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

2. 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

3. 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

4. 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

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

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

7. 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

8. Barbiturates Chemical Name: Sodium thiopental
IUPAC Name: Sodium 5 - ethyl oxo pentan yl sulfanylidene - pyrimidin olate
Molecular Formula: C11H17N2NaO2S

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

11. 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

12. 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

13. 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

14. 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

15. 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.”

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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