Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea, and confusion. It is often necessary to lower the daily dose of levodopa by about 30% in the first 48 hours to avoid or reverse such complications. Other adverse effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine. Tolcapone may cause an increase in liver enzyme levels and has been associated rarely with death from acute hepatic failure; accordingly, it should not be used in patients with abnormal liver function test results. Its use in the USA requires signed patient consent (as provided in the product labeling) plus monitoring of liver function tests every 2–4 weeks during the first 6 months and periodically but less frequently thereafter. The medication should be withdrawn and not reintroduced if hepatic damage becomes evident. No such toxicity has been reported with entacapone.


Pharmacology_Katzung

Pharmacology_Katzung. The commercial preparation named Stalevo consists of a combination of levodopa with both carbidopa and entacapone. It is available in three strengths: Stalevo 50 (50 mg levodopa plus 12.5 mg carbidopa and 200 mg entacapone), Stalevo 100 (100 mg, 25 mg, and 200 mg, respectively), and Stalevo 150 (150 mg, 37.5 mg, and 200 mg, respectively). Use of this preparation simplifies the drug regimen and requires the consumption of fewer tablets than otherwise. Stalevo is priced at or below the price of its individual components. The combination agent may provide greater symptomatic benefit than carbidopa-levodopa alone. However, despite the convenience of a single combination preparation, use of Stalevo rather than carbidopa-levodopa has been associated with earlier occurrence and increased frequency of dyskinesia. An investigation as to whether the use of Stalevo is associated with an increased risk for cardiovascular events (myocardial infarction, stroke, cardiovascular death) is ongoing.


Pharmacology_Katzung

Pharmacology_Katzung. Subcutaneous injection of apomorphine hydrochloride (Apokyn), a potent nonergoline dopamine agonist that interacts with post-synaptic D2 receptors in the caudate nucleus and putamen, is effective for the temporary relief (“rescue”) of off-periods of akinesia in patients on optimized dopaminergic therapy. It is rapidly taken up in the blood and then the brain, leading to clinical benefit that begins within about 10 minutes of injection and persists for up to 2 hours. The optimal dose is identified by administering increasing test doses until adequate benefit is achieved or a maximum of 0.6 mL (6 mg) is reached, with the supine and standing blood pressures monitored before injection and then every 20 minutes for an hour after it. Most patients require a dose of 0.3–0.6 mL (3–6 mg), and this should be given usually no more than about three times daily, but occasionally up to five times daily.


Pharmacology_Katzung

Pharmacology_Katzung. Nausea is often troublesome, especially at the initiation of apomorphine treatment; accordingly, pretreatment with the anti-emetic trimethobenzamide (300 mg three times daily) for 3 days is recommended before apomorphine is introduced and is then continued for at least 1 month, if not indefinitely. Other adverse effects include dyskinesias, drowsiness, insomnia, chest pain, sweating, hypotension, syncope, constipation, diarrhea, mental or behavioral disturbances, panniculitis, and bruising at the injection site. Apomorphine should be prescribed only by physicians familiar with its potential complications and interactions. It should not be used in patients taking serotonin 5-HT3 antagonists because severe hypotension may result.


Pharmacology_Katzung

Pharmacology_Katzung. Amantadine, an antiviral agent, was by chance found to have relatively weak antiparkinsonism properties. Its mode of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. It has been reported to antagonize the effects of adenosine at adenosine A2A receptors, which may inhibit D2 receptor function. Release of catecholamines from peripheral stores has also been documented. Amantadine is an antagonist of the NMDA-type glutamate receptor, suggesting an antidyskinetic effect. Peak plasma concentrations of amantadine are reached 1–4 hours after an oral dose. The plasma half-life is between 2 and 4 hours, with most of the drug being excreted unchanged in the urine.


Pharmacology_Katzung

Pharmacology_Katzung. Peak plasma concentrations of amantadine are reached 1–4 hours after an oral dose. The plasma half-life is between 2 and 4 hours, with most of the drug being excreted unchanged in the urine. Amantadine is less efficacious than levodopa, and its benefits may be short-lived, often disappearing after only a few weeks of treatment. Nevertheless, during that time it may favorably influence the bradykinesia, rigidity, and tremor of parkinsonism. The standard dosage is 100 mg orally two or three times daily. Amantadine may also help in reducing iatrogenic dyskinesias in patients with advanced disease. Amantadine has a number of undesirable central nervous system effects, all of which can be reversed by stopping the drug. These include restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, and confusion. Overdosage may produce an acute toxic psychosis. With doses several times higher than recommended, convulsions have occurred.


Pharmacology_Katzung

Pharmacology_Katzung. Livedo reticularis sometimes occurs in patients taking amantadine and usually clears within 1 month after the drug is withdrawn. Other dermatologic reactions have also been described. Peripheral edema, another well-recognized complication, is not accompanied by signs of cardiac, hepatic, or renal disease and responds to diuretics. Other adverse reactions to amantadine include headache, heart failure, postural hypotension, urinary retention, and gastrointestinal disturbances (eg, anorexia, nausea, constipation, and dry mouth). Amantadine should be used with caution in patients with a history of seizures or heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. Amantadine should be used with caution in patients with a history of seizures or heart failure. A number of centrally acting antimuscarinic preparations are available that differ in their potency and in their efficacy in different patients. Some of these drugs were discussed in Chapter 8. These agents may improve the tremor and rigidity of parkinsonism but have little effect on bradykinesia. They are more effective than placebo. Some of the more commonly used drugs are listed in Table 28–1. Treatment is started with a low dose of one of the drugs in this category, the dosage gradually being increased until benefit occurs or until adverse effects limit further increments. If patients do not respond to one drug, a trial with another member of the drug class is warranted and may be successful.


Pharmacology_Katzung

Pharmacology_Katzung. Antimuscarinic drugs have a number of undesirable central nervous system and peripheral effects (see Chapter 8) and are poorly tolerated by the elderly or cognitively impaired. Dyskinesias occur in rare cases. Acute suppurative parotitis sometimes occurs as a complication of dryness of the mouth. TABLE 28–1 Some drugs with antimuscarinic properties used in parkinsonism. If medication is to be withdrawn, this should be accomplished gradually rather than abruptly to prevent acute exacerbation of parkinsonism. For contraindications to the use of antimuscarinic drugs, see Chapter 8. Ablative surgical procedures for parkinsonism have generally been replaced by functional, reversible lesions induced by high-frequency deep brain stimulation, which has a lower morbidity.


Pharmacology_Katzung

Pharmacology_Katzung. Ablative surgical procedures for parkinsonism have generally been replaced by functional, reversible lesions induced by high-frequency deep brain stimulation, which has a lower morbidity. Stimulation of the subthalamic nucleus or globus pallidus by an implanted electrode and stimulator has yielded good results for the management of the clinical fluctuations or the dyskinesias occurring in moderate parkinsonism. The anatomic substrate for such therapy is indicated in Figure 28–1. Such procedures are contraindicated in patients with secondary or atypical parkinsonism, dementia, or failure to respond to dopaminergic medication. The level of antiparkinsonian medication can often be reduced in patients undergoing deep brain stimulation, and this may help to ameliorate dose-related adverse effects of medication.


Pharmacology_Katzung

Pharmacology_Katzung. In a controlled trial of the transplantation of dopaminergic tissue (fetal substantia nigra tissue), symptomatic benefit occurred in younger (less than 60 years old) but not older parkinsonian patients. In another trial, benefits were inconsequential. Furthermore, uncontrollable dyskinesias occurred in some patients in both studies, perhaps from a relative excess of dopamine from continued fiber outgrowth from the transplant. Additional basic studies are required before further trials of cellular therapies— in particular, stem cell therapies—are undertaken, and such approaches therefore remain investigational.


Pharmacology_Katzung

Pharmacology_Katzung. Among the compounds that have been investigated as potential neuroprotective agents to slow disease progression are antioxidants, antiapoptotic agents, glutamate antagonists, intraparenchymally administered glial-derived neurotrophic factor, and anti-inflammatory drugs. None of these agents has been shown to be effective in this context, however, and their use for therapeutic purposes is not indicated at this time. Coenzyme Q10, creatine, pramipexole, and pioglitazone have not been found to be effective despite early hopes to the contrary. The possibility that rasagiline has a protective effect was discussed earlier. Active and passive immunization against α-synuclein is being explored.


Pharmacology_Katzung

Pharmacology_Katzung. Several phase 1 (safety) or phase 2 trials of gene therapy for Parkinson’s disease have been completed in the USA. All trials involved infusion into the striatum of adeno-associated virus type 2 as the vector for the gene. The genes were for glutamic acid decarboxylase (GAD, to facilitate synthesis of GABA, an inhibitory neurotransmitter), infused into the subthalamic nucleus to cause inhibition; for aromatic acid decarboxylase (AADC), infused into the putamen to increase metabolism of levodopa to dopamine; and for neurturin (a growth factor that may enhance the survival of dopaminergic neurons), infused into the putamen. All agents were deemed safe, and the data suggested efficacy. A phase 2 study of the GAD gene has been completed and the results are encouraging, but one for neurturin infused into the substantia nigra as well as the putamen was disappointing. A phase 2 trial of AADC is planned. The results of a European study involving bilateral intrastriatal delivery of ProSavin, a


Pharmacology_Katzung

Pharmacology_Katzung. into the substantia nigra as well as the putamen was disappointing. A phase 2 trial of AADC is planned. The results of a European study involving bilateral intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy with three genes (decarboxylase, tyrosine hydroxylase and GTP-cyclohydrolase 1) aimed at restoring local and continuous dopamine production in patients with advanced Parkinson’s disease, have also been encouraging.


Pharmacology_Katzung

Pharmacology_Katzung. Persons with cognitive decline may respond to rivastigmine (1.5–6 mg twice daily), memantine (5–10 mg daily), or donepezil (5–10 mg daily) (see Chapter 60); with affective disorders to antidepressants or anxiolytic agents (see Chapter 30); with psychosis to atypical antipsychotic agents or pimavanserin; with excessive daytime sleepiness to modafinil (100–400 mg in the morning) (see Chapter 9); and with bladder and bowel disorders to appropriate symptomatic therapy (see Chapter 8).


Pharmacology_Katzung

Pharmacology_Katzung. Parkinson’s disease generally follows a progressive course. Moreover, the benefits of levodopa therapy often diminish as the disease advances, and serious adverse effects may complicate longterm levodopa treatment. Nevertheless, dopaminergic therapy at a relatively early stage may be most effective in alleviating motor symptoms of parkinsonism and may also favorably affect the mortality rate due to the disease. Therefore, several strategies have evolved for optimizing dopaminergic therapy, as summarized in Figure 28–5. Symptomatic treatment of mild parkinsonism is probably best avoided until there is some degree of disability or functional limitation or until symptoms begin to impact the patient’s lifestyle or cause significant social impairment.


Pharmacology_Katzung

Pharmacology_Katzung. When symptomatic treatment becomes necessary, a trial of rasagiline, selegiline, amantadine, or an antimuscarinic drug (in young patients) may be worthwhile. With disease progression, dopaminergic therapy becomes necessary. This can conveniently be initiated with a dopamine agonist, either alone or in combination with low-dose carbidopa-levodopa therapy, unless risk factors for impulse control disorders are present. Alternatively, especially in older patients, a dopamine agonist can be omitted and the patient started immediately on carbidopa-levodopa, which is the most effective symptomatic treatment of the motor disturbances of parkinsonism. Physical therapy is helpful in improving mobility. In patients with severe parkinsonism and long-term complications of levodopa therapy such as the on-off phenomenon, a trial of treatment with the newer extended-release formulation of carbidopa-levodopa (Rytary), a COMT inhibitor, or rasagiline may be helpful. Regulation of dietary protein intake


Pharmacology_Katzung

Pharmacology_Katzung. phenomenon, a trial of treatment with the newer extended-release formulation of carbidopa-levodopa (Rytary), a COMT inhibitor, or rasagiline may be helpful. Regulation of dietary protein intake may also improve response fluctuations. Deep brain stimulation is often helpful in patients with response fluctuations or dyskinesias who fail to respond adequately to these measures. Treating patients who are young or have mild parkinsonism with rasagiline may delay disease progression and merits consideration, although evidence of benefit is incomplete.


Pharmacology_Katzung

Pharmacology_Katzung. Reserpine and the related drug tetrabenazine deplete biogenic monoamines from their storage sites, whereas haloperidol, metoclopramide, and the phenothiazines block dopamine receptors. These drugs may therefore produce a parkinsonian syndrome, usually within 3 months after introduction. The disorder tends to be symmetric, with inconspicuous tremor, but this is not always the case. The syndrome is related to high dosage and clears over several weeks or months after withdrawal. If treatment is necessary, antimuscarinic agents are preferred. Levodopa is of no help if neuroleptic drugs are continued and may in fact aggravate the mental disorder for which antipsychotic drugs were prescribed originally. In 1983, a drug-induced form of parkinsonism was discovered in individuals who attempted to synthesize and use a narcotic drug related to meperidine but actually synthesized and self-administered MPTP, as discussed in the Box: MPTP & Parkinsonism.


Pharmacology_Katzung

Pharmacology_Katzung. Several disorders characterized by parkinsonism differ from classic Parkinson’s disease because of inconspicuous tremor, symmetry of the neurologic findings, and the presence of additional findings (eg, dysautonomia, cerebellar deficits, eye movement abnormalities, or early cognitive and behavioral changes). These disorders include multisystem atrophy, progressive supranuclear palsy, corticobasal degeneration, and diffuse Lewy body disease. The prognosis is worse than for Parkinson’s disease, and the response to antiparkinsonian treatment may be limited. Treatment is symptomatic.


Pharmacology_Katzung

Pharmacology_Katzung. Tremor consists of rhythmic oscillatory movements. Physiologic postural tremor, which is a normal phenomenon, is enhanced in amplitude by anxiety, fatigue, thyrotoxicosis, and intravenous epinephrine or isoproterenol. Propranolol reduces its amplitude and, if administered intra-arterially, prevents the response to isoproterenol in the perfused limb, presumably through some peripheral action. Certain drugs—especially the bronchodilators, valproate, tricyclic antidepressants, and lithium—may produce a dose-dependent exaggeration of the normal physiologic tremor that is reversed by discontinuing the drug. Although the tremor produced by sympathomimetics such as terbutaline (a bronchodilator) is blocked by propranolol, which antagonizes both β1 and β2 receptors, it is not blocked by metoprolol, a β1-selective antagonist; this suggests that such tremor is mediated mainly by the β2 receptors.


Pharmacology_Katzung

Pharmacology_Katzung. Essential tremor is a postural tremor, sometimes familial with autosomal dominant inheritance, which is clinically similar to physiologic tremor. At least three gene loci (ETM1 on 3q13, ETM2 on 2p24.1, and a locus on 6p23) have been described, as having associations with various other mapped loci. Dysfunction of β1 receptors has been implicated in some instances, since the tremor may respond dramatically to standard doses of metoprolol as well as to propranolol. The tremor may involve the hands, head, voice, and—much less commonly—the legs. Patients may become functionally limited or socially withdrawn, quality of life is affected, and some patients report being seriously disabled by the tremor.


Pharmacology_Katzung

Pharmacology_Katzung. The most useful therapeutic approach is with propranolol, but whether the response depends on a central or peripheral action is unclear. The pharmacokinetics, pharmacologic effects, and adverse reactions of propranolol are discussed in Chapter 10. Total daily doses of propranolol on the order of 120 mg or more (range, 60–320 mg) are usually required, divided into two doses; reported adverse effects have been few. Propranolol should be used with caution in patients with heart failure, heart block, asthma, depression, or hypoglycemia. Other adverse effects include fatigue, malaise, lightheadedness, and impotence. Patients can be instructed to take their own pulse and call the physician if significant bradycardia develops. Long-acting propranolol is also effective and is preferred by many patients because of its convenience. Some patients prefer to take a single dose of propranolol when they anticipate their tremor is likely to be exacerbated, for example, by social situations.


Pharmacology_Katzung

Pharmacology_Katzung. many patients because of its convenience. Some patients prefer to take a single dose of propranolol when they anticipate their tremor is likely to be exacerbated, for example, by social situations. Metoprolol is sometimes useful in treating tremor when patients have concomitant pulmonary disease that contraindicates use of propranolol.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs potentiating GABAA receptors in the central nervous system (such as phenobarbital, primidone, topiramate, and benzodiazepines) also improve tremor, but phenobarbital is not used clinically because of its sedating effect. Primidone (an antiepileptic drug; see Chapter 24), in gradually increasing doses up to 250 mg three times daily, is also effective in providing symptomatic control in some cases. Patients with tremor are very sensitive to primidone and often cannot tolerate the doses used to treat seizures; they should be started on 50 mg once daily and the daily dose increased by 50 mg every 2 weeks depending on response. In many instances a dose of 125 mg two or three times daily is sufficient.


Pharmacology_Katzung

Pharmacology_Katzung. Topiramate, another antiepileptic drug, may also be helpful in a dose of 400 mg daily, built up gradually. Alprazolam (in doses up to 3 mg daily) or gabapentin (100–2400 mg/d; typically 1200 mg/d) is helpful in some patients. Gabapentin binds to the α2δ subunit of calcium channels. It produces less consistent relief of tremor but is associated with fewer side effects than primidone. Other patients are helped by intramuscular injections of botulinum toxin, but dose-dependent weakness may complicate symptomatic benefit. Thalamic stimulation by an implanted electrode and stimulator is often worthwhile in advanced cases refractory to pharmacotherapy. Magnetic resonance imaging-guided focused ultrasound thalamotomy shows promise. Diazepam, chlordiazepoxide, mephenesin, and antiparkinsonism agents have been advocated in the past but are generally of little benefit. Small quantities of alcohol may suppress essential tremor for a short time but should not be recommended as a treatment


Pharmacology_Katzung

Pharmacology_Katzung. agents have been advocated in the past but are generally of little benefit. Small quantities of alcohol may suppress essential tremor for a short time but should not be recommended as a treatment strategy because of possible behavioral and other complications of alcohol.


Pharmacology_Katzung

Pharmacology_Katzung. Reports in the early 1980s of a rapidly progressive form of par-kinsonism in young persons opened a new area of research in the etiology and treatment of parkinsonism. The initial report described apparently healthy young people who attempted to support their opioid habit with a meperidine analog synthesized by an amateur chemist. They unwittingly self-administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and subsequently developed a very severe form of parkinsonism. MPTP is a protoxin that is converted by monoamine oxi-dase B to N-methyl-4-phenylpyridinium (MPP+). MPP+ is selec-tively taken up by cells in the substantia nigra through an active mechanism normally responsible for dopamine reuptake. MPP+ inhibits mitochondrial complex I, thereby inhibiting oxida-tive phosphorylation. The interaction of MPP+ with complex I probably leads to cell death and thus to striatal dopamine deple-tion and parkinsonism. Recognition of the effects of MPTP suggested that spontane-ously


Pharmacology_Katzung

Pharmacology_Katzung. The interaction of MPP+ with complex I probably leads to cell death and thus to striatal dopamine deple-tion and parkinsonism. Recognition of the effects of MPTP suggested that spontane-ously occurring Parkinson’s disease may result from exposure to an environmental toxin that is similarly selective in its target. However, no such toxin has yet been identified. It also suggested a successful means of producing an experimental model of Parkinson’s disease in animals, especially nonhuman primates. This model is useful in the development of new antiparkinson-ism drugs. Pretreatment of exposed animals with a monoamine oxidase B inhibitor such as selegiline prevents the conversion of MPTP to MPP+ and thus protects against the occurrence of par-kinsonism. This observation has provided one reason to believe that selegiline or rasagiline may retard the progression of Parkin-son’s disease in humans.


Pharmacology_Katzung

Pharmacology_Katzung. Intention tremor is present during movement but not at rest; sometimes it occurs as a toxic manifestation of alcohol or drugs such as phenytoin. Withdrawal or reduction in dosage provides dramatic relief. There is no satisfactory pharmacologic treatment for intention tremor due to other neurologic disorders. Rest tremor is usually due to parkinsonism. Huntington’s disease is an autosomal dominant inherited disorder caused by an abnormality (expansion of a CAG trinucleotide repeat that codes for a polyglutamine tract) of the huntingtin gene on chromosome 4. An autosomal recessive form may also occur. Huntington disease-like (HDL) disorders are not associated with an abnormal CAG trinucleotide repeat number of the huntingtin gene. Autosomal dominant (HDL1, 20pter-p12; HDL2, 16q24.3) and recessive forms (HDL3, 4p15.3) occur.


Pharmacology_Katzung

Pharmacology_Katzung. Huntington’s disease is characterized by progressive chorea and dementia that usually begin in adulthood. The development of chorea seems to be related to an imbalance of dopamine, acetylcholine, GABA, and perhaps other neurotransmitters in the basal ganglia (Figure 28–6). Pharmacologic studies indicate that chorea results from functional overactivity in dopaminergic nigrostriatal pathways, perhaps because of increased responsiveness of postsynaptic dopamine receptors or deficiency of a neurotransmitter that normally antagonizes dopamine. Drugs that impair dopaminergic neurotransmission, either by depleting central monoamines (eg, reserpine, tetrabenazine) or by blocking dopamine receptors (eg, phenothiazines, butyrophenones), often alleviate chorea, whereas dopamine-like drugs such as levodopa tend to exacerbate it.


Pharmacology_Katzung

Pharmacology_Katzung. Both GABA and the enzyme (glutamic acid decarboxylase) concerned with its synthesis are markedly reduced in the basal ganglia of patients with Huntington’s disease, and GABA receptors are usually implicated in inhibitory pathways. There is also a FIGURE 28–6 Schematic representation of the sequence of neurons involved in Huntington’s chorea. Top: Dopaminergic neurons (red) originating in the substantia nigra normally inhibit the output of the spiny GABAergic neurons from the striatum, whereas cholinergic neurons (green) exert an excitatory effect. Bottom: In Huntington’s chorea, some cholinergic neurons may be lost, but even more GABAergic neurons (black) degenerate.


Pharmacology_Katzung

Pharmacology_Katzung. significant decline in concentration of choline acetyltransferase, the enzyme responsible for synthesizing acetylcholine, in the basal ganglia of these patients. These findings may be of pathophysiologic significance and have led to attempts to alleviate chorea by enhancing central GABA or acetylcholine activity, but with disappointing results. As a consequence, the most commonly used drugs for controlling dyskinesia in patients with Huntington’s disease are still those that interfere with dopamine activity. With all the latter drugs, however, reduction of abnormal movements may be associated with iatrogenic parkinsonism.


Pharmacology_Katzung

Pharmacology_Katzung. Tetrabenazine (12.5–50 mg orally three times daily) depletes cerebral dopamine and reduces the severity of chorea. It has less troublesome adverse effects than reserpine, which has also been used for this purpose. Tetrabenazine is metabolized by cytochrome P450 (CYP2D6), and genotyping has therefore been recommended to determine metabolizer status (CYP2D6 expression) in patients needing doses exceeding 50 mg/d. For poor metabolizers, the maximum recommended dose is 50 mg daily (25 mg/dose); otherwise, a maximum dose of 100 mg daily can be used. Treatment with postsynaptic dopamine receptor blockers such as phenothiazines and butyrophenones may also be helpful. Haloperidol is started in a small dose, eg, 1 mg twice daily, and increased every 4 days depending on the response. If haloperidol is not helpful, treatment with increasing doses of fluphenazine in a similar dose, eg, 1 mg twice daily, sometimes helps. Several recent reports suggest that olanzapine may also be useful; the dose


Pharmacology_Katzung

Pharmacology_Katzung. is not helpful, treatment with increasing doses of fluphenazine in a similar dose, eg, 1 mg twice daily, sometimes helps. Several recent reports suggest that olanzapine may also be useful; the dose varies with the patient, but 10 mg daily is often sufficient, although doses as high as 30 mg daily are sometimes required. The pharmacokinetics and clinical properties of these drugs are considered in greater detail elsewhere in this book. Selective serotonin reuptake inhibitors may reduce depression, aggression, and agitation. However, strong CYP2D6 inhibitors should be used with caution, as it may be necessary to decrease the dose of tetrabenazine taken concurrently.


Pharmacology_Katzung

Pharmacology_Katzung. A novel agent, deutetrabenazine, which is a selective inhibitor of the vesicular monoamine 2 transporter (VMAT2) that modulates dopamine stores was approved by the FDA for the chorea of Huntington’s disease while this book was in press. The dose is built up weekly from 6 mg daily to a maximum of 24 mg twice daily with food (18 mg twice daily in poor CYP2DG metabolizers). Deutetrabenazine is contraindicated in patients on monoamine oxidase inhibitors, reserpine, or tetrabenazine, and in those who are severely depressed or suicidal. Other important aspects of management include genetic counseling, speech therapy, physical and occupational therapy, dysphagia precautions, and provision of social services. Other Forms of Chorea


Pharmacology_Katzung

Pharmacology_Katzung. Other Forms of Chorea Benign hereditary chorea is inherited (usually autosomal dominant; possibly also autosomal recessive) or arises spontaneously. Chorea develops in early childhood and does not progress during adult life; dementia does not occur. In patients with TITF-1 gene mutations, thyroid and pulmonary abnormalities may also be present (brain-thyroid-lung syndrome). Familial chorea may also occur as part of the chorea-acanthocytosis syndrome, together with orolingual tics, vocalizations, cognitive changes, seizures, peripheral neuropathy, and muscle atrophy; serum β-lipoproteins are normal. Mutations of the gene encoding chorein at 9q21 may be causal. Treatment of these hereditary disorders is symptomatic. Tetrabenazine (0.5 mg/kg/d for children and 37.5 mg/d for adults) may improve chorea in some instances.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment is directed at the underlying cause when chorea occurs as a complication of general medical disorders such as thyrotoxicosis, polycythemia vera rubra, systemic lupus erythematosus, hypocalcemia, and hepatic cirrhosis. Drug-induced chorea is managed by withdrawal of the offending substance, which may be levodopa, an antimuscarinic drug, amphetamine, lithium, phenytoin, or an oral contraceptive. Neuroleptic drugs may also produce an acute or tardive dyskinesia (discussed below). Sydenham’s chorea is temporary and usually so mild that pharmacologic management of the dyskinesia is unnecessary, but dopamine-blocking drugs are effective in suppressing it. The biochemical basis of ballismus is unknown, but the pharmacologic approach to management is the same as for chorea. Treatment with tetrabenazine, haloperidol, perphenazine, or other dopamine-blocking drugs may be helpful.


Pharmacology_Katzung

Pharmacology_Katzung. The physiologic basis of these disorders is unknown, and there is no satisfactory medical treatment for them. A subset of patients respond well to levodopa medication (dopa-responsive dystonia), which is therefore worthy of trial. Occasional patients with dystonia may respond to diazepam, amantadine, antimuscarinic drugs (in high dosage), carbamazepine, baclofen, haloperidol, or phenothiazines. A trial of these pharmacologic approaches is worthwhile, though often not successful. Patients with focal dystonias such as blepharospasm or torticollis often benefit from injection of botulinum toxin into the overactive muscles. Deep brain stimulation may be helpful in medically intractable cases. The role of repetitive transcranial magnetic stimulation and transcranial direct current stimulation to induce plastic changes in the brain is being explored.


Pharmacology_Katzung

Pharmacology_Katzung. The pathophysiologic basis of tics is unknown. Chronic multiple tics (Gilles de la Tourette syndrome) may require symptomatic treatment if the disorder is severe or is having a significant impact on the patient’s life. Education of patients, family, and teachers is important. Pharmacologic therapy may be necessary when tics interfere with social life or otherwise impair activities of daily living.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment is with drugs that block dopamine receptors or deplete dopamine stores, such as fluphenazine, pimozide, and tetrabenazine. These drugs reduce the frequency and intensity of tics by about 60%. Pimozide, a dopamine receptor antagonist, may be helpful in patients as a first-line treatment or in those who are either unresponsive to or intolerant of the other agents mentioned. Treatment is started at 1 mg/d, and the dosage is increased by 1 mg every 5 days; most patients require 7–16 mg/d. It has similar side effects to haloperidol but may cause irregularities of cardiac rhythm. Haloperidol has been used for many years to treat tic disorders. Patients are better able to tolerate this drug if treatment is started with a small dosage (eg, 0.25 or 0.5 mg daily) and then increased gradually (eg, by 0.25 mg every 4 or 5 days) over the following weeks depending on response and tolerance. Most patients ultimately require a total daily dose of 3–8 mg. Adverse effects include


Pharmacology_Katzung

Pharmacology_Katzung. gradually (eg, by 0.25 mg every 4 or 5 days) over the following weeks depending on response and tolerance. Most patients ultimately require a total daily dose of 3–8 mg. Adverse effects include extrapyramidal movement disorders, sedation, dryness of the mouth, blurred vision, and gastrointestinal disturbances. Aripiprazole (see Chapter 29) has also been found effective in treating tics.


Pharmacology_Katzung

Pharmacology_Katzung. Although not approved by the US Food and Drug Administration (FDA) for the treatment of tics or Tourette syndrome, certain α2-adrenergic agonists may be preferred as an initial treatment because they are less likely to cause extrapyramidal side effects than neuroleptic agents. Clonidine reduces motor or vocal tics in about 50% of children so treated. It may act by reducing activity in noradrenergic neurons in the locus coeruleus. It is introduced at a dose of 2–3 mcg/kg/d, increasing after 2 weeks to 4 mcg/ kg/d and then, if required, to 5 mcg/kg/d. It may cause an initial transient fall in blood pressure. The most common adverse effect is sedation; other adverse effects include reduced or excessive salivation and diarrhea. Guanfacine, another α2-adrenergic agonist, has also been used. Both of these drugs may be particularly helpful for behavioral symptoms, such as impulse control disorders.


Pharmacology_Katzung

Pharmacology_Katzung. Atypical antipsychotics, such as risperidone and aripiprazole, may be especially worthwhile in patients with significant behavioral problems. Clonazepam and carbamazepine have also been used. The pharmacologic properties of these drugs are discussed elsewhere in this book. Injection of botulinum toxin A at the site of problematic tics is sometimes helpful when these are focal simple tics. Treatment of any associated attention deficit disorder (eg, with clonidine patch, guanfacine, pemoline, methylphenidate, or dextroamphetamine) or obsessive-compulsive disorder (with selective serotonin reuptake inhibitors or clomipramine) may be required. Deep brain stimulation is sometimes worthwhile in otherwise intractable cases.


Pharmacology_Katzung

Pharmacology_Katzung. Deep brain stimulation is sometimes worthwhile in otherwise intractable cases. Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson’s disease; dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide; and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacologic basis of the acute dyskinesia or dystonia sometimes precipitated by the first few doses of a phenothiazine is not clear. In most instances, parenteral administration of an antimuscarinic drug such as benztropine (2 mg intravenously), diphenhydramine (50 mg intravenously), or biperiden (2–5 mg intravenously or intramuscularly) is helpful, whereas in other instances diazepam (10 mg intravenously) alleviates the abnormal movements.


Pharmacology_Katzung

Pharmacology_Katzung. Tardive dyskinesia, a disorder characterized by a variety of abnormal movements, is a common complication of long-term neuroleptic or metoclopramide drug treatment (see Chapter 29). Its precise pharmacologic basis is unclear. A reduction in dose of the offending medication, a dopamine receptor blocker, commonly worsens the dyskinesia, whereas an increase in dose may suppress it. The drugs most likely to provide immediate symptomatic benefit are those interfering with dopaminergic function, either by depletion (eg, reserpine, tetrabenazine) or receptor blockade (eg, phenothiazines, butyrophenones). Paradoxically, the receptor-blocking drugs are the ones that also cause the dyskinesia. Deutetrabenazine and valbenazine are selective inhibitors of VMAT2, which modulates dopamine release. They both show great promise for ameliorating tardive dyskinesia. Deutetrabenazine has been approved by the FDA for Huntington’s disease, and valbenazine for tardive dyskinesia.


Pharmacology_Katzung

Pharmacology_Katzung. Tardive dystonia is usually segmental or focal; generalized dystonia is less common and occurs in younger patients. Treatment is the same as for tardive dyskinesia, but anticholinergic drugs may also be helpful; focal dystonias may also respond to local injection of botulinum A toxin. Tardive akathisia is treated similarly to drug-induced parkinsonism. Rabbit syndrome, another neuroleptic-induced disorder, is manifested by rhythmic vertical movements about the mouth; it may respond to anticholinergic drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Because the tardive syndromes that develop in adults are often irreversible and have no satisfactory treatment, care must be taken to reduce the likelihood of their occurrence. Antipsychotic medication should be prescribed only when necessary and should be withheld periodically to assess the need for continued treatment and to unmask incipient dyskinesia. Thioridazine, a phenothiazine with a piperidine side chain, is an effective antipsychotic agent that seems less likely than most to cause extrapyramidal reactions, perhaps because it has little effect on dopamine receptors in the striatal system. Finally, antimuscarinic drugs should not be prescribed routinely in patients receiving neuroleptics, because the combination may increase the likelihood of dyskinesia.


Pharmacology_Katzung

Pharmacology_Katzung. Neuroleptic malignant syndrome, a rare complication of treatment with neuroleptics, is characterized by rigidity, fever, changes in mental status, and autonomic dysfunction (see Table 16–4). Symptoms typically develop over 1–3 days (rather than minutes to hours as in malignant hyperthermia) and may occur at any time during treatment. Treatment includes withdrawal of antipsychotic drugs, lithium, and anticholinergics; reduction of body temperature; and rehydration. Dantrolene, dopamine agonists, levodopa, or amantadine may be helpful, but there is a high mortality rate (up to 20%) with neuroleptic malignant syndrome.


Pharmacology_Katzung

Pharmacology_Katzung. Restless legs syndrome is characterized by an unpleasant creeping discomfort that seems to arise deep within the legs and occasionally the arms. Symptoms occur particularly when patients are relaxed, especially when they are lying down or sitting, and they lead to an urge to move about. Such symptoms may delay the onset of sleep. A sleep disorder associated with periodic movements during sleep may also occur. The cause is unknown, but the disorder is especially common among pregnant women and also among uremic or diabetic patients with neuropathy. In most patients, no obvious predisposing cause is found, but several genetic loci have been associated with it.


Pharmacology_Katzung

Pharmacology_Katzung. Symptoms may resolve with correction of coexisting iron-deficiency anemia and often respond to dopamine agonists, levodopa, diazepam, clonazepam, gabapentin, or opiates. Dopaminergic therapy is the preferred treatment for restless legs syndrome and should be initiated with long-acting dopamine agonists (eg, pramipexole 0.125–0.75 mg or ropinirole 0.25–4.0 mg once daily) or with the rotigotine skin patch to avoid the augmentation that may be associated especially with carbidopa-levodopa (25/100 or 50/200 taken about 1 hour before bedtime). Augmentation refers to the earlier onset or enhancement of symptoms; earlier onset of symptoms at rest; and a briefer response to medication. When augmentation occurs with levodopa, a dopamine agonist should be substituted. If it occurs in patients receiving an agonist, the daily dose should be divided, another agonist tried, or other medications substituted. Dopamine agonist therapy may be associated with development of impulse control disorders.


Pharmacology_Katzung

Pharmacology_Katzung. an agonist, the daily dose should be divided, another agonist tried, or other medications substituted. Dopamine agonist therapy may be associated with development of impulse control disorders. Gabapentin is effective in reducing the severity of restless legs syndrome and is taken once or twice daily (in the evening and before sleep). The starting dose is 300 mg daily, building up depending on response and tolerance (to approximately 1800 mg daily). Oral gabapentin enacarbil (600 or 1200 mg once daily) may also be helpful. A recent study suggests that pregabalin, a related drug, is also effective at a daily total dosage of 150–300 mg, taken in divided doses. Clonazepam, 1 mg daily, is also sometimes helpful, especially for those with intermittent symptoms. When opiates are required, those with long half-lives or low addictive potential should be used. Oxycodone is often effective; the dose is individualized.


Pharmacology_Katzung

Pharmacology_Katzung. A recessively inherited (13q14.3–q21.1) disorder of copper metabolism, Wilson’s disease is characterized biochemically by reduced serum copper and ceruloplasmin concentrations, pathologically by markedly increased concentration of copper in the brain and viscera, and clinically by signs of hepatic and neurologic dysfunction. Neurologic signs include tremor, choreiform movements, rigidity, hypokinesia, and dysarthria and dysphagia. Siblings of affected patients should be screened for asymptomatic Wilson’s disease.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment involves the removal of excess copper, followed by maintenance of copper balance. Dietary copper should also be kept below 2 mg daily. Penicillamine (dimethylcysteine) has been used for many years as the primary agent to remove copper. It is a chelating agent that forms a ring complex with copper (see Chapter 57). It is readily absorbed from the gastrointestinal tract and rapidly excreted in the urine. A common starting dose in adults is 500 mg three or four times daily. After remission occurs, it may be possible to lower the maintenance dose, generally to not less than 1 g daily, which must thereafter be continued indefinitely. Adverse effects include nausea and vomiting, nephrotic syndrome, a lupus-like syndrome, pemphigus, myasthenia, arthropathy, optic neuropathy, and various blood dyscrasias. In about 10% of instances, neurologic worsening occurs with penicillamine. Treatment should be monitored by frequent urinalysis and complete blood counts.


Pharmacology_Katzung

Pharmacology_Katzung. Trientine hydrochloride, another chelating agent, is preferred by many over penicillamine because of the lesser likelihood of drug reactions or neurologic worsening. It may be used in a daily dose of 1–1.5 g. Trientine appears to have few adverse effects other than mild anemia due to iron deficiency in a few patients. Tetrathiomolybdate may be better than trientine for preserving neurologic function in patients with neurologic involvement and is taken both with and between meals. It is not yet commercially available.


Pharmacology_Katzung

Pharmacology_Katzung. Zinc acetate administered orally increases the fecal excretion of copper and can be used in combination with these other agents. The dose is 50 mg three times a day. Zinc sulfate (200 mg/d orally) has also been used to decrease copper absorption. Zinc blocks copper absorption from the gastrointestinal tract by induction of intestinal cell metallothionein. Its main advantage is its low toxicity compared with that of other anticopper agents, although it may cause gastric irritation when introduced. Liver transplantation is sometimes necessary. The role of hepatocyte transplantation and gene therapy is currently under investigation.


Pharmacology_Katzung

Pharmacology_Katzung. Liver transplantation is sometimes necessary. The role of hepatocyte transplantation and gene therapy is currently under investigation. SUMMARY Drugs Used for Movement Disorders Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions • Levodopa Transported into the central nervous system (CNS) and converted to dopamine (which does not enter the CNS); also converted to dopamine in the periphery Ameliorates all motor symptoms of Parkinson’s disease and causes significant peripheral dopaminergic effects (see text) Parkinson’s disease: Most efficacious therapy but not always used as the first drug due to development of disabling response fluctuations over time Oral • ~6–8 h effect • Toxicity: Gastrointestinal upset, arrhythmias, dyskinesias, on-off and wearing-off phenomena, behavioral disturbances • Interactions: Use with carbidopa greatly diminishes required dosage and is now standard • use with


Pharmacology_Katzung

Pharmacology_Katzung. COMT or MAO-B inhibitors prolongs duration of effect + carbidopa (Sinemet, others): Carbidopa inhibits peripheral metabolism of levodopa to dopamine and reduces required dosage and toxicity; carbidopa does not enter CNS + carbidopa + entacapone (Stalevo): Entacapone is a catechol-O-methyltransferase (COMT) inhibitor (see below) • Ropinirole: Similar to pramipexole; nonergot; relatively pure D2 agonist • Bromocriptine: • Apomorphine: Nonergot; subcutaneous route useful for rescue treatment in levodopa-induced dyskinesia; high incidence of nausea and vomiting DOPAMINE AGONISTS • PramipexoleDirect agonist at D3 receptors, nonergot Reduces symptoms of parkinsonism•smoothsoutfluctuations in levodopa response Parkinson’s disease: Can be used as initial therapy•alsoeffectivein on-off phenomenon Oral•~8heffect•Toxicity: Nausea and vomiting, postural hypotension, dyskinesias, confusion, impulse control disorders, sleepiness • Selegiline:


Pharmacology_Katzung

Pharmacology_Katzung. Like rasagiline, adjunctive use with levodopa; may be less potent than rasagiline • Safinamide: Also used as adjunct to levodopa in patients with response fluctuations ANTIMUSCARINIC AGENTS • BenztropineAntagonist at M receptors in basal ganglia Reduces tremor and rigidity •littleeffectonbradykinesiaParkinson’s disease Oral•Toxicity: Typical antimuscarinic effects—sedation, mydriasis, urinary retention, constipation, confusion, dry mouth • Biperiden, orphenadrine, procyclidine, trihexyphenidyl: Similar antimuscarinic agents with CNS effects • Haloperidol, fluphenazine, other neuroleptics, olanzapine: Dopamine receptor blockers, sometimes helpful • Clonidine, guanfacine: Effective in ~50% of patients; see Chapter 11 for basic pharmacology • Phenothiazines, atypical antipsychotics, clonazepam, carbamazepine: Sometimes of value Amantadine Generic, Symmetrel Benztropine Generic, Cogentin Bromocriptine Generic, Parlodel Carbidopa/levodopa Generic, Sinemet, Parcopa, Rytary


Pharmacology_Katzung

Pharmacology_Katzung. Amantadine Generic, Symmetrel Benztropine Generic, Cogentin Bromocriptine Generic, Parlodel Carbidopa/levodopa Generic, Sinemet, Parcopa, Rytary Carbidopa/levodopa/entacapone Generic, Stalevo Entacapone Generic, Comtan Levodopa Dopar, others Orphenadrine Generic, various Penicillamine Cuprimine, Depen Pergolide * Permax, other Pramipexole Generic, Mirapex Ropinirole Generic, Requip, Requip XL Trihexyphenidyl Generic, Artane, others *Not available in the USA. Angot E et al: Are synucleinopathies prion-like disorders? Lancet Neurol 2010;9:1128. Antonini A et al: Role of pramipexole in the management of Parkinson’s disease. CNS Drugs 2010;24:829. Bestha DP et al: Management of tics and Tourette’s disorder: An update. Expert Opin Pharmacother 2010;11:1813. Brewer GJ: The use of copper-lowering therapy with tetrathiomolybdate in medicine. Expert Opin Investig Drugs 2009;18:89.


Pharmacology_Katzung

Pharmacology_Katzung. Brewer GJ: The use of copper-lowering therapy with tetrathiomolybdate in medicine. Expert Opin Investig Drugs 2009;18:89. Bronstein JM et al: Deep brain stimulation for Parkinson disease: An expert consensus and review of key issues. Arch Neurol 2010;68:165. Chang KH et al: Efficacy and safety of topiramate for essential tremor: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2015;94:e1809. Cho HJ, Hallett M: Non-invasive brain stimulation for treatment of focal hand dystonia: Update and future direction. J Mov Disord 2016;9:55. Christine CW et al: Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009;73:1662. Connolly BS et al: Pharmacological treatment of Parkinson’s disease: A review. JAMA 2014;311:1670. Cornelius JR et al: Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: A case control study. Sleep 2010;33:81.


Pharmacology_Katzung

Pharmacology_Katzung. Cornelius JR et al: Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: A case control study. Sleep 2010;33:81. Cummings J et al: Pimavanserin for patients with Parkinson’s disease psychosis: A randomised, placebo-controlled phase 3 trial. Lancet 2014;383:533. David FJ et al: Exercise improves cognition in Parkinson’s disease: The PRET-PD randomized, clinical trial. Mov Disord 2015;30:1657. Earley CJ et al: Restless legs syndrome and periodic leg movements in sleep. Handb Clin Neurol 2011;99:913. Elias WJ et al: A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2013;369:640. Follett KA et al: Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. N Engl J Med 2010;362:2077. Fox SH et al: The Movement Disorders Society evidence-based medicine review update: Treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2011;26(Suppl 3):S2.


Pharmacology_Katzung

Pharmacology_Katzung. Fox SH et al: The Movement Disorders Society evidence-based medicine review update: Treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2011;26(Suppl 3):S2. Garcia-Borreguero D et al: Treatment of restless legs syndrome with pregabalin: A double-blind, placebo-controlled study. Neurology 2010;74:1897. Gottwald MD, Aminoff MJ: Therapies for dopaminergic-induced dyskinesias in Parkinson disease. Ann Neurol 2011;69:919. Hartmann A, Worbe Y: Pharmacological treatment of Gilles de la Tourette syndrome. Neurosci Biobehav Rev 2013;37:1157. Hauser RA et al: Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson’s disease and motor fluctuations; a phase 3 randomised, double-blind trial. Lancet Neurol 2013;12:346. Huster D: Wilson disease. Best Pract Res Clin Gastroenterol 2010;24:531. Jankovic J: Medical treatment of dystonia. Mov Disord 2013;28:1001.


Pharmacology_Katzung

Pharmacology_Katzung. Huster D: Wilson disease. Best Pract Res Clin Gastroenterol 2010;24:531. Jankovic J: Medical treatment of dystonia. Mov Disord 2013;28:1001. Kalia LV, Kalia SK, Lang AE: Disease-modifying strategies for Parkinson’s disease. Mov Disord 2015;30:1442. Kimber TE: An update on Tourette syndrome. Curr Neurol Neurosci Rep 2010;10:286. Kordower JH et al: Transplanted dopaminergic neurons develop PD pathologic changes: A second case report. Mov Disord 2008;23:2303. LeWitt PA et al: AAV2-GAD gene therapy for advanced Parkinson’s disease: A double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 2011;10:309. Lorincz MT: Neurologic Wilson’s disease. Ann N Y Acad Sci 2010;1184:173. Lyons KE, Pahwa R: Outcomes of rotigotine clinical trials: Effects on motor and nonmotor symptoms of Parkinson’s disease. Neurol Clin 2013;31(3 Suppl):S51. Olanow CW et al: A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009;361:1268.


Pharmacology_Katzung

Pharmacology_Katzung. Olanow CW et al: A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 2009;361:1268. Ondo W: Essential tremor: What we can learn from current pharmacotherapy. Tremor Other Hyperkinet Mov (NY) 2016;6:356. Palfi S et al: Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: A dose escalation, open-label, phase 1/2 trial. Lancet 2014;383:1138. PD MED Collaborative Group: Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): A large, open-label, pragmatic randomized trial. Lancet 2014;384:1196. Perez-Lloret S et al: Adverse drug reactions to dopamine agonists: A comparative study in the French Pharmacovigilance Database. Mov Disord 2010;25:1876. Sadeghi R, Ondo WG: Pharmacological management of essential tremor. Drugs 2010;70:2215.


Pharmacology_Katzung

Pharmacology_Katzung. Sadeghi R, Ondo WG: Pharmacological management of essential tremor. Drugs 2010;70:2215. Schapira AH et al: Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson disease and motor fluctuations: A randomized clinical trial. JAMA Neurol 2017;74:216. Schilsky ML: Wilson disease: Current status and the future. Biochimie 2009;91:1278. Scott LJ: Gabapentin enacarbil: In patients with restless legs syndrome. CNS Drugs 2012;26:1073. Seeberger LC, Hauser RA: Levodopa/carbidopa/entacapone in Parkinson’s disease. Expert Rev Neurother 2009;9:929. Servello D et al: Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: The surgery and stimulation. J Neurol Neurosurg Psychiatry 2008;79:136.


Pharmacology_Katzung

Pharmacology_Katzung. Servello D et al: Deep brain stimulation in 18 patients with severe Gilles de la Tourette syndrome refractory to treatment: The surgery and stimulation. J Neurol Neurosurg Psychiatry 2008;79:136. Simpson DM et al: Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2016;86:1818. Singer HS: Treatment of tics and Tourette syndrome. Curr Treat Options Neurol 2010;12:539. Stocchi F et al: Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: The STRIDE-PD study. Ann Neurol 2010;68:18. Tamara P et al: Tourette syndrome and other tic disorders of childhood. Handb Clin Neurol 2013;112:853.


Pharmacology_Katzung

Pharmacology_Katzung. Tamara P et al: Tourette syndrome and other tic disorders of childhood. Handb Clin Neurol 2013;112:853. Taylor RM et al: Triethylene tetramine dihydrochloride (trientine) in children with Wilson disease: Experience at King’s College Hospital and review of the literature. Eur J Pediatr 2009;168:1061. Thomas R, Cavanna AE: The pharmacology of Tourette syndrome. J Neural Transm 2013;120:689. Trenkwalder C, Paulus W: Restless legs syndrome: Pathophysiology, clinical presentation and management. Nat Rev Neurol 2010;6:337. Van Holst RJ et al: Brain imaging studies in pathological gambling. Curr Psychiatry Rep 2010;12:418. Videnovic A: Treatment of Huntington disease. Curr Treat Options Neurol 2013;15:424. Vijayakumar D, Jankovic J: Drug-induced dyskinesias (2 parts). Drugs 2016;76:759 and 779. Voon V et al: Impulse control disorders in Parkinson’s disease: A multicenter case-control study. Ann Neurol 2011;69:986.


Pharmacology_Katzung

Pharmacology_Katzung. Voon V et al: Impulse control disorders in Parkinson’s disease: A multicenter case-control study. Ann Neurol 2011;69:986. Weaver FM et al: Randomized trial of deep brain stimulation for Parkinson disease: Thirty-six-month outcomes. Neurology 2012;79:55. Wiggelinkhuizen M et al: Systematic review: Clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease. Aliment Pharmacol Ther 2009;29:947. Zesiewicz TA et al: Update on treatment of essential tremor. Curr Treat Options Neurol 2013;15:410.


Pharmacology_Katzung

Pharmacology_Katzung. Zesiewicz TA et al: Update on treatment of essential tremor. Curr Treat Options Neurol 2013;15:410. The history is suggestive of parkinsonism, but the incon-spicuous tremor and early cognitive changes raise the possi-bility of atypical parkinsonism rather than classic Parkinson’s disease. The prognosis of these disorders is worse than that of classic Parkinson’s disease. Given the cognitive changes and his age, the use of a dopamine agonist was unwise, as these agents are more likely than levodopa to exacerbate or precipitate behavioral and cognitive disturbances. Sleep attacks may occur spontaneously but are especially noted in patients receiving dopamine agonists. The patient has also developed punding, which is a recognized adverse effect of dopaminergic medication. Surgical treatment (deep brain stimulation) is contraindicated in patients with cognitive changes or atypical parkinsonism.


Pharmacology_Katzung

Pharmacology_Katzung. Charles DeBattista, MD * severe akathisia. Although more costly, lurasidone is then prescribed, which, over the course of several weeks of treatment, improves his symptoms and is tolerated by the patient. What signs and symptoms would support an initial diagnosis of schizophrenia? In the treatment of schizophre-nia, what benefits do the second-generation antipsychotic drugs offer over the traditional agents such as haloperidol? In addition to the management of schizophrenia, what other clinical indications warrant consideration of the use of drugs nominally classified as antipsychotics? A 19-year-old male student is brought into the clinic by his mother who has been concerned about her son’s erratic behavior and strange beliefs. He destroyed a TV because he felt the TV was sending harassing messages to him. In addition, he reports hearing voices telling him that fam-ily members are trying to poison his food. As a result, he is not eating. After a diagnosis is made, haloperidol is


Pharmacology_Katzung

Pharmacology_Katzung. messages to him. In addition, he reports hearing voices telling him that fam-ily members are trying to poison his food. As a result, he is not eating. After a diagnosis is made, haloperidol is prescribed at a gradually increasing dose on an outpatient basis. The drug improves the patient’s positive symptoms but ultimately causes intolerable adverse effects including


Pharmacology_Katzung

Pharmacology_Katzung. Antipsychotic drugs are able to reduce psychotic symptoms in a wide variety of conditions, including schizophrenia, bipolar disorder, psychotic depression, psychoses associated with dementia, and drug-induced psychoses. They are also able to improve mood and reduce anxiety and sleep disturbances, but they are not the treatment of choice when these symptoms are the primary disturbance in nonpsychotic patients. A neuroleptic is a subtype of antipsychotic drug that produces a high incidence of extrapyramidal side effects (EPS) at clinically effective doses, or catalepsy in laboratory animals. The second-generation or “atypical” antipsychotic drugs are now the most widely used type of antipsychotic drug. Reserpine and chlorpromazine were the first drugs found to be useful to reduce psychotic symptoms in schizophrenia. Reserpine The author thanks Herbert Meltzer, MD, PhD, for his contributions to prior editions of this chapter.


Pharmacology_Katzung

Pharmacology_Katzung. was used only briefly for this purpose and is no longer of interest as an antipsychotic agent. Chlorpromazine is a neuroleptic agent; that is, it produces catalepsy in rodents and EPS in humans. The discovery that its antipsychotic action was related to dopamine (D or DA)-receptor blockade led to the identification of other compounds as antipsychotics between the 1950s and 1970s. The discovery of clozapine in 1959 led to the realization that antipsychotic drugs need not cause EPS in humans at clinically effective doses. Clozapine was called an “atypical” antipsychotic drug because of this dissociation; it produces fewer EPS at equivalent antipsychotic doses in man and laboratory animals. As a result, there has been a major shift in clinical practice away from typical or first-generation antipsychotic drugs toward the use of an ever-increasing number of atypical or second-generation drugs, which have other advantages as well. The introduction of antipsychotic drugs led to massive


Pharmacology_Katzung

Pharmacology_Katzung. antipsychotic drugs toward the use of an ever-increasing number of atypical or second-generation drugs, which have other advantages as well. The introduction of antipsychotic drugs led to massive changes in disease management, including brief instead of life-long hospitalizations. These drugs have also proved to be of great value in studying the pathophysiology of schizophrenia and other psychoses. It should be noted that schizophrenia and bipolar disorder are no longer believed by many to be separate disorders but rather to be part of a continuum of brain disorders with psychotic features.


Pharmacology_Katzung

Pharmacology_Katzung. Nature of Psychosis & Schizophrenia The term “psychosis” denotes a variety of mental disorders that are characterized by the inability to distinguish between what is real and what is not: the presence of delusions (false beliefs); various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory; and grossly disorganized thinking in a clear sensorium. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking and perceptual disturbance. Schizophrenia is the most common psychotic disorder, present in about 1% of the population and responsible for approximately half of long-term psychiatric hospitalizations. Psychosis is not unique to schizophrenia and is not present in all patients with schizophrenia at all times.


Pharmacology_Katzung

Pharmacology_Katzung. Schizophrenia is considered to be a neurodevelopmental disorder. This implies that structural and functional changes in the brain are present even in utero in some patients, or that they develop during childhood and adolescence, or both. Twin, adoption, and family studies have established that schizophrenia is a genetic disorder with high heritability. No single gene is involved. Current theories involve multiple genes with common and rare mutations, including large deletions and insertions (copy number variations), combining to produce a very variegated clinical presentation and course.


Pharmacology_Katzung

Pharmacology_Katzung. The discovery that indole hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists led to the search for endogenous hallucinogens in the urine, blood, and brains of patients with schizophrenia. This proved fruitless, but the identification of many 5-HT-receptor subtypes led to the pivotal discovery that 5-HT2A-receptor and possibly 5-HT2C stimulation was the basis for the hallucinatory effects of these agents.


Pharmacology_Katzung

Pharmacology_Katzung. It has been found that 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of second-generation antipsychotic drugs, of which clozapine is the prototype and which includes, in order of their introduction around the world, melperone, risperidone, zotepine, blonanserin, olanzapine, quetiapine, ziprasidone, aripiprazole, sertindole, paliperidone, iloperidone, asenapine, lurasidone, cariprazine, and brexpiprazole. These drugs are inverse agonists of the 5-HT2A receptor; that is, they block the constitutive activity of these receptors. These receptors modulate the release of dopamine, norepinephrine, glutamate, GABA, and acetylcholine, among other neurotransmitters in the cortex, limbic region, and striatum. Stimulation of 5-HT2A receptors leads to depolarization of glutamate neurons, but also stabilization of N-methyl-d-aspartate (NMDA) receptors on postsynaptic neurons. It has been found that hallucinogens can modulate the stability of a complex


Pharmacology_Katzung

Pharmacology_Katzung. of glutamate neurons, but also stabilization of N-methyl-d-aspartate (NMDA) receptors on postsynaptic neurons. It has been found that hallucinogens can modulate the stability of a complex consisting of 5-HT2A and NMDA receptors.


Pharmacology_Katzung

Pharmacology_Katzung. 5-HT2C-receptor stimulation provides a further means of modulating cortical and limbic dopaminergic activity. Stimulation of 5-HT2C receptors leads to inhibition of cortical and limbic dopamine release. Many atypical antipsychotic drugs, eg, clozapine, asenapine, and olanzapine, are 5-HT2C inverse agonists. 5-HT2C agonists are currently being studied as antipsychotic agents. The dopamine hypothesis for schizophrenia was the second neurotransmitter-based concept to be developed but is no longer considered adequate to explain all aspects of schizophrenia, especially the cognitive impairment. Nevertheless, it is still highly relevant to understanding the major dimensions of schizophrenia, such as positive (hallucinations, delusions) and negative symptoms (emotional blunting, social withdrawal, lack of motivation), cognitive impairment, and possibly depression. It is also essential to understanding the mechanisms of action of most and probably all antipsychotic drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Several lines of evidence suggest that excessive limbic dopaminergic activity plays a role in psychosis. (1) Many antipsychotic drugs strongly block postsynaptic D2 receptors in the central nervous system, especially in the mesolimbic and striatal-frontal system; this includes partial dopamine agonists, such as aripiprazole, brexpiprazole, and bifeprunox. (2) Drugs that increase dopaminergic activity, such as levodopa, amphetamines, and bromocriptine and apomorphine, either aggravate schizophrenia psychosis or produce psychosis de novo in some patients. (3) Dopamine-receptor density has been found postmortem to be increased in the brains of schizophrenics who have not been treated with antipsychotic drugs. (4) Some but not all postmortem studies of schizophrenic subjects have reported increased dopamine levels and D2-receptor density in the nucleus accumbens, caudate, and putamen. (5) Imaging studies have shown increased amphetamine-induced striatal dopamine release, increased


Pharmacology_Katzung

Pharmacology_Katzung. increased dopamine levels and D2-receptor density in the nucleus accumbens, caudate, and putamen. (5) Imaging studies have shown increased amphetamine-induced striatal dopamine release, increased baseline occupancy of striatal D2 receptors by extracellular dopamine, and other measures consistent with increased striatal dopamine synthesis and release.


Pharmacology_Katzung

Pharmacology_Katzung. However, the dopamine hypothesis is far from a complete explanation of all aspects of schizophrenia. Diminished cortical or hippocampal dopaminergic activity has been suggested to underlie the cognitive impairment and negative symptoms of schizophrenia. Postmortem and in vivo imaging studies of cortical, limbic, nigral, and striatal dopaminergic neurotransmission in schizophrenic subjects have reported findings consistent with diminished dopaminergic activity in these regions. Decreased dopaminergic innervation in medial temporal cortex, dorsolateral prefrontal cortex, and hippo-campus, and decreased levels of DOPAC, a metabolite of dopamine, in the anterior cingulate have been reported in postmortem studies. Imaging studies have found increased prefrontal D1-receptor levels that correlated with working memory impairments.


Pharmacology_Katzung

Pharmacology_Katzung. The fact that several of the atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizophrenia has redirected attention to the role of other dopamine receptors and to nondopamine receptors. Serotonin receptors— particularly the 5-HT2A-receptor subtype—may mediate synergistic effects or protect against the extrapyramidal consequences of D2 antagonism. As a result of these considerations, the direction of research has changed to a greater focus on compounds that may act on several transmitter-receptor systems, eg, serotonin and glutamate. The atypical antipsychotic drugs share the property of weak D2-receptor antagonism and more potent 5-HT2A-receptor blockade.


Pharmacology_Katzung

Pharmacology_Katzung. Glutamate is the major excitatory neurotransmitter in the brain (see Chapter 21). Phencyclidine (PCP) and ketamine are noncompetitive inhibitors of the NMDA receptor that exacerbate both cognitive impairment and psychosis in patients with schizophrenia. PCP and a related drug, MK-801, increase locomotor activity and, acutely or chronically, a variety of cognitive impairments in rodents and primates. These effects are widely employed as a means to develop novel antipsychotic and cognitive-enhancing drugs. Selective 5-HT2A antagonists, as well as atypical antipsychotic drugs, are much more potent than D2 antagonists in blocking these effects of PCP and MK-801. This was the starting point for the hypothesis that hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal function, contributed to schizophrenia. The diminished GABAergic activity can induce disinhibition of downstream glutamatergic activity, which can lead to


Pharmacology_Katzung

Pharmacology_Katzung. diminished inhibitory influences on neuronal function, contributed to schizophrenia. The diminished GABAergic activity can induce disinhibition of downstream glutamatergic activity, which can lead to hyperstimulation of cortical neurons through non-NMDA receptors. Preliminary evidence suggests that LY2140023, a drug that acts as an agonist of the metabotropic 2/3 glutamate receptor (mGLuR2/3), may be effective in schizophrenia.


Pharmacology_Katzung

Pharmacology_Katzung. The NMDA receptor, an ion channel, requires glycine for full activation. It has been suggested that in patients with schizophre nia, the glycine site of the NMDA receptor is not fully saturated. There have been several trials of high doses of glycine to promote glutamatergic activity, but the results are far from convincing. Currently, glycine transport inhibitors are in development as pos sible psychotropic agents. Ampakines are drugs that potentiate currents mediated by AMPA-type glutamate receptors. In behavioral tests, ampakines of schizophrenia and depression. They protect neurons against neurotoxic insults, in part by mobilizing growth factors such as brain-derived neurotrophic factor (BDNF, see also Chapter 30). A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups as shown in Figures 29–1 and 29–2. in the nucleus


Pharmacology_Katzung

Pharmacology_Katzung. A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups as shown in Figures 29–1 and 29–2. in the nucleus FIGURE 29–1 Structural formulas of some older antipsychotic drugs: phenothiazines, thioxanthenes, and butyrophenones. Only representative members of each type are shown. FIGURE 29–2 Structural formulas of some newer antipsychotic drugs. A. Phenothiazine Derivatives Three subfamilies of phenothiazines, based primarily on the side chain of the molecule, were once the most widely used of the antipsychotic agents. Aliphatic derivatives (eg, chlorpromazine) and piperidine derivatives (eg, thioridazine) are the least potent. These drugs produce more sedation and weight gain. Piperazine derivatives are more potent (effective in lower doses) but not necessarily more efficacious. The piperazine derivatives are also more selective in their pharmacologic effects (Table 29–1).


Pharmacology_Katzung

Pharmacology_Katzung. The National Institute of Mental Health (NIMH)-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) reported that perphenazine, a piperazine derivative, was as effective as atypical antipsychotic drugs, with the modest exception of olanzapine, and concluded that first-generation antipsychotic drugs are the treatment of choice for schizophrenia based on their lower cost. However, there were numerous flaws in the design, execution, and analysis of this study, leading to it having only modest impact on clinical practice. In particular, it TABLE 29–1 Antipsychotic drugs: Relation of chemical structure to potency and toxicities. 1Ratio of affinity for D2 receptors to affinity for 5-HT2A receptors. 2At dosages below 8 mg/d.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 29–1 Antipsychotic drugs: Relation of chemical structure to potency and toxicities. 1Ratio of affinity for D2 receptors to affinity for 5-HT2A receptors. 2At dosages below 8 mg/d. failed to consider issues such as dosage of olanzapine, inclusion of treatment resistant patients, encouragement of patients to switch medications inherent in the design, risk for tardive dyskinesia following long-term use of even low-dose typical antipsychotics, and the necessity of large sample sizes in equivalency studies. B. Thioxanthene Derivatives This group of drugs is exemplified primarily by thiothixene. C. Butyrophenone Derivatives


Pharmacology_Katzung

Pharmacology_Katzung. B. Thioxanthene Derivatives This group of drugs is exemplified primarily by thiothixene. C. Butyrophenone Derivatives This group, of which haloperidol is the most widely used, has a very different structure from those of the two preceding groups. Haloperidol, a butyrophenone, is the most widely used first-generation antipsychotic drug, despite its high level of EPS relative to other typical antipsychotic drugs. Diphenylbutylpiperidines are closely related compounds. The butyrophenones and congeners tend to be more potent and to have fewer autonomic effects but greater extrapyramidal effects than phenothiazines (Table 29–1). D. Miscellaneous Structures Pimozide and molindone are first-generation antipsychotic drugs. There is no significant difference in efficacy between these newer typical and the older typical antipsychotic drugs. E. Second-Generation Antipsychotic Drugs


Pharmacology_Katzung

Pharmacology_Katzung. E. Second-Generation Antipsychotic Drugs Clozapine, asenapine, olanzapine, quetiapine, paliperidone, risperidone, sertindole, ziprasidone, zotepine, brexpiprazole, cariprazine, and aripiprazole are second-generation antipsychotic drugs (some of which are shown in Figure 29–2). Clozapine is the prototype. Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. Risperidone is rapidly converted to 9-hydroxyrisperidone in vivo in most patients, except for about 10% of patients who are poor metabolizers. Sertindole is approved in some European countries but not in the USA. These drugs have complex pharmacology, but they share a greater ability to alter 5-HT2A-receptor activity than to interfere with D2-receptor action. In most cases, they act as partial agonists at the 5-HT1A receptor, which produces synergistic effects with 5-HT2A receptor antagonism. Most are either 5-HT6 or 5-HT7 receptor antagonists.


Pharmacology_Katzung

Pharmacology_Katzung. Sulpride and sulpiride constitute another class of atypical agents. They have equivalent potency for D2 and D3 receptors, but they are also 5-HT7 antagonists. They dissociate EPS and anti-psychotic efficacy. However, they also produce marked increases in serum prolactin levels and are not as free of the risk of tardive dyskinesia as are drugs such as clozapine and quetiapine. They are not approved in the USA. Cariprazine represents another second-generation agent. In addition to D2/5-HT2 antagonism, cariprazine is also a D3 partial agonist with selectivity for the D3 receptor. Cariprazine’s selectivity for the D3 receptor may be associated with greater effects on the negative symptoms of schizophrenia. This drug was approved in 2015 in the USA. F. Glutamatergic Antipsychotics


Pharmacology_Katzung

Pharmacology_Katzung. F. Glutamatergic Antipsychotics No glutamate-specific agents are currently approved for the treatment of schizophrenia. However, several agents are in late clinical testing. Among these is bitopertin, a glycine transporter 1 (GlyT1) inhibitor. As noted earlier, glycine is a required co-agonist with glutamate at NMDA receptors. Initial phase 2 studies indicated that bitopertin used adjunctively with standard antipsychotics significantly improved negative symptoms of schizophrenia, but subsequent trials have been disappointing. Sarcoserine (N-methylglycine), another GlyT1 inhibitor, in combination with a standard antipsychotic has also shown benefit in improving both negative and positive symptoms of schizophrenia in acutely ill as well as in more chronic patients with schizophrenia.


Pharmacology_Katzung

Pharmacology_Katzung. Another class of investigational antipsychotic agents includes the metabotropic glutamate receptor agonists. Eight metabotropic glutamate receptors are divided into three groups: group I (mGluR1,5), group II (mGluR2,3), and group III (mGluR4,6,7,8). mGluR2,3 inhibits glutamate release presynaptically. Several mGluR2,3 agents are being investigated in the treatment of schizophrenia. One agent, pomaglumetad methionil, showed antipsychotic efficacy in early phase 2 trials, but subsequent trials failed to show benefit in either positive or negative symptoms of schizophrenia. Other metabotropic glutamate receptor agonists are being explored for the treatment of negative and cognitive symptoms of schizophrenia. A. Absorption and Distribution


Pharmacology_Katzung

Pharmacology_Katzung. A. Absorption and Distribution Most antipsychotic drugs are readily but incompletely absorbed. Furthermore, many undergo significant first-pass metabolism. Thus, oral doses of chlorpromazine and thioridazine have systemic availability of 25–35%, whereas haloperidol, which has less first-pass metabolism, has an average systemic availability of about 65%. Most antipsychotic drugs are highly lipid soluble and protein bound (92–99%). They tend to have large volumes of distribution (usually more than 7 L/kg). They generally have a much longer clinical duration of action than would be estimated from their plasma half-lives. This is paralleled by prolonged occupancy of D2 dopamine receptors in the brain by the typical antipsychotic drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug. Long-acting injectable formulations may cause some blockade of D2 receptors 3–6 months after the last injection. Time to recurrence of psychotic symptoms is highly variable after discontinuation of antipsychotic drugs. The average time for relapse in stable patients with schizophrenia who discontinue their medication is 6 months. Clozapine is an exception in that relapse after discontinuation is usually rapid and severe. Thus, clozapine should never be discontinued abruptly unless clinically needed because of adverse effects such as myocarditis or agranulocytosis, which are true medical emergencies. B. Metabolism


Pharmacology_Katzung

Pharmacology_Katzung. B. Metabolism Most antipsychotic drugs are almost completely metabolized by oxidation or demethylation, catalyzed by liver microsomal cytochrome P450 enzymes. CYP2D6, CYP1A2, and CYP3A4 are the major isoforms involved (see Chapter 4). Drug-drug interactions should be considered when combining antipsychotic drugs with various other psychotropic drugs or drugs—such as ketoconazole—that inhibit various cytochrome P450 enzymes. At the typical clinical doses, antipsychotic drugs do not usually interfere with the metabolism of other drugs. The first phenothiazine antipsychotic drugs, with chlorpromazine as the prototype, proved to have a wide variety of central nervous system, autonomic, and endocrine effects. Although efficacy of these drugs is primarily driven by D2-receptor blockade, their adverse actions were traced to blocking effects at a wide range of receptors including α adrenoceptors and muscarinic, H1 histaminic, and 5-HT2 receptors. A. Dopaminergic Systems


Pharmacology_Katzung

Pharmacology_Katzung. Five dopaminergic systems or pathways are important for understanding schizophrenia and the mechanism of action of antipsychotic drugs. The first pathway—the one most closely related to behavior and psychosis—is the mesolimbic-mesocortical pathway, which projects from cell bodies in the ventral tegmentum in separate bundles of axons to the limbic system and neocortex. The second system—the nigrostriatal pathway—consists of neurons that project from the substantia nigra to the dorsal striatum, which includes the caudate and putamen; it is involved in the coordination of voluntary movement. Blockade of the D2 receptors in the nigrostriatal pathway is responsible for EPS. The third pathway—the tuberoinfundibular system—arises in the arcuate nuclei and periventricular neurons and releases dopamine into the pituitary portal circulation. Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary. The fourth dopaminergic system—the


Pharmacology_Katzung

Pharmacology_Katzung. dopamine into the pituitary portal circulation. Dopamine released by these neurons physiologically inhibits prolactin secretion from the anterior pituitary. The fourth dopaminergic system—the medullaryperiventricular pathway—consists of neurons in the motor nucleus of the vagus whose projections are not well defined. This system may be involved in eating behavior. The fifth pathway— the incertohypothalamic pathway—forms connections from the medial zona incerta to the hypothalamus and the amygdala. It appears to regulate the anticipatory motivational phase of copulatory behavior in rats.


Pharmacology_Katzung

Pharmacology_Katzung. After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP synthesized by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was a key factor in the development of the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block the effect of dopamine, (D2 receptors inhibit the activity of adenylyl cyclase in the mesolimbic system). B. Dopamine Receptors and Their Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Dopamine Receptors and Their Effects At present, five dopamine receptors have been described, consisting of two separate families, the D1-like (D1, D5) and D2-like (D2, D3, D4) receptor groups. The D1 receptor is coded by a gene on chromosome 5, increases cAMP by Gs-coupled activation of adenylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle and cortex. The other member of this family, D5, is coded by a gene on chromosome 4, also increases cAMP, and is found in the hippocampus and hypothalamus. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the D1 receptor (Figure 29–3, top) nor did a selective D1 antagonist prove to be an effective antipsychotic in patients with schizophrenia. 0.1


Pharmacology_Katzung

Pharmacology_Katzung. 0.1 FIGURE 29–3 Correlations between the therapeutic potency of antipsychotic drugs and their affinity for binding to dopamine D1 (top) or D2 receptors (bottom). Potency is indicated on the horizontal axes; it decreases to the right. Binding affinity for D1 receptors was measured by displacing the selective D1 ligand SCH 23390; affinity for D2 receptors was similarly measured by displacing the selective D2 ligand haloperidol. Binding affinity decreases upward. (Reprinted, with permission, of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc., from Seeman P: Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1987;1:133.)


Pharmacology_Katzung

Pharmacology_Katzung. The D2 receptor is coded on chromosome 11, decreases cAMP (by Gi-coupled inhibition of adenylyl cyclase), and inhibits calcium channels but opens potassium channels. It is found both preand postsynaptically on neurons in the caudate-putamen, nucleus accumbens, and olfactory tubercle. A second member of this family, the D3 receptor, also coded by a gene on chromosome 11, is thought to also decrease cAMP and is located in the frontal cortex, medulla, and midbrain. D4 receptors also decrease cAMP and are concentrated in the cortex.


Pharmacology_Katzung

Pharmacology_Katzung. The first-generation antipsychotic agents block D2 receptors stereoselectively for the most part, and their binding affinity is very strongly correlated with clinical antipsychotic and extrapyramidal potency (Figure 29–3, bottom). In vivo imaging studies of D2-receptor occupancy indicate that for antipsychotic efficacy, the typical antipsychotic drugs must be given in sufficient doses to achieve at least 60% occupancy of striatal D2 receptors. This is not required for some second-generation antipsychotic drugs such as clozapine and olanzapine, which are effective at lower occupancy levels of 30–50%, most likely because of their concurrent high occupancy of 5-HT2A receptors. The first-generation antipsychotic drugs produce EPS when the occupancy of striatal D2 receptors reaches 80% or higher.


Pharmacology_Katzung

Pharmacology_Katzung. Positron emission tomography (PET) studies with aripiprazole show very high occupancy of D2 receptors, but this drug does not cause EPS because it is a partial D2-receptor agonist. Aripiprazole also gains therapeutic efficacy through its 5-HT2A antagonism and possibly 5-HT1A partial agonism. These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both highand low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms.


Pharmacology_Katzung

Pharmacology_Katzung. It has not been convincingly demonstrated that antagonism of any dopamine receptor other than the D2 receptor plays a role in the action of antipsychotic drugs. Selective and relatively specific D1-, D3-, and D4-receptor antagonists have been tested repeatedly with no evidence of antipsychotic action. Most of the newer atypical antipsychotic agents and some of the traditional ones have a higher affinity for the 5-HT2A receptor than for the D2 receptor (Table 29–1), suggesting an important role for the serotonin 5-HT system in the etiology of schizophrenia and the action of these drugs. C. Differences among Antipsychotic Drugs


Pharmacology_Katzung

Pharmacology_Katzung. C. Differences among Antipsychotic Drugs Although all effective antipsychotic drugs block D2 receptors, the degree of this blockade in relation to other actions on receptors varies considerably among drugs. Vast numbers of ligand-receptor binding experiments have been performed in an effort to discover a single receptor action that would best predict antipsychotic efficacy. A summary of the relative receptor-binding affinities of several key agents in such comparisons illustrates the difficulty in drawing simple conclusions from such experiments: Chlorpromazine: α1 = 5-HT2A > D2 > D1 Haloperidol: D2 > α1 > D4 > 5-HT2A > D1 > H1 Clozapine: D4 = α1 > 5-HT2A > D2 = D1 Olanzapine: 5-HT2A > H1 > D4 > D2 > α1 > D1 Aripiprazole: D2 = 5-HT2A > D4 > α1 = H1 >> D1 Quetiapine: H1 > α1 > M1,3 > D2 > 5-HT2A


Pharmacology_Katzung

Pharmacology_Katzung. Clozapine: D4 = α1 > 5-HT2A > D2 = D1 Olanzapine: 5-HT2A > H1 > D4 > D2 > α1 > D1 Aripiprazole: D2 = 5-HT2A > D4 > α1 = H1 >> D1 Quetiapine: H1 > α1 > M1,3 > D2 > 5-HT2A Thus, most of the second-generation and some first-generation antipsychotic agents are at least as potent in inhibiting 5-HT2 receptors as they are in inhibiting D2 receptors. Aripiprazole and brexpiprazole appear to be partial agonists of D2 receptors. Varying degrees of antagonism of α2 adrenoceptors are also seen with risperidone, clozapine, olanzapine, quetiapine, and aripiprazole. TABLE 29–2 Adverse pharmacologic effects of antipsychotic drugs. Current research is directed toward discovering novel antipsychotic compounds that are either more selective for the mesolimbic system (to reduce their effects on the extrapyramidal system) or have effects on central neurotransmitter receptors—such as those for acetylcholine and excitatory amino acids—that have been proposed as new targets for antipsychotic action.


Pharmacology_Katzung

Pharmacology_Katzung. In contrast to the difficult search for receptors responsible for antipsychotic efficacy, the differences in receptor effects of various antipsychotics do explain many of their toxicities (Tables 29–1 and 29–2). In particular, extrapyramidal toxicity appears to be consistently associated with high D2 potency. D. Psychological Effects Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals. The mild to severe EPS, including akathisia, sleepiness, restlessness, and autonomic effects are unlike any associated with more familiar sedatives or hypnotics. Nevertheless, low doses of some of these drugs, particularly quetiapine, are used to promote sleep onset and maintenance, although there is no approved indication for such usage.


Pharmacology_Katzung

Pharmacology_Katzung. People without psychiatric illness given antipsychotic drugs, even at low doses, experience impaired performance as judged by a number of psychomotor and psychometric tests. Psychotic individuals, however, may actually show improvement in their performance as the psychosis is alleviated. The ability of the second-generation anti-psychotic drugs to improve some domains of cognition in patients with schizophrenia and bipolar disorder is controversial. Some individuals experience marked improvement, and for that reason, cognition should be assessed in all patients with schizophrenia and a trial of an atypical agent considered, even if positive symptoms are well controlled by first-generation agents. E. Electroencephalographic Effects


Pharmacology_Katzung

Pharmacology_Katzung. E. Electroencephalographic Effects Antipsychotic drugs produce shifts in the pattern of electroencephalographic (EEG) frequencies, usually slowing them and increasing their synchronization. The slowing (hypersynchrony) is sometimes focal or unilateral, which may lead to erroneous diagnostic interpretations. Both the frequency and the amplitude changes induced by psychotropic drugs are readily apparent and can be quantitated by sophisticated electrophysiologic techniques. Some antipsychotic agents lower the seizure threshold and induce EEG patterns typical of seizure disorders; however, with careful dosage titration, most can be used safely in epileptic patients. F. Endocrine Effects


Pharmacology_Katzung

Pharmacology_Katzung. F. Endocrine Effects Older typical antipsychotic drugs, as well as risperidone and paliperidone, produce elevations of prolactin (see Adverse Effects, below). Newer antipsychotics such as olanzapine, quetiapine, aripiprazole, and brexpiprazole cause no or minimal increases of prolactin and reduce the risks of extrapyramidal system dysfunction and tardive dyskinesia, reflecting their diminished D2 antagonism. G. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. G. Cardiovascular Effects The low-potency phenothiazines frequently cause orthostatic hypotension and tachycardia. Mean arterial pressure, peripheral resistance, and stroke volume are decreased. These effects are predictable from the autonomic actions of these agents (Table 29–2). Abnormal electrocardiograms have been recorded, especially with thioridazine. Changes include prolongation of QT interval and abnormal configurations of the ST segment and T waves. These changes are readily reversed by withdrawing the drug. Since thioridazine is associated with torsades de pointes and an increased risk of sudden death, the branded drug was removed from the market in 2005, and its use currently is as a second-line agent if other drugs have proven intolerable or ineffective.


Pharmacology_Katzung

Pharmacology_Katzung. Among the newest antipsychotics, prolongation of the QT or QTc interval has received much attention. Because this was believed to indicate an increased risk of dangerous arrhythmias, ziprasidone and quetiapine are accompanied by warnings. There is, however, no evidence that this has actually translated into increased incidence of arrhythmias. The atypical antipsychotics are also associated with a metabolic syndrome that may increase the risk of coronary artery disease, stroke, and hypertension. A. Psychiatric Indications Schizophrenia is the primary indication for antipsychotic agents. However, in the last decade, the use of antipsychotics in the treatment of mood disorders such as bipolar disorder (BP1), psychotic depression, and treatment-resistant depression has eclipsed their use in the treatment of schizophrenia.


Pharmacology_Katzung

Pharmacology_Katzung. Catatonic forms of schizophrenia are best managed by intravenous benzodiazepines. Antipsychotic drugs may be needed to treat psychotic components of that form of the illness after catatonia has ended, and they remain the mainstay of treatment for this condition. Unfortunately, many patients show little response, and virtually none show a complete response. Antipsychotic drugs are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. No fundamental difference between these two diagnoses has been reliably demonstrated. It is most likely that they are part of a continuum with bipolar psychotic disorder. The psychotic aspects of the illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproic acid.


Pharmacology_Katzung

Pharmacology_Katzung. The manic phase in bipolar affective disorder often requires treatment with antipsychotic agents, although lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Recent controlled trials support the efficacy of monotherapy with second-generation antipsychotics in the acute phase (up to 4 weeks) of mania. In addition, several second-generation antipsychotics are approved in the maintenance treatment of bipolar disorder. They appear more effective in preventing mania than in preventing depression. As mania subsides, the antipsychotic drug may be withdrawn, although maintenance treatment with atypical anti-psychotic agents has become more common. Nonmanic excited states may also be managed by antipsychotics, often in combination with benzodiazepines.


Pharmacology_Katzung

Pharmacology_Katzung. An increasingly common use of antipsychotics is in the mono-therapy of acute bipolar depression and the adjunctive use of antipsychotics with antidepressants in the treatment of unipolar depression. Several antipsychotics are now approved by the US Food and Drug Administration (FDA) in the management of bipolar depression including quetiapine, lurasidone, and olanzapine (in a combination formulation with fluoxetine). The antipsychotics appear more consistently effective than antidepressants in the treatment of bipolar depression and also do not increase the risk of inducing mania or increasing the frequency of bipolar cycling. Likewise, several antipsychotics, including aripiprazole, quetiapine, brexpiprazole, and olanzapine (with fluoxetine), are now approved in the adjunctive treatment of unipolar depression. Although many drugs are combined with antidepressants in the adjunctive treatment of major depression, antipsychotic agents are the only class of agents that have been formally


Pharmacology_Katzung

Pharmacology_Katzung. unipolar depression. Although many drugs are combined with antidepressants in the adjunctive treatment of major depression, antipsychotic agents are the only class of agents that have been formally evaluated for FDA approval for this purpose. Residual symptoms and partial remission are common, with antipschotics showing consistent benefit in improving overall antidepressant response.


Pharmacology_Katzung

Pharmacology_Katzung. Some of the intramuscular antipsychotics have been approved for the control of agitation associated with bipolar disorder and schizophrenia. Antipsychotics such as haloperidol have long been used in the ICU setting to manage agitation in delirious and postsurgical patients. The intramuscular forms of ziprasidone, olanzapine, and aripiprazole have been shown to improve agitation within 1–2 hours, with fewer extrapyramidal symptoms than typical agents such as haloperidol.


Pharmacology_Katzung

Pharmacology_Katzung. Other indications for the use of antipsychotics include Tourette syndrome and possibly disturbed behavior in patients with Alzheimer’s disease. However, controlled trials of antipsychotics in the management of behavioral symptoms in dementia patients have generally not demonstrated efficacy. Furthermore, second-generation as well as some first-generation antipsychotics have been associated with increased mortality in these patients. Antipsychotics are not indicated for the treatment of various withdrawal syndromes, eg, opioid withdrawal. In small doses, antipsychotic drugs have been promoted (wrongly) for the relief of anxiety associated with minor emotional disorders. The antianxiety sedatives (see Chapter 22) are preferred in terms of both safety and acceptability to patients.