid (GHB) targets GABAB receptors, which are located on both cell types. However, GABA neurons are


Pharmacology_Katzung

Pharmacology_Katzung. and other cannabinoids mainly act through presynaptic inhibition. Bottom: Gamma-hydroxybutyric acid (GHB) targets GABAB receptors, which are located on both cell types. However, GABA neurons are more sensitive to GHB than are DA neurons, leading to disinhibition at concentrations typically obtained with recreational use. CB1R, cannabinoid receptors.


Pharmacology_Katzung

Pharmacology_Katzung. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


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Pharmacology_Katzung. 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).


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

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


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Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


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Pharmacology_Katzung. 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.


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Pharmacology_Katzung. 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 (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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 longer-acting 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


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Pharmacology_Katzung. CHAPTER 32 Drugs of Abuse 585 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


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Pharmacology_Katzung. 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.


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Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.”


Pharmacology_Katzung

Pharmacology_Katzung. In the peripheral nervous system, cocaine inhibits voltage-gated 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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 context-dependent. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 32–4 Mechanism of action of cocaine and amphetamine on synaptic terminal of dopamine (DA) neurons. Left: Cocaine inhibits the dopamine transporter (DAT), decreasing DA clearance from the synaptic cleft and causing an increase in extracellular DA concentration. Right: Since amphetamine (Amph) is a substrate of the DAT, it competitively inhibits DA transport. In addition, once in the cell, amphetamine interferes with the vesicular monoamine transporter (VMAT) and impedes the filling of synaptic vesicles. As a consequence, vesicles are depleted and cytoplasmic DA increases. This leads to a reversal of DAT direction, strongly increasing nonvesicular release of DA, and further increasing extracellular DA concentrations. vesicles contain less transmitter), whereas nonvesicular release increases. Similar mechanisms apply for other biogenic amines (serotonin and norepinephrine).


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

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


Pharmacology_Katzung

Pharmacology_Katzung. 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 CHAPTER 32 Drugs of Abuse 587 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. 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.


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Pharmacology_Katzung. 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.


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Pharmacology_Katzung. 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 rapid-acting 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 drug-associated 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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.


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Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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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Pharmacology_Katzung. Partial agonist of nicotinic acetylcholine receptor of the α4β2-type • Cytisine: Natural analog (extracted from laburnum flowers) of varenicline •Oxazepam,others Positive modulators of the GABAA receptors, increase frequency of channel opening Enhances GABAergic synaptic transmission; attenuates withdrawal symptoms (tremor, hallucinations, anxiety) in alcoholics•preventswithdrawal seizures Delirium tremens Half-life4–15h•pharmacokineticsnotaffected by decreased liver function • Lorazepam:Alternatetooxazepamwithsimilarproperties Creed M, Pascoli VJ, Lüscher C: Addiction therapy. Refining deep brain stimulation to emulate optogenetic treatment of synaptic pathology. Science 2015; 347:659. 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.


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Pharmacology_Katzung. 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. Pharmacology of 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. Morton J: Ecstasy: Pharmacology and neurotoxicity. Curr Opin Pharmacol 2005;5:79. Nichols DE: Hallucinogens. Pharmacol Ther 2004;101:131. 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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Pharmacology_Katzung. Pascoli V, Terrier J, Hiver A, Lüscher C: Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction. Neuron 2015;88:1054. Snead OC, Gibson KM: Gamma-hydroxybutyric acid. N Engl J Med 2005;352:2721. Sulzer D et al: Mechanisms of neurotransmitter release by amphetamines: A review. Prog Neurobiol 2005;75:406. Tan KR et al: Neural basis for addictive properties of benzodiazepines. Nature 2010;463:769.


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Pharmacology_Katzung. Tan KR et al: Neural basis for addictive properties of benzodiazepines. Nature 2010;463:769. 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 dif-ficult 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. SECTION VI DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT James L. Zehnder, MD*


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Pharmacology_Katzung. 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 examina-tion reveals a pale woman with diminished vibration sen-sation, 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 atro-phy of the lingual papillae. Laboratory testing reveals a mac-rocytic anemia based on a hematocrit of 30% (normal for women, 37–48%), a hemoglobin concentration of 9.4 g/dL, an erythrocyte mean cell volume (MCV) of 123 fL (nor-mal, 84–99 fL), an erythrocyte mean cell hemoglobin con-centration (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


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Pharmacology_Katzung. con-centration (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?


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Pharmacology_Katzung. 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.


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Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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.


Pharmacology_Katzung

Pharmacology_Katzung. 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. Iron-containing heme is also an essential component of myoglobin, cytochromes, and other proteins with diverse biologic functions.


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Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. Sickle cell disease is an important genetic cause of hemo-lytic anemia, a form of anemia due to increased erythrocyte destruction, instead of the reduced mature erythrocyte pro-duction 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 preva-lence 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 com-pensated 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 dam-age. 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,


Pharmacology_Katzung

Pharmacology_Katzung. 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


Pharmacology_Katzung

Pharmacology_Katzung. 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 pain-ful crises in adults and children with severe sickle cell disease. Its adverse effects include hematopoietic depression, gastrointesti-nal effects, and teratogenicity in pregnant women.


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Pharmacology_Katzung. TfR RBC production F HCP1 Fe2+ DMT1 Fe Blood Intestinal epithelial cells Tf F F Hgb 4 Spleen, other tissues macrophage TfR Senescent RBC HgbHgb 1 Gut lumen 2 Bone marrow erythrocyte precursor Heme 3 Hepatocyte Erythroferrone DB FP FP Hepcidin Hepcidin FP – – – –


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 33–1 Absorption, transport, and storage of iron. Intestinal epithelial cells actively absorb inorganic iron via the divalent metal transporter 1 (DMT1) and heme iron via the heme carrier protein 1 (HCP1). Iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood by ferroportin (FP) and stored as ferritin (F). In the blood, iron is transported by transferrin (Tf) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) in red blood cells (RBC); (2) or to hepatocytes for storage as ferritin (3). The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized. After release of iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to


Pharmacology_Katzung

Pharmacology_Katzung. is released. Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4). Hepatocytes use several mechanisms to take up iron and store the iron as ferritin. High hepatic iron stores increase hepcidin synthesis, and hepcidin inhibits ferroportin; low hepatocyte iron and increased erythroferrone inhibits hepcidin and enhances iron absorption via ferroportin. Ferrous iron (Fe2+), blue diamonds, squares; ferric iron (Fe3+), red; DB, duodenal cytochrome B; F, ferritin; (Modified and reproduced, with permission, from Trevor A et al: Pharmacology Examination & Board Review, 9th ed. McGraw-Hill, 2010. Copyright © The McGraw-Hill Companies, Inc.) either increased iron requirements (eg, growing children, pregnant women) or increased losses of iron (eg, menstruating women), iron requirements can exceed normal dietary supplies, and iron deficiency can develop.


Pharmacology_Katzung

Pharmacology_Katzung. A. Absorption The average American diet contains 10–15 mg of elemental iron daily. A normal individual absorbs 5–10% of this iron, or about 0.5–1 mg daily. Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary. Iron absorption increases in response to low iron stores or increased iron requirements. Total iron absorption increases to 1–2 mg/d in menstruating women and may be as high as 3–4 mg/d in pregnant women.


Pharmacology_Katzung

Pharmacology_Katzung. Iron is available in a wide variety of foods but is especially abundant in meat. The iron in meat protein can be efficiently absorbed, because heme iron in meat hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (Figure 33–1). Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption. Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferrireductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells. Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active transport of ferrous iron by the divalent metal transporter DMT1, and absorption of iron complexed with heme (Figure 33–1). Together with iron split


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 33–1 Iron distribution in normal adults.1 1Values are based on data from various sources and assume that normal men weigh 80 kg and have a hemoglobin level of 16 g/dL and that normal women weigh 55 kg and have a hemoglobin level of 14 g/dL. Adapted, with permission, from Kushner JP: Hypochromic anemias. In: Wyngaarden JB, Smith LH (editors). Cecil Textbook of Medicine, 18th ed. Saunders, 1988. Copyright Elsevier. from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known as ferroportin and oxidized to ferric iron (Fe3+) by the ferroxidase hephaestin. The liver-derived hepcidin inhibits intestinal cell iron release by binding to ferroportin and triggering its internalization and destruction. Excess iron is stored in intestinal epithelial cells as ferritin, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin.


Pharmacology_Katzung

Pharmacology_Katzung. B. Transport Iron is transported in the plasma bound to transferrin, a β-globulin that can bind two molecules of ferric iron (Figure 33–1). The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism. Transferrin receptors—integral membrane glycoproteins present in large numbers on proliferating erythroid cells—bind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis. In endosomes, the ferric iron is released, reduced to ferrous iron, and transported by DMT1 into the cytoplasm, where it is funneled into hemoglobin synthesis or stored as ferritin. The transferrintransferrin receptor complex is recycled to the cell membrane, where the transferrin dissociates and returns to the plasma. This process provides an efficient mechanism for supplying the iron required by developing red blood cells.


Pharmacology_Katzung

Pharmacology_Katzung. Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells and a reduction in hepatic hepcidin release. Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin. C. Storage In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells (Figure 33–1). The mobilization of iron from macrophages and hepatocytes is primarily controlled by hepcidin regulation of ferroportin activity. Low hepcidin concentrations result in iron release from these storage sites; high hepcidin concentrations inhibit iron release. Ferritin is detectable in serum. Since the ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues, the serum ferritin level can be used to estimate total body iron stores. D. Elimination


Pharmacology_Katzung

Pharmacology_Katzung. D. Elimination There is no mechanism for excretion of iron. Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat. These losses account for no more than 1 mg of iron per day. Because the body’s ability to excrete iron is so limited, regulation of iron balance must be achieved by changing intestinal absorption and storage of iron in response to the body’s needs. As noted below, impaired regulation of iron absorption leads to serious pathology. A. Indications for the Use of Iron


Pharmacology_Katzung

Pharmacology_Katzung. A. Indications for the Use of Iron The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia. This manifests as a hypochromic, microcytic anemia in which the erythrocyte mean cell volume (MCV) and the mean cell hemoglobin concentration are low (Table 33–2). Iron deficiency is commonly seen in populations with increased iron requirements. These include infants, especially premature infants; children during rapid growth periods; pregnant and lactating women; and patients with chronic kidney disease who lose erythrocytes at a relatively high rate during hemodialysis and also form them at a high rate as a result of treatment with the erythrocyte growth factor erythropoietin (see below). Inadequate iron absorption also can cause iron deficiency. This is seen after gastrectomy and in patients with severe small bowel disease that results in generalized malabsorption. TABLE 33–2 Distinguishing features of the nutritional anemias.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 33–2 Distinguishing features of the nutritional anemias. MCV, mean cell volume; MCHC, mean cell hemoglobin concentration; SI, serum iron; TIBC, transferrin iron-binding capacity. The most common cause of iron deficiency in adults is blood loss. Menstruating women lose about 30 mg of iron with each menstrual period; women with heavy menstrual bleeding may lose much more. Thus, many premenopausal women have low iron stores or even iron deficiency. In men and postmenopausal women, the most common site of blood loss is the gastrointestinal tract. Patients with unexplained iron deficiency anemia should be evaluated for occult gastrointestinal bleeding. B. Treatment


Pharmacology_Katzung

Pharmacology_Katzung. B. Treatment Iron deficiency anemia is treated with oral or parenteral iron preparations. Oral iron corrects the anemia just as rapidly and completely as parenteral iron in most cases if iron absorption from the gastrointestinal tract is normal. An exception is the high requirement for iron of patients with advanced chronic kidney disease who are undergoing hemodialysis and treatment with erythropoietin; for these patients, parenteral iron administration is preferred. 1. Oral iron therapy—A wide variety of oral iron preparations is available. Because ferrous iron is most efficiently absorbed, ferrous salts should be used. Ferrous sulfate, ferrous gluconate, and ferrous fumarate are all effective and inexpensive and are recommended for the treatment of most patients.


Pharmacology_Katzung

Pharmacology_Katzung. Different iron salts provide different amounts of elemental iron, as shown in Table 33–3. In an iron-deficient individual, about 50–100 mg of iron can be incorporated into hemoglobin daily, and about 25% of oral iron given as ferrous salt can be absorbed. Therefore, 200–400 mg of elemental iron should be given daily to correct iron deficiency most rapidly. Patients unable to tolerate such large doses of iron can be given lower daily doses of iron, which results in slower but still complete correction of iron deficiency. Treatment with oral iron should be continued for 3–6 months after correction of the cause of the iron loss. This corrects the anemia and replenishes iron stores.


Pharmacology_Katzung

Pharmacology_Katzung. Common adverse effects of oral iron therapy include nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea. These effects are usually dose-related and often can be overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals. Some patients have less severe TABLE 33–3 Some commonly used oral iron preparations. gastrointestinal adverse effects with one iron salt than another and benefit from changing preparations. Patients taking oral iron develop black stools; this has no clinical significance in itself but may obscure the diagnosis of continued gastrointestinal blood loss.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Parenteral iron therapy—Parenteral therapy should be reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic anemia who cannot be maintained with oral iron alone. This includes patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin, various postgastrectomy conditions and previous small bowel resection, inflammatory bowel disease involving the proximal small bowel, and malabsorption syndromes.


Pharmacology_Katzung

Pharmacology_Katzung. The challenge with parenteral iron therapy is that parenteral administration of inorganic free ferric iron produces serious dose-dependent toxicity, which severely limits the dose that can be administered. However, when the ferric iron is formulated as a colloid containing particles with a core of iron oxyhydroxide surrounded by a core of carbohydrate, bioactive iron is released slowly from the stable colloid particles. In the United States, the three traditional forms of parenteral iron are iron dextran, sodium ferric gluconate complex, and iron sucrose. Two newer preparations are available (see below).


Pharmacology_Katzung

Pharmacology_Katzung. Iron dextran is a stable complex of ferric oxyhydroxide and dextran polymers containing 50 mg of elemental iron per milliliter of solution. It can be given by deep intramuscular injection or by intravenous infusion, although the intravenous route is used most commonly. Intravenous administration eliminates the local pain and tissue staining that often occur with the intramuscular route and allows delivery of the entire dose of iron necessary to correct the iron deficiency at one time. Adverse effects of intravenous iron dextran therapy include headache, light-headedness, fever, arthralgias, nausea and vomiting, back pain, flushing, urticaria, bronchospasm, and, rarely, anaphylaxis and death. Owing to the risk of a hypersensitivity reaction, a small test dose of iron dextran should always be given before full intramuscular or intravenous doses are given. Patients with a strong history of allergy and patients who have previously received parenteral iron dextran are more likely to have


Pharmacology_Katzung

Pharmacology_Katzung. be given before full intramuscular or intravenous doses are given. Patients with a strong history of allergy and patients who have previously received parenteral iron dextran are more likely to have hypersensitivity reactions after treatment with parenteral iron dextran. The iron dextran formulations used clinically are distinguishable as high-molecular-weight and low-molecular-weight forms. In the United States, the INFeD preparation is a low-molecular-weight form while Dexferrum is a high-molecular-weight form. Clinical data—primarily from observational studies—indicate that the risk of anaphylaxis is largely associated with high-molecular-weight formulations.


Pharmacology_Katzung

Pharmacology_Katzung. Sodium ferric gluconate complex and iron-sucrose complex are alternative parenteral iron preparations. Ferric carboxymaltose is a colloidal iron preparation embedded within a carbohydrate polymer. Ferumoxytol is a superparamagnetic iron oxide nanoparticle coated with carbohydrate. The carbohydrate shell is removed in the reticuloendothelial system, allowing the iron to be stored as ferritin, or released to transferrin. Ferumoxytol may interfere with magnetic resonance imaging (MRI) studies. Thus if imaging is needed, MRI should be performed prior to ferumoxytol therapy or alternative imaging modality used if needed soon after dosing. The U.S. Food and Drug Administration (FDA) has issued a black box warning about risk of potentially fatal allergic reactions associated with the use of ferumoxytol.


Pharmacology_Katzung

Pharmacology_Katzung. For patients treated chronically with parenteral iron, it is important to monitor iron storage levels to avoid the serious toxicity associated with iron overload. Unlike oral iron therapy, which is subject to the regulatory mechanism provided by the intestinal uptake system, parenteral administration—which bypasses this regulatory system—can deliver more iron than can be safely stored. Iron stores can be estimated on the basis of serum concentrations of ferritin and the transferrin saturation, which is the ratio of the total serum iron concentration to the total iron-binding capacity (TIBC). A. Acute Iron Toxicity


Pharmacology_Katzung

Pharmacology_Katzung. Acute iron toxicity is seen almost exclusively in young children who accidentally ingest iron tablets. As few as 10 tablets of any of the commonly available oral iron preparations can be lethal in young children. Adult patients taking oral iron preparations should be instructed to store tablets in child-proof containers out of the reach of children. Children who are poisoned with oral iron experience necrotizing gastroenteritis with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea. Subsequently, improvement is often noted, but this may be followed by severe metabolic acidosis, coma, and death. Urgent treatment is necessary. Whole bowel irrigation (see Chapter 58) should be performed to flush out unabsorbed pills. Deferoxamine, a potent iron-chelating compound, can be given intravenously to bind iron that has already been absorbed and to promote its excretion in urine and feces. Activated charcoal, a highly effective adsorbent for most toxins, does


Pharmacology_Katzung

Pharmacology_Katzung. can be given intravenously to bind iron that has already been absorbed and to promote its excretion in urine and feces. Activated charcoal, a highly effective adsorbent for most toxins, does not bind iron and thus is ineffective. Appropriate supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided.


Pharmacology_Katzung

Pharmacology_Katzung. B. Chronic Iron Toxicity Chronic iron toxicity (iron overload), also known as hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas, and other organs. It can lead to organ failure and death. It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, individuals with β-thalassemia).


Pharmacology_Katzung

Pharmacology_Katzung. Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy. One unit of blood can be removed every week or so until all of the excess iron is removed. Iron chelation therapy using parenteral deferoxamine or the oral iron chelators deferasirox or deferiprone (see Chapter 57) is less efficient as well as more complicated, expensive, and hazardous, but it may be the only option for iron overload that cannot be managed by phlebotomy, as is the case for many individuals with inherited and acquired causes of refractory anemia such as thalassemia major, sickle cell anemia, aplastic anemia, etc. Deferiprone rarely has been associated with agranulocytosis; thus weekly monitoring of the CBC is required for patients treated with this drug.


Pharmacology_Katzung

Pharmacology_Katzung. Vitamin B12 (cobalamin) serves as a cofactor for several essential biochemical reactions in humans. Deficiency of vitamin B12 leads to megaloblastic anemia (Table 33–2), gastrointestinal symptoms, and neurologic abnormalities. Although deficiency of vitamin B12 due to an inadequate supply in the diet is unusual, deficiency of B12 in adults—especially older adults—due to inadequate absorption of dietary vitamin B12 is a relatively common and easily treated disorder.


Pharmacology_Katzung

Pharmacology_Katzung. Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide. Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the active forms. The ultimate source of vitamin B12 is from microbial synthesis; the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin B12 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12.


Pharmacology_Katzung

Pharmacology_Katzung. The average American diet contains 5–30 mcg of vitamin B12 daily, 1–5 mcg of which is usually absorbed. The vitamin is avidly stored, primarily in the liver, with an average adult having a total vitamin B12 storage pool of 3000–5000 mcg. Only trace amounts of vitamin B12 are normally lost in urine and stool. Because the normal daily requirements of vitamin B12 are only about 2 mcg, it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption were stopped. Vitamin B12 is absorbed after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin B12 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor–vitamin B12 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin B12 deficiency in humans most often results from