Sedative-Hypnotics Teresita N. Avendano-Batanes, M.D., DPBA Department of Anesthesiology College of Mediciane UERMMMCI

Sedative - Hypnotics Sedative Anxiolytic exerts a calming effect makes one less responsive to stimulation with decreased spontaneous activity  Hypnotic encourages onset maintains sleep usually attained at higher doses of a sedative Anxiolytic – reduces anxiety

Sedative - Hypnotics Death Coma A Anesthesia B Hypnosis Sedation Increasing Dose Drug A: older Sed.-hypnotics, e.g. Barbiturates Drug B: greater margin of safety, e.g. benzodiazepines

Benzodiazepines  aryl-1,4-benzodiazepines  7-position substituent: halogen or nitro-group - required for sedative- hypnotic activity The term benzodiazepine refers to the portion of the structure composed of a benzene ring (A) fused to a seven-membered diazepine ring (B). However, since all of the important benzodiazepines contain an aryl substituent ring C) and a 1, 4-diazepine ring, the term has come to mean the aryl-1,4-benzodiazepines. Benzodiazepines: 1,4-benzodiazepine structures with carboxamide group in the 7-membered heterocyclic ring

Benzodiazepine • Flumazenil (Anexate) – antagonist of benzodiazepine • a synthetic benzodiazepine derivative MOA: competitive antagonism at the GABAA receptor

Benzodiazepines for sedative-hypnotic activity Diazepam (Valium) 4. substitution in the 7- position, such as with a halogen or nitro group is required Triazolam (Halcion) Flurazepam (Dalmane) 5. Midazolam (Dormicum) Lorazepam (Ativan) 6. Estazolam (Esilgan) *Flumazenil (Anexate) – antagonist of benzodiazepine MOA: competitive antagonism at the GABAA receptor a synthetic benzodiazepine derivative

Barbiturates Structure – Activity Relationships 1. Substitution at C5 determines a. Hypnotic potency: long-branched chain > short straight chain b. Anti-convulasant activity: phenyl group is anti- convulsive  2. Replacing O2 at C2 (Oxybarbiturate) with S (Thiobarbiturate)  lipid solubility   onset of action  3. Short duration of action–methyl substitution at N1

Barbiturates Chemical Name: Sodium thiopental IUPAC Name: Sodium 5 - ethyl - 6 - oxo - 5 - pentan - 2 - yl - 2 - sulfanylidene - pyrimidin - 4 - olate Molecular Formula: C11H17N2NaO2S

Sedative-Hypnotics Alcohols: Ethanol, Chloral Hydrate Ethers New Drugs: Other Drugs with *Buspirone - anxiolytic Sedative Effects * Zolpidem - hypnotic 1. Clonidine * Zaleplon – hypnotic 2. Antipsychotic tranquilizeres 3. Tricyclic Antidepressants 4. Antihistamines

Benzodiazepines and Barbiturates Pharmacokinetics Routes of Admi/Absorption: po, rectal, IV, IM, SQ Distribution major role of lipid solubility to gain entry into CNS thiobarbiturates more lipid vs. oxybarbiturates rapid redistribution which termination CNS effects all cross placental barrier neonatal depression (+) in breast milk depression in breastfed babies extensive protein binding: benzodiazepines: 60 – 90% chloral hydrate displaces warfarin from plasma protein binding site  anticoagulant effect of warfarin

Benzodiazepines Biotransformation/Excretion by microsomal drug metabolizing enzymes (liver) to water-soluble metabolites  excretion via the kidneys  Table M. Some benzodiazepines with their metabolites: Drug Metabolite Remarks Diazepam Desmethyl- Multple dosing Clorazepate diazepam excessive Chlordiazepoxide ~46 hrs.half-life drowsiness Prazepam active metabolite Lorazepam inactive Less chance of Estazolam metabolites having residual Oxazepam CNS effects

Barbiturates - inactive metabolites w/ few exceptions *Phenobarbital – 20 – 30% excreted unchanged; elimination half-life of 4 – 5 days multiple dosing  cumulative CNS effects biodisposition affected by hepatic changes due to: old age, diseases, microsomal enzyme activity

Benzodiazepines and Barbiturates Pharmacodynamics Mechanism of Action: bind Benzodiazepines molecular components of barbiturates* GABAA receptors in CNS  opening of Chloride ion channels   Chloride ion conductance  *Do not substitute for GABA but appear to enhance effects of GABA

Organ Level Effects Sedation may be with by euphoria, impaired judgement anterograde amnesia – cannot recall events happening during the drug’s action (benzodaazepines) 2. Hypnosis time to fall asleep is , duration of stage 2 NREM sleep is ; duration of REM sleep is  use of sedative-hypnotics for > 1 – 2 weeks may lead to some tolerance to their effects on sleep patterns 3. Anesthesia some sedative-hypnotics  stage III of GA large doses contribute to post-op resp. depression no analgesic property, used as adjuncts, “conscious sed.”

Organ Level Effects Anti-Convulsant Effect - inhibit development and spread of seizure activity in CNS - benzodiazepines: clonazepam (for absence seizure), lorazepam, diazepam (drug of choice for status epilepticus) - barbiturates: Phenobarbital, metharbital 2. Muscle Relaxation inhibitory effects:polysynaptic reflexes/internuncial trans. relax contracted skel. muscle/muscle spasm: treat spasticity 3. Effects on Respiratory and Cardiovascular Functions significant resp. depression in pxs with pulmonary disease significant CV depression in pxs who are hypovolemic, w/ congestive heart failure or w/ impaired CV function

Benzodiazepine Antagonist: Flumazenil MOA: competitive antagonism at GABAA receptor 1,4- benzodiazepine (synthetic) derivative does not antagonize the CNS effects of other sedative- hypnotics, ethanol, opioids or general anesthetics IV; half-life = 0.7 – 1.3 hrs. due to rapid hepatic clearance Watch/O for recurrence of benzodiazepine-caused CNS dep. Adverse Effects: agitation, confusion, dizziness, nausea, abstinence symptoms in dependent patients  Drug Interaction: benzodiazepine + tricyclic antidep. + flumazenil Sz, cardiac arrhythmias

New Anxiolytic BUSPIRONE: for relief of Anxiety no marked sedation/euphoria; less psychomotor impair. does not potentiate CNS actions of other drugs  Mechanism of Action: partial agonist at 5-HT1A receptor Onset of Action: > one week to establish Not for panic states, only for general anxiety states Liver dysfunction may decrease clearance Drug Interactions: Buspirone + MAOI   BP antagonized by flumazenil

New Hypnotics ZOLPIDEM (Stilnox): a hypnotic  Mechanism of Action: binds selectively with BZ1 (omega1) subtype of benzodiazepine receptor  facilitate GABA-mediated neuronal inhibition antagonized by flumazenil; elim.half-life: 1.5 – 3.5 hrs. DI:  dose in pxs w/ liver dysfunction, elderly, on cimetidine Rifampicin (C P450 inducer)  half-life of zolpidem C/I: children <15 yrs., pregnant/lactating pxs Prep: tab 10mg

New Hypnotics 2. ZALEPLON: a hypnotic, resembles zolpidem Mechanism of Action: binds selectively with BZ1 receptor subtype of benzodiazepine receptor  facilitate GABA inhibitory action decreases sleep latency, has little effect on total sleep time SE: amnestic effects; next-day impair. of psychomotor fx may potetiate CNS depression from ethanol no reports of tolerance or withdrawal symptoms Pharmacokinetics: absorbed rapidly from the GIT metabolized by hep.aldehyde oxidase, cytochrome p450 metabolism is inhibited by cimetidine

Sedative - Hypnotics DRUG INTERACTIONS 1.  Additive Effects with Other CNS Depressants alcoholic beverages, opioidcs, anti-convulsants, phenothiazines, antihistamines, TCAD, antihypertensives  2.  Altered Activity of Hepatic Drug-Metabolizing Enzyme System Barbiturates - metabolism of dicumarol, phenytoin, digitalis, griseofulvin Diazepam – half-life doubled by cimetidine (inhib. metab Chloral Hydrate – may displace warfarin from plasma protein binding sites  anticoagulant effect of warfarin

Clinical Toxicology of the Sed-Hyps CNS Depression - severe toxicity: resp. dep., aspiration, loss of vasomotor control from brainstem, direct myocardial depression - treatment:secure airway and breathing, maintain plasma volume, renal output,maintain cardiac function, reversal of benzodiazepine effects by flumazenil 2. Hypersensitivity Reactions – skin rashes 3.  Teratogenicity – piperidindiones, some benzodiazepines 4.  Enhance Porphyrin Synthesis - barbiturates are contraindicated in patients with acute intermittent porphyria, variegated porphyria, hereditary coproporphyria or symptomatic porphyria

Alterations in Drug Response 1. Tolerance - decreased responsiveness to a drug following repeated exposure depends on dosage, duration of use, chronic abusers consume very large doses w/o experiencing severe toxicity  Cross-Tolerance – exists between different sedative- hypnotics, including ethanol  2.      Physiologic Dependence altered physiologic state requiring continued drug administration to prevent the appearance of abstinence Sx withdrawal Sx: restlessness, anxiety, weakness, orthostatic hypotension, hyperactive reflexes, generalized seizures Cross-Dependence – the ability of a substituted drug to suppress abstinence Sx from D/C of another drug