Sedatives (Anxiolytic;

minor tranquilizers) and

Hypnotics
Jin-Chung Chen
Department of Pharmacology and
Physiology
Room 664, x 5282

Symptoms of severe anxiety are similar to fear (tachycardia,

swea8ng, trembling, palpita8on) which involve sympathe8c
ac8va8on.
Seda%ve-hypno%c drugs are used to induce seda8on (relief of
anxiety) or to encourage sleep. An eec%ve seda8ve
(anxioly/c) is to promote the calming eect in anxious pa%ents
with minimal eect on CNS depression. A hypotonic drug is to
produce drowsiness and encourage the onset and maintenance
of sleep, thus cause pronounced depression of CNS func%on.

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

Chemical structure of Benzodiazepines

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)

Structure of GABAA receptor ( subunits)

Most common form of
GABA-A receptors:
two 1, two 2, one 2

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:

a. Hepa%c metabolism accounts for the clearance of BZs. Most BZs

undergo microsomal oxida%on (dealkyla%on, hydroxyla%on)
followed by phase II glucuronida%on

b. Phase I metabolites are usually ac%ve: would cause unwanted

CNS depression and day%me seda%on (desmethyldiazepam from
prazepam, diazepam, clorazepate)
c. Oxazepam, lorazepam and alprazolam are short-lived and form
inac%ve glucuronides

C. Adverse effects and Drug interaction

1. Compared to barbiturates, it has less side eects. Pa%ents
might complain with prolonged %me.
2. Suicidal tendency with high dosage
3. Development of tolerance ( >14 days). Dependence if use for
more than 6 months, i.e. withdrawal syndromes (insomnia,
anxiety, tremor, loss of appe%te, perceptual disturbance)
occurred a_er abrupt cessa8on.
4. Anterograde amnesia: temporary impairment (1 eect)
5. Cross-tolerance with alcohol and barbiturates, should be
careful when mul%ple-drug interac%on

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.

Long ac%ng: 8h,e.g. phenobarbital (sleeping disorder)

Intermediate: 6-8h, e.g. amobarbital (insomnia)
Short ac%ng : 3-6h, e.g. secobarbital; pentobarbital (seda8ves)
Ultra-short ac%ng :15-45 min, e.g. thiopental (short anesthesia)

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

Chemical structure of barbiturates

BZs increase the frequency of inhibi%on; barbiturates enhance

the dura/on of inhibi%on

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)

D. Adverse eects and drug interac8on

1. Low therapeu8c index: at high dose, barbiturates could stop
respira8on and heart beat
2. More severe tolerance and withdrawal syndromes than
benzodiazepams; cause coma in toxic doses.
3. Interac%on with profound liver microsomal enzyme system,
thus interfere metabolism of other drugs
4. Cross-tolerance with alcohol and BZs

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)

B. Zolpidem (S/lnox) and Zaleplon

1. Acts on a subset of BZ receptor family, BZ1 (1-GABAA).
2. No an%convulsant or muscle-relaxing proper%es.
3. No withdrawal eects, minimal rebound insomnia and lihle
tolerance with prolonged use
4. Rapid onset and short-ac%ng T1/2 (2-3 hr) to treat insomnia

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

2. Diphenhydramine and Doxylamine

a. carry seda%ve proper%es and are eec%ve in

trea%ng mild insomnia

b. Over-the-counter nonprescrip%on drugs

Alcohol (ethanol, EtOH,C2H5OH)

Social drug more than as a therapeu%c agent, the doseresponse rela%onship evaluated by blood alcohol
concentra/on (BAC):
1) BAC of 0.05 g/dl (0.05%): euphoria
2) BAC of 0.1-0.2 g/dl: motor in coordina8on, error judgment, loud
voice and aggressive behaviors
3) BAC of 0.2-0.3 g/dl: amnesia and anesthesia
4) BAC of 0.3-0.4 g/dl: coma
5) BAC of 0.4-0.5 g/dl: fatal dose due to medulla suppression

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)

Metabolism of ethanol by ADH and ALDH

C. Adverse effects and drug interaction

1. Liver: cirrhosis, hepatoma
2. CNS: Wernicke-Korsakos syndrome (due to vitamin
B1 thiamine deciency): alcohol amnesic disorder
with cerebellar degenera%on and ataxia
3. Fetal alcohol syndromes: growth retarda%on, altered
morphogenesis (microcephaly and ahern face),
hyperac%vity and low IQ
4. Gastrointes8nal tract: gastri%s, pep%c ulcer, gastric
cancer, pancrea%%s, pancrease cancer
5. Cardiovascular: cardiomyopathy, portal hypotension,
cardiac dyshymias.