Sedative-Hypnotic Drugs

CNS DEPRESSANTSSEDATIVE-HYPNOTIC DRUGSDr. Hiwa K. Saaed, BSc, HD, MSc. PhDDepartment of Pharmacology & ToxicologyCollege of Pharmacy/ University of Sulaimani2014-2015

1ANXIETYUnlike 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.11/3/201422ANXIETY DISORDERSIt usually involves both: Mental features worry, fear, difficulty concentration, sleep problems.Physical symptoms Tachycardia; muscle aches, nausea, shortness of breath, trembling, pacing

11/3/20143ANXIETY CLASSIFICATION#PrimaryGeneralized anxiety disorder (GAD): apprehensive and tense for no particular reason.Panic disorder: unexpected attacks of anxiety.Phobic disorders: fears certain situation agoraphobiaObsessive compulsive disorder: repetitive, anxiety driven behavior or obsessive thoughts and doubts (check things more than once)Post-traumatic stress disorder (rape or warefare)#Secondary due to medical causes or substances

11/3/20144SEDATIVE-HYPNOTIC DRUGSThe sedative-hypnotics belong to a chemically heterogeneous class of drug.

The most important are:Benzodiazepines (BZs), Diazepam, Non benzodiazepines: buspirone, zolpidem, and ZaleplonBarbiturates: phenobarbital, Miscellaneous: carbamates, alcohol

11/3/201455SEDATIVE-HYPNOTIC DRUGS SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultrashortacting acting Intermediate Short Buspirone acting acting Chloral hydrate Long Long Zaleplon acting acting Zolpidem Ramelteon Tasimelteon611/3/2014THE EFFECTS OF CNS DEPRESSANTSSedatives cause mild depression and relaxationAnxiolyticdrugs that relieve anxietySite of action is on the limbic system which regulates thought and mental function.

Hypnotics induce drowsiness and encourage sleep Amnesiac effects can cause the loss of memorySite of action is on the midbrain and ascending RAS which maintain wakefulness.

11/3/20147THE EFFECTS OF CNS DEPRESSANTS (continued)The same drug can cause different effects based on dose.Low dose (sedativesrelieve anxiety and promote relaxation)Higher doses (hypnoticscan cause drowsiness and promote sleep)Even higher doses (anestheticscan cause anesthesia and are used for patient management during surgery)11/3/201488

DOSE-DEPENDENT DEPRESSION OF CNS11/3/201499Most S-H drugs facilitate the actions of GABA, a major inhibitory transmitter in the CNS, GABAA receptor activation leads to increased Cl- ion influx; GABAB receptor activation causes increased efflux of K+. Both mechanisms result in membrane hyperpolarization.SEDATIVE HYPNOTICMECHANISMS OF ACTION11/3/20141010

GABAA RECEPTOR The pentapeptide structure of the GABAA receptor has binding sites for BZs and for other drugs, including Barbiturates and ethanol.11/3/201411

11BENZODIZEPINESSedative (Anxiolytics) : Alprazolam Chlordiazepoxide oxazepam Diazepam lorazepam

Hypnotics : Triazolam Diazepam AlprazolamLorazepam Estazolam Temazepam Flurazepam Nitrazepam Quazepam Preanesthetics :Diazepam- Midazolam

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11/3/201412DURATION OF ACTION OF BZSShort acting (2-8 hrs)midazolam triazolamIntermediate (10-20 hrs) temazepam, lorazepam, alprazolam, oxazepam, nitrazepam, estrazolamLong acting (1-3 days): chlordiazepoxide, diazepam, flurazepam, clonazepam, chlorazepate

11/3/20141313BENZODIAZEPINEMECHANISMS OF ACTION Affect neurons that have receptors for the neurotransmitter GABABZs potentiate GABA increase frequency of Cl- ion channel opening causes hyperpolarization raise firing threshold and thus inhibits the formation of action potentials inhibitory effect on different sites of the brain especially motor cortex, and limbic system.

GABAinhibitory transmitter in brain regions Limbic system (alter mood) RAS (cause drowsiness) Motor cortex (relax muscles)11/3/201414

11/3/20141515PHARMACOKINETICSMost of them are well absorbed orally.Bzs are lipid soluble and widely distributedRedistribution from CNS to skeletal muscles, adipose tissue.Cross placental barrier during pregnancy and are excreted in milk (Fetal & neonatal depression). Highly bound to plasma protein.

11/3/201416PHARMACOKINETICSAll Bzs are metabolized in the liver Phase I: ( liver microsomal system) Phase II: glucouronide conjugation and excreted in the urine.Many of Phase I metabolites are active: Increase elimination half life of the parent compound , cumulative effect with multiple doses.EXCEPT No active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam.

11/3/201417METABOLISM

11/3/20141818BZs have neither antipsychotic activity nor analgesic. They dont affect ANSReduction of anxiety at low dose: alprazolam, lorazepam, oxazepam, diazepam and chlordiazepoxide.Alprazolam has anxiolytic-antidepressant effect.Diazepam is preferred in acute panic-anxiety.Chlordiazepoxide is preferred in chronic anxiety states.Sedative and hypnotic actions at higher dose: not all, three most commonly prescribed BZs are:long acting flurazepam, intermediate temazepam short acting triazolam. and Two non BZs: Zolpidem & Zaleplon.

11/3/201419ACTIONS AND THERAPEUTIC DOSES:19Anterograde amnesia: short acting BZs used in premedication for endoscopic, bronchoscopic, angioplasty.In anesthesia : Preanesthetic medication diazepam Induction of balanced anesthesia (Midazolam)Anticonvulsant: Treatment of epilepsyDiazepam Lorazepam: Status epilepticusClonazepam-Clorazepate: absence , myoclonic seizures.11/3/201420ACTIONS AND THERAPEUTIC DOSES:20To control Alcohol withdrawal symptoms: chlordiazepoxide, chlorazepate, diazepam & oxazepamMuscle relaxant at higher doses; diazepam is useful in the Rx of skeletal muscle spasmOther actions: in higher doses BZs decrease BP and increase HR. diazepam decreases nocturnal gastric acid secretion11/3/201421ACTIONS AND THERAPEUTIC DOSES:21

11/3/201422INDICATIONS AND DRUG CHARACTERISTICS22Tolerance: reduction in drug effect requiring an increase in dosage to maintain the same response.Chronic use leads to tolerance (cross with other S-H drugs), possibly via downregulation of BZ receptors. The antianxiety effects of the BZ are less subject to tolerance than sedative and hypnotic effects.

11/3/201423TOLERANCE23DEPENDENCEPhysiological dependence: removal of the drug evokes unpleasant symptoms, usually the opposite of the drugs effectsPsychological dependence: the drug taker feels compelled to use the drug & suffers anxiety when separated from drug.

11/3/20142424WITHDRAWAL SYMPTOMSAbrupt discontinuation, particularly if high doses used for prolong period. Confusion, anxiety, agitation, restlessness, insomnia tension WD symptoms with BZs are less intense than with ethanol or barbiturates;

11/3/20142525ADVERSE EFFECTS OF BZSDrowsiness and confusionAtaxia at high doses-precludes activities like drivingCognitive impairment: long term recall, acquisition of knowledge11/3/20142626FLUMAZENIL BZS ANTAGONISTFlumazenil: I.V only, reverses the effect of the BZs (competitive antagonist), onset is rapid, and duration is short. 11/3/20142727MISCELLANEOUS; NON BENZODIAZEPINESZolpidem and Zaleplon they:act on BZ1 (a subtype of BZ receptor family), are more selective hypnoticsare not effective in chronic anxiety, seizure disorders, or muscle relaxing.Possibly less tolerance occur with prolong use and lower abuse liability and dependence than BZs. they show no withdrawal effects, Minimal rebound insomnia

11/3/20142828ZOLPIDEM AND ZALEPLONRapidly absorbed, rapid onset with short duration (2-3 hrs)Zaleplon is very similar to zolpidem in its hypnotic action, but ZALEPLON causes fewer residual effect on pseudomotor and cognitive function compared with zolpidem or the BZs due to short t1/2 < 1hr

11/3/20142929BUSPIRONEtotally different anxiolytic from BZs, no effects on GABA systems, possible partial agonist at 5-HT1A receptors some affinity for D2 & 5-HT2A.

Indication:Indicated for generalized anxiety disorders but takes 1 to 2 weeks to exert anxiolytic effects. 11/3/20143030Buspirone lucks anticonvulsant and Muscle relaxant property of BZs and cause minimal sedation. No additive CNS depression with other drugs.Adverse effects:hypothermia, increase prolactin, headache, dizziness, nervousness

11/3/201431BUSPIRONE31BARBITURATESFormerly used as sedative hypnotic replaced by BZs, because barbiturates induce: tolerance, drug metabolizing enzyme, physical dependence and very severe withdrawal symptom.Flumazenil does not block the effects of barbiturates.

Bayere dicoverer of barbiturates.11/3/201432interact with GABA receptors, the binding site is distinct from that of the BZs.potentiate GABA action on Cl- entry into the neuron by increase the duration of Cl- ion channel opening.In addition, barbiturates can block excitatory glutamate receptor (sub anesthetic dose).at high doses (anesthetics conc. of pentobarbital-reticular activating system inhibition), alsoopen Cl- ion channels directly and block high frequency Na+ channels).

BARBITURATES MECHANISM OF ACTION11/3/20143333Duration of Action of BarbituratesLong acting (1-2 days) AnticonvulsantPhenobarbital; Short (3-8hrs) Sedative & Hypnotic Pentobarbital, secobarbital and amobarbital:Ultrashort (20 min) I.V induction of anesthesiaThiopental

11/3/20143434ADVERSE EFFECTS OF BARBITURATESDose-dependent CNS depression, with nystagmus and ataxia progressing to respiratory depression, coma, and possible mortality. no specific antidote in overdose. Additive CNS depression with other drugs.11/3/20143535PHARMACOKINETICS All barbiturates are weak acids, lipid soluble, absorbed orally. distribute throughout the body Thiopentone is highly lipid soluble (high rate of entry into CNS- quick onset of action).Redistribute in the body from the brain to skeletal muscles- adipose tissues. metabolized in the liver to inactive metabolites Excreted in the urine. Alkalinization increases excretion (NaHCO3) Cross the placenta ( pregnancy).

11/3/201436METABOLISMHepatic metabolism (some to active metabolite). Induction of Cytochrome P450 is characteristic and may lead to drug interactions. Because of increase heme synthesis, they are contraindicated in porphyrias Porphyrias: a hereditary disorder of hemoglobin metabolism causing:-mental disturbance, -extreme sensitivity to light -and excretion of dark pigments in the urine. 11/3/20143737WHY BENZODIZEPINES HAS REPLACED BARBITURATES?BZSBARBITURATESThey do not produce anesthesia in high doses & patient can be aroused.These are not enzyme inducers,Very low abuse liability.Lesser distortion of normal hypnogram.Bzs have no hyperalgesia.Bzs can be used as day time anxiolytic.Do not effect respiratory or cvs function.There is a specific antagonist-Flumazenil.Produce loss of consciousness and have low margin of safety enzyme inducers.High abuse liability.Marked suppression of REM sleep.Hyperalgesic action.Unacceptable drowsiness is seen.

Causes respiratory and depression & hypotension.No specific antagonist.

11/3/201438MISCELLANEOUS Antihistamines: it has low tendency for habituation and thus is useful for patients wit anxiety who have a history of drug abuse. hydroxyzine, diphenhydramine doxylamine; Melatonin: synthesized from 5HT, significant role in diurnal cycles and sleep-wake behavior.

11/3/20143939MISCELLANEOUS Ramelteon: melatonin receptor (MT1 and MT2) agonist with sleep promoting activities. It has been approved for chronic insomnia and considered free from dependence potential.TasimelteonPROPRANOLOL has efficacy in performance anxiety and social phobias.Tricyclicantidepressants (TCA) and SSRIOpiod analgesicsEthanol

11/3/201440SOME OUTDATED HYPNOTICS:Chloral hydrate: is a trichlorinated derivative of acetaldehyde that is converted to the active metabolite, trichloroethanol in the body.Paraldehyde: little effect on respiration and BP in therapeutic dose. Large doses suppress all type of convulsions with rapid onset of action. It has strong aromatic odor and unpleasant taste.11/3/2014414111/3/2014Thank you 42