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

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

Benzodiazepine

• Flumazenil (Anexate) – antagonist of benzodiazepine

• a synthetic benzodiazepine derivative

Benzodiazepines

• for sedative-hypnotic activity

1. Diazepam (Valium) 4. substitution in the 7-position, such as with a halogen or nitro group is required Triazolam (Halcion)

2. Flurazepam (Dalmane) 5. Midazolam (Dormicum)

3. Lorazepam (Ativan) 6. Estazolam (Esilgan)

• *Flumazenil (Anexate) – antagonist of benzodiazepine

• MOA: competitive antagonism at the GABAA receptor

• a synthetic benzodiazepine derivative

BarbituratesStructure – 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

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 BarbituratesPharmacokinetics 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 Effects1. 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 patterns3. 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 Effects1. 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, metharbital2. Muscle Relaxation• inhibitory effects:polysynaptic reflexes/internuncial trans.• relax contracted skel. muscle/muscle spasm: treat spasticity3. 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 Anxiolytic1. 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 Hypnotics1. 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 Hypnotics2. 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

1. 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 flumazenil2. Hypersensitivity Reactions – skin rashes3.  Teratogenicity – piperidindiones, some benzodiazepines4.  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