Sedative-Hypnotic Drugs PDF

Sedative-Hypnotic Drugs Prepared by PhD candidate: Anwer Mahmood AL-juboure Supervised by department of pharmacology in Al-Mosul collage of medicine 1 ANXIETY Unlike other mental disorders, anxiety can be both...

Sedative-Hypnotic Drugs Prepared by PhD candidate: Anwer Mahmood AL-juboure Supervised by department of pharmacology in Al-Mosul collage of medicine 1 ANXIETY Unlike other mental disorders, anxiety can be both: a normal emotion. and a psychiatric illness. It is a universal human emotion, and a certain amount is useful to the individual, acting as a stimulant and increasing efficiency. but when it becomes excessive and disproportionate to the situation, an anxiety state develops; it becomes a pathological (disabling) and needs treatment. Prepared by Msc Anwer Mahmood AL-Jubuori 2  Anxiety and Anxiolytic Drugs anxiety are among the most common mental disorders. Anxiety is an unpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an 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. Severe, chronic, anxiety may be treated with antianxiety drugs (sometimes called anxiolytics). Prepared by Msc Anwer Mahmood AL-Jubuori 3  ANXIETY CLASSIFICATION ❖Primary 1. Generalized anxiety disorder (GAD): apprehensive and tense for no particular reason. 2. Panic disorder: unexpected attacks of anxiety. 3. Phobic disorders: fears certain situation “agoraphobia” 4. Obsessive compulsive disorder: repetitive, anxiety driven behavior or obsessive thoughts and doubts (check things more than once) 5. Post-traumatic stress disorder (rape or warfare) ❖Secondary due to medical causes or substances Prepared by Msc Anwer Mahmood AL-Jubuori 4  Anxiolytic and Hypnotic Drugs Sedative is a drug that reduces excitement and calms the person. Hypnotic is a drug that produces sleep-resembling normal sleep. Sedative-hypnotic drugs: in small dose (Sedative) & in large dose (Hypnotic). Both sedation and hypnosis are different grades of CNS depression. Prepared by Msc Anwer Mahmood AL-Jubuori 5 Prepared by Msc Anwer Mahmood AL-Jubuori 6 Prepared by Msc Anwer Mahmood AL-Jubuori 7  CLASSIFICATION OF SEDATIVES AND HYPNOTICS 1. Benzodiazepines (BZDs):diazepame 2. Barbiturates: Phenobarbitone 3. Nonbenzodiazepine hypnotics: Zolpidem, zopiclone, zaleplon, eszopiclone. 4. Others: Melatonin, ramelteon suvorexant. Prepared by Msc Anwer Mahmood AL-Jubuori 8  Benzodiazepines They are widely used anxiolytic drugs. They replaced barbiturates in the treatment of anxiety and insomnia, because BZD are generally considered to be safer and more effective. Though BZD are commonly used, they are not necessarily the best choice for anxiety or insomnia. Certain antidepressants with anxiolytic action, such as the selective serotonin reuptake inhibitors (SSRIs), are preferred in many cases, and nonbenzodiazepine hypnotics and antihistamines may be preferable for insomnia Prepared by Msc Anwer Mahmood AL-Jubuori 9  Pharmacokinetics of BZD ❖BZDs are usually given orally or IV and occasionally by rectal route (diazepam) in children. ❖The rate of absorption following oral administration is variable; absorption is erratic from i.m. route; hence rarely used. ❖The absorption of triazolam is extremely rapid ❖They have a large volume of distribution. ❖They have a short duration of action on occasional use because of rapid redistribution, even though elimination half-life is long. Prepared by Msc Anwer Mahmood AL-Jubuori 10 Prepared by Msc Anwer Mahmood AL-Jubuori 11  Pharmacokinetics of BZD ❖BZDs are metabolized in liver. Some undergo enterohepatic recycling. ❖Some of them produce active metabolites which have long half-life; hence, cumulative effects may be seen. ❖Oxazepam is not significantly metabolized in liver. ❖The metabolites are excreted in urine. ❖Clorazepate, a prodrug, is converted to its active form, (nordiazepam), by acid hydrolysis in the stomach. ❖BZDs cross placental barrier not recommended for use during pregnancy. ❖Nursing infants may also be exposed to the drugs in breast milk. Prepared by Msc Anwer Mahmood AL-Jubuori 12 Prepared by Msc Anwer Mahmood AL-Jubuori 13 Prepared by Msc Anwer Mahmood AL-Jubuori 14  Molecular Pharmacology of the GABAA Receptor GABA is the principle inhibitory neurotransmitter in CNS. GABA acts via GABA receptors (GABA A and GABA B). Multiple forms of α, β, and γ subunits are arranged in different pentameric combinations so that GABA receptors is formed α1 subunits → sedation, amnesia, and ataxic effects, α2 and α3 subunits → anxiolytic and muscle- relaxing actions. α5 subtype → memory impairment.  Molecular Pharmacology of the GABAA Receptor A major isoform of the GABAA receptor that is found in many regions of the brain consists of two α1 subunits, two β2 subunits, and one γ2 subunit.. GABA appears to interact at two sites between α and β subunits triggering CL channel opening with → membrane hyperpolarization.  MOA of BZDs BZDs bind to GABA A receptors→ this binding site is different from GABA-binding site. benzodiazepines potentiate GABAergic inhibition at all levels of the neuraxis, including the spinal cord, hypothalamus, hippocampus, substantia nigra, and cerebral cortex Binding of benzodiazepines and the newer hypnotic drugs such as zolpidem occurs at a single site between α and γ subunits  MOA of BZDs BZDs ↑ affinity of GABA for receptor. GABA ↑ chloride ion conduction through receptor. This action is potentiated by BZDs. BZDs enhance frequency of CL channel opening in response to GABA. ↑ CL entry in neurons leads to hyperpolarization → CNS inhibition. Prepared by Msc Anwer Mahmood AL-Jubuori 19  Pharmacological Actions Reduction of anxiety: ▪ At low doses, the benzodiazepines are anxiolytic. ▪ They are thought to reduce anxiety by selectively enhancing GABAergic transmission, thereby inhibiting neuronal circuits in the limbic system of the brain. Anterograde amnesia: Temporary impairment of memory with the use of the benzodiazepines is also mediated by the GABAA receptors. The ability to learn and form new memories is also impaired. Prepared by Msc Anwer Mahmood AL-Jubuori 20  Pharmacological Actions Sedative/hypnotic: ▪ All benzodiazepines have sedative and calming properties, and some can produce hypnosis (artificially produced sleep) at higher doses. ▪ The general effects of benzodiazepines and older sedative-hypnotics on patterns of normal sleep are as follows: 1. the latency of sleep onset is decreased (time to fall asleep); 2. the duration of stage 2 NREM (non-rapid eye movement) sleep is increased; 3. the duration of REM (rapid eye movement) sleep is decreased; and 4. the duration of stage 4 NREM slow-wave sleep is decreased. Prepared by Msc Anwer Mahmood AL-Jubuori 21  Pharmacological Actions Anticonvulsant: ▪ This effect is partially, although not completely, mediated by GABAA receptors. Muscle relaxant: At high doses, the BZD relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord, where the GABA A receptors are largely located. Prepared by Msc Anwer Mahmood AL-Jubuori 22  Uses of BZDs ❖Anxiolytic: BZD used for anxiety disorder. They also used in anxiety related to depression and schizophrenia. They drugs should be reserved for severe anxiety and should not be used to manage the stress of everyday life. Because of their addictive potential, they should only be used for short periods of time. The longer-acting agents, such as clonazepam, lorazepam, and diazepam, are often preferred in patients with anxiety that require prolonged treatment. The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic effects. For panic disorders, alprazolam is effective for short- and long-term treatment Prepared by Msc Anwer Mahmood AL-Jubuori 23  Uses of BZDs ❖Insomnia: BZDs ↓ time required to fall asleep (↓ sleep latency). The total sleep time is ↑. BZDs reduce night awakenings and produce refreshing sleep. 1. Short-acting triazolam used with problems falling asleep. Higher risk of withdrawal and rebound insomnia is with triazolam than with other agents. 2. Intermediate-acting temazepam useful for frequent awakenings and have difficulty staying asleep. 3. Long-acting flurazepam 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. In general, hypnotics should be used for only a limited time, usually 1 to 3 weeks. Prepared by Msc Anwer Mahmood AL-Jubuori 24  Uses of BZDs ❖Muscular disorders: Diazepam is useful in the treatment of skeletal muscle spasms and in treating spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy. ❖Anticonvulsants: Diazepam, lorazepam, clonazepam, clobazam, etc. have anticonvulsant effect. IV diazepam/lorazepam is used to control life-threatening seizures in status epilepticus, tetanus, drug-induced convulsions, febrile convulsions, etc. Clonazepam is used in the treatment of absence seizures. Prepared by Msc Anwer Mahmood AL-Jubuori 25  Uses of BZDs ❖Diagnostic (endoscopies) and minor operative procedures(dental procedures): i.v. BZDs are used because of their sedative–amnesic and muscle relaxant properties. ❖Preanaesthetic medication and general anaesthesia (GA): These drugs are used as preanaesthetic medication because of their sedative–amnesic and anxiolytic effects. Hence, the patient cannot recall the perioperative events later. i.v. diazepam, lorazepam, midazolam, etc. are combined with other CNS depressants to produce GA. ❖To treat alcohol-withdrawal symptoms: Long-acting BZDs, such as chlordiazepoxide and diazepam are used. Prepared by Msc Anwer Mahmood AL-Jubuori 26  Adverse Effects BZDs have a wide margin of safety. They are generally well tolerated. The common side effects are drowsiness, confusion, amnesia, lethargy, weakness, blurred vision, ataxia, daytime sedation, impaired motor coordination hence avoid driving Paradoxical irritability and anxiety is seen in few patients Tolerance and dependence: less potential compared to barbiturates. Prepared by Msc Anwer Mahmood AL-Jubuori 27  Adverse Effects Withdrawal symptoms are mild and slow in onset for long-acting BZDs. Withdrawal symptoms more intensive and abrupt in short-acting BZDs. Withdrawal after chronic use causes symptoms like tremor, insomnia, restlessness, nervousness and anorexia. When administered to pregnant women during labor neonate can develop hypotonia and respiratory depression. Prepared by Msc Anwer Mahmood AL-Jubuori 28  Tolerance and Dependence ❖Tolerance: decrease in responsiveness occurs when sedative hypnotics are used chronically. It occures when used for more than 1-2 weeks. It is associated with a decrease in GABA receptor density. The antianxiety effects of the BDZs are less subject to tolerance than sedative and hypnotic effects. Prepared by Msc Anwer Mahmood AL-Jubuori 29  Tolerance and Dependence ❖Dependence occurs within weeks to months of continued use. ❖Physiological dependence: removal of the drug evokes unpleasant symptoms, usually the opposite of the drugs effects ❖Psychological dependence: the drug taker feels compelled to use the drug & suffers anxiety when separated from drug. Prepared by Msc Anwer Mahmood AL-Jubuori 30  Benzodiazepine Antagonist (Flumazenil) ❖Flumazenil competitively reverses the effects of both BZD agonists (CNS depression) and BZD inverse agonists(β-Carboline). ❖Flumazenil is not used orally because of its high first-pass metabolism. ❖It is given by i.v. route and has a rapid onset of action. Prepared by Msc Anwer Mahmood AL-Jubuori 31  Benzodiazepine Antagonist (Flumazenil) ❖Flumazenil is used in the treatment of BZD overdosage and to reverse the sedative effect of BZDs during GA. ❖It can also be used to reverse the hypnotic effect of zolpidem, zaleplon and eszopiclone. ❖Adverse effects include confusion, dizziness and nausea. ❖Can we use it in dependent subject? Rationalize ❖It may precipitate withdrawal symptoms (anxiety and convulsions) in dependent subjects. Prepared by Msc Anwer Mahmood AL-Jubuori 32  barbiturates ❖The barbiturates were formerly the mainstay of treatment to sedate patients or to induce and maintain sleep. ❖They replaced by the BZD, because barbiturates induce tolerance and physical dependence, are lethal in overdose, ❖And are associated with severe withdrawal symptoms. Prepared by Msc Anwer Mahmood AL-Jubuori 33  barbiturates ❖Classification 1. Ultra short-acting→ Thiopentone 2. Short-acting → Pentobarbitone 3. Long-acting → Phenobarbitone Prepared by Msc Anwer Mahmood AL-Jubuori 34  Pharmacokinetics Good oral absorption. Wide tissue distribution High lipid solubility so have a rapid onset e.g., Thiopentone Redistributed to adipose tissue so have a short duration of action e.g Thiopentone Potent microsomal enzyme inducers These agents are metabolized in the liver, and Inactive metabolites are excreted in urine. Barbiturates readily cross the placenta and can depress the fetus. Prepared by Msc Anwer Mahmood AL-Jubuori 35  Mechanism of action The sedative–hypnotic action of the barbiturates is due to their interaction with GABA A receptors, which enhances GABAergic transmission. The binding site of barbiturates on the GAB A receptor is distinct from that of the BZD. Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings. In addition, barbiturates can block excitatory glutamate receptors. These molecular actions lead to decreased neuronal activity. At high concentrations, barbiturates have GABA-mimetic effect (i.e. barbiturates can directly increase Cl conductance into the neuron). Prepared by Msc Anwer Mahmood AL-Jubuori 36 Prepared by Msc Anwer Mahmood AL-Jubuori 37  Pharmacological action ❖Depress all excitable tissues(except liver)→ CNS is most sensitive. ❖CNS: Sedation and hypnosis 1. they induces sleep. Prolongs duration of sleep. 2. Residual sedation and hangover on awakening. 3. They reduces anxiety, impairs short-term memory and judgment. 4. Produces euphoria → so has addiction potential. 5. Anesthesia: In high doses. Seen with conventional doses of ultra short-acting barbiturates IV thiopentone 6. Anticonvulsant: All barbiturates are anticonvulsants in conventional doses. This effect Seen with sub-hypnotic doses of phenobarbitone Prepared by Msc Anwer Mahmood AL-Jubuori 38  Pharmacological action ❖Respiratory system: Significant respiratory depression. Additional direct paralysis of medullary center. Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and overdose is followed by respiratory depression and death. ❖CVS: Hypnotic doses, causes slight ↓ in BP and HR. Toxic doses, causes significant ↓ in BP due to direct depression of myocardium and vasomotor center. how? ❖Skeletal muscles: ↓ Excitability ❖Liver :induction of liver enzyme ❖(possibly via facilitation of the actions of adenosine, leading to circulatory collapse) 8* Prepared by Msc Anwer Mahmood AL-Jubuori 39  Therapeutic uses ❖Not preferred nowadays because of respiratory depression and abuse potential ❖Sedation and hypnosis: However, BZD are preferred ❖Anticonvulsant: Phenobarbitone has anticonvulsant effect and is used in the treatment of status epilepticus and generalized tonic–clonic seizures. Phenobarbital can depress cognitive development in children and decrease cognitive performance in adults, and it should be used for seizures only if other therapies have failed. Prepared by Msc Anwer Mahmood AL-Jubuori 40  Therapeutic uses ❖Anesthesia: The ultra–short-acting barbiturates have been historically used intravenously to induce anesthesia but have been replaced by other agents. ❖Neonatal jaundice ∴ Phenobarbitone is a microsomal enzyme inducer. It increase production of glucoronyl transferase. This enzyme metabolizes and excretes excess bilirubin so helps in clearance of jaundice. Prepared by Msc Anwer Mahmood AL-Jubuori 41  Adverse reactions Hangover due to residual CNS depression Mood distortion Impaired judgment and fine motor skills Excitement and irritability In children Respiratory depression. It is severe in patients with respiratory disorders even in therapeutic dose Tolerance on prolonged use Physical and psychological dependence Hence there is high abuse potential Withdrawal symptoms: Anxiety, restlessness, hallucinations, delirium and convulsions. Prepared by Msc Anwer Mahmood AL-Jubuori 42  Drug Interactions ❖ Hepatic Microsomal Enzyme Induction → increase metabolism of other drugs e.g. increase metabolism of oral anticoagulants, hypoglycemic & contraceptives. ❖Barbiturates + Ethyl alcohol → Synergism → Severe ↓↓C.N.S. ❖Additive effects can be predicted with concomitant use of 1. alcoholic beverages, 2. opioid analgesics, 3. anticonvulsants, 4. antihistamines, 5. antihypertensive agents, 6. tricyclic antidepressants, and phenothiazines. Prepared by Msc Anwer Mahmood AL-Jubuori 43  Other Anxiolytic Agents (Z drug) ❖Newer agents e.g., Zolpidem, zopiclone, eszopiclone zaleplone ❖They are oral non-BZDs But produce their effects by bind to GABA A receptor Facilitate inhibitory transmission ❖Lesser incidence of dependence and tolerance compared to BZDs ❖ Insignificant alteration of sleep pattern ❖Used for short duration in insomnia ❖Rapid onset and short duration of action so there is less hangover ❖ Flumazenil blocks/ reverses actions Prepared by Msc Anwer Mahmood AL-Jubuori 44 ❖ Zolpidem: Good hypnotic. Weak anticonvulsant, anxiolytic, and muscle relaxant Short-acting (t½ of 2 h). Sleep duration – 8 h. ADR Dizziness, diarrhea ❖ ZOPICLONE used for short-term treatment of insomnia. The side effects are headache, drowsiness, GI disturbances and metallic taste. ❖ ZALEPLON Useful for patients with long sleep latency. Long time to fall sleep. It is the shortest acting non-BZD hypnotic. ❖ ESZOPICLONE used for short- and long-term treatment of insomnia. Prepared by Msc Anwer Mahmood AL-Jubuori 45  Melatonin-receptor agonist ❖MELATONIN: It is the hormone secreted by the pineal gland; involved in the maintenance of sleep– wake cycle and circadian rhythm. ❖RAMELTEON: It is a melatonin-receptor (MT1 and MT2) agonist, can be used orally for the treatment of sleep onset insomnia. It reduces sleep latency and prolongs total duration of sleep. There is no rebound insomnia on withdrawal; does not cause tolerance on chronic use. The important adverse effects are fatigue and dizziness. It ↑ prolactin levels. fluvoxamine increases the peak plasma concentration of ramelteon more than 50- fold! ❖Tasimelteon is similar and is approved for non-24-hour sleep-wake disorder Prepared by Msc Anwer Mahmood AL-Jubuori 46  Orexin Receptor Antagonist ❖Orexin A and B are peptides found in specific hypothalamic neurons that are involved in the control of wakefulness and that are silent during sleep ❖Orexin levels increase in the day and decrease at night. ❖Loss of orexin neurons is associated with narcolepsy, a disorder characterized by daytime sleepiness and cataplexy. ❖SUVOREXANT: It prevents orexin from maintaining wakefulness by blocking orexin receptors. It is useful in chronic insomnia. Prepared by Msc Anwer Mahmood AL-Jubuori 47  Buspirone Buspirone useful for chronic treatment of GAD. It has a slow onset of action and is not effective for short-term or “as-needed” treatment of acute anxiety. its mode of action differs from that BZD. It has 5-HT1A receptors as a partial agonist. Buspirone lacks the anticonvulsant and muscle-relaxant properties of the BZD. Adverse effects: the most common effects being headache, dizziness, nervousness, nausea, and light-headedness. Sedation and cognitive dysfunction are minimal, and dependence is unlikely. Buspirone does not potentiate the CNS depression of alcohol. The drug appears to be safe in pregnancy (category B). Prepared by Msc Anwer Mahmood AL-Jubuori 48  Antidepressants Many of this drug used for chronic anxiety disorders. SSRIs such as escitalopram or paroxetine or SNRIs, such as venlafaxine or duloxetine may be used alone or in combination with a BZD during the first week of treatment. After 4 to 6 weeks, when the antidepressant begins to produce an anxiolytic effect, the BZD dose can be tapered. Prepared by Msc Anwer Mahmood AL-Jubuori 49  Antihistamines Antihistamines with sedating properties, such as diphenhydramine, hydroxyzine, and doxylamine, are effective in treating mild situational insomnia. they have undesirable adverse effects (such as anticholinergic effects) that make them less useful than the BZD and the non-BZD. Sedative antihistamines are marketed in numerous over-the-counter products. Prepared by Msc Anwer Mahmood AL-Jubuori 50 Prepared by Msc Anwer Mahmood AL-Jubuori 51