Drugs Affecting The Central Nervous System PDF

UNIT III Drugs Affecting the Central Nervous System Drugs for Neurodegenerative Diseases Jose A. Rey...

UNIT III Drugs Affecting the Central Nervous System Drugs for Neurodegenerative Diseases Jose A. Rey 8 I. OVERVIEW ANTI-PARKINSON DRUGS Amantadine SYMMETREL Most drugs that affect the central nervous system (CNS) act by altering Apomorphine APOKYN some step in the neurotransmission process. Drugs affecting the CNS may Benztropine COGENTIN act presynaptically by influencing the production, storage, release, or ter- Biperiden AKINETON mination of action of neurotransmitters. Other agents may activate or block Bromocriptine PARLODEL postsynaptic receptors. This chapter provides an overview of the CNS, with Carbidopa LODOSYN a focus on those neurotransmitters that are involved in the actions of the Entacapone COMTAN clinically useful CNS drugs. These concepts are useful in understanding the Levodopa (w/Carbidopa) SINEMET, etiology and treatment strategies for the neurodegenerative disorders that PARCOPA respond to drug therapy: Parkinson’s disease, Alzheimer’s disease, mul- Pramipexole MIRAPEX tiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) (Figure 8.1). Procyclidine KEMADRIN Rasagiline AZILECT Ropinirole REQUIP Rotigotine NEUPRO II. NEUROTRANSMISSION IN THE CNS Selegiline (Deprenyl) ELDEPRYL, ZELAPAR Tolcapone TASMAR In many ways, the basic functioning of neurons in the CNS is similar to Trihexyphenidyl ARTANE that of the autonomic nervous system (ANS) described in Chapter 3. ANTI-ALZHEIMER DRUGS For example, transmission of information in both the CNS and in the Donepezil ARICEPT periphery involves the release of neurotransmitters that diffuse across Galantamine RAZADYNE the synaptic space to bind to specific receptors on the postsynaptic neu- Memantine NAMENDA ron. In both systems, the recognition of the neurotransmitter by the mem- Rivastigmine EXELON brane receptor of the postsynaptic neuron triggers intracellular changes. However, several major differences exist between neurons in the periph- eral ANS and those in the CNS. The circuitry of the CNS is much more Figure 8.1 complex than that of the ANS, and the number of synapses in the CNS Summary of agents used in the treatment of Parkinson’s disease, is far greater. The CNS, unlike the peripheral ANS, contains powerful Alzheimer’s disease, multiple sclerosis, networks of inhibitory neurons that are constantly active in modulating and amyotrophic lateral sclerosis. the rate of neuronal transmission. In addition, the CNS communicates (Figure continues on next page.) 107 108 8. Drugs for Neurodegenerative Diseases ANTI-MULTIPLE SCLEROSIS DRUGS through the use of multiple neurotransmitters, whereas the ANS uses Azathioprine AZASAN, IMURAN only two primary neurotransmitters, acetylcholine and norepinephrine. Cyclophosphamide CYTOXAN Dalfampridine AMPYRA Dexamethasone BAYCADRON, DECADRON III. SYNAPTIC POTENTIALS Dimethyl fumarate TECFIDERA Fingolimod GILENYA In the CNS, receptors at most synapses are coupled to ion channels. Glatiramer COPAXONE Binding of the neurotransmitter to the postsynaptic membrane receptors Interferon β1a AVONEX, REBIF results in a rapid but transient opening of ion channels. Open channels Interferon β1b BETASERON, EXTAVIA allow specific ions inside and outside the cell membrane to flow down Mitoxantrone NOVANTRONE their concentration gradients. The resulting change in the ionic composi- Natalizumab TYSABRI tion across the membrane of the neuron alters the postsynaptic potential, Prednisone DELTASONE producing either depolarization or hyperpolarization of the postsynap- Teriflunomide AUBAGIO tic membrane, depending on the specific ions and the direction of their ANTI-ALS DRUGS movement. Riluzole RILUTEK A. Excitatory pathways Figure 8.1 (continued) Neurotransmitters can be classified as either excitatory or inhibitory, Summary of agents used in the treatment of Parkinson’s disease, depending on the nature of the action they elicit. Stimulation of excit- Alzheimer’s disease, multiple atory neurons causes a movement of ions that results in a depolar- sclerosis, and amyotrophic lateral ization of the postsynaptic membrane. These excitatory postsynaptic sclerosis (ALS). potentials (EPSP) are generated by the following: 1) Stimulation of an excitatory neuron causes the release of neurotransmitter mole- cules, such as glutamate or acetylcholine, which bind to receptors on A Receptor empty ((no agonists) g ) the postsynaptic cell membrane. This causes a transient increase in the permeability of sodium (Na+) ions. 2) The influx of Na+ causes a Empty receptor is inactive, and the weak depolarization, or EPSP, that moves the postsynaptic potential coupled sodium channel is closed. toward its firing threshold. 3) If the number of stimulated excitatory neurons increases, more excitatory neurotransmitter is released. This POSTSYNAPTIC NEURON MEMBRANE Na+ ultimately causes the EPSP depolarization of the postsynaptic cell to pass a threshold, thereby generating an all-or-none action potential. [Note: The generation of a nerve impulse typically reflects the activa- tion of synaptic receptors by thousands of excitatory neurotransmitter Acetylcholine molecules released from many nerve fibers.] Figure 8.2 shows an receptor Sodium channel example of an excitatory pathway. (closed) B. Inhibitory pathways B Receptor binding of excitatory Stimulation of inhibitory neurons causes movement of ions that neurotransmitter results in a hyperpolarization of the postsynaptic membrane. These inhibitory postsynaptic potentials (IPSP) are generated by the fol- Binding of acetylcholine causes the sodium ion channel to open. lowing: 1) Stimulation of inhibitory neurons releases neurotrans- mitter molecules, such as γ-aminobutyric acid (GABA) or glycine, Acetylcholine Na+ which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of specific ions, such as potassium (K+) and chloride (Cl−). 2) The influx of Cl− and efflux of K+ cause a weak hyperpolarization, or IPSP, that moves the post- Acetylcholine synaptic potential away from its firing threshold. This diminishes the receptor generation of action potentials. Figure 8.3 shows an example of an Na+ Na+ inhibitory pathway. Entry of Na+ depolarizes the cell and increases neural excitability. C. Combined effects of the EPSP and IPSP Most neurons in the CNS receive both EPSP and IPSP input. Thus, Figure 8.2 several different types of neurotransmitters may act on the same Binding of the excitatory neurotransmitter, acetylcholine, causes depolarization of the neuron. V. Overview of Parkinson’s Disease 109 neuron, but each binds to its own specific receptor. The overall action is the summation of the individual actions of the various neurotrans- A Receptor empty (no agonists) mitters on the neuron. The neurotransmitters are not uniformly dis- tributed in the CNS but are localized in specific clusters of neurons, the axons of which may synapse with specific regions of the brain. Many neuronal tracts, thus, seem to be chemically coded, and this Empty receptor is inactive, and the coupled chloride may offer greater opportunity for selective modulation of certain neu- channel is closed. ronal pathways. IV. NEURODEGENERATIVE DISEASES Cl– POSTSYNAPTIC NEURON MEMBRANE Neurodegenerative diseases of the CNS include Parkinson’s disease, Alzheimer’s disease, MS, and ALS. These devastating illnesses are char- GABA receptor acterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or Chloride both. channel (closed) V. OVERVIEW OF PARKINSON’S DISEASE Parkinsonism is a progressive neurological disorder of muscle move- ment, characterized by tremors, muscular rigidity, bradykinesia (slow- B Receptor binding ness in initiating and carrying out voluntary movements), and postural of inhibitory and gait abnormalities. Most cases involve people over the age of 65, neurotransmitter among whom the incidence is about 1 in 100 individuals. Binding of GABA causes the chloride A. Etiology ion channel to open. The cause of Parkinson’s disease is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the Cl– substantia nigra with a consequent reduction of dopamine actions in the corpus striatum, parts of the basal ganglia system that are GABA involved in motor control. GABA receptor 1. Substantia nigra: The substantia nigra, part of the extrapyrami- dal system, is the source of dopaminergic neurons (shown in red - in Figure 8.4) that terminate in the neostriatum. Each dopaminer- Cl– Cl– Cl– Cl– gic neuron makes thousands of synaptic contacts within the neo- striatum and, therefore, modulates the activity of a large number Entry of Cl– hyperpolarizes of cells. These dopaminergic projections from the substantia nigra the cell, making it more difficult to depolarize and, fire tonically rather than in response to specific muscular move- thereby, reducing neural ments or sensory input. Thus, the dopaminergic system appears to excitability. serve as a tonic, sustaining influence on motor activity, rather than participating in specific movements. Figure 8.3 2. Neostriatum: Normally, the neostriatum is connected to the Binding of the inhibitory substantia nigra by neurons (shown in orange in Figure 8.4) that neurotransmitter, γ-aminobutyric acid secrete the inhibitory transmitter GABA at their termini. In turn, (GABA), causes hyperpolarization of cells of the substantia nigra send neurons back to the neostria- the neuron. tum, secreting the inhibitory transmitter dopamine at their ter- mini. This mutual inhibitory pathway normally maintains a degree of inhibition of both areas. In Parkinson’s disease, destruction of cells in the substantia nigra results in the degeneration of the nerve terminals that secrete dopamine in the neostriatum. Thus, the normal inhibitory influence of dopamine on cholinergic neurons 110 8. Drugs for Neurodegenerative Diseases in the neostriatum is significantly diminished, resulting in over- Loss of the inhibitory effect production or a relative overactivity of acetylcholine by the stim- 2 of dopamine results in more production of acetylcholine, ulatory neurons (shown in green in Figure 8.4). This triggers a which triggers a chain of chain of abnormal signaling, resulting in loss of the control of abnormal signaling leading muscle movements. to impaired mobility. Connections to musc muscle 3. Secondary parkinsonism: Drugs such as the phenothiazines through motor cortex and haloperidol, whose major pharmacologic action is blockade of and spinal chord dopamine receptors in the brain, may produce parkinsonian symp- Neuron toms (also called pseudoparkinsonism). These drugs should be used with caution in patients with Parkinson’s disease. STIMULATORY ACh NEURON NEOSTRIATUM B. Strategy of treatment INHIBITORY In addition to an abundance of inhibitory dopaminergic neurons, INHIBITORY DA NEURON GABA NEURON the neostriatum is also rich in excitatory cholinergic neurons that Neuron oppose the action of dopamine (Figure 8.4). Many of the symptoms SUBSTANTIA of parkinsonism reflect an imbalance between the excitatory cho- NIGRA linergic neurons and the greatly diminished number of inhibitory dopaminergic neurons. Therapy is aimed at restoring dopamine in Cell death results in less dopamine the basal ganglia and antagonizing the excitatory effect of choliner- 1 release in the neostriatum. gic neurons, thus reestablishing the correct dopamine/acetylcholine balance. Figure 8.4 Role of substantia nigra in Parkinson’s disease. DA = dopamine; VI. DRUGS USED IN PARKINSON’S DISEASE GABA = γ-aminobutyric acid; ACh = acetylcholine. Many currently available drugs aim to maintain CNS dopamine levels as constant as possible. These agents offer temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease. A. Levodopa and carbidopa Levodopa [lee-voe-DOE-pa] is a metabolic precursor of dopamine (Figure 8.5). It restores dopaminergic neurotransmission in the neostriatum by enhancing the synthesis of dopamine in the surviv- ing neurons of the substantia nigra. In early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about 20% of normal) is adequate for conversion of levodopa to dopamine. Thus, in new patients, the therapeutic response to levodopa is consis- tent, and the patient rarely complains that the drug effects “wear off.” Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of converting exogenously administered levodopa to dopamine. Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa [kar-bi-DOE-pa], a dopamine decarboxylase inhibitor that does not cross the blood–brain barrier. 1. Mechanism of action: a. Levodopa: Dopamine does not cross the blood–brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and converted to dopamine (Figure 8.5). Levodopa VI. Drugs Used in Parkinson’s Disease 111 Tyrosine Tyrosine A. Fate of administered levodopa Dopa Dopa Dopamine Administered levodopa Synaptic Dopamine vesicle Metabolism in Metabolism in peripheral tissues GI tract Undesirable side effects B. Fate of administered levodopa plus carbidopa Neuron Dopa Administered levodopa Carbi- dopa Decreased metabolism Decreased metabolism in peripheral tissues in GI tract Dopamine receptor Fewer undesirable side effects Figure 8.5 Synthesis of dopamine from levodopa in the absence and presence of carbidopa, an inhibitor of dopamine decarboxylase in the peripheral tissues. GI = gastrointestinal. must be administered with carbidopa. Without carbidopa, much of the drug is decarboxylated to dopamine in the periphery, result- ing in nausea, vomiting, cardiac arrhythmias, and hypotension. b. Carbidopa: Carbidopa, a dopamine decarboxylase inhibitor, diminishes the metabolism of levodopa in the periphery, thereby increasing the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by four- to fivefold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine. 2. Therapeutic uses: Levodopa in combination with carbidopa is an efficacious drug regimen for the treatment of Parkinson’s disease. It decreases rigidity, tremors, and other symptoms of parkinson- ism. In approximately two-thirds of patients with Parkinson’s dis- ease, levodopa–carbidopa substantially reduces the severity of symptoms for the first few years of treatment. Patients typically experience a decline in response during the 3rd to 5th year of ther- apy. Withdrawal from the drug must be gradual. 3. Absorption and metabolism: The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. This may produce fluctuations in motor response, which generally correlate with the plasma concentration of levodopa, or perhaps give rise to the more troublesome “on–off” phenomenon, in which the motor fluctuations are not related to plasma levels in a simple way. Motor fluctuations may cause the 112 8. Drugs for Neurodegenerative Diseases patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Anorexia Thus, levodopa should be taken on an empty stomach, typically 30 minutes before a meal. 4. Adverse effects: a. Peripheral effects: Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone Nausea (Figure 8.6). Tachycardia and ventricular extrasystoles result from dopaminergic action on the heart. Hypotension may also develop. Adrenergic action on the iris causes mydriasis. In some individuals, blood dyscrasias and a positive reaction to the Coombs test are seen. Saliva and urine are a brownish color because of the melanin pigment produced from catechol- Tachycardia amine oxidation. b. CNS effects: Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur. These effects are the opposite of parkinsonian symptoms and reflect over- activity of dopamine in the basal ganglia. Levodopa can also BP cause mood changes, depression, psychosis, and anxiety. Hypotension 5. Interactions: The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness (Figure 8.7). Concomitant administration of levodopa and non-selective mono- amine oxidase inhibitors (MAOIs), such as phenelzine, can pro- duce a hypertensive crisis caused by enhanced catecholamine production. Therefore, concomitant administration of these agents Psychiatric is contraindicated. In many psychotic patients, levodopa exac- problems erbates symptoms, possibly through the buildup of central cat- echolamines. Cardiac patients should be carefully monitored for the possible development of arrhythmias. Antipsychotic drugs are Figure 8.6 generally contraindicated in Parkinson’s disease, because they Adverse effects of potently block dopamine receptors and may augment parkinso- levodopa. nian symptoms. However, low doses of atypical antipsychotics are sometimes used to treat levodopa-induced psychotic symptoms. Diminished effect due B. Selegiline and rasagiline to increased peripheral metabolism Selegiline [seh-LEDGE-ah-leen], also called deprenyl [DE-pre-nill], selectively inhibits monoamine oxidase (MAO) type B (metabolizes dopamine) at low to moderate doses. It does not inhibit MAO type A Pyridoxine (metabolizes norepinephrine and serotonin) unless given above rec- ommended doses, where it loses its selectivity. By decreasing the Levodopa metabolism of dopamine, selegiline increases dopamine levels in the brain (Figure 8.8). When selegiline is administered with levodopa, MAO it enhances the actions of levodopa and substantially reduces the inhibitors required dose. Unlike nonselective MAOIs, selegiline at recommended doses has little potential for causing hypertensive crises. However, Hypertensive crisis due the drug loses selectivity at high doses, and there is a risk for severe to increased catecholamines hypertension. Selegiline is metabolized to methamphetamine and amphetamine, whose stimulating properties may produce insomnia if Figure 8.7 the drug is administered later than mid-afternoon. Rasagiline [ra-SA- Some drug interactions observed gi-leen], an irreversible and selective inhibitor of brain MAO type B, with levodopa. MAO = monoamine oxidase. VI. Drugs Used in Parkinson’s Disease 113 has five times the potency of selegiline. Unlike selegiline, rasagiline is not metabolized to an amphetamine-like substance. Levels of dopamine increase C. Catechol-O-methyltransferase inhibitors Normally, the methylation of levodopa by catechol-O-methyltrans- Dopamine ferase (COMT) to 3-O-methyldopa is a minor pathway for levodopa MAO B Selegiline metabolism. However, when peripheral dopamine decarboxyl- ase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active Metabolites transport into the CNS (Figure 8.9). Entacapone [en-TAK-a-pone] and tolcapone [TOLE-ka-pone] selectively and reversibly inhibit COMT. Figure 8.8 Inhibition of COMT by these agents leads to decreased plasma con- Action of selegiline (deprenyl) in centrations of 3-O-methyldopa, increased central uptake of levodopa, dopamine metabolism. MAO B = and greater concentrations of brain dopamine. Both of these agents monoamine oxidase type B. reduce the symptoms of “wearing-off” phenomena seen in patients on levodopa−carbidopa. The two drugs differ primarily in their pharmaco- kinetic and adverse effect profiles. 1. Pharmacokinetics: Oral absorption of both drugs occurs read- ily and is not influenced by food. They are extensively bound to plasma albumin, with a limited volume of distribution. Tolcapone has a relatively long duration of action (probably due to its affinity for the enzyme) compared to entacapone, which requires more frequent dosing. Both drugs are extensively metabolized and elimi- nated in feces and urine. The dosage may need to be adjusted in patients with moderate or severe cirrhosis. 2. Adverse effects: Both drugs exhibit adverse effects that are observed in patients taking levodopa–carbidopa, including diar- rhea, postural hypotension, nausea, anorexia, dyskinesias, hallu- cinations, and sleep disorders. Most seriously, fulminating hepatic necrosis is associated with tolcapone use. Therefore, it should be used, along with appropriate hepatic function monitoring, only in patients in whom other modalities have failed. Entacapone does not exhibit this toxicity and has largely replaced tolcapone. A When peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration B Inhibition of COMT by entacapone leads to decreased plasma concentrations of 3-O-methyldopa, of 3-O-methyldopa is formed, which competes increased central uptake of levodopa, and with levodopa for active transport into the CNS. greater concentrations of brain dopamine. 3-O-Methyldopa 3-O-Methyldopa COMT Entacapone COMT Administered Levodopa Dopa Administered Levodopa Dopa in CNS levodopa Carbi- levodopa in CNS dopa Carbi- dopa Decreased metabolism Decreased metabolism in GI tract and peripheral tissues in GI tract and peripheral tissues Figure 8.9 Effect of entacapone on dopa concentration in the central nervous system (CNS). COMT = catechol-O-methyltransferase. 114 8. Drugs for Neurodegenerative Diseases D. Dopamine receptor agonists ZZ Z This group of antiparkinsonian compounds includes bromocriptine, Sedation an ergot derivative, the nonergot drugs, ropinirole [roe-PIN-i-role], pramipexole [pra-mi-PEX-ole], rotigotine [ro-TIG-oh-teen], and the newer agent, apomorphine [A-poe-more-feen]. These agents have a longer duration of action than that of levodopa and are effective in patients exhibiting fluctuations in response to levodopa. Initial therapy with these drugs is associated with less risk of developing dyskinesias and motor fluctuations as compared to patients started on levodopa. Hallucinations Bromocriptine, pramipexole, and ropinirole are effective in patients with Parkinson’s disease complicated by motor fluctuations and dys- kinesias. However, these drugs are ineffective in patients who have not responded to levodopa. Apomorphine is an injectable dopamine agonist that is used in severe and advanced stages of the disease to supplement oral medications. Side effects severely limit the utility of Confusion the dopamine agonists (Figure 8.10). 1. Bromocriptine: The actions of the ergot derivative bromocriptine [broe-moe-KRIP-teen] are similar to those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypo- tension are more common, whereas dyskinesia is less prominent. In psychiatric illness, bromocriptine may cause the mental con- Nausea dition to worsen. It should be used with caution in patients with a history of myocardial infarction or peripheral vascular disease. Because bromocriptine is an ergot derivative, it has the potential to cause pulmonary and retroperitoneal fibrosis. BP 2. Apomorphine, pramipexole, ropinirole, and rotigotine: These are nonergot dopamine agonists that are approved for the treat- Hypotension ment of Parkinson’s disease. Pramipexole and ropinirole are orally active agents. Apomorphine and rotigotine are available in inject- able and transdermal delivery systems, respectively. Apomorphine is used for acute management of the hypomobility “off” phenom- Figure 8.10 enon in advanced Parkinson’s disease. Rotigotine is adminis- Some adverse effects of tered as a once-daily transdermal patch that provides even drug dopamine agonists. levels over 24 hours. These agents alleviate the motor deficits in patients who have never taken levodopa and also in patients with advanced Parkinson’s disease who are treated with levodopa. Dopamine agonists may delay the need to use levodopa in early Parkinson’s disease and may decrease the dose of levodopa in advanced Parkinson’s disease. Unlike the ergotamine derivatives, these agents do not exacerbate peripheral vascular disorders or cause fibrosis. Nausea, hallucinations, insomnia, dizziness, consti- pation, and orthostatic hypotension are among the more distress- ing side effects of these drugs, but dyskinesias are less frequent than with levodopa (Figure 8.11). Pramipexole is mainly excreted unchanged in the urine, and dosage adjustments are needed in renal dysfunction. Cimetidine inhibits renal tubular secretion of organic bases and may significantly increase the half-life of pramipexole. The fluoroquinolone antibiotics and other inhibitors of the cytochrome P450 (CYP450) 1A2 isoenzyme (for example, fluoxetine) may inhibit the metabolism of ropinirole, requiring an adjustment in ropinirole dosage. Figure 8.12 summarizes some properties of dopamine agonists. VII. Drugs Used in Alzheimer’s Disease 115 E. Amantadine Dopamine agonists delay motor It was accidentally discovered that the antiviral drug amantadine complications and are most [a-MAN-ta-deen], used to treat influenza, has an antiparkinsonian commonly initiated before action. Amantadine has several effects on a number of neurotrans- levodopa in patients who have mild disease and a mitters implicated in parkinsonism, including increasing the release of younger age of onset because 75 they may delay the need to dopamine, blocking cholinergic receptors, and inhibiting the N-methyl- start levodopa therapy. Percentage of patients with motor complications D-aspartate (NMDA) type of glutamate receptors. Current evidence supports action at NMDA receptors as the primary action at thera- peutic concentrations. [Note: If dopamine release is already at a maxi- mum, amantadine has no effect.] The drug may cause restlessness, 54% agitation, confusion, and hallucinations, and, at high doses, it may 50 45% induce acute toxic psychosis. Orthostatic hypotension, urinary reten- tion, peripheral edema, and dry mouth also may occur. Amantadine is Levodopa Levodopa less efficacious than levodopa, and tolerance develops more readily. However, amantadine has fewer side effects. Pramipexole 25 24.5% Ropinirole F. Antimuscarinic agents 20% The antimuscarinic agents are much less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. The actions of benztropine [BENZ-troe-peen], trihexyphenidyl [tri-hex-ee-FEN- i-dill], procyclidine [pro-SYE-kli-deen], and biperiden [bi-PER-i-den] 0 At 5 years At 4 years are similar, although individual patients may respond more favorably to one drug. Blockage of cholinergic transmission produces effects similar to augmentation of dopaminergic transmission, since it helps to correct the imbalance in the dopamine/acetylcholine ratio (Figure 8.4). These agents can induce mood changes and produce xerosto- Figure 8.11 Motor complications in patients mia (dryness of the mouth), constipation, and visual problems typical treated with levodopa or dopamine of muscarinic blockers (see Chapter 5). They interfere with gastroin- agonists. testinal peristalsis and are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis. VII. DRUGS USED IN ALZHEIMER’S DISEASE Dementia of the Alzheimer type has three distinguishing features: 1) accumulation of senile plaques (β-amyloid accumulations), 2) forma- tion of numerous neurofibrillary tangles, and 3) loss of cortical neu- rons, particularly cholinergic neurons. Current therapies aim to either improve cholinergic transmission within the CNS or prevent excitotoxic actions resulting from overstimulation of NMDA-glutamate receptors in Characteristic Pramipexole Ropinirole Rotigotine Bioavailability >90% 55% 45% Vd 7 L/kg 7.5 L/kg 84 L/kg Half-life 8 hours1 6 hours 7 hours3 Metabolism Negligible Extensive Extensive Elimination Renal Renal2 Renal2 Figure 8.12 Pharmacokinetic properties of dopamine agonists pramipexole, ropinirole, and rotigotine. Vd = volume of distribution. 1Increases to 12 hours in patients older than 65 years; 2Less than 10% excreted unchanged; 3 Administered as a once-daily transdermal patch. 116 8. Drugs for Neurodegenerative Diseases selected areas of the brain. Pharmacologic intervention for Alzheimer’s disease is only palliative and provides modest short-term benefit. None of the available therapeutic agents alter the underlying neurodegenera- Tremors tive process. A. Acetylcholinesterase inhibitors Numerous studies have linked the progressive loss of cholinergic neu- rons and, presumably, cholinergic transmission within the cortex to the memory loss that is a hallmark symptom of Alzheimer’s disease. It Bradycardia is postulated that inhibition of acetylcholinesterase (AChE) within the CNS will improve cholinergic transmission, at least at those neurons that are still functioning. The reversible AChE inhibitors approved for the treatment of mild to moderate Alzheimer’s disease include done- pezil [doe-NE-peh-zil], galantamine [ga-LAN-ta-meen], and rivastig- mine [ri-va-STIG-meen]. All of them have some selectivity for AChE Nausea in the CNS, as compared to the periphery. Galantamine may also augment the action of acetylcholine at nicotinic receptors in the CNS. At best, these compounds provide a modest reduction in the rate of loss of cognitive functioning in Alzheimer patients. Rivastigmine is the only agent approved for the management of dementia associated with Parkinson’s disease and also the only AChE inhibitor available as a transdermal formulation. Rivastigmine is hydrolyzed by AChE to Diarrhea a carbamylate metabolite and has no interactions with drugs that alter the activity of CYP450 enzymes. The other agents are substrates for CYP450 and have a potential for such interactions. Common adverse effects include nausea, diarrhea, vomiting, anorexia, tremors, brady- cardia, and muscle cramps (Figure 8.13). Anorexia B. NMDA receptor antagonist Stimulation of glutamate receptors in the CNS appears to be criti- cal for the formation of certain memories. However, overstimulation of glutamate receptors, particularly of the NMDA type, may result in excitotoxic effects on neurons and is suggested as a mechanism for neurodegenerative or apoptotic (programmed cell death) processes. Myalgia Binding of glutamate to the NMDA receptor assists in the opening of an ion channel that allows Ca2+ to enter the neuron. Excess intracellular Ca2+ can activate a number of processes that ultimately damage neu- rons and lead to apoptosis. Memantine [meh-MAN-teen] is an NMDA receptor antagonist indicated for moderate to severe Alzheimer’s dis- Figure 8.13 ease. It acts by blocking the NMDA receptor and limiting Ca2+ influx Adverse effects of AChE inhibitors. into the neuron, such that toxic intracellular levels are not achieved. Memantine is well tolerated, with few dose-dependent adverse events. Expected side effects, such as confusion, agitation, and restlessness, are indistinguishable from the symptoms of Alzheimer’s disease. Given its different mechanism of action and possible neuroprotective effects, memantine is often given in combination with an AChE inhibitor. VIII. DRUGS USED IN MULTIPLE SCLEROSIS Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the CNS. The course of MS is variable. For some, MS may consist of one or two acute neurologic episodes. In others, it is a chronic, relapsing, VIII. Drugs Used in Multiple Sclerosis 117 or progressive disease that may span 10 to 20 years. Historically, cor- ticosteroids (for example, dexamethasone and prednisone) have been used to treat acute exacerbations of the disease. Chemotherapeutic agents, such as cyclophosphamide and azathioprine, have also been used. A. Disease-modifying therapies Drugs currently approved for MS are indicated to decrease relapse rates or in some cases to prevent accumulation of disability. The major target of these medications is to modify the immune response through inhibition of white blood cell–mediated inflammatory processes that eventually lead to myelin sheath damage and decreased or inappro- priate axonal communication between cells. 1. Interferon β1a and interferon β1b: The immunomodulatory effects of interferon [in-ter-FEER-on] help to diminish the inflam- matory responses that lead to demyelination of the axon sheaths. Adverse effects of these medications may include depression, local injection site reactions, hepatic enzyme increases, and flu- like symptoms. 2. Glatiramer: Glatiramer [gluh-TEER-a-mur] is a synthetic poly- peptide that resembles myelin protein and may act as a decoy to T-cell attack. Some patients experience a postinjection reaction that includes flushing, chest pain, anxiety, and itching. It is usually self-limiting. 3. Fingolimod: Fingolimod [fin-GO-li-mod] is an oral drug that alters lymphocyte migration, resulting in fewer lymphocytes in the CNS. Fingolimod may cause first-dose bradycardia and is associated with an increased risk of infection and macular edema. 4. Teriflunomide: Teriflunomide [te-ree-FLOO-no-mide] is an oral pyrimidine synthesis inhibitor that leads to a lower concentration of active lymphocytes in the CNS. Teriflunomide may cause elevated liver enzymes. It should be avoided in pregnancy. 5. Dimethyl fumarate: Dimethyl fumarate [dye-METH-il FOO-ma- rate] is an oral agent that may alter the cellular response to oxida- tive stress to reduce disease progression. Flushing and abdominal pain are the most common adverse events. 6. Natalizumab: Natalizumab [na-ta-LIZ-oo-mab] is a monoclonal antibody indicated for MS in patients who have failed first-line therapies. 7. Mitoxantrone: Mitoxantrone [my-toe-ZAN-trone] is a cytotoxic anthracycline analog that kills T cells and may also be used for MS. B. Symptomatic treatment Many different classes of drugs are used to manage symptoms of MS such as spasticity, constipation, bladder dysfunction, and depres- sion. Dalfampridine [DAL-fam-pre-deen], an oral potassium channel blocker, improves walking speeds in patients with MS. It is the first drug approved for this use. 118 8. Drugs for Neurodegenerative Diseases IX. DRUGS USED IN AMYOTROPHIC LATERAL SCLEROSIS ALS is characterized by progressive degeneration of motor neurons, resulting in the inability to initiate or control muscle movement. Riluzole [RIL-ue-zole], an NMDA receptor antagonist, is currently the only drug indicated for the management of ALS. It is believed to act by inhibiting glutamate release and blocking sodium channels. Riluzole may improve survival time and delay the need for ventilator support in patients suffer- ing from ALS. Study Questions Choose the ONE best answer. 8.1 Which one of the following combinations of antiparkin- Correct answer = B. To reduce the dose of levodopa and its sonian drugs is an appropriate treatment plan? peripheral side effects, the peripheral decarboxylase inhibitor, A. Amantadine, carbidopa, and entacapone. carbidopa, is coadministered. As a result of this combination, B. Levodopa, carbidopa, and entacapone. more levodopa is available for metabolism by catechol-O- methyltransferase (COMT) to 3-O-methyldopa, which com- C. Pramipexole, carbidopa, and entacapone. petes with levodopa for the active transport processes into D. Ropinirole, selegiline, and entacapone. the CNS. By administering entacapone (an inhibitor of E. Ropinirole, carbidopa, and selegiline. COMT), the competing product is not formed, and more levodopa enters the brain. The other choices are not appro- priate, because neither peripheral decarboxylase nor COMT nor monoamine oxidase metabolizes amantadine or the direct-acting dopamine agonists, ropinirole and pramipexole. 8.2 Peripheral adverse effects of levodopa, including Correct answer = C. Carbidopa inhibits the peripheral nausea, hypotension, and cardiac arrhythmias, can be decarboxylation of levodopa to dopamine, thereby dimin- diminished by including which of the following drugs in ishing the gastrointestinal and cardiovascular side effects of the therapy? levodopa. The other agents listed do not ameliorate adverse A. Amantadine. effects of levodopa. B. Ropinirole. C. Carbidopa. D. Tolcapone. E. Pramipexole. 8.3 Which of the following antiparkinsonian drugs may cause vasospasm? Correct answer = B. Bromocriptine is a dopamine receptor agonist that may cause vasospasm. It is contraindicated in A. Amantadine. patients with peripheral vascular disease. Ropinirole directly B. Bromocriptine. stimulates dopamine receptors, but it does not cause vaso- C. Carbidopa. spasm. The other drugs do not act directly on dopamine receptors. D. Entacapone. E. Ropinirole. 8.4 Modest improvement in the memory of patients with Correct answer = B. AChE inhibitors, such as rivastigmine, Alzheimer’s disease may occur with drugs that increase increase cholinergic transmission in the CNS and may transmission at which of the following receptors? cause a modest delay in the progression of Alzheimer’s dis- A. Adrenergic. ease. Increased transmission at the other types of recep- B. Cholinergic. tors listed does not result in improved memory. C. Dopaminergic. D. GABAergic. E. Serotonergic. Study Questions 119 8.5 Which medication is a glutamate receptor antagonist that Correct answer = D. When combined with an acetylcholin- can be used in combination with an acetylcholinesterase esterase inhibitor, memantine has modest efficacy in keep- inhibitor to manage the symptoms of Alzheimer’s disease? ing patients with Alzheimer’s disease at or above baseline A. Rivastigmine. for at least 6 months and may delay disease progression. B. Ropinirole. C. Fluoxetine. D. Memantine. E. Donepezil. 8.6 Which of the following agents is available as a patch Correct answer = A. Rivastigmine is the only agent avail- for once-daily use and is likely to provide steady drug able as a transdermal delivery system for the treatment of levels to treat Alzheimer’s disease? Alzheimer’s disease. It may also be used for dementia asso- A. Rivastigmine. ciated with Parkinson’s disease. B. Donepezil. C. Memantine. D. Galantamine. E. Glatiramer. 8.7 Which of the following is the only medication that is Correct answer = D. Riluzole continues to be the only agent approved for the management of amyotrophic lateral FDA approved for the debilitating and lethal illness of ALS. sclerosis? It is used to, ideally, delay the progression and need for ven- A. Pramipexole. tilator support in severe patients. B. Selegiline. C. Galantamine. D. Riluzole. E. Glatiramer. 8.8 Which of the following medications reduces immune Correct answer = C. Teriflunomide is believed to exert its system–mediated inflammation via inhibition of disease modifying and anti-inflammatory effects by inhibit- pyrimidine synthesis to reduce the number of activated ing the enzyme dihydro-orotate dehydrogenase to reduce lymphocytes in the CNS? pyrimidine synthesis. A. Riluzole. B. Rotigotine. C. Teriflunomide. D. Dexamethasone. 8.9 Which of the following agents may cause tremors as Correct answer = C. Though rivastigmine is an acetyl- a side effect and, thus, should be used with caution in cholinesterase inhibitor, which can cause tremors as an patients with Parkinson’s disease, even though it is also adverse effect, its use is not contraindicated in patients with indicated for the treatment of dementia associated with Parkinson’s disease, as this agent is also the only medi- Parkinson’s disease? cation approved for dementia associated with Parkinson’s A. Benztropine. disease. It should be used with caution, as it may worsen the parkinsonian-related tremors. A risk–benefit discussion B. Rotigotine. should occur with the patient and the caregiver before riv- C. Rivastigmine. astigmine is used. D. Dimethyl fumarate. 8.10 Which of the following agents exerts its therapeutic Correct answer = A. Dalfampridine is a potassium channel effect in multiple sclerosis via potassium channel blocker and is the only agent that is indicated to improve blockade? walking speed in patients with MS. A. Dalfampridine. B. Donepezil. C. Riluzole. D. Bromocriptine. Anxiolytic and Hypnotic Drugs Jose A. Rey 9 I. OVERVIEW BENZODIAZEPINES Disorders involving anxiety are among the most common mental disorders. Alprazolam XANAX Anxiety is an unpleasant state of tension, apprehension, or uneasiness Chlordiazepoxide LIBRIUM (a fear that arises from either a known or an unknown source). The physical Clonazepam KLONOPIN symptoms of severe anxiety are similar to those of fear (such as tachy- Clorazepate TRANXENE cardia, sweating, trembling, and palpitations) and involve sympathetic acti- Diazepam VALIUM, DIASTAT vation. Episodes of mild anxiety are common life experiences and do not Estazolam warrant treatment. However, severe, chronic, debilitating anxiety may be Flurazepam DALMANE treated with antianxiety drugs (sometimes called anxiolytics) and/or some Lorazepam ATIVAN form of psychotherapy. Because many antianxiety drugs also cause some Midazolam VERSED sedation, they may be used clinically as both anxiolytic and hypnotic (sleep- Oxazepam inducing) agents. Figure 9.1 summarizes the anxiolytic and hypnotic agents. Quazepam DORAL Some antidepressants are also indicated for certain anxiety disorders; how- Temazepam RESTORIL ever, they are discussed with other antidepressants (see Chapter 10). Triazolam HALCION BENZODIAZEPINE ANTAGONIST Flumazenil ROMAZICON II. BENZODIAZEPINES OTHER ANXIOLYTIC DRUGS Antidepressants VARIOUS (SEE CHAPTER 10) Benzodiazepines are widely used anxiolytic drugs. They have largely Buspirone BUSPAR replaced barbiturates and meprobamate in the treatment of anxiety and insomnia, because benzodiazepines are generally considered to be safer BARBITURATES and more effective (Figure 9.2). Though benzodiazepines are commonly Amobarbital AMYTAL used, they are not necessarily the best choice for anxiety or insomnia. Pentobarbital NEMBUTAL Certain antidepressants with anxiolytic action, such as the selective sero- Phenobarbital LUMINAL SODIUM tonin reuptake inhibitors, are preferred in many cases, and nonbenzodiaz- Secobarbital SECONAL epine hypnotics and antihistamines may be preferable for insomnia. Thiopental PENTOTHAL OTHER HYPNOTIC AGENTS A. Mechanism of action Antihistamines VARIOUS (SEE CHAPTER 30) The targets for benzodiazepine actions are the γ-aminobutyric acid Doxepin SILENOR (GABAA) receptors. [Note: GABA is the major inhibitory neurotrans- Eszopiclone LUNESTA mitter in the central nervous system (CNS).] The GABAA receptors Ramelteon ROZEREM are composed of a combination of five α, β, and γ subunits that span Zaleplon SONATA the postsynaptic membrane (Figure 9.3). For each subunit, many Zolpidem AMBIEN, INTERMEZZO, ZOLPIMIST subtypes exist (for example, there are six subtypes of the α subunit). Binding of GABA to its receptor triggers an opening of the central ion channel, allowing chloride through the pore (Figure 9.3). The influx of Figure 9.1 chloride ions causes hyperpolarization of the neuron and decreases Summary of anxiolytic and hypnotic neurotransmission by inhibiting the formation of action potentials. drugs. 121 122 9. Anxiolytic and Hypnotic Drugs Benzodiazepines modulate GABA effects by binding to a specific, Benzodiazepines are relatively high-affinity site (distinct from the GABA-binding site) located at the safe, because the lethal dose is over 1000-fold greater than interface of the α subunit and the γ subunit on the GABAA receptor the typical therapeutic dose. (Figure 9.3). [Note: These binding sites are sometimes labeled “benzo- diazepine (BZ) receptors.” Common BZ receptor subtypes in the CNS are designated as BZ1 or BZ2 depending on whether the binding site Morphine includes an α1 or α2 subunit, respectively.] Benzodiazepines increase hlorpromazine Chlorpromazine the frequency of channel openings produced by GABA. [Note: Binding of a benzodiazepine to its receptor site increases the affinity of GABA Phenobarbital for the GABA-binding site (and vice versa).] The clinical effects of the Diazepam various benzodiazepines correlate well with the binding affinity of each drug for the GABA receptor–chloride ion channel complex. 0 20 40 1000 Ratio = Lethal dose B. Actions Effective dose All benzodiazepines exhibit the following actions to some extent: Figure 9.2 Ratio of lethal dose to effective 1. Reduction of anxiety: At low doses, the benzodiazepines are dose for morphine (an opioid, see anxiolytic. They are thought to reduce anxiety by selectively Chapter 14), chlorpromazine enhancing GABAergic transmission in neurons having the α2 sub- (an antipsychotic, see Chapter 11), unit in their GABAA receptors, thereby inhibiting neuronal circuits in and the anxiolytic, hypnotic drugs, the limbic system of the brain. phenobarbital and diazepam. Cl– A Receptor empty (no agonists) Cl– β α α β γ Empty receptor is inactive, α and the coupled chloride channel is closed. Cl– B Receptor GABA binding GABA Binding of GABA causes the chloride ion channel to open, leading to hyper- polarization of the cell. Cl– Cl– C Receptor GABA Benzodiazepine binding GABA and benzodiazepine Binding of GABA is enhanced by benzo- diazepine, resulting in a Entry of Cl– hyperpolarizes the cell, making greater entry of chloride it more difficult to depolarize, and therefore ion. reduces neural excitability. Cl– Cl– Cl– Figure 9.3 Schematic diagram of benzodiazepine–GABA–chloride ion channel complex. GABA = γ-aminobutyric acid. II. Benzodiazepines 123 2. Sedative/hypnotic: All benzodiazepines have sedative and calm- ing properties, and some can produce hypnosis (artificially pro- duced sleep) at higher doses. The hypnotic effects are mediated by the α1-GABAA receptors. 3. Anterograde amnesia: Temporary impairment of memory with use of the benzodiazepines is also mediated by the α1-GABAA receptors. The ability to learn and form new memories is also impaired. 4. Anticonvulsant: Several benzodiazepines have anticonvulsant activity. This effect is partially, although not completely, mediated by α1-GABAA receptors. 5. Muscle relaxant: At high doses, the benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located. Baclofen [BAK-loe-fen] is a muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord. C. Therapeutic uses The individual benzodiazepines show small differences in their rela- tive anxiolytic, anticonvulsant, and sedative properties. However, the duration of action varies widely among this group, and pharmacoki- netic considerations are often important in choosing one benzodiaz- epine over another. 1. Anxiety disorders: Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder, generalized anxiety disorder (GAD), social anxiety disorder, performance anxi- ety, posttraumatic stress disorder, obsessive–compulsive disorder, and extreme anxiety associated with phobias, such as fear of flying. The benzodiazepines are also useful in treating anxiety related to depression and schizophrenia. These drugs should be reserved for severe anxiety only and not used to manage the stress of everyday life. Because of their addiction potential, they should only be used for short periods of time. The longer-acting agents, such as clonaze- pam [kloe-NAZ-e-pam], lorazepam [lor-AZ-e-pam], and diazepam [dye-AZ-e-pam], are often preferred in those patients with anxiety that may require prolonged treatment. The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects. [Note: Tolerance (that is, decreased responsiveness to repeated doses of the drug) occurs when used for more than 1 to 2 weeks. Tolerance is associated with a decrease in GABA recep- tor density. Cross-tolerance exists between the benzodiazepines and ethanol.] For panic disorders, alprazolam [al-PRAY-zoe-lam] is effec- tive for short- and long-term treatment, although it may cause with- drawal reactions in about 30% of patients. 2. Sleep disorders: A few of the benzodiazepines are useful as hyp- notic agents. These agents decrease the latency to sleep onset and increase stage II of non–rapid eye movement (REM) sleep. Both REM sleep and slow-wave sleep are decreased. In the treat- ment of insomnia, it is important to balance the sedative effect needed at bedtime with the residual sedation (“hangover”) upon 124 9. Anxiolytic and Hypnotic Drugs awakening. Commonly prescribed benzodiazepines for sleep dis- orders include intermediate-acting temazepam [te-MAZ-e-pam] and short-acting triazolam [try-AY-zoe-lam]. Long-acting fluraz- epam [flure-AZ-e-pam] is rarely used, due to its extended half-life, which may result in excessive daytime sedation and accumulation of the drug, especially in the elderly. Estazolam [eh-STAY-zoe-lam] DURATION OF ACTION and quazepam [QUAY-ze-pam] are considered intermediate- and OF BENZODIAZEPINES long-acting agents, respectively. a. Temazepam: This drug is useful in patients who experience frequent wakening. However, because the peak sedative effect Long-acting occurs 1 to 3 hours after an oral dose, it should be given 1 to 2 hours before bedtime. b. Triazolam: Whereas temazepam is useful for insomnia caused by the inability to stay asleep, short-acting triazolam is effec- tive in treating individuals who have difficulty in going to sleep. Tolerance frequently develops within a few days, and withdrawal of the drug often results in rebound insomnia. Therefore, this Clorazepate drug is not a preferred agent, and it is best used intermittently. Chlordiazepoxide In general, hypnotics should be given for only a limited time, Diazepam Flurazepam usually less than 2 to 4 weeks. Quazepam 3. Amnesia: The shorter-acting agents are often employed as pre- medication for anxiety-provoking and unpleasant procedures, such Intermediate-acting as endoscopy, dental procedures, and angioplasty. They cause a form of conscious sedation, allowing the person to be receptive to 24 instructions during these procedures. Midazolam [mi-DAY-zoe-lam] is a benzodiazepine used to facilitate amnesia while causing seda- 18 6 tion prior to anesthesia. 12 4. Seizures: Clonazepam is occasionally used as an adjunctive ther- apy for certain types of seizures, whereas lorazepam and diazepam 10–20 Hours are the drugs of choice in terminating status epilepticus (see Alprazolam Chapter 12). Due to cross-tolerance, chlordiazepoxide [klor-di-az-e- Estazolam Lorazepam POX-ide], clorazepate [klor-AZ-e-pate], diazepam, lorazepam, and Temazepam oxazepam [ox-AZ-e-pam] are useful in the acute treatment of alco- hol withdrawal and reduce the risk of withdrawal-related seizures. 5. Muscular disorders: Diazepam is useful in the treatment of skel- Short-acting etal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis 12 1 11 2 and cerebral palsy. 10 9 3 8 4 D. Pharmacokinetics 7 5 6 1. Absorption and distribution: The benzodiazepines are lipophilic. 3–8 Hours They are rapidly and completely absorbed after oral administra- tion, distribute throughout the body and penetrate into the CNS. Oxazepam Triazolam 2. Duration of action: The half-lives of the benzodiazepines are important clinically, because the duration of action may deter- mine the therapeutic usefulness. The benzodiazepines can be Figure 9.4 roughly divided into short-, intermediate-, and long-acting groups Comparison of the durations of action (Figure 9.4). The longer-acting agents form active metabolites of the benzodiazepines. with long half-lives. However, with some benzodiazepines, the III. Benzodiazepine Antagonist 125 clinical duration of action does not correlate with the actual half-life (otherwise, a dose of diazepam could conceivably be given only every other day, given its active metabolites). This may be due to receptor dissociation rates in the CNS and subsequent redistribu- tion to fatty tissues and other areas. 3. Fate: Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the hepatic microsomal system to compounds that are also active. For these benzodiazepines, the apparent half-life of the drug represents the combined actions of the parent drug and its metabolites. Drug effects are terminated not only by excretion but also by redistribution. The benzodiazepines are excreted in the urine as glucuronides or oxidized metabolites. All benzodiazepines cross the placenta and may depress the CNS of the newborn if given before birth. The benzodiazepines are not recommended for use during pregnancy. Nursing infants may also be exposed to the drugs in breast milk. E. Dependence Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given for a prolonged period. All benzodiazepines are controlled substances. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including con- fusion, anxiety, agitation, restlessness, insomnia, tension, and (rarely) seizures. Benzodiazepines with a short elimination half-life, such as triazolam, induce more abrupt and severe withdrawal reactions than those seen with drugs that are slowly eliminated such as flurazepam The drugs that are more potent and rapidly eliminated (Figure 9.5). (for example, triazolam) have more frequent and severe withdrawal problems. F. Adverse effects Drowsiness and confusion are the most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activi- ties that require fine motor coordination, such as driving an automo- bile. Cognitive impairment (decreased long-term recall and retention Triazolam of new knowledge) can occur with use of benzodiazepines. Triazolam Alprazolam often shows a rapid development of tolerance, early morning insom- Temazepam nia, and daytime anxiety, as well as amnesia and confusion. Diazepam Benzodiazepines should be used cautiously in patients with liver dis- Flurazepam zepam ease. These drugs should be avoided in patients with acute angle- closure glaucoma. Alcohol and other CNS depressants enhance the -40 0 -20 0 20 40 60 80 sedative–hypnotic effects of the benzodiazepines. Benzodiazepines Increase in total wake are, however, considerably less dangerous than the older anxiolytic time from baseline (%) and hypnotic drugs. As a result, a drug overdose is seldom lethal unless The less potent and more other central depressants, such as alcohol, are taken concurrently. slowly eliminated drugs (for example, flurazepam ) continue to improve sleep even after discontinuation. III. BENZODIAZEPINE ANTAGONIST Flumazenil [floo-MAZ-eh-nill] is a GABA receptor antagonist that can rap- Figure 9.5 idly reverse the effects of benzodiazepines. The drug is available for intra- Frequency of rebound insomnia venous (IV) administration only. Onset is rapid, but the duration is short, resulting from discontinuation of with a half-life of about 1 hour. Frequent administration may be necessary benzodiazepine therapy. 126 9. Anxiolytic and Hypnotic Drugs Initiate therapy with a benzodiazepine, such as lorazepam Daily mg dose escitalopram Daily mg dose lorazepam 1 10 Concomitant therapy with Tapered antidepressant, such withdrawal as escitalopram of benzodiazepine 0 0 0 14 Days 28 42 56 Figure 9.6 Treatment guideline for persistent anxiety. to maintain reversal of a long-acting benzodiazepine. Administration of flumazenil may precipitate withdrawal in dependent patients or cause Note that seizures if a benzodiazepine is used to control seizure activity. Seizures buspirone shows may also result if the patient has a mixed ingestion with tricyclic antide- less interference with motor pressants or antipsychotics. Dizziness, nausea, vomiting, and agitation functions, a benefit are the most common side effects. that is particulary important in elderly patients. IV. OTHER ANXIOLYTIC AGENTS Nausea 8 A. Antidepressants 0 Many antidepressants are effective in the treatment of chronic 7 17 anxiety disorders and should be considered as first-line agents, Dizziness especially in patients with concerns for addiction or dependence. 0 10 Selective serotonin reuptake inhibitors (SSRIs, such as escitalo- pram or paroxetine) or serotonin/norepinephrine reuptake inhibitors 3 13 (SNRIs), such as venlafaxine or duloxetine) may be used alone or Headache 7 prescribed in combination with a low dose of a benzodiazepine dur- ing the first weeks of treatment (Figure 9.6). After 4 to 6 weeks, 0 10 when the antidepressant begins to produce an anxiolytic effect, the Decreased concentration 33 benzodiazepine dose can be tapered. SSRIs and SNRIs have a lower potential for physical dependence than the benzodiazepines and have become first-line treatment for GAD. While only certain 0 10 SSRIs or SNRIs have been approved for the treatment of GAD, Drowsiness 30 the efficacy of these drugs for GAD is most likely a class effect. Thus, the choice among these antidepressants should be based 10 upon side effects and cost. Long-term use of antidepressants and Fatigue 27 benzodiazepines for anxiety disorders is often required to maintain ongoing benefit and prevent relapse. Buspirone Alprazolam B. Buspirone Buspirone [byoo-SPYE-rone] is useful for the chronic treatment of Figure 9.7 GAD and has an efficacy comparable to that of the benzodiazepines. Comparison of common adverse It has a slow onset of action and is not effective for short-term or effects of buspirone and alprazolam. Results are expressed as the “as-needed” treatment of acute anxiety states. The actions of buspi- percentage of patients showing each rone appear to be mediated by serotonin (5-HT1A) receptors, although symptom. it also displays some affinity for D2 dopamine receptors and 5-HT2A V. Barbiturates 127 serotonin receptors. Thus, its mode of action differs from that of the benzodiazepines. In addition, buspirone lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines. The frequency of adverse effects is low, with the most common effects being headaches, dizziness, nervousness, nausea, and light-headedness. Sedation and psychomotor and cognitive dysfunction are minimal, and dependence is unlikely. Buspirone does not potentiate the CNS depression of alco- hol. Figure 9.7 compares some common adverse effects of buspirone and the benzodiazepine alprazolam. DURATION OF ACTION OF BARBITURATES V. BARBITURATES The barbiturates were formerly the mainstay of treatment to sedate Long-acting patients or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance and physical dependence and are associated with very severe withdrawal symptoms. All barbiturates are controlled substances. Certain barbiturates, such as the very short-acting thiopental, have been used to induce anesthesia but are infrequently used today due to the advent of newer agents with fewer adverse effects. Phenobarbital A. Mechanism of action The sedative–hypnotic action of the barbiturates is due to their interac- tion with GABAA receptors, which enhances GABAergic transmission. Short-acting The binding site of barbiturates on the GABA receptor is distinct from 12 that of the benzodiazepines. Barbiturates potentiate GABA action on 11 1 2 chloride entry into the neuron by prolonging the duration of the chlo- 10 9 3 ride channel openings. In addition, barbiturates can block excitatory 8 4 glutamate receptors. Anesthetic concentrations of pentobarbital also 7 5 6 block high-frequency sodium channels. All of these molecular actions lead to decreased neuronal activity. 3–8 Hours Pentobarbital B. Actions Secobarbital Amobarbital Barbiturates are classified according to their duration of action (Figure 9.8). For example, ultra–short-acting thiopental [thye-oh- PEN-tal] acts within seconds and has a duration of action of about Ultra-short-acting 30 minutes. In contrast, long-acting phenobarbital [fee-noe-BAR-bi- tal] has a duration of action greater than a day. Pentobarbital [pen- toe-BAR-bi-tal], secobarbital [see-koe-BAR-bi-tal], amobarbital 0 [am-oh-BAR-bi-tal], and butalbital [bu-TAL-bi-tal] are short-acting 50 10 barbiturates. 40 20 30 1. Depression of CNS: At low doses, the barbiturates produce sedation (have a calming effect and reduce excitement). At higher 20 Minutes doses, the drugs cause hypnosis, followed by anesthesia (loss Thiopental of feeling or sensation), and, finally, coma and death. Thus, any degree of depression of the CNS is possible, depending on the dose. Barbiturates do not raise the pain threshold and have no Figure 9.8 analgesic properties. They may even exacerbate pain. Chronic use Barbiturates classified according to leads to tolerance. their durations of action. 128 9. Anxiolytic and Hypnotic Drugs 2. Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and overdosage is followed by respiratory depression and death. Potential for addiction C. Therapeutic uses 1. Anesthesia: The ultra–sho