Anxiolytic and Hypnotic Drugs PDF

# Anxiolytic and Hypnotic Drugs Anxiety is an unpleasant state of tension, apprehension, or uneasiness—a fear that seems to arise from a sometimes unknown source. The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and in...

# Anxiolytic and Hypnotic Drugs Anxiety is an unpleasant state of tension, apprehension, or uneasiness—a fear that seems to arise from a sometimes unknown source. The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. Episodes of mild anxiety are common life experiences and do not warrant treatment. However, the symptoms of severe, chronic, debilitating anxiety may be treated with antianxiety drugs (sometimes called anxiolytic or minor tranquilizers) and/or some form of behavioral or psychotherapy. Because many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic (sleep-inducing) agents. In addition, some have anticonvulsant activity. ## Benzodiazepines - Benzodiazepines are the most widely used anxiolytic drugs. - They have largely replaced barbiturates and meprobamate in the treatment of anxiety, because the benzodiazepines are safer and more effective. ## Mechanism of action - The targets for benzodiazepine actions are the γ-aminobutyric acid (GABA) receptors. - GABA is the major inhibitory neurotransmitter in the central nervous system. - Benzodiazepines modulate the GABA effects by binding to a specific, high-affinity site located at the interface of the α subunit and the γ subunit. - These binding sites are sometimes labeled benzodiazepine receptors. - Two benzodiazepine receptor subtypes commonly found in the CNS have been designated as BZ1 and BZ2 receptor depending on whether their composition includes the α1 subunit or the α2 subunit, respectively. - Binding of GABA to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride conductance. - Benzodiazepines increase the frequency of channel openings produced by GABA. - The influx of chloride ions causes a small hyperpolarization that moves the postsynaptic potential away from its firing threshold and, thus, inhibits the formation of action potentials. - Binding of a benzodiazepine to its receptor site will increase the affinity of GABA for the GABA-binding site without actually changing the total number of sites. ## Actions - The benzodiazepines have neither antipsychotic activity nor analgesic action, and they do not affect the autonomic nervous system. - All benzodiazepines exhibit the following actions to a greater or lesser extent: ### Reduction of anxiety: - At low doses, the benzodiazepines are anxiolytic. - They are thought to reduce anxiety by selectively enhancing GABAergic transmission in neurons having the α2 subunit in their GABA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain. ### Sedative and hypnotic actions: - All of the benzodiazepines used to treat anxiety have some sedative properties, and some can produce hypnosis (artificially produced sleep) at higher doses. - Their effects have been shown to be mediated by the α1-GABA receptors. ### Anterograde amnesia: - The temporary impairment of memory with use of the benzodiazepines is also mediated by the α1-GABA receptors. - This also impairs a person's ability to learn and form new memories. ### Anticonvulsant: - Several of the benzodiazepines have anticonvulsant activity and some are used to treat epilepsy (status epilepticus) and other seizure disorders. - This effect is partially, although not completely, mediated by α1-GABA receptors. ### 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-GABA receptors are largely located. - Baclofen is a muscle relaxant that is believed to affect GABAB receptors at the level of the spinal cord. ## Therapeutic uses ### Anxiety disorders: - Benzodiazepines are effective for the treatment of the anxiety symptoms. - These drugs should **NOT** be used to alleviate the normal stress of everyday life. - They should be reserved for continued severe anxiety, and then should only be used for short periods of time because of their addiction potential. - The longer-acting agents, such as clonazepam, lorazepam, and diazepam, are often preferred in those patients with anxiety that may require treatment for prolonged periods of time. - The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects. - Tolerance—that is, decreased responsiveness to repeated doses of the drug—occurs when used for more than one to two weeks. - Cross-tolerance exists among this group of agents with ethanol. - It has been shown that tolerance is associated with a decrease in GABA receptor density. ### Muscular disorders: - Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy. ### Amnesia: - The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty. - They also cause a form of conscious sedation, allowing the person to be receptive to instructions during these procedures. - Midazolam is an injectable-only benzodiazepine also used for the induction of anesthesia. ### Seizures: - Clonazepam is occasionally used in the treatment of certain types of epilepsy, whereas diazepam and lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status epilepticus. ### Sleep disorders: - Not all benzodiazepines are useful as hypnotic agents, although all have sedative or calming effects. - Commonly prescribed benzodiazepines for sleep disorders include long-acting flurazepam, intermediate-acting temazepam, and short-acting triazolam. - Unlike the benzodiazepines, at usual hypnotic doses, the nonbenzodiazepine drugs, zolpidem, and zaleplon, do not significantly alter the various sleep stages and, hence, are often the preferred hypnotics. - This may be due to their relative selectivity for the BZ1 receptor. #### Flurazepam: - This long-acting benzodiazepine significantly reduces both sleep-induction time and the number of awakenings, and it increases the duration of sleep. - Flurazepam has a long-acting effect and causes little rebound insomnia. - Flurazepam and its active metabolites have a half-life of approximately 85 hours, which may result in daytime sedation and accumulation of the drug. #### Temazepam: - This drug is useful in patients who experience frequent wakening; it should be given 1 to 2 hours before the desired bedtime. #### Triazolam: - Has a relatively short duration of action and, therefore, is used to induce sleep in patients with recurring insomnia. - Triazolam is effective in treating individuals who have difficulty in going to sleep. - In general, hypnotics should be given for only a limited time, usually less than 2 to 4 weeks. ## Pharmacokinetics ### Absorption and distribution: - The benzodiazepines are lipophilic, and they are rapidly and completely absorbed after oral administration and distribute throughout the body. ### 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. - The drugs' effects are terminated not only by excretion but also by redistribution. - The benzodiazepines are excreted in the urine as glucuronides or oxidized metabolites. - All the benzodiazepines cross the placental barrier and may depress the CNS of the newborn if given before birth. - Nursing infants may also become exposed to the drugs in breast milk. ## Dependence - Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over a prolonged period. - Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, 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. ## Adverse effects - **Drowsiness and confusion:** Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. - **Precautions:** Benzodiazepines should be used cautiously in treating patients with liver disease. Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines. ## Benzodiazepine Antagonist - **Flumazenil** is a GABA-receptor antagonist that can rapidly reverse the effects of benzodiazepines. - The drug is available for intravenous administration only. - Onset is rapid but duration is short, with a half-life of about 1 hour. - Frequent administration may be necessary to maintain reversal of a long-acting benzodiazepine. - Administration of flumazenil may precipitate withdrawal in dependent patients or cause seizures if a benzodiazepine is used to control seizure activity. - Dizziness, nausea, vomiting, and agitation are the most common side effects. # Other Anxiolytic Agents ## Buspirone - Buspirone is useful in the treatment of generalized anxiety disorder and has an efficacy comparable to that of the benzodiazepines. - The actions of buspirone appear to be mediated by serotonin (5-HT1A) receptors, although other receptors could be involved, because buspirone displays some affinity for DA2 dopamine receptors and 5-HT2A serotonin receptors. - Thus, its mode of action differs from that of the benzodiazepines. - Buspirone has the disadvantage of a slow onset of action. ## Hydroxyzine - Hydroxyzine is an antihistamine with antiemetic activity. - It has a low tendency for habituation and, thus, is useful for patients with anxiety who have a history of drug abuse. - It is also often used for sedation prior to dental procedures or surgery. - Drowsiness is a possible adverse effect. ## Antidepressants - Many antidepressants have proven efficacy in managing the long-term symptoms of chronic anxiety disorders and should be seriously considered as first-line agents, especially in patients with concerns for addiction or dependence or a history of addiction or dependence to other substances. - The SSRIs, TCAs, venlafaxine, duloxetine and MAOIs all have potential usefulness in treating anxiety. # Pharmacology 4th class ## Drugs Affecting the central nervous system ### (treatment of neurodegenerative disease) ## Overview - Most drugs that affect the central nervous system (CNS) act by altering some step in the neurotransmission process. - Drugs CNS may act presynaptically by influencing the production, storage, release, or termination of action of neurotransmitter agents may activate or block postsynaptic receptors. ## Neurotransmission in the CNS - In many ways, the basic functioning of neurons in the CNS is similar to that of the autonomic nervous system described in [insert missing document text] For example, transmission of information in the CNS and in the periphery both involve the release of neurotransmitters that diffuse across the synaptic space to bind to specific receptors on the postsynaptic neuron. - In both systems, the recognition of the neurotransmitter by the membrane receptor [insert missing document text] of the postsynaptic neuron triggers intracellular changes. ## Synaptic Potentials - In the CNS, receptors at most synapses are coupled to ion channels; that is, binding of the neurotransmitter to the postsynaptic membrane receptors results in a rapid but transient opening of ion channels. - Open channels allow specific ions inside and cell membrane to flow down their concentration gradients. - The resulting change in the ionic composition across the membrane neuron alters the postsynaptic potential, producing either depolarization or hyperpolarization of the postsynaptic membrane depending on the specific ions that move and the direction of their movement. ### A. Excitatory pathways - Neurotransmitters can be classified as either excitatory or inhibitory, depending on the nature of the action they elicit. - Excitatory neurons causes a movement of ions that results in a depolarization of the postsynaptic membrane. - These excit postsynaptic potentials (EPSP) are generated by the following: - Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or acetylcholine, which bind to receptors on the postsynaptic cell membra causes a transient increase in the permeability of sodium (Na+) ions. - The influx of Na+ causes a weak depolarization or moves the postsynaptic potential toward its firing threshold. - If the number of stimulated excitatory neurons increases, excitatory neurotransmitter is released. ### B. Inhibitory pathways - Stimulation of inhibitory neurons causes movement of ions that results in a hyperpolarization of the postsynaptic membrane. - These inhibitory postsynaptic potentials (IPSP) are generated by the following: - Stimulation of inhibitory neurons releases neurotransmitter molecules, such as d-aminobutyric acid (GABA) or glycine, 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-) ions. - The influx of Cl- and efflux of K+ cause a weak hyperpolarization or IPSP that moves the postsynapticpotential away from its firing threshold. This diminishes the generation of action potentials. ## Neurodegenerative Diseases - Neurodegenerative diseases of the CNS include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. - These devastating illnesses are characterized by the progressive loss of selected neurons in discrete brain areas, resulting characteristic disorders of movement, cognition, or both. - For example, Alzheimer's disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Maynert, whereas Parkinson's disease is associated with a loss of dopaminergic neurons in the substantia nigra. - The most prevalent of these disorders is Alzheimer's disease. ## V. Overview of Parkinson's Disease - Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. - Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals. ### A. Etiology - The cause of Parkinson's disease is unknown for most patients. - The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum—parts of the brain's basal ganglia system that are involved in motor control. The loss of dopamine neurons in the substantia nigra is evidenced by diminished overall uptake of dopamine precursors in this region. - Genetic factors do not play a dominant role in the etiology of Parkinson's disease, although they may exert some influence on an individual's susceptibility to the disease. ### Secondary parkinsonism: - Parkinsonian symptoms infrequently follow viral encephalitis or multiple small vascular lesions. - Drugs such as the phenothiazines and haloperidol, whose major pharmacologic action is blockade of dopamine receptors in the brain, may also produce parkinsonian symptoms. - These drugs should not be used in parkinsonian patients. ### B. Strategy of treatment - In addition to an abundance of inhibitory dopaminergic neurons, the neostriatum is also rich in excitatory cholinergic neurons oppose the action of dopamine. - Many of the symptoms of parkinsonism reflect an imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory dopaminergic neurons. - Therapy is aimed at restoring dopamine the basal ganglia and antagonizing the excitatory effect of cholinergic neurons, thus reestablishing the correct dopamine/acetylcholine balance. - Because long-term treatment with levodopa is limited by fluctuations in therapeutic responses, strategies to maintain dopamine levels as constant as possible have been devised. ## Drugs Used in Parkinson's Disease - Currently available drugs offer temporary relief from the symptoms of the disorder, but they do not arrest or reverse the neuronal degeneration caused by the disease. ### (Levodopa and carbidopa) - Levodopa is a metabolic precursor of dopamine. - It restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. - In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra (typically about [insert missing text] percent of normal) is adequate for conversion of levodopa to dopamine. - Thus, in new patients, the therapeutic response to levodopa consistent. - Unfortunately, with time, the number of neurons decreases, and fewer cells are capable of taking up exogenously administered levodopa and converting it to dopamine for subsequent storage and release. - Consequently, motor control fluctuation develops. - Relief provided by levodopa is only symptomatic, and it lasts only while the drug is present in the body. #### Mechanism of action: - **Levodopa:** Because parkinsonism results from insufficient dopamine in specific regions of the brain, attempts have been made to replenish the dopamine deficiency. - Dopamine itself does not cross the blood-brain barrier, but its immediate precursor, levodopa, is actively transported into the CNS and is converted to dopamine in the brain. - Large doses of levodopa are required, because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. - **Carbidopa:** The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa [kar-bi-DOE-pa], a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. - Carbidopa diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues; thus, it increases the availability of levodopa to the CNS. - The addition of carbidopa lowers the dose of levodopa needed by four- to five-fold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine. #### Actions: - Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism. #### Therapeutic uses: - Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson's disease. - In approximately two-thirds of patients with Parkinson's disease, levodopa-carbidopa treatment substantially reduces the severity of the disease for the first few years of treatment. #### Absorption and metabolism: 1. The drug is absorbed rapidly from the small intestine (when empty of food). 2. 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 concentrations of levodopa. - Motor fluctuations may cause the patient to suddenly lose normal mobility and experience tremors, cramps, and immobility. 3. Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa [insert missing text] into the CNS. 4. Large, neutral amino acids (for example, leucine and isoleucine) compete with levodopa [insert missing text] for absorption from the gut and for transport across the blood-brain barrier. 5. Levodopa should be taken on an empty stomach, typically 45 minutes before a meal. 6. Withdrawal from the drug must be gradual. #### Adverse effects: - **Peripheral effects:** Anorexia, nausea, and vomiting occur because of stimulation of the chemoreceptor trigger zone of the medulla. (Tachycardia and ventricular extra systoles result from dopaminergic action on the heart. Hypotension may also develop. - **CNS effects:** Visual and auditory hallucinations and abnormal involuntary movements (dyskinesias) may occur. These CNS effects are the opposite of parkinsonian symptoms and reflect the overactivity of dopamine at receptors in the basal ganglia. - Levodopa can also cause mood changes, depression, psychosis, and anxiety. #### Interactions: - The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness. - Concomitant administration of levodopa and monoamine oxidase (MAO) inhibitors, such as phenelzine, can produce a hypertensive crisis caused by enhanced catecholamine production. ### (Selegiline and Rasagiline):- - Selegiline, also called deprenyl selectively inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses but does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin) unless given at above recommended doses, where it loses its selectivity. - By thus decreasing the metabolism of dopamine, selegiline has been found to increase dopamine levels in the brain. - Therefore, it enhances the actions of levodopa when these drugs are administered together. - Selegiline substantially reduces the required dose of levodopa. - Rasagiline, an irreversible and selective inhibitor of brain (MAO) Type B, has five times the potency of selegiline. Unlike selegiline. ## Catechol-O-methyltransferase inhibitors - Normally, the methylation of levodopa by catechol-O-methyltransferase (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism. - However, when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS. - Inhibition of COMT by entacapone or tolcapone leads to decreased plasma concentrations of 3-O-methyldopa, increased central uptake of levodopa, and greater concentrations of brain dopamine. #### Pharmacokinetics: 1. Oral absorption of both drugs occurs readily and is not influenced by food. 2. They are extensively bound to plasma albumin (>98 percent), with limited volumes of distribution. 3. Tolcapone differs from entacapone in that the former penetrates the blood-brain barrier and inhibits COMT in the CNS. - However, the inhibition of COMT in the periphery appears to be the primary therapeutic action. 4. Tolcapone has a relatively long duration of action (probably due to its affinity for the enzyme) compared to entacapone, which requires more frequent dosing. 5. Both drugs are extensively metabolized and eliminated in the feces and urine. Dosage may need to be adjusted in patients with moderate or severe cirrhosis. #### Adverse effects: - Both drugs exhibit adverse effects that are observed in patients taking levodopa-carbidopa, including diarrhea, postural hypotension, nausea, anorexia, dyskinesias, hallucinations, and sleep disorders. - Most seriously, fulminating hepatic necrosis is associated with tolcapone use. - Therefore, it should be used-along with appropriate hepatic function monitoringâ€"only in patients in whom other modalities have failed. - Entacapone does not exhibit this toxicity and has largely replaced tolcapone. ## Dopamine-receptor agonists - This group of anti-Parkinson compounds includes bromocriptine, and pergolide an ergot derivative, and two newer, nonergot drugs, ropinirole, pramipexole and rotigotine. - These agents have durations of action longer than that of levodopa and, thus, have been effective in patients exhibiting fluctuations in their response to levodopa. - Initial therapy with the newer drugs is associated particularly with less risk of developing dyskinesias and motor fluctuations when compared to patients started with levodopa therapy. - Bromocriptine, pramipexole, and ropinirole are all effective in patients with advanced Parkinson's disease complicated by motor fluctuations and dyskinesias. - However, these drugs are ineffective in patients who have shown no therapeutic response to levodopa. - Apomorphine is also used in severe and advanced stages of the disease as an injectable dopamine agonist to supplement the oral medications commonly prescribed. ### (Bromocriptine): - Bromocriptine, a derivative of the vasoconstrictive alkaloid, ergotamine, is a dopamine-receptor agonist. - The dose is increased gradually during a period of 2 to 3 months. - Side effects severely limit the utility of the dopamine agonists. - The actions of bromocriptine are similar to those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent. ### (Apomorphine, pramipexole, ropinirole, and rotigotine):- - These are nonergot dopamine agonists that have been approved for the treatment of Parkinson's disease. - Pramipexole and ropinirole are agonists at dopamine receptors. - Apomorphine and rotigotine are newer dopamine agonists available in injectable and transdermal delivery systems, respectively. ## (Amantadine) - It was accidentally discovered that the antiviral drug amantadine which is effective in the treatment of influenza, has an antiparkinsonism action. - Amantadine has several effects on a number of neurotransmitters implicated in causing parkinsonism, including 1. increasing the release of dopamine, 2. blockading cholinergic receptors. 3. inhibiting the N-methyl-D-aspartate (NMDA) type of glutamate receptors. - Current evidence supports an action at NMDA receptors as the primary action at therapeutic concentrations. - [insert missing text] dopamine release is already at a maximum, amantadine has no effect.] #### Side effects: - The drug may cause restlessness, agitation, confusion, and hallucinations, and at high doses, it may induce acute toxic psychosis. - Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur. - Amantadine is less efficacious than levodopa, and tolerance develops more readily. - However, amantadine has fewer side effects. ## Antimuscarinic agents:- - The antimuscarinic agents are much less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. - The actions of benztropine ,trihexyphenidyl, procyclidine, and biperiden, orphenadrine are similar, although individual patients may respond more favorably to one drug. - All of these drugs can induce mood changes and produce xerostomia (dryness of the mouth) and visual problems, as do all muscarinic blockers. - They interfere with gastrointestinal peristalsis and are contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis. #### Adverse effects: - are similar to those caused by high doses of atropine, for example, pupillary dilation, confusion, hallucination, sinus tachycardia, urinary retention, constipation, and dry mouth.