ANXIETY CNS DEPRESSANTS SEDATIVE-HYPNOTIC DRUGS 10/25/18

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1 CNS DEPRESSANTS SEDATIVE-HYPNOTIC DRUGS Dr. Hiwa K. Saaed, BSc, HD, MSc, PhD Department f Pharmaclgy & Txiclgy Cllege f Pharmacy/ University f Sulaimani ANXIETY Anxiety the mst cmmn mental disrders, is an unpleasant state f tensin, apprehensin, r uneasiness (a fear that arises frm either a knwn r an unknwn surce). It usually invlves bth: Mental & Physical Symptms Mental features: wrry, fear, difficulty cncentratin, sleep prblems. Physical symptms: are similar t thse f fear (sympathetic activatin) Tachycardia; sweating, muscle aches, nausea, shrtness f breath, trembling, and palpitatins. 2 1

2 ANXIETY Unlike ther mental disrders, anxiety can be bth a nrmal emtin and a psychiatric illness. It is a universal human emtin, and a certain amunt is useful t the individual, acting as a stimulant and increasing efficiency. but when it becmes excessive and disprprtinate t the situatin, an anxiety state develps; it becmes a pathlgical (disabling) and needs treatment. 3 Primary ANXIETY CLASSIFICATION Generalized anxiety disrder (GAD): apprehensive and tense fr n particular reasn. Panic disrder: unexpected attacks f anxiety. Phbic disrders: fears certain situatin agraphbia Obsessive cmpulsive disrder: repetitive, anxiety driven behavir r bsessive thughts and dubts (check things mre than nce) Pst-traumatic stress disrder (rape r warfare) Secndary due t medical causes r substances 4 2

3 SEDATIVE-HYPNOTIC DRUGS a chemically hetergeneus class f drug. The mst imprtant are: Benzdiazepines (BZs), Barbiturates: phenbarbital, Other hypntics: Nn benzdiazepines: zlpidem, Zalepln and Eszpiclne Antihistamines: diphenhydramine, hydrxyzine, and dxylamine antidepressants: Dxepin Melatnin agnist: Ramelten Other Anxilytics: Buspirne, antidepressants: SSRIs, such as escitalpram r parxetine (BZs) Alprazlam, Chlrdiazepxide, Clnazepam Clrazepate, Diazepam, Estazlam, Flurazepam, Lrazepam, Midazlam, Oxazepam, Quazepam, Temazepam Triazlam r sertnin/nrepinephrine reuptake inhibitrs (SNRIs), such as venlafaxine r dulxetine) 5 THE EFFECTS OF CNS DEPRESSANTS Sedatives cause mild depressin and relaxatin Anxilytic drugs that relieve anxiety, Site f actin is n the limbic system which regulates thught and mental functin. Hypntics induce drwsiness and encurage sleep Amnesiac effects can cause the lss f memry Site f actin is n the midbrain and ascending RAS which maintain wakefulness. The same drug can cause different effects based n dse. Lw dse (sedatives relieve anxiety and prmte relaxatin) Higher dses (hypntics can cause drwsiness and prmte sleep) Even higher dses (anesthetics can cause anesthesia and are used fr patient management during surgery) 6 3

4 DOSE-DEPENDENT DEPRESSION OF CNS 7 BENZODIZEPINES Benzdiazepines are widely used anxilytic drugs. They have largely replaced barbiturates and meprbamate in the treatment f anxiety and insmnia, because benzdiazepines are generally cnsidered t be safer and mre effective. Selective sertnin reuptake inhibitrs (SSRI), are preferred in in many cases Nnbenzdiazepine hypntics and antihistamines may be preferable fr insmnia. 8 4

5 BENZODIAZEPINE MECHANISMS OF ACTION The targets fr benzdiazepine actins are the GABAA receptrs. GABA is the majr inhibitry neurtransmitter in the CNS. The GABAA receptrs are cmpsed f a cmbinatin f five α, β, and γ subunits that span the pstsynaptic membrane. Fr each subunit, many subtypes exist (fr example, there are six subtypes f the α subunit). 9 BENZODIAZEPINE MECHANISMS OF ACTION Benzdiazepines mdulate GABA effects by binding t a specific, high-affinity site (distinct frm the GABA-binding site) lcated at the interface f the α subunit and the γ subunit n the GABAA receptr Cmmn BZ receptr subtypes in the CNS are designated as BZ 1 r BZ 2 depending n whether the binding site includes an α 1 r α 2 subunit, respectively. Benzdiazepines increase the frequency f channel penings prduced by GABA. Binding f a benzdiazepine t its receptr site increases the affinity f GABA fr the GABA-binding site (and vice versa). 10 5

6 BENZODIAZEPINE MECHANISMS OF ACTION BZs ptentiate GABA increase frequency f Cl - in channel pening causes hyperplarizatin raise firing threshld and thus inhibits the frmatin f actin ptentials inhibitry effect n different sites f the brain especially mtr crtex, and limbic system

7 BZ Receptr BZ 1 receptrs: mainly in the cerebellum and are related t anxiety and sedatin. BZ 2 receptrs: mainly in the basal ganglia and hippcampus and are assciated with muscle relaxatin, as well as memry and learning. This helps explain; why sme are superir as anxilytics and sme as hypntics. Fr example, midazlam strngly acts n the BZ 2 receptrs, causing amnesia. Other receptrs in this cmplex are assciated with seizure activity. This explains the use f sme f the benzdiazepines in epilepsy and in ther cnvulsive cnditins. 13 ACTIONS All benzdiazepines exhibit the fllwing actins t sme extent: 1. Reductin f anxiety: At lw dses, the benzdiazepines are anxilytic, by selectively enhancing GABAergic transmissin in neurns having the α 2 subunit in their GABAA receptrs, in the limbic system f the brain. 2. Sedative/hypntic: All benzdiazepines have sedative and calming prperties, and sme can prduce hypnsis (artificially prduced sleep) at higher dses. The hypntic effects are mediated by the α 1 -GABAA receptrs. 14 7

8 ACTIONS 3. Antergrade amnesia: Temprary impairment f memry with use f the benzdiazepines is als mediated by the α 1 - GABAA receptrs. The ability t learn and frm new memries is als impaired. 4. Anticnvulsant: This effect is partially, althugh nt cmpletely, mediated by α 1 -GABAA receptrs. 5. Muscle relaxant: At high dses, the benzdiazepines relax the spasticity f skeletal muscle, prbably by increasing presynaptic inhibitin in the spinal crd, where the α 2 -GABAA receptrs are largely lcated. 15 THERAPEUTIC USES 1. Anxiety disrders: anxiety symptms secndary t panic disrder, alprazlam generalized anxiety disrder (GAD), scial anxiety disrder, perfrmance anxiety, psttraumatic stress disrder (PTSD), bsessive cmpulsive disrder (OCD), anxiety related t depressin and schizphrenia, and extreme anxiety assciated with phbias, such as fear f flying. The lnger-acting agents, such as clnazepam, lrazepam, and diazepam, are ften preferred in thse patients with anxiety that may require prlnged treatment. 16 8

9 THERAPEUTIC USES 2. Sleep disrders: A few f the benzdiazepines are useful as hypntic agents. Cmmnly prescribed benzdiazepines fr sleep disrders include: intermediate-acting temazepam shrt-acting triazlam. Lng-acting flurazepam: is rarely used, due t its extended half-life, which may result in excessive daytime sedatin and accumulatin f the drug, especially in the elderly. Estazlam (intermediate) and quazepam (lng-acting agents). In the treatment f insmnia, it is imprtant t balance the sedative effect needed at bedtime with the residual sedatin ( hangver ) upn awakening. 17 THERAPEUTIC USES a. Temazepam: This drug is useful in patients wh experience frequent wakening. Hwever, because the peak sedative effect ccurs 1 t 3 hurs after an ral dse, it shuld be given 1 t 2 hurs befre bedtime. b. Triazlam: is effective in treating individuals wh have difficulty in ging t sleep. Tlerance frequently develps within a few days, and withdrawal f the drug ften results in rebund insmnia. Therefre, this drug is nt a preferred agent, and it is best used intermittently. In general, hypntics shuld be given fr nly a limited time, usually less than 2 t 4 weeks. 18 9

10 THERAPEUTIC USES 3. Amnesia: The shrter-acting agents are ften emplyed as premedicatin fr anxiety-prvking and unpleasant prcedures, such as endscpy, dental prcedures, and angiplasty. They cause a frm f cnscius sedatin, allwing the persn t be receptive t instructins during these prcedures. Midazlam is a benzdiazepine used t facilitate amnesia while causing sedatin prir t anesthesia. 4. Seizures: Clnazepam is ccasinally used as an adjunctive therapy fr certain types f seizures, whereas lrazepam and diazepam are the drugs f chice in terminating status epilepticus. 19 THERAPEUTIC USES 3. alchl withdrawal-related seizures: Due t crss-tlerance, chlrdiazepxide, clrazepate, diazepam, lrazepam, and xazepam are useful in the acute treatment. 4. Muscular disrders: Diazepam is useful in the treatment f skeletal muscle spasms, such as ccur in muscle strain, and in treating spasticity frm degenerative disrders, such as multiple sclersis and cerebral palsy

11 PHARMACOKINETICS Ø Mst f them are well absrbed rally. Ø Bzs are lipid sluble and widely distributed Ø Redistributin frm CNS t skeletal muscles, adipse tissue. Ø Crss placental barrier during pregnancy and are excreted in milk (Fetal & nenatal depressin). Ø Highly bund t plasma prtein. 21 DURATION OF ACTION OF BZS Shrt acting (2-8 hrs) midazlam triazlam Intermediate (10-20 hrs) temazepam, lrazepam, alprazlam, xazepam, nitrazepam, estrazlam Lng acting (1-3 days): chlrdiazepxide, diazepam, flurazepam, clnazepam, chlrazepate 22 11

12 PHARMACOKINETICS Ø All Bzs are metablized in the liver Phase I: ( livermicrsmal system) Phase II: glucurnide cnjugatin andexcreted in the urine. Ø Many f Phase I metablites are active: Increase eliminatin half life f the parent cmpund, cumulative effect with multiple dses. Ø EXCEPT N active metablites are frmed fr (LEO) Lrazepam, Estazlam, Oxazepam. 23 METABOLISM 24 12

13 Tlerance & Dependence The antianxiety effects f the benzdiazepines are less subject t tlerance than the sedative and hypntic effects. Tlerance (that is, decreased respnsiveness t repeated dses f the drug) ccurs when used fr mre than 1 t 2 weeks. Tlerance is assciated with a decrease in GABA receptr density. Crss-tlerance exists between the benzdiazepines and ethanl. Physilgical dependence: remval f the drug evkes unpleasant symptms, usually the ppsite f the drugs effects Psychlgical dependence: the drug taker feels cmpelled t use the drug & suffers anxiety when separated frm drug. 25 WITHDRAWAL SYMPTOMS Abrupt discntinuatin, particularly if high dses used fr prlng perid. WD symptms with BZs are less intense than with ethanl r barbiturates. WITHDRAWAL SYMPTOMS Cnfusin, anxiety, agitatin, restlessness insmnia tensin ADVERSE EFFECTS OF BZS Drwsiness and cnfusin Ataxia at high dses-precludes activities like driving Cgnitive impairment: lng term recall, acquisitin f knwledge 26 13

14 FLUMAZENIL BZS ANTAGONIST Flumazenil: I.V nly, reverses the effect f the BZs (cmpetitive antagnist), nset is rapid, and duratin is shrt. 27 Other Hypntic Agents NON BENZODIAZEPINES Zlpidem and Zalepln act n BZ 1 (a subtype f BZ receptr family), are mre selective hypntics, NOT effective in chrnic anxiety, seizure disrders, r muscle relaxing. Pssibly less tlerance ccur with prlng use and lwer abuse liability and dependence than BZs. they shw n withdrawal effects, Minimal rebund insmnia Rapidly absrbed, rapid nset with shrt duratin (2-3 hrs) Zalepln causes fewer residual effect n pseudmtr and cgnitive functin cmpared with zlpidem r the BZs due t shrt t 1/2 < 1hr 28 14

15 BUSPIRONE ttally different anxilytic frm BZs, n effects n GABA systems, pssible partial agnist at 5-HT 1A receptrs sme affinity fr D 2 & 5- HT 2A. Indicatin: Indicated fr chrnic generalized anxiety disrders but takes 1 t 2 weeks t exert anxilytic effects. It is nt effective fr shrt-term r as-needed treatment f acute anxiety states. Buspirne lucks anticnvulsant and Muscle relaxant prperty f BZs and cause minimal sedatin. N additive CNS depressin with ther drugs. Adverse effects: hypthermia, increase prlactin, headache, dizziness, nervusness 29 BARBITURATES The barbiturates were frmerly the mainstay f treatment t sedate patients r t induce and maintain sleep. Tday, they have been largely replaced by the benzdiazepines, primarily because barbiturates induce: 1. tlerance, 2. drug metablizing enzyme, 3. physical dependence 4. and very severe withdrawal symptm. 5. Flumazenil des nt blck the effects f barbiturates. Bayere discverer f barbiturates

16 BARBITURATES MECHANISM OF ACTION interact with GABA receptrs, the binding site is distinct frm that f the BZs. ptentiate GABA actin n Cl - entry int the neurn by increase the duratin f Cl - in channel pening. In additin, barbiturates can blck excitatry glutamate receptr (sub anesthetic dse). at high dses (anesthetics cnc. f RAS inhibitin), als pen Cl - in channels directly and blck high frequency Na + channels. 31 Duratin f Actin f Barbiturates Lng acting (1-2 days) Anticnvulsant Phenbarbital; Shrt (3-8hrs) Sedative & Hypntic Pentbarbital, secbarbital and ambarbital: Ultrashrt (20 min) I.V inductin f anesthesia: Thipental 32 16

17 ADVERSE EFFECTS OF BARBITURATES Dse-dependent CNS depressin, with nystagmus and ataxia prgressing t respiratry depressin, cma, and pssible mrtality. n specific antidte in verdse. Additive CNS depressin with ther drugs. 33 PHARMACOKINETICS All barbiturates are weak acids, lipid sluble, absrbed rally. distribute thrughut the bdy Thipentne is highly lipid sluble (high rate f entry int CNS- quick nset f actin). All barbiturates redistribute frm the brain t the splanchnic areas, t skeletal muscle, and, finally, t adipse tissue. metablized in the liver t inactive metablites Excreted in the urine. Alkalinizatin increases excretin (NaHCO3) Crss the placenta (pregnancy)

18 METABOLISM Hepatic metablism (sme t active metablite). Inductin f Cytchrme P450 is characteristic and may lead t drug interactins. Because f increase heme synthesis, they are cntraindicated in prphyrias Prphyrias: a hereditary disrder f hemglbin metablism causing: -mental disturbance, -extreme sensitivity t light -and excretin f dark pigments in the urine. 35 WHY BENZODIZEPINES HAS REPLACED BARBITURATES? BZS BARBITURATES They d nt prduce anesthesia in high dses & patient can be arused. Prduce lss f cnsciusness and have lw margin f safety These are nt enzyme inducers, enzyme inducers. Very lw abuse liability. High abuse liability. Lesser distrtin f nrmal hypngram. Marked suppressin f REM sleep. Bzs have n hyperalgesia. Hyperalgesic actin. Bzs can be used as day time anxilytic. Unacceptable drwsiness is seen. D nt effect respiratry r CVS functin. There is a specific antagnist-flumazenil. Causes respiratry and depressin & hyptensin. N specific antagnist

19 Other anxilytics Antihistamines: it has lw tendency fr habituatin and thus is useful fr patients wit anxiety wh have a histry f drug abuse: hydrxyzine, diphenhydramine, dxylamine. Melatnin: synthesized frm 5HT, significant rle in diurnal cycles and sleep-wake behavir. Ramelten: melatnin receptr (MT1 and MT2) agnist with sleep prmting activities. It has been apprved fr chrnic insmnia and cnsidered free frm dependence ptential. Tasimelten: is the first and nly medicatin that's been prven t treat peple with Nn-24-Hur Sleep- Wake Disrder. 37 MISCELLANEOUS PROPRANOLOL has efficacy in perfrmance anxiety and scial phbias. Antidepressants: The use f sedating antidepressants with strng antihistamine prfiles has been nging fr decades. Dxepin, an lder tricyclic agent with SNRI mechanisms f antidepressant and anxilytic actin, was recently apprved at lw dses fr the management f insmnia. Other antidepressants, such as trazdne, mirtazapine and ther lder TCA with strng antihistamine prperties are used ff-label fr the treatment f insmnia. Opid analgesics Ethanl 38 19

20 SOME OUTDATED HYPNOTICS: Chlral hydrate: is a trichlrinated derivative f acetaldehyde that is cnverted t the active metablite, trichlrethanl in the bdy. Paraldehyde: little effect n respiratin and BP in therapeutic dse. Large dses suppress all type f cnvulsins with rapid nset f actin. It has strng armatic dr and unpleasant taste. 39 Thank yu 40 20