Sedative, Hypnotic & Anxiolytics PDF 2016 Exam Notes

3. Sedatives, Hypnotics, and Anxiolytics 1 9/2/2024 Sedatives, Hypnotics, and Anxiolytics  Sedative: a substance that induces sedation by reducing irritability and excitement.  Hypnotics: drug that produce drowsiness and encourage the onset and mai...

3. Sedatives, Hypnotics, and Anxiolytics 1 9/2/2024 Sedatives, Hypnotics, and Anxiolytics  Sedative: a substance that induces sedation by reducing irritability and excitement.  Hypnotics: drug that produce drowsiness and encourage the onset and maintenance of a state of sleep.  involve more pronounced CNS depression than sedation  hypnotics are prescribe in insomnia. Anxiolytic: A drug that reduces anxiety, a sedative. an agent which ↓worriness manifested as the psychic awareness of anxiety which is accompanied with ↑ vigilance, motor tension, and autonomic hyperreactivity. 2 9/2/2024  Cont…… Types of anxiety disorders  Generalized anxiety disorder (GAD):  Panic disorder  Phobia: A fear from a certain psychological irritant.  Post-traumatic stress disorder  Obsessive compulsive disorder.  Cont…… Generalized anxiety disorder (GAD):  characterized by excessive, uncontrollable and often irrational worry about everyday things that is disproportionate to the actual source of worry.  Restlessness , Being easily fatigued.  Difficulty concentrating or mind going blank.  Shortness of breath, Heart palpitation, Irritability.  Muscle tension, Headache, stomachache, muscle, unexplained pain  Sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep) Sedative-Hypnotics…  Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics.  A hypnotic at law dose may act as a sedative & at high dose can produce general anesthesia General Sedation Hypnosis Anesthesia 5 9/2/2024  Classification of sedative –hypnotics Barbiturates Benzodiazepines Miscellaneous A.Ultra–short acting Thiopental sodium Flurazepam Chloral hydrate Hexobarbital Alprazolam Meprobamate Methohexital Lorazepam Paraldehyde oxazepam Ethchlorrynol Nitrazepam Antihistamines B. Short-immediate Fluntrazepam Pentobarbital Temazepam Secobarbital Triazolame Amobarbital Midazolam Diazepam C. Long acting Phenobarbital 9/2/2024 6 Barbital  Treatment of anxiety Psychotherapy Anxiolytics 7 9/2/2024 Classification of anxiolytic drugs:  1-Benzodiazepines ( BDZ ). 2-5HT1A agonists. 3-Beta-adrenergic blockers 4-5HT reuptake inhibitors 5-Tricyclic Antidepressants  A. Benzodiazepines  Can be classified according to the duration of action into short, medium & long- acting Short Acting: 3-8hr, Oxazepam, triazolam Intermediate Acting:10 -20 hr,Alprazolam,Estazolam,Lorazepam, Temazepam Long acting: 1-3 day, Diazepam, clorazepate,Flurazepam, chloradezipioxide Pharmacokinetics:  Well absorbed orally, the rate of oral absorption varies depending on each drug’s lipophilicity. Can be given parenterally , IV, IM(with slow absorption  Chlordiazepoxide- Diazepam (IV only NOT IM  Cont…..  Absorption of triazolam is extremely rapid.  Diazepam & the active metabolite of clorazepate (nordiazepam) have more rapid absorption than other BZP.  Clorazepate is a prodrug converted to (nordiazepam) by acid hydrolysis in the stomach.  They bind strongly to plasma proteins & accumulate in body fats with high Vd, Widely distributed  metabolized by oxidation and hydroxylation by CyP450 especially, CYP3A4 (phase I).  The metabolites are subsequently conjugated (phase II) to form glucuronides that are excreted in the urine.  Pharmacodynamics  BZPs are the most widely used anxiolytic drugs  They are safe and effective  complete absorbed from the gut hence it can be given orally Mechanism of Action:  The BZDs receptors are found only in CNS, they are separate but adjacent to GABA receptors.  The binding of BZDS enhance the affinity of GABA receptors for GABA, resulting in a more frequent opening of adjacent chloride channels.  Enhanced hyper polarization & further inhibition of neuronal excitations 11 9/2/2024 12 9/2/2024  Cont…..  GABA receptor is a pentameric receptor consisting from five subunits in variant isoforms.  The major isoform is composed of five subunits comprising of 2α, 2β, and one γ subunits Three types of ligand-BZP receptor interactions: 1. Agonists: facilitate GABA actions. 2. Antagonists: flumazenil which blocks the action of BZP, escopiclone, zaleplon, and zolpidem but not barbiturates, meprobamate or ethanol. 3. Inverse agonists act as a negative allosteric modulators of GABA receptor function. They produce anxiety and seizures. E.g β-carbolines  Cont…… Pharmacological Effects:  Anxiolytic action  Depression of cognitive and psychomotor function  Sedative & hypnotic actions  Anterograde amnesia  Minimal depressant effects on cardiovascular system & respiratory system  Some have anticonvulsant effect:  Clonazepam, diazepam.  Pharmacological Effects: 1. Reduction of anxiety & aggression:  active against all types of anxiety, Short term relief of severe anxiety  General anxiety disorder  Obsessive compulsive disorder  Panic attack with depression  Alprazolam is an anxiolytic as well as an antidepressant  B/c of the short half life of triazolam, severe rebound occurs after abrupt discontinuation. 2. Sedation: Exert calming effects 3. Sleep disorders(Insomnia): Triazolam, Lorazepam, Flurazepam  Cont….. 4. Induction of Sleep (Hypnotic)  ↓ the time taken to fall to sleep (decrease sleep latency)  ↑ total duration of sleep without the fluctuation of sleep & non-sleep alternating cycles throughout a night  The duration of stage 2 NREM sleep is ↑  The duration of REM sleep is ↓  The duration of stage 4 NREM slow-wave sleep is ↓  In general: interruption of REM sleep causes anxiety and irritability followed by a rebound increase in REM sleep.  REM rebound can be detected following abrupt cessation of drug treatment with older sedatives  Cont…..  In anesthesia  Pre-anesthetic medication (diazepam).  Induction of anesthesia (Midazolam, IV) 5. Reduction of Muscle Tone and Coordination:  ↑muscle tone is feature of anxiety, leads to muscle aches & headache.  BZP- high doses, they may depress transmission at the skeletal NMJ.  Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone 6. Anterograde Amnesia:  Cont…. Anticonvulsant Effects:  More effective against chemically induced convulsions caused by leptazol & bicuculline, but not strychnine due to the different MOA.  Less effective against electrical- induced convulsions.  Some drugs of the BZP have greater selectivity for convulsion without marked CNS depression e.g. clonazepam, nitrazepam, lorazepam, and diazepam.  Zlpidem, zaleplon, and eszopiclone lack anticonvulsant activity Cont….. Effects on Respiration and Cardiovascular Functions:  At therapeutic doses, sedatives-hypnotics can produce respiratory depression in patients with pulmonary disease.  In hypovolemic state & heart failure, normal doses of sedative- hypnotics can cause cardiovascular depression.  Respiratory and CV effects are marked when the doses given IV Decreased nocturnal acid secretion  BZPs therapeutic use  Sedative-hypnotic , , ,  Diazepam flurazepam temazepam triazolam  Anxiety disorders  Chlorodiazepoxide, clonazepam, lorazepam, oxazepam  Anticonvulsant  Diazepam, clonazepam, nitrazepam  Muscle relaxant  Diazepam  Pre-anesthetic medication  Diazepam  In peptic ulcer e.g chlorodiazepoxide  Sedative effects can be reversed with flumazenil 21 9/2/2024  Adverse Effects generally well tolerated, safe In contrast to barbiturates and other general CNS depressants, bzps.  CNS depression  Hangover: (drowsiness, confusion) , lightheadedness incoordination & difficult concentration Ataxia (motor incoordination)  Anterograde amnesia  Impaired recall of events that take place after dosing  Especially troublesome with triazolam  Respiratory depression : weak respiratory depressants (orally)  Combination cause significant respiratory depression.  Cognitive impairment, Tolerance & dependence  Risk of withdrawal symptoms(Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion)  Adverse effects  Abuse BZPs…  Have low abuse potential, classified under schedule IV.  Use in pregnancy and lactation  Are highly lipid soluble and can readily cross the placental barrier.  Increased risk of congenital malformation  Use near term can cause CNS depression in the neonate  All sedative-hypnotics cross the placental barrier during pregnancy- leads Fetal depression  Accumulate (Excreted) in milk (neonatal depression). 23 9/2/2024 Drug interactions  Additive effects to other CNS depressants (including ETOH, BZPs… Antihistamine)& can lead to respiratory depression, coma,& death.  CYP450 inhibitor: Cimetidine, Erythromycin  CYP450 inducer: Rifampin, Phenytoin  Diazepam may increase the plasma levels of digoxin and phenytoin.  flumazenil :IV It is a competitive antagonist, Binds competetivly to GABA receptors then displacing BZP.  Specific Antidote for BZP poisoning, Sedative effects reversed with it 24 9/2/2024  A. Barbiturates Pharmacokinetics:  are absorbed rapidly after their oral administration.  Phenobarbital is the only excreted unchanged in the urine (20–30%),  Elimination can be ↑significantly by alkalinization of the urine where it is considered a weak acid.  Metabolic pathway involves oxidation by hepatic enzymes to form substances which appears in the urine as glucuronide conjugates  Barbiturates……. Pharmacodynamics:  They enhance the action of GABA by prolonging the duration of chloride channel opening.  In addition, barbiturates can block excitatory glutamate receptors.  At high doses, act directly on GABA’s receptor.  They have a depressant effect similar to general anesthetics due to their broad inhibitory effect on various CNS receptors  cause relatively non-selective depression of CNS function.  Can be used for day time sedation  Induction of sleep  Suppression of seizures  And general anesthesia  Barbiturates … Classification  grouped in to 3 classes based on duration of action  The duration of action is inversely related to lipid solubility.  The duration of action influences, the clinical application of barbiturates. Characteristics of barbiturate subgroups Subgroup Drug Lipid Onset DOA Applications solubility (min) (hr) Ultra short- Thiopental High 0.5 0.2 Induction of acting anesthesia, treatment of seizures Short to Secobarbital Moderate 10-15 3 – 4 Treatment of intermediate- insomnia acting Long-acting Phenobarbital Low 60 10-12 Treatment of 27 seizure 9/2/2024  Cont…..  Have been replaced by newer and safer drugs- primarily by benzodiazepines.  Still have important application in seizure control and anesthesia. E.g. thiopental.  Barbiturates:  Tolerance and dependence  Have a high abuse potential  subject to multiple drug interaction  are powerful respiratory depressants (fatal in overdose) 28 9/2/2024  Barbiturates … Pharmacologic effects  CNS depression  Responses progress from sedation to sleep to general anesthesia.  Considered nonselective CNS depressants (except Phenobarbital)  Cardiovascular effects  At hypnotic dose causes in BP and heat rate.  Toxic doses cause profound hypotension and shock  Induction of hepatic drug-metabolizing enzymes Pharmacokinetics  rapid redistribution occurs in highly lipid- soluble agents 29 low –lipid solubility has prolonged duration with long half-lives. 9/2/2024  Barbiturates … Therapeutic uses  Seizure disorder – Phenobarbital and mephobarbital  Suppress seizure at doses that are essentially nonsedative  induction of anesthesia – thiopental  insomnia  Replaced by benzodiazepines Adverse effects  respiratory depression (over dosage resulting in death),  exacerbation of intermittent porphyria,  paradoxical excitement, hyperalgesia, hangovers;  should not be used in pregnancy  potential for abuse. 30 9/2/2024  Barbiturates … Drug interactions and toxicity –  interacts with other CNS depressants  since it stimulates hepatic drug – metabolizing enzymes, some medications need increased dosages (warfarin, oral contraceptives, phenytoin).  Miscellaneous sedative – hypnotics  similar to barbiturates;  all are potentially dangerous and include chloral hydrate, glutethimide, meprobamate, paraldehyde and ethchlorvynol. 31 9/2/2024  Cont….. BZP Gained popularity over barbiturates because  BZPs have a high therapeutic index  Hypnotic doses do not affect respiration & CVS functions  no effect on rapid eye movement phase of sleep, hence there is no hangover  Produce less physical dependence  BZPs do not alter the disposition of other drugs by microsomal enzyme inhibition  Benzodiazepine – like drugs  zolpidem, zaleplon, and eszopidone  not benzodiazepines but appear to exert their CNS effects via interaction with certain benzodiazepine receptors,  In contrast to BZPs, these drugs bind more selectively, interacting only with GABAA receptor  Their CNS depressant effects can be antagonized by flumazenil. 33 9/2/2024  5-HT agonists (Buspirone)  Acts as a partial agonist at brain 5HT1A receptors, presynapticaly inhibiting 5HT release.  is rapidly absorbed orally, undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. Its t½ is 2-4h.  Adaptive changes after chronic treatment , reduction in 5HT2 receptors in cortex  effects appear late only after two weeks from administration.  Pharmacodynamic effects Only anxiolytic Not- anticonvulsant No hypnotic No potentiation of effect. Other CNS Not muscle depressants relaxant. Minimal psychomotor & No withdrawal Cognitive signs dysfunctions. Minimal risk of Does not affect dependence driving skills Disadvantage of Buspirone Slow onset of action (delayed effect) Not effective in severe anxiety/panic disorder GIT upset, dizziness, drowsiness Drug Interactions with CYT P450 inducers and inhibitors Clinical Uses: Used in generalized anxiety states, but is not very effective in panic disorders Drug Interaction:  Blood pressure may be ↑ in patients receiving MAO inhibitors.  Rifampin ↓ the half-life.  CYP3A3 inhibitors (erythromycin, ketoconazole)↑its plasma levels.  The drug does not potentiate effects of sedative-hypnotics, ethanol, or tricyclic antidepressants  Remelteon :A melatonin agonist MOA  ramelteone activates receptors for melatonin which are key mediators of the normal sleep – wakefulness cycle. Beta Blockers eg, propranolol  may be used as antianxiety agents in situations such as performance anxiety (the anxiety, fear, or persistent phobia which may be aroused in an individual by the requirement toperform in front of an audience, whether actually or potentially). 37 9/2/2024  Tricyclic antidepressants (doxepin, imipramine, and desipramine)  Act by reducing the uptake of 5HT and norepinephrine Clinical uses: Used for anxiety especially in those associated with depression.  TCA are considered effective for panic attacks. They, however, have a delayed onset of action up to weeks. Side effects:  atropine-like effect (dry mouth and blurred vision),  α-blocking activity (postural hypotension),  sexual dysfunction, and weight gain.  Selective serotonin reuptake inhibitors (SSRI) - (fluoxetine) PK : fluoxetine is given by the oral route.  With having a long half life. PD: Acts by blocking the reuptake of 5HT.  Weeks elapse before their onset of action starts to appear. Clinical uses: It is used for panic disorders, obsessive compulsive disorder(OCD), generalized anxiety disorders (GAD), and phobia. Side Effects: nausea, diarrhea, sexual dysfunction, dry mouth, seizures, sleep disturbance Monoamine oxidase (MAO) inhibitors (phenelzine) Pharmacodynamics:  Phenelzine acts by blocking the action of MAO enzyme which is essential in the degradation of NE , serotonin, and tyramine Clinical Uses: used for panic attacks and phobia Side Effects:  dry mouth, constipation, diarrhea, restlessness, dizziness, postural hypotension, and weight gain  They require dietary restriction. Avoid the consumption of wine, beer, or fermented foods such as old cheese which contain tyramine.