Sedative – Hypnotics

Dr. Arlene M. Diaz, M.D.

MHAM - SWU
Sedative – Hypnotics
- Are agents that is use as adjuncts in the treatment of
organic or emotional disorders in order to produce a
calming effect (sedation) or to induce sleep (Hypnosis)

Classification of Sedative – Hypnotics

1. Barbiturates
2. Benzodiazepine hypnotics
3. Miscellaneous group

A. Chloral Hydrate F. Methyprylon

B. Paraldehyde G. OTC products containing:
C. Ethchlorvynol Diphenhydramine or
D. Ethinamate Doxylamine (Antihistamines)
E. Glutethimide H. Buspirone, Zolpidem, Zaleplon
Barbiturates:

H
l
N O
l ll N C
H H (R1 )
HO - C H 1 6
0=C
+ C O= C
H 5

HO–C H C2 H (R2)
l 3 4
N ll N C
l O l ll
H Malonic Acid H O
Barbituri
UREA
c
Acid
 The majority of the clinically useful barbiturates are
obtained by making appropriate substitutions in
position 5 of the molecule, in order to have a central
depressant activity. H O
ll
l (R1 )
C
Barbiturates with an ethyl group; N 5
O= C
longer chain; branched chain at C2
N C (R2 )
position 5 have greater hypnotic
l ll
activity. (R3) O

Barbiturates containing a phenyl group in the 5 position are

less potent hypnotics, but have enhanced anticonvulsant and
antiepileptic activity.

Replacement of Oxygen in the z position by Sulfur

(thiobarbiturates) causes a marked increase in the
lipid solubility of the drug.
 Mech of Action:
 Barbiturates potentiate GABAA – induced chloride influxes into
neuronal tissues. GABA is an inhibitory neurotransmitter of the brain.
Potentiation of neuronal GABA activity produces a Central depressant
action.
The Barbiturates and

Barbiturates
Classification of Barbiturates
 Are classified on the basis of their onset and duration
of action.
A. Ultra -Short Acting = acts within seconds and their
duration of action is 30 minutes. They have high lipid
solubility which allows rapid transport across the blood –
brain barrier. They are use principally as intravenous
adjuvants to anesthesia.
B. Short – Acting = have a duration of action of about 2
hours; use principally as hypnotics
C. Intermediate Acting = have an effect lasting 3 to 5
hours, they have a “Hangover” liability if use as hypnotics,
the result of residual depression of the CNS.
D. Long – Acting = have a duration of action greater than 6
hours; the least lipid soluble. They are dose effective
hypnotics and sedatives and at a low dose are use as an
antiepileptic agents; but they are likely to cause hangover.
 Duration Barbiturate Substituents in Hypnotic
of Action Position 5 Dose
R1 R2
A. Ultra – Short Thiopental Ethyl ; l-methyl
(Contains (Pentothal) butyl
sulfur Thiamylal Allyl ; l-methyl
at position 2 (Surital) butyl
instead of
0xygen). Thio- Hexabarbital Methyl; cyclohexe
barbiturates (Evipal) nyl

B. Short – Acting Secobarbital Allyl; l-methyl 0.1 – 0.2 g

(Seconal) butyl

Pentobarbital Ethyl; l-methyl 0.1 g

(Nembutal) butyl
C. Intermediate Butabarbital Ethyl; See- 0.1 -0.2 g
Acting (Butisol) butyl

Amobarbital Ethyl; Iso amyl 0.05 - 0.2 g

(Amytal)

Vinbarbital Ethyl; l-methyl 0.1 – 0.2 g

(Delvinal) l-butenyl

D. Long Acting Phenobarbital Ethyl; phenyl 0.1 – 0.2 g

(Luminal)

Mephobarbital Ethyl; phenyl 0.1 – 0.2 g

(Mebaral) (CH3 group is
attached to a
Nitrogen Atom)

Barbital Ethyl; ethyl 0.3 – 0.5 g

(Verome)
 Pharmacokinetics behaviour of three barbiturate
in relation of their lipid solubility.
Characteristics Phenobarbital Secobarbital Thiopental
Lipid to water
partition 3 52 580
coefficient

Absorption from Slow Rapid Not used

stomach orally

Plasma Protein 2% 44 % 65 %
binding

Rate of entry into Slow Rapid Very Rapid

CNS

Renal excretion of 30 % Negligible Negligible

unchanged drug
Pharmacologic Effects:
A. CNS – depress all levels in a dose dependent fashion.
REM sleep (Rapid Eye Movement) – paradoxical
sleep is reduced, but do not totally obliterate it.
“Hangover” may result.
B. Analgesic – they are not analgesics , but ­ comfort
maybe achieve by combining with aspirin
C. Anesthesia – capable of producing anesthesia but only
the ultra – short acting are useful as intravenous
anesthetics.
D. All barbiturates – suppress convulsant activity if given
in sufficient doses but only the long acting are use as
anti-convulsant.
E. Cardiovascular – Not significant,but b.p is due
inhibition of central neurogenic component of the
hypertensives.
F. Respiration – at therapeutic doses resp. depression is
similar to that in normal sleep. But in larger doses causes
reduction of minute volume and hypoxic drive (respond to
CD2) fails. Death from acute barbiturate poisoning is
usually due to Respiratory failure
G. Liver – most barbiturates, but esp. phenobarbital are
capable of inducing the hepatic drug – microsomal enzyme
system this result in:

1. Increased degradation of the barbiturate ultimately

leading to barbiturate tolerance.

2. It also cause increase inactivation of other cpds such

as anticoagulants , leading to serious problem with drug
interactions. (others – tetracycline ; quinidine)
Drug Interactions:
 Drugs that increases the actions of barbiturates esp.
the resp. depressant effect.

1. Other sedative – hypnotics

2. General anesthetics
3. Neuromuscular blocking agents
4. Alcohol
5. Anti-anxiety drugs

 acute Ethanol intoxication = increases CNS depression,

decrease biotransformation of barbiturate
 Chronic ethanol abuse = decrease effect of Barbiturate
due to increase biotransformation)
Toxicity:
A. Acute Toxicity – stupor or coma and resp depression
(slow or rapid respiration or cheyne – strokes pattern)

1. treatment – removal of the unabsorb drug

from the stomach by gastric lavage
2. performing hemodialysis
3. preventing complications

B. Chronic Toxicity – similar to alcohol intoxication

mental changes include impairment of intellectual
activity , defective judgement , loss of emotional
control and accentuation of pathological personalities.
Treatment of Chronic Toxicity
Hospitalized patient & stabilize with a low dose, then slowly
withdraw for 2 to 3 weeks.
 Idiosyncrasy – excitement and inebriation ; headache
nausea ; vomiting ; diarrhea ; myalgia , neuralgia ; arthralgia.
 Hypersensitivity : Skin – Exfoliative dermatitis Blood &
Blood forming organs – agrarulocytosis , thrombocytopenic
purpura
Clinical Uses:
1. Sedation & Hypnosis
2. Anticonvulsant & Antiepileptic (Phenobarbital)
3. Preanesthetic Medication (Pentobarbital
,Secobarbital ; Amobarbital)
4. Treatment of Hyperbilirubinemia and Neonate
5. Anesthetics – ultra – short acting
Members of Benzodiazepines

Short acting Intermediate acting Long – acting

3 – 8 hrs 10 - 20 hrs. 1 – 3 days
a. Chlorazepate
a. Triazolam a. Lorazepam
(Tranxene)
(Halcion) (Ativan)
b. Chlordiazepoxide
b. Oxazepam b. Alprazolam
(Librium)
(Serapax) (Xanor)
c. Diazepam (Valium)
c. Midazolam c. Temazepam
(Dormicom) (Temaze)
d. Flueazepam
(Dalmane)
d. Estazolam
(Esilgan)
e. Quazepam
 Actions / Effects of Benzodiazepines
1. Reduction of Anxiety
2. Sedative and Hypnotic Action
3. Anticonvulsant
4. Muscle relaxant
Hypnotic Benzodiazepines
1. Flurazepam – long acting, significantly reduces sleep
induction time and number of awakenings, it increases the
duration of sleep.
 It causes little rebound insomnia, if continually use and
then discontinued because its effectiveness is maintained
up to 4 weeks, because it is converted to an active
metabolite and cause daytime sedation.
2. Estazolam - intermediate acting hypnotic benzodiazepine,
can also cause daytime sedation.
3. Temazepam – useful in patients who had freq. awakenings.
4. Triazolam – short duration is effective in patients who
have difficulty of going to sleep
5. Midazolam – is a short acting , sleep-inducing
benzodiazepine.
 rapid onset of action (less than 20 mins)
 short sojourn in the body
 shortens onset of sleep and prolongs duration of sleep
without
 impairment of REM sleep
has also anticonvulsant, anxiolytic and muscle relaxant
property
 wide therapeutic margin, and can be given over a period
of up to 150 days without any signs of tolerance or
accumulation. On correct discontinuation of the drug, no
withdrawal symptoms or rebound insomnia were observed.
No accumulation of the active ingredient occurs.
 hepatic dysfunction and advance age has no influence on its
pharmacokinetics.
absorption is more rapid and complete after I.M , I.V and
rectal administration.
metabolize to an active metabolite which has a shorter half
life =Alpha-hydoxy - midazolam, which is then glucuronidated,
then eliminated by the kidneys.
USES = 1. As a hypnotic
2. A premedication before surgery or diagnostic
proceed.
DOSE = 7.5mgs – 15mgs (½ -1 tab) before retiring.
ADVERSE EFFECTS OF BENZODIAZEPINES
= psychomotor dysfunction : cognitive impairment, ataxia,
daytime drowsiness.
= fatigue, amnesia and resp. depression, tolerance
Drug interaction:
Produces additive effect -more CNS depression if use with alcohol,
antihistaminics,antipsychotics , opioid analgesic, barbiturates and
tricyclic anti-depressants.
Miscellaneous Group
A. Chloral hydrate
 an aldehyde hydrate which has a pungent odor & causes
caustic taste – induces sleep in 30 min & may last up to 6
hrs.
 It is metabolized in the liver by alcohol dehydrogenase
to trichloroetharol which is the active metabolite
producing the CNS depression. Trichloroethanol (as well as
chloral hydrate) are oxidized to trichloroacetic acid which
is excreted in the kidney as a glucoronide conjugate
 The CNS depressant effect is potentiated by alcohol
(“ knockout drops “ ; “ Mickey Finn “)
This drug should be used cautiously in the presence of
severe hepatic, renal or cardiac disease oral administration
should be avoiding in pnts with esophagitis, gastritis or
duodenal ulcer
Clinical use – short term treatment of insomnia in elderly and
children
 B. Paraldehyde – a trimer of acetaldehyde produces sleep
in 15 min & last up to 4 – 8 hrs. CNS effect is similar with
chloral hydrate & alcohol and barbiturate
 If is useful in patients with hepatic or renal is because
it is eliminated via the lungs.
C. Ethchorvynol – a tertiary alcohol which has sedative
 Hypnotic prop; muscle relaxant prop and anti-convulsant
prop.
 Absorbed from GIT & onset of action is 30 min & lasts for
% hours
 Untoward effects include or auditory hallucinations.
 A daily dose of 2g may cause physical dependence &
withdrawal may result to gen. toxic – clonic seizures or
psyhotic behaviour
D. Ethinamate – resembles pentobarbital and secobarbital in
its effect
E. Glutethimide – resembles pentobarbital in its hypnotic
effect.
 If has high addiction liability, severe withdrawal
symptoms.
F. Methyprylon – resembles secobarbital in its onset and
duration of actions
G. Buspirone – has affinity to DA2 (dopamine) & a partil
agonist at 5 HT serotonin receptor. It relieves anxiety
without sedation and hypnosis. It is use to treat chronic
generalized anxiety. It can cause tachycardia and G.I
distress.
H. Hydroxyzine – an antihistaminic with anti-emetic and
anti-anxiety property.
I. Trazodone -a selective serotonin re-uptake inhibitor,
highly sedating . It is use also as anti-depressant.
I. Zolpidem – acts on a subset of benzodiazepam receptor.
It has no anticonvulsant or muscle relaxing properties. No
withdrawal effects and exhibits minimal rebound insomnia
 Melatonin

Melatonin is derived from

serotonin within the pineal
gland and the retina, where
the necessary N-
acetyltransferase enzyme is
found.

The pineal parenchymal cells

secrete melatonin into the
blood and cerebrospinal fluid.
Synthesis and secretion of
melatonin increases during
the dark period of the day
between 2-3a.m and is
maintained at a low level
during daylight hours.
Comparison of plasma levels of melatonin
Natural medicines

Valerian Root is a perennial herb that is

harvested in its natural environment in India and
Western Asia, without pesticides, herbicides, or
synthetic fertilizers. The pungent root has been
used since ancient times for restlessness and
nervous disturbances in sleep.
 Exercise

Meditation ,
Relaxation
Avoidance of Stressors
 GOOD NIGHT!
SLEEP TIGHT!
DO LET YOUR
BEDBUGS BITE
YOU TONIGHT !!!
A computer programmer
complains of feeling
tired during the day.He
says his wife is the
cause because she
snores too much. She
says he stays too late
working with his new
programs and sleep only
2 hours a day . He
claims he had difficulty
of falling asleep and
when he does sleep he
had to wake up many
times during the night.