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CNS Pharmacology - Leaderboard
CNS Pharmacology - Details
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| Adsorption distribution analgesics | Most sedative-hypnotic drugs are lipid-soluble and are absorbed well from the gastrointestinal tract, with good distribution to the brain. Drugs with the highest lipid solubility (eg, thiopental) enter the CNS rapidly and can be used as induction agents in anesthesia. The CNS effects of thiopental are terminated by rapid redistribution of the drug from brain to other highly perfused tissues, including skeletal muscle. Other drugs with a rapid onset of CNS action include eszopiclone, zaleplon, and zolpidem |
| Lorazepam oxazepam metabolism | Lorazepam and oxazepam undergo extrahepatic conjugation and do not form active metabolites. |
| Barbiturates metabolism | With the exception of phenobarbital, which is excreted partly unchanged in the urine, the barbiturates are extensively metabolized. |
| Metabolism stuff | Rapid metabolism by liver enzymes is responsible for the short duration of action of zolpidem. A biphasic release form of zolpidem extends its plasma half-life.Zaleplon undergoes even more rapid hepatic metabolism by aldehyde oxidase and cytochrome P450. Eszopiclone is also metabolized by cytochrome P450 with a half-life of 6 h. |
| Duration cns actives | The duration of CNS actions of sedative-hypnotic drugs ranges from just a few hours (eg, zaleplon < zolpidem = triazolam = eszopiclone < chloral hydrate) to more than 30 h (eg, chlordiazepoxide, clorazepate, diazepam, phenobarbital). |
| Benzodiazepines areas | Receptors for benzodiazepines (BZ receptors) are present in many brain regions, including the thalamus, limbic structures, and the cerebral cortex. |
| Benzodiazepine action | The BZ receptors form part of a GABAA receptorchloride ion channel macromolecular complex, a pentameric structure assembled from 5 subunits each with 4 transmembrane domains. A major isoform of the GABAA receptor consists of 2 α1, 2 β2, and 1 γ 2 subunits. In this isoform, the binding site for benzodiazepines is between an α1 and the γ 2 subunit. However, benzodiazepines also bind to other GABAA receptor isoforms that contain α2, α3, and α5 subunits.Binding of benzodiazepines facilitates the inhibitory actions of GABA, which are exerted through increased chloride ion conductance Benzodiazepines increase the frequency of GABA-mediated chloride ion channel opening. |
| Benzodiazepines reversal | Flumazenil reverses the CNS effects of benzodiazepines and is classified as an antagonist at BZ receptors. Certain β-carbolines have a high affinity for BZ receptors and can elicit anxiogenic and convulsant effects.These drugs are classified as inverse agonists |
| Barbiturates action area | Barbiturates depress neuronal activity in the midbrain reticular formation, facilitating and prolonging the inhibitory effects of GABA and glycine. |
| Barbiturates action | Barbiturates also bind to multiple isoforms of the GABAA receptor but at different sites from those with which benzodiazepines interact.Barbiturates increase the duration of GABA-mediated chloride ion channel opening. They may also block the excitatory transmitter glutamic acid, and, at high concentration, sodium channels. |
| Other cns drugs | The hypnotics zolpidem, zaleplon, and eszopiclone are not benzodiazepines but appear to exert their CNS effects via interaction with certain benzodiazepine receptors, classified as BZ1 or ω1 these drugs bind more selectively, interacting only with GABAA receptor isoforms that contain α1 subunits. Their CNS depressant effects can be antagonized by flumazenil |
| Sedation | Sedative actions, with relief of anxiety, occur with all drugs in this class. Anxiolysis is usually accompanied by some impairment of psychomotor functions, and behavioral disinhibition may also occur. In animals, most conventional sedative-hypnotics release punishment-suppressed behavior. |
| Hypnosis | Sedative-hypnotics can promote sleep onset and increase the duration of the sleep state.(REM) sleep duration is usually decreased at high doses; a rebound increase in REM sleep may occur on withdrawal from chronic drug use. Effects on sleep patterns occur infrequently with newer hypnotics such as zaleplon and zolpidem. |
| Anaesthesia | At high doses of most older sedative-hypnotics, loss of consciousness may occur, with amnesia and suppression of reflexes. Anterograde amnesia is more likely with benzodiazepines than with other sedative-hypnotics. Anesthesia can be produced by most barbiturates (eg, thiopental) and certain benzodiazepines (eg, midazolam). |
| Anticonvulsant effects | Suppression of seizure activity occurs with high doses of most of the barbiturates and some of the benzodiazepines, but this is usually at the cost of marked sedation. Selective anticonvulsant action(ie, suppression of convulsions at doses that do not cause severe sedation) occurs with only a few of these drugs (eg, phenobarbital, clonazepam). High doses of intravenous diazepam, lorazepam, or phenobarbital are used in status epilepticus. In this condition, heavy sedation is desirable. |
| Muscle relaxation | Relaxation of skeletal muscle occurs only with high doses of most sedative-hypnotics. However, diazepam is effective at sedative dose levels for specific spasticity states, including cerebral palsy. Meprobamate also has some selectivity as a muscle relaxant. |
| Medullary depression | High doses of conventional sedative-hypnotics, especially alcohols and barbiturates, can cause depression of medullary neurons, leading to respiratory arrest, hypotension, and cardiovascular collapse. These effects are the cause of death in suicidal overdose. |
| Tolerance and dependance | Tolerance—a decrease in responsiveness—occurs when sedative hypnotics are used chronically or in high dosage. Cross-tolerance may occur among different chemical subgroups. Psychological dependence occurs frequently with most sedative-hypnotics and is manifested by the compulsive use of these drugs to reduce anxiety. Physiologic dependence constitutes an altered state that leads to an abstinence syndrome (withdrawal state) when the drug is discontinued. Withdrawal signs, which may include anxiety, tremors, hyperreflexia, and seizures, occur more commonly with shorter-acting drugs. The dependence liability of zolpidem, zaleplon, and eszopiclone may be less than that of the benzodiazepines since withdrawal symptoms are minimal after their abrupt discontinuance. |
| Anxiety states | Benzodiazepines are favored in the drug treatment of acute anxiety states and for rapid control of panic attacks. Although it is difficult to demonstrate the superiority of one drug over another, alprazolam and clonazepam have greater efficacy than other benzodiazepines in the longer term treatment of panic and phobic disorders. |
| Sleep disorders | Benzodiazepines, including estazolam, flurazepam, and triazolam, have been widely used in primary insomnia and for the management of certain other sleep disorders. Lower doses should be used in elderly patients who are more sensitive to their CNS depressant effects. More recently there has been increasing use of zolpidem, zaleplon, and eszopiclone in insomnia, since they have rapid onset with minimal effects on sleep patterns and cause less daytime cognitive impairment than benzodiazepines. Note that sedativehypnotic drugs are not recommended for breathing-related sleep disorders, eg, sleep apnea. |
| Other uses | Thiopental is commonly used for the induction of anesthesia, and certain benzodiazepines (eg, diazepam, midazolam) are used as components of anesthesia protocols including those used in day surgery. Special uses include the management of seizure disorders (eg, clonazepam, phenobarbital) and bipolar disorder (eg, clonazepam) and treatment of muscle spasticity (eg, diazepam). Longer acting benzodiazepines (eg, chlordiazepoxide, diazepam) are used in the management of withdrawal states in persons physiologically dependent on ethanol and other sedative-hypnotics. |
| Psychomotor dysfunction | This includes cognitive impairment, decreased psychomotor skills, and unwanted daytime sedation. These are more common with benzodiazepines that have active metabolites with long half-lives (eg, diazepam, flurazepam), but can also occur after a single dose of a short-acting benzodiazepine such as triazolam. The dosage of a sedative-hypnotic should be reduced in elderly patients, who are more susceptible to drugs that cause psychomotor dysfunction. In such patients excessive daytime sedation has been shown to increase the risk of falls and fractures. Anterograde amnesia may also occur with benzodiazepines, especially when used at high dosage, an action that forms the basis for their criminal use in cases of “date rape.” Zolpidem and the newer hypnotics cause modest day-after psychomotor depression with few amnestic effects. However, all prescription drugs used as sleep aids may cause functional impairment, including “sleep driving,” defined as “driving while not fully awake after ingestion of a sedative-hypnotic product, with no memory of the event.” |
| Additive cns depression | This occurs when sedative-hypnotics are used with other drugs in the class as well as with alcoholic beverages, antihistamines, antipsychotic drugs, opioid analgesics, and tricyclic antidepressants. This is the most common type of drug interaction involving sedative-hypnotics. |
| Overdosage | Overdosage of sedative-hypnotic drugs causes severe respiratory and cardiovascular depression; these potentially lethal effects are more likely to occur with alcohols, barbiturates, and carbamates than with benzodiazepines or the newer hypnotics such as zolpidem. Management of intoxication requires maintenance of a patent airway and ventilatory support. Flumazenil may reverse CNS depressant effects of benzodiazepines, eszopiclone, zolpidem, and zaleplon but has no beneficial actions in overdosage with other sedative-hypnotics. |
| Other adverse effects | Barbiturates and carbamates (but not benzodiazepines, eszopiclone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize drugs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects. |
| Buspirone | Buspirone is a selective anxiolytic, with minimal CNS depressant effects (it does not affect driving skills) and has no anticonvulsant or muscle relaxant properties. The drug interacts with the 5-HT1A subclass of brain serotonin receptors as a partial agonist, but the precise mechanism of its anxiolytic effect is unknown.it has a slow onset of action (>1 week) and is used in gads, but is less effective in panic disorders. Tolerance development is minimal with chronic use, and there is little rebound anxiety or withdrawal symptoms on discontinuance |
| Buspirone pharmaco and adverse effects | Buspirone is metabolized by CYP3A4, and its plasma levels are markedly increased by drugs such as erythromycin and ketoconazole. Side effects of buspirone include tachycardia, paresthesias, pupillary constriction, and gastrointestinal distress. Buspirone has minimal abuse liability and is not a schedule-controlled drug. The drug appears to be safe in pregnancy. |
| Ramelteon | Ramelteon activates melatonin receptors in the suprachiasmatic nuclei of the CNS and decreases the latency of sleep onset with minimal rebound insomnia or withdrawal symptoms.it has no direct effects on GABA-ergic neurotransmission in the CNS. Unlike conventional hypnotics ramelteon appears to have minimal abuse liability, and it is not a controlled substance. |
| RMeolton pharmaco and adverse effects | The drug is metabolized by hepatic cytochrome P450, forming an active metabolite. The P450 inducer rifampin markedly reduces plasma levels of ramelteon and its metabolite. Conversely, inhibitors of CYP1A2 (eg, fluvoxamine) or CYP2C9 (eg, fluconazole) increase plasma levels of ramelteon. The adverse effects of the drug include dizziness, fatigue, and endocrine changes including decreased testosterone and increased prolactin. Tasimelteon, a similar melatonin receptor agonist, has recently been approved. |
| Orexin antagonist | Orexin is a peptide found in the hypothalamus and is involved in wakefulness. Suvorexant, a recently approved antagonist at orexin receptors, has hypnotic properties. |
| Anxiety | Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that seems to arise from a unknown source). Disorders involving anxiety are the most common mental disturbances. The physical symptoms of severe anxiety are 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 anxiolytic and/or some form of behavioral therapy or psychotherapy. Because many of the anti-anxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic. some have anticonvulsant activity as well. |
| Effect of benzodiazepines | 1. 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 GABAA receptors, thereby inhibiting neuronal circuits in the limbic system of the brain. 2. Sedative and hypnotic actions: All are 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-GABAA receptors. 3. Anterograde amnesia: The temporary impairment of memory w/ use is also mediated by the α1-GABAA receptors. This also impairs ability to learn and form new memories. 4. 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-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 is a muscle relaxant that is believed to affect GABA receptors at the level of the spinal cord. |
| Anxiety disorder | 1. Anxiety disorders: Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder,(GAD), social anxiety disorder, performance anxiety,ptsd,ocd, and anxiety associated with specific phobias such as fear of flying. The benzodiazepines are also useful in treating the anxiety that accompanies some forms of depression and schizophrenia. 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 who may require treatment for prolonged periods of time. The anti-anxiety 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. 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.] For panic disorders, alprazolam is effective for shortand long-term treatment, although it may cause withdrawal reactions in about 30 percent of sufferers. |
| Muscular disorder | 2. 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 | 3. 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 a benzodiazepine also used for the induction of anesthesia. |
| Seizure | 4. 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. Due to cross-tolerance, chlordiazepoxide, clorazepate , diazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reducing the risk of withdrawal-related seizures. |
| Sleep disorder | 5. Sleep disorders:They tend to decrease the latency to sleep onset and increase Stage II of nonrapid eye movement (REM) sleep. Both REM sleep and slow-wave sleep are decreased. In the treatment of insomnia, it is important to balance the sedative effect needed at bedtime with the residual sedation (“hangover”) upon awakening. Commonly prescribed benzodiazepines for sleep disorders include long-acting flurazepam, intermediate-acting temazepam, and short-acting triazolam |
| Flurazepam | 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 longacting effect and causes little rebound insomnia. With continued use, the drug has been shown to maintain its effectiveness for up to 4 weeks. 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 | B. Temazepam: This drug is useful in patients who experience frequent wakening. However, because the peak sedative effect occurs 1 to 3 hours after an oral dose it should be given 1 to 2 hours before the desired bedtime. |
| Triazolam | C. Triazolam: This benzodiazepine has a relatively short duration of action and, therefore, is used to induce sleep in patients with recurring insomnia. Whereas temazepam is useful for insomnia caused by the inability to stay asleep, triazolam is effective 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, leading the patient to demand another prescription or higher dose. Therefore, this drug is best used intermittently rather than daily. In general, hypnotics should be given for only a limited time, usually less than 2 to 4 weeks. |
| Benzodiazepine | 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 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. |
| Adverse effects benzodiazepines | Drowsiness and confusion: These effects are the two most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. Cognitive impairment (decreased longterm recall and retention of new knowledge) can occur with use of benzodiazepines. Triazolam, one of the most potent oral benzodiazepines with rapid elimination, often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety as well as amnesia and confusion. 2. Precautions: Benzodiazepines should be used cautiously in treating patients with liver disease. These drugs should be avoided in patients with acute narrow-angle glaucoma. Alcohol and other CNS depressants enhance the sedative-hypnotic efects of the benzodiazepines. Benzodiazepines are, however, considerably less dangerous than the older anxiolytic and hypnotic drugs. As a result, a drug overdose is seldom lethal unless other central depressants, such as alcohol, are taken concurrently. |
| Flumazenil | Flumazenil is a GABA-receptor antagonist that can rapidly reverse the effects of benzodiazepines. The drug is available for intravenous (IV) administration only. Onset is rapid, but duration is short, with a halflife 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. Seizures may also result if the patient ingests tricyclic antidepressants (TCAs). Dizziness, nausea, vomiting, and agitation are the most common side effects. |
| 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. |
| Ssri and snri | Selective serotonin reuptake inhibitors (SSRIs, such a escitalopram), or selective serotonin and norepinephrine reuptake inhibitors (SNRIs, such as venlafaxine) may be used alone, or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment. After four to six weeks, when the antidepressantbegins to produce an anxiolytic effect, the 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. TLong-term use of antidepressants and benzodiazepines for anxiety disorders is often required to maintain ongoing benefit and prevent relapse. |
| Buspirone mechanism and use | Buspirone is useful for the chronic treatment of GAD and has an efficacy comparable to that of the benzodiazepines. This agent is not effective for short-term or “as-needed” treatment of acute anxiety states. 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 receptorsand 5-HT2A 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 and causes only minimal sedation. |
| Buspirone adverse effects and etc | However, it does cause hypothermia and can increase prolactin and growth hormone. The frequency of adverse effects is low, with the most common effects being headaches, dizziness, nervousness, and light-headedness. Sedation and psychomotor and cognitive dysfunction are minimal, and dependence is unlikely. It does not potentiate the CNS depression of alcohol. Buspirone has the 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. disadvantage low onset |
| Benzodiazepines time of action | Thiopental acts within seconds and has a duration of action of about 30 minutes, is used in the IV induction of anesthesia. By contrast, phenobarbital, which has a duration of action greater than a day, is useful in the treatment of seizures. Pentobarbital, secobarbital, and amobarbital are short-acting barbiturates, which are effective as sedative and hypnotic (but not anti-anxiety) agents. |
| Barbiturates adverse effects | 1. Depression of CNS: At low doses, the barbiturates produce sedation (have a calming effect and reduce excitement). At higher doses, the drugs cause hypnosis, followed by anesthesia (loss 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 analgesic properties. They may even exacerbate pain. Chronic use leads to tolerance. 2. Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and overdosage is followed by respiratory depression and death. Enzyme induction: Barbiturates induce cytochrome P450 (CYP450) microsomal enzymes in the liver. Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on CYP450 metabolism to reduce their concentration. |
| Theraupetic uses barbiturates | 1. Anesthesia: Selection of a barbiturate is strongly influenced by the desired duration of action. The ultrashort-acting barbiturates, such as thiopental, are used intravenously to induce anesthesia. 2. Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus, and eclampsia. Phenobarbital has been regarded as the drug of choice for treatment of young children with recurrent febrile seizures. However, phenobarbital can depress cognitive performance in children, and the drug should be used cautiously. Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression. 3. Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. When used as hypnotics, they suppress REM sleep more than other stages. However, most have been replaced by the benzodiazepines. |
| Cns barbiturates adverse | 1. CNS: Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness.The CNS depressant effects of barbiturates synergize with those of ethanol |
| Barbiturates adverse drug hangover | Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes. This drug hangover may lead to impaired ability to function normally for many hours after waking. Occasionally, nausea and dizziness occur. |
| Barbiturates precaution | 3. Precautions: barbiturates induce the CYP450 system and, therefore, may decrease the duration of action of drugs that are metabolized by these hepatic enzymes. Barbiturates increase porphyrin synthesis and are contraindicated in patients with acute intermittent porphyria. |
| Dependance precaution barbiturates | 4. Physical dependence: Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest. Withdrawal is much more severe than that associated with opiates and can result in death. |
| Barbiturates poisoning effect | 5. Poisoning: Barbiturate poisoning has been a leading cause of death resulting from drug overdoses for many decades. Severe depression of respiration is coupled with central cardiovascular depression and results in a shock-like condition with shallow, infrequent breathing. Treatment includes artificial respiration and purging the stomach of its contents if the drug has been recently taken. [Note: No specific barbiturate antagonist is available.] Hemodialysis may be necessary if large quantities have been taken. Alkalinization of the urine often aids in the elimination of phenobarbital. |
| Zolpidem | The hypnotic zolpidem is not a benzodiazepine in structure, but it acts on a subset of the benzodiazepine receptor family, BZ1.Zolpidem has no anticonvulsant or muscle-relaxing properties.Zolpidem is rapidly absorbed from the (GI) tract, and it has a rapid onset of action and short elimination half-life (about 2 to 3 hours) and provides a hypnotic effect for approximately 5 hours. |
| Zolpidem adverse effects | It shows few withdrawal effects and exhibits minimal rebound insomnia and little or no tolerance occurs with prolonged use. Zolpidem undergoes hepatic oxidation by the CYP450 system to inactive products. Thus, drugs such as rifampin, which induce this enzyme system, shorten the half-life of zolpidem, and drugs that inhibit the CYP3A4 isoenzyme may increase the half-life this drug. Adverse effects of zolpidem include nightmares, agitation, headache, GI upset, dizziness, and daytime drowsiness. |
| Zolpidem zaleplon eszopiclone | Unlike the benzodiazepines, at usual hypnotic doses, the nonbenzodiazepine drugs, zolpidem, zaleplon, and eszopiclone, 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. |
| Zaleplon | Zaleplon is very similar to zolpidem in its hypnotic actions, but zaleplon causes fewer residual effects on psychomotor and cognitive functions compared to zolpidem or the benzodiazepines. This may be due to its rapid elimination, with a half-life of approximately 1 hour. The drug is metabolized by CYP3A4 |
| Eszopiclone | Eszopiclone is an oral nonbenzodiazepine hypnotic (also using the BZ1 receptor similar to zolpidem and zaleplon) and is also used for treating insomnia. Eszopiclone been shown to be effective for up to 6 months compared to a placebo. Eszopiclone is rapidly absorbed (time to peak, 1 hour), extensively metabolized by oxidation and demethylation via the CYP450 system, and mainly excreted in urine.Elimination half-life is approximately 6 hours. |
| Adverse effects eszopiclone | Adverse effects with eszopiclone include anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste. |
| Ramelteon | Ramelteon is a selective agonist at the MT1 and MT2 subtypes of melatonin receptors. Normally, light stimulating the retina transmits a signal to the suprachiasmatic nucleus (SCN) of the hypothalamus that, in turn, relays a signal via a lengthy nerve pathway to the pineal gland that inhibits the release of melatonin from the gland. As darkness falls and light ceases to strike the retina, melatonin release from the pineal gland is no longer inhibited, and the gland begins to secrete melatonin. Stimulation of MT1 and MT2 receptors by melatonin in the SCN is able to induce and promote sleep and is thought to maintain the circadian rhythm underlying the normal sleep–wake cycle. Ramelteon is indicated for the treatment of insomnia in which falling asleep (increased sleep latency) is the primary complaint. |
| Adverse effect of ramelteon | The potential for abuse of ramelteon is believed to be minimal, and no evidence of dependence or withdrawal effects has been observed. Therefore, ramelteon can be administered long term. Common adverse effects of ramelteon include dizziness, fatigue, and somnolence. Ramelteon may also increase prolactin levels. |
| Antihistamines | Some antihistamines with sedating properties, such as diphenhydramine, hydroxyzine and doxylamine, are effective in treating mild types of insomnia. However, these drugs are usually ineffective for all but the milder forms of situational insomnia. Furthermore, they have numerous undesirable side effects (such as anticholinergic effects) that make them less useful than the benzodiazepines. Some sedative antihistamines are marketed in numerous over-the-counter products. |
| Ethanol adverse effects | Ethanol synergizes with many other sedative agents and can produce severe CNS depression when used in conjunction with benzodiazepines, antihistamines, or barbiturates. Chronic consumption can lead to severe liver disease, gastritis, and nutritional deficiencies. Cardiomyopathy is also a consequence of heavy drinking. The treatment of choice for alcohol withdrawal is the benzodiazepines. Carbamazepine is effective in treating convulsive episodes during withdrawal |
| Ethanol | Ethanol (ethyl alcohol) has anxiolytic and sedative effects, but its toxic potential outweighs its benefits. Ethanol is a CNS depressant, producing sedation and, ultimately, hypnosis with increasing dosage. Because ethanol has a shallow dose–response curve, sedation occurs over a wide dosage range. It is readily absorbed orally and has a volume of distribution close to that of total body water. Ethanol is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenase and then to acetate by aldehyde dehydrogenase. Elimination is mostly through the kidney, but a fraction is excreted through the lungs. |
| Disulfiram | Disulfiram: Disulfiram blocks the oxidation of acetaldehyde to acetic acid by inhibiting aldehyde dehydrogenase. This results in the accumulation of acetaldehyde in the blood, causing flushing, tachycardia, hyperventilation, and nausea. Disulfiram has found some use in the patient seriously desiring to stop alcohol ingestion. A conditioned avoidance response is induced so that the patient abstains from alcohol to prevent the unpleasant effects of disulfiram-induced acetaldehyde accumulation. |
| Naltrexone | 2. Naltrexone: Naltrexone is a long-acting opiate antagonist that should be used in conjunction with supportive psychotherapy. Naltrexone is better tolerated than disulfiram and does not produce the aversive reaction that disulfiram does. |
| Acamprosate | 3. Acamprosate: Acamprosate is an agent used in alcohol dependence treatment programs with an as yet poorly understood mechanism of action. This agent should also be used in conjunction with supportive psychotherapy |
| Most drugs act on cns by: | Most drugs that act on the central nervous system (CNS) appear to do so by changing ion flow through transmembrane channels of nerve cells. |
| Voltage gated ion channels | Voltage-gated ion channels respond to changes in membrane potential. They are concentrated on the axons of nerve cells and include the sodium channels responsible for action potential propagation. Cell bodies and dendrites also have voltage-sensitive ion channels for potassium and calcium. |
| A. Types of Ion Channels | Ion channels of neuronal membranes are of 2 major types: voltage gated and ligand gated. |
| Ligand gated ion channel | Ligand-gated ion channels, also called ionotropic receptors, respond to chemical neurotransmitters that bind to receptor subunits present in their macromolecular structure. Neurotransmitters also bind to G protein-coupled receptors (metabotropic receptors) that can modulate voltage-gated ion channels. Neurotransmitter-coupled ion channels are found on cell bodies and on both the presynaptic and postsynaptic sides of synapses. |
| Types of Receptor-Channel Coupling | Coupling may be through a receptor that acts directly on the channel protein (panel B), through a receptor that is coupled to the ion channel through a G protein (C), or through a receptor coupled to a G protein that modulates the formation of diffusible second messengers, including (cAMP), (IP3), and (DAG), which secondarily modulate ion channels (D). |
| A few neurotoxic substances damage or kill nerve cells. | A few neurotoxic substances damage or kill nerve cells. For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is cytotoxic to neurons of the nigrostriatal dopaminergic pathway. |
| Brain nueronal systems | The CNS contains 2 types of neuronal systems: hierarchical and diffuse. |
| Heiarchal systems | These systems are delimited in their anatomic distribution and generally contain large myelinated, rapidly conducting fibers. Hierarchical systems control major sensory and motor functions. The major excitatory transmitters in these systems are aspartate and glutamate. These systems also include numerous small inhibitory interneurons, which use γ-aminobutyric acid (GABA) or glycine as transmitters. Drugs that affect hierarchical systems often have profound effects on the overall excitability of the CNS. |
| Norepinephrine | Noradrenergic neuron cell bodies are mainly located in the brain stem and the lateral tegmental area of the pons. These neurons fan out broadly to provide most regions of the CNS with diffuse noradrenergic input. Excitatory effects are produced by activation of α1 and β1 receptors. Inhibitory effects are caused by activation of α2 and β2 receptors. CNS stimulants (eg, amphetamines, cocaine), monoamine oxidase inhibitors (eg, phenelzine), and tricyclic antidepressants (eg, amitriptyline) are examples of drugs that enhance the activity of noradrenergic pathways. |
| Serotonnin receptors | Most serotonin (5-hydroxytryptamine; 5-HT) pathways originate from cell bodies in the raphe or midline regions of the pons and upper brain stem; these pathways innervate most regions of the CNS. Multiple 5-HT receptor subtypes have been identified and, with the exception of the 5-HT3 subtype, all are metabotropic. |
| Serotonnin pathways | 5-HT1A receptors and GABAB receptors share the same potassium channel. Serotonin can cause excitation or inhibition of CNS neurons depending on the receptor subtype activated. Both excitatory and inhibitory actions can occur on the same neuron if appropriate receptors are present. Most of the agents used in the treatment of major depressive disorders affect serotonergic pathways (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors). |
| Role of the Ion Current Carried by the Channel | (EPSPs) are usually generated by the opening of sodium or calcium channels. In some synapses, similar depolarizing potentials result from the closing of potassium channels.(IPSPs) are usually generated by the opening of potassium or chloride channels. For example, activation of postsynaptic metabotropic receptors increases the efflux of potassium. Presynaptic inhibition can occur via a decrease in calcium influx elicited by activation of metabotropic receptors. |
| SITES & MECHANISMS OF DRUG ACTION | A small number of agents exert their effects through direct interactions with molecular components of ion channels on axons. Examples include certain anticonvulsants (eg, carbamazepine, phenytoin), local anesthetics, and some drugs used in general anesthesia. However, the effects of most important CNS drugs are exerted mainly at synapses. drugs may act presynaptically to alter the synthesis, storage, release, reuptake, or metabolism of transmitter chemicals. Other drugs can activate or block both pre- and postsynaptic receptors for specific transmitters or can interfere with the actions of second messengers. |
| Action of cns stimulants serotonnin | The actions of some CNS stimulants and newer antipsychotic drugs (eg, olanzapine) also appear to be mediated via effects on serotonergic transmission. Reserpine, which may cause severe depression of mood, depletes vesicular stores of both serotonin and norepinephrine in CNS neurons. |
| Drugs that influence gabaa | Drugs that influence GABAA receptor systems include sedative-hypnotics (eg, barbiturates, benzodiazepines, zolpidem) and some anticonvulsants (eg, gabapentin, tiagabine, vigabatrin). Glycine receptors, which are more numerous in the cord than in the brain, are blocked by strychnine, a spinal convulsant. |
| Gaba and glycine | GABA is the primary neurotransmitter mediating IPSPs in neurons in the brain; it is also important in the spinal cord. GABAA receptor activation opens chloride ion channels. GABAB receptors (activated by baclofen, a centrally acting muscle relaxant) are coupled to G proteins that either open potassium channels or close calcium channels. Fast IPSPs are blocked by GABAA receptor antagonists, and slow IPSPs are blocked by GABAB receptor antagonists. |
| Endocannabinoids | These are widely distributed brain lipid derivatives (eg, 2-arachidonyl-glycerol) that bind to receptors for cannabinoids found in marijuana. They are synthesized and released postsynaptically after membrane depolarization but travel backward acting presynaptically (retrograde) to decrease transmitter release, via their interaction with a specific cannabinoid receptor. |
| Neurotransmission in cns | The CNS communicates through the use of more than 10 (and perhaps as many as 50 ) different neurotransmitters. In contrast, the ans uses only two primary neurotransmitters, acetylcholine and norepinephrine. |
| Diffuse stystem | Diffuse or nonspecific systems are broadly distributed, with single cells frequently sending branches to many different areas. The axons are fine and branch repeatedly to form synapses with many cells. Axons commonly have periodic enlargements (varicosities) that contain transmitter vesicles. |
| Transmitters and drugs affecting diffuse systems | The transmitters in diffuse systems are often amines (norepinephrine, dopamine, serotonin) or peptides that commonly exert actions on metabotropic receptors. Drugs that affect these systems often have marked effects on such CNS functions as attention, appetite, and emotional states. |
| Criteria for Transmitter Status | To be accepted as a neurotransmitter, a candidate chemical must (1) be present in higher concentration in the synaptic area than in other areas (ie, must be localized in appropriate areas), (2) be released by electrical or chemical stimulation via a calcium-dependent mechanism, and (3) produce the same sort of postsynaptic response that is seen with physiologic activation of the synapse (ie, must exhibit synaptic mimicry). |
| Acetylcholine | Approximately 5% of brain neurons have receptors for acetylcholine (ACh). Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M1 receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer’s disease (eg, rivastigmine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine). |
| Dopamine | Dopamine exerts slow inhibitory actions at synapses in specific neuronal systems, commonly via G protein-coupled activation of potassium channels (postsynaptic) or inhibition of calcium channels (presynaptic). The D2 receptor is the main dopamine subtype in basal ganglia neurons, and it is widely distributed at the supraspinal level. Dopaminergic pathways include the nigrostriatal, mesolimbic, and tuberoinfundibular tracts. |
| Dopaminergic pathwasys effects | Drugs that block the activity of dopaminergic pathways include older antipsychotics (eg, chlorpromazine, haloperidol), which may cause parkinsonian symptoms. Drugs that increase brain dopaminergic activity include CNS stimulants (eg, amphetamine), and commonly used antiparkinsonism drugs (eg, levodopa). |
| Glutamic acid | Most neurons in the brain are excited by glutamic acid. High concentrations of glutamic acid in synaptic vesicles are achieved by the vesicular glutamate transporter (VGLUT). Both ionotropic and metabotropic receptors have been characterized. Subtypes of glutamate receptors include the N-methyl-d-aspartate (NMDA) receptor, which is blocked by phencyclidine (PCP) and ketamine. NMDA receptors appear to play a role in synaptic plasticity related to learning and memory. Memantine is an NMDA antagonist introduced for treatment of Alzheimer’s dementia. Excessive activation of NMDA receptors after neuronal injury may be responsible for cell death. Glutamate metabotropic receptor activation can result in G protein-coupled activation of phospholipase C or inhibition of adenylyl cyclase. |
| Peptide transmitters | Many peptides have been identified in the CNS, and some meet most or all of the criteria for acceptance as neurotransmitters. The best-defined peptides are the opioid peptides (beta-endorphin, met- and leu-enkephalin, and dynorphin), which are distributed at all levels of the neuraxis. |
| Peptide descr | Some of the important therapeutic actions of opioid analgesics (eg, morphine) are mediated via activation of receptors for these endogenous peptides. Another peptide, substance P, is a mediator of slow EPSPs in neurons involved in nociceptive sensory pathways in the spinal cord and brain stem. Peptide transmitters differ from nonpeptide transmitters in that (1) the peptides are synthesized in the cell body and transported to the nerve ending via axonal transport, and (2) no reuptake or specific enzyme mechanisms have been identified for terminating their actions. |
| Epsp | Stimulation of excitatory neurons causes a movement of ions that results in a depolarization of the postsynaptic membrane. These (EPSP) are generated by the following: 1) Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or acetylcholine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of sodium (Na+) ions. 2) The infl ux of Na+ causes a weak depolarization, or EPSP, that moves the postsynaptic potential toward its firing threshold. 3) If the number of stimulated excitatory neurons increases, more excitatory neurotransmitter is released. This ultimately causes the EPSP depolarization of the postsynaptic cell to pass a threshold, thereby generating an all-or-none action potential. [The generation of a nerve impulse typically reflects the activation of synaptic receptors by thousands of excitatory neurotransmitter molecules released from many nerve fibers.] |
| Inhibitory pathway | 1) Stimulation of inhibitory neurons releases neurotransmitter molecules, such as γ-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. 2) The influx of Cl– and efflux of K+ cause a weak hyperpolarization, or IPSP, that moves the postsynaptic potential away from its firing threshold. This diminishes the generation of action potentials. |
| Combined effects of the EPSP and IPSP | Most neurons in the CNS receive both EPSP and IPSP input. Thus, several different types of neurotransmitters may act on the same neuron, but each binds to its own specific receptor. The overall resultant action is due to the summation of the individual actions of the various neurotransmitters on the neuron. The neurotransmitters are not uniformly distributed 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 may offer greater opportunity for selective modulation of certain neuronal pathway |
| Neurodegenerative diseases | Neurodegenerative diseases of the CNS include Parkinson disease, Alzheimer disease, MS and ALS. These devastating illnesses are characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both. For example, Alzheimer disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Maynert, whereas Parkinson disease is associated with a loss of dopaminergic neurons in the substantia nigra. The number of cases is expected to increase as the proportion of elderly people in the population increases. |