Download Sedative - Hypnotics

Sedative-Hypnotics
Teresita N. Avendano-Batanes, M.D., DPBA
Department of Anesthesiology
College of Mediciane
UERMMMCI
Sedative - Hypnotics
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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
• Anesthesia
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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 sedativehypnotic activity
Benzodiazepine
• Flumazenil (Anexate) – antagonist of benzodiazepine
• a synthetic benzodiazepine derivative
Benzodiazepines
• for sedative-hypnotic activity
1. Diazepam (Valium)
4. substitution in the 7position, 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
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 anticonvulsive
• 2. Replacing O2 at C2 (Oxybarbiturate) with
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S (Thiobarbiturate)
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 lipid solubility   onset of action
• 3. Short duration of action–methyl substitution at N1
Barbiturates
Sedative-Hypnotics
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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
Diazepam
Clorazepate
Chlordiazepoxide
Prazepam
Lorazepam
Estazolam
Oxazepam
Metabolite
Remarks
DesmethylMultple dosing
diazepam
excessive
~46 hrs.half-life
drowsiness
active metabolite
inactive
Less chance of
metabolites
having residual
Barbiturates
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- 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
1. 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
1. 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 sedativehypnotics, 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
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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
1. ZOLPIDEM (Stilnox): a hypnotic
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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
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 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 sedativehypnotics, 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