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Drug Classifications:
1. Benzodiazepines
2. Barbiturates
3. Alcohol
Coma
Barbiturate
Alcohol
anesthesia
Hypnosis
Benzodiazepam
Sedation
Increasing dose
Dose-dependent curve for two hypothetical sedativehypnotics.
Benzodiazepines (BZs)
1. Long-ac8ng (30-80 hrs) : diazapam (valium),
urazepam, prazepam, quazepam,
clorazepate
2. Intermediate ac8ng (3-25 hrs) : lorazepem,
temazepam, oxazepam, alprazolam,
estazolam
3. Short-term (1-5 hr): triazolam
FM2: unitrizopam 2 mg
A. Pharmacology
1. Site of ac%on: poten%ate GABAA receptormediated
inhibi%on via Cl- inux and hyperpolariza8on
2. Major treatment: an%-anxiety (2 eect), control of insomnia
(not aect REM sleep) (1 eect) and produce seda%ve eect
(1 eect); higher therapeu%c index, thus considered to be drug
of choice.
3. Treatment of epilepsy (1 eect)
4. Muscle relaxant: high dose eect via increasing presynap%c
inhibi%on in the spinal cord (2 eect)
5. Pre-medica%on of anesthesia
6. Treatment for alcohol withdrawal syndromes
7. Panic disorder: alprazolam (quick on-set)
BZ binds at the
interface of the
and 2 subunt
B. Pharmacokinetics
1. Absorp8on: Usually given orally. Rate of absorp%on depends on
lipophilicity. Oral absorp%on of triazolam, diazepam and
clorazepate are more rapid than others. Plasma binding does not
limit its bioavailability.
2. All seda8ve-hypno8cs can cross the placental barrier during
pregnancy and exist in the breast milk.
3. Biotransforma8on:
Benzodiazepam antagonist
1. Flumazenil: block the ac%on of BZs, but not other seda%vehypno%cs or ethanol.
2. Reverse CNS depressant eect of BZ over-dosage (available
only through IV)
3. Short T1/2 (0.7-1.3 hr): requires repeated administra%ons to
overcome the long-dura%on of BZ
4. Adverse eect: agita%on, confusion, dizziness, nausea.
Precipitated withdrawal syndromes in BZ dependent
pa%ents
Barbiturates
A. Classifications:
1.
2.
3.
4.
B. Pharmacology:
1. Site of ac%on: poten%ate GABAA receptor-mediated inhibi%on;
also inhibit glutamate receptor and high frequency sodium
channels
2. Control of insomnia (but reduce REM sleep, so cause hangoverlike symptom the following day)
3. Have an%-convulsion ability
4. As an intravenous induc%on of anesthe%c, e.g. thiopental
C. Pharmacokine8cs
1. Oral: on-set is approximately 10-60 min dependent on fas%ng
2. i.v. injec%on for short-ac%ng methohexital and thiopental
3. Metabolized via microsomal enzyme system by oxida%on,
hydroxyla%on, desulfura%on or glucuronida%on and eliminated
via kidney (usually inac%ve metabolites)
4. Quick develop drug tolerance due to induc%on of microsomal
P450 enzyme to drug self (metabolic tolerance)
Non-BZ/-barbiturate Anxiolytic/Hypnotics
A. Buspirone
New anxiely%c has less seda%ve-eect, euphoria and drug
dependence. It also has less interac%on with other drugs. Due
to slow on-set, it is not appropriate for acute pa%ent
Molecular mechanism: 5-HT1A receptor par%al agonist and
block D2 dopamine receptor; lacks an%convulsant and musclerelaxant proper%es of BZ
Side eects: minimal seda%on; tachycardia, headache,
nervousness, GI distress, palpita%ons
Metabolism: by CYP3A4 (lengthened if taken with
erythromycin; shortened if taken with rifampin)
C. Chloral hydrate
1. A trichlorinated deriva%ve of acetaldehyde.
2. Eec%ve seda%ve and hypno%c that induces sleep between 30 min
to 6 hours.
3. Side eects: GI irrita%ng, epigastric distress, unpleasant taste
sensa%on
D. An8histamines
1. Hydroxyzine
a. An an%histamine with an%-eme%c ac%vity
b. Low tendency for habitua%on; side eect of drowsiness
c. Applica%on: seda%on prior to surgery and dental procedure
A. Pharmacology
1. Treatment of methanol and ethylene glycol poisoning
[ complete with alcohol dehydrogenase (ADH), thus
decrease toxic formaldehyde and formic acid ]
2. An8sep8c (70%)
3. Reduce body temperature
4. Site of ac8on:
a. Decrease synap%c transmission due to lipid solubility
b. Non-selec%ve eect on membrane receptors:
GABAA, nico%nic cholinergic, glutamate receptor
and voltage-dependent calcium channel
B. Pharmacokinetics
1. More than 90% is metabolized by ADH followed by
aldehyde dehydrogenase (ALDH) in liver
2. First-pass metabolism: ADH ac%vity in stomach of
woman is only 50% of men. Thus, high incidence of
acute alcohol intoxica%on among woman
50% oriental miss ac%ve ALDH which result in ushing body.
This enzyme is inhibited by disulram which is used to treat
alcohol addic%on (accumula%on of acetaldehyde in the
blood will causing ushing, tachycardia, nausea and
hyperven%la%on condi:oned avoidance response)