Download Sedative-Hypnotic Drugs

Barbiturates
4th Year Pharmacy
2015-2016
Introduction
• The barbiturates were used extensively as
sedative–hypnotic drugs. Except for a few
specialized uses, they have been replaced
largely by the much safer benzodiazepine.
• Barbiturates act throughout the CNS
Ⅱ.BARBITURATES
Classification
(1)Ultra-short-acting barbiturates: act within
seconds, and their duration of action is
30min. Therapeutic use of Thiopental:
anesthesia
(2)Short-acting barbiturates: have a duration
of action of about 2h. The principal use of
Secobarbital : sleep-inducing hypnotics.
• (3)Intermediate-acting barbiturates: have and effect
lasting 3-5h. The principal use of Amobarbital is
as hypnotics.
• (4)Long-acting barbiturates: have a duration of
action greater than 6h. Such as Barbital and
Phenobarbital. Therapeutic uses: hypnotics and
sedative, and antiepileptic agents at low doses
BARBITURATES
Barbiturates depress the CNS at all level in
a dose-dependent fashion. Now it mainly
used in anaesthesia and treatment of
epilepsy; use as sedative-hypnotic agents is
no longer recommended.
BARBITURATES
Reasons:
(1) have a narrow therapeutic-to-toxic dosage
range.
(2) suppress REM sleep.
(3) Tolerance develops relatively quickly.
(4) have a high potential for physical
dependence and abuse.
(5) potent inducers of hepatic drugmetabolizing enzymes.
MECHANISM OF ACTION
(1) Barbiturates share with benzodiazepines
the ability to enhance the action of GABA,
but they bind a different site on the GABAreceptor/chloride channel, and their action
seems to prolong the duration of the
opening of GABA-activated chloride
channels.
MECHANISM OF ACTION
(2) At high doses, barbiturates can inhibit the
release of the Ca2+-dependent
neurotransmitter.
Synthesis of Barbiturates
• Diethyl malonate + Urea = B.A.
Barbiturates
Barbiturates are 5,5 disubstituted
barbituric acid
Structure activity relationship of BA
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General SAR
1- 1,3 disubstituted barbiturate is inactive
2-1,3 disubstituted thio barbiturate is inactive
3- 5-mono substituted BA is inactive
4- 5-mono substituted thio BA is inactive
5- 1,3,5 trisustituted BA is inactive
6-1,3,5 trisubstituted thio BA is inactive.
5,5,disubstituted BA is active
5,5 disubstituted thio BA is active.
• Position 2 O, S
• Increase lipophlic Thio barbituate increase onset (
Thiopental)
• Position 5
• 1. Both hydrogen atoms at position 5 should be substituted
(pka ≈ 7.6). The unsubstituted or monosubstituted are very
acidic (pka ≈ 4) so the compounds are largely ionized at
physiological pHs, with little lipid soluble compound
available to cross the BBB
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2. Polar functions at C5.
3. Methylene and benzylidene moiety.
4. Substituents with total number of carbon
atoms greater than 9
Metabolism of BA
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1- Ring Hydroxylation
2- OMEG &OMEA -1 Oxidation
3- Replacement O by S
4- Ring cleavage
• H.W: Draw equation for the metabolism?
Pharmacokinetics
• High lipid solubility allows rapid transport across
the blood-brain barrier and results in a short onset.
• Removal from the brain occurs via redistribution
to the other tissues results in short duration of
action.
• Barbiturates and their metabolites the excretion
via the renal route. Alkalinization of the urine
expedites the excretion of barbiturates. Treatment
of acute overdosage: Sodium bicarbonate.
Therapeutic uses
• Sedative-hypnotic agents
• Be used in the emergency treatment of
convulsions as in status epilepticus.
• Anesthetic (or be given before anesthetic)
• Combination with antipyretic-analgesic
• Treatment of hyperbilirubinemia and
kernicterus in the neonate.
Adverse effects
• After effect: hangover---dizzy, drowsiness,
amnesia, impaired judgment, disorientation.
• Tolerance: decreased responsiveness to a drug
following repeated exposure because of downregulation of receptors and induction of hepatic
drug-metabolising enzymes.
Adverse effects
• Dependence: including psychological and
physiologic dependence. Withdrawal symptoms:
excitation, insomnia, tremor, anxiety,
hallucinations and sometimes convulsions.
• Depressant effect on respiration: can cross the
placental barrier during pregnancy and secrete to
breast milk.
• Others: Skin eruptions and porphyria
Treatment of acute overdosage
• An overdose can result in coma, diminished
reflexes, severe respiratory depression,
hypotension leading to cardiovascular collapse,
and renal failure.
• Treatment (A.B.C):
(1) supporting respiration and circulation.
(2) alkalinizing the urine and promoting diuresis.
(3) Hemodialysis or peritoneal dialysis.
Ⅲ.Nonbarbiturate sedativehypnotics
• AMIDES AND IMIDES
• Alcohols
• Carbamate
• Aldehyde
Ethchlorvynol, USP.
• 1-chloro-3-ethyl-1-penten-4-yn-3-ol (Placidyl),
• is a mild sedative–hypnotic with
• a quick onset and short duration of action (t1/2
5.6 hours).
• Because of its highly lipophilic character, it is
extensively metabolized to its secondary alcohol
(90%) prior to itsexcretion. It reportedly induces
microsomal hepatic enzymes.
Amides & Imides
• Glutethimide, 2-ethyl-2-phenylglutarimide
• (Doriden), is one of the most active nonbarbiturate
hypnotics that is structurally similar to the
barbiturates,especially phenobarbital. Because of
glutethimide’s low aqueous solubility,
• Glutethimide is used as a racemic mixture with the
( +) enantiomer being primarily metabolized on
the glutarimide ring and the ( - ) enantiomer on the
phenyl ring.
Meprobamate, USP.
• 2-methyl-2-propyltrimethylene dicarbamate,
2-methyl-2-propyl-1,3- propanediol
dicarbamate (Equanil)
• Meprobamate is also a centrally acting
skeletal muscle relaxant. The agents in this
group find use in several conditions, such as
strains and sprains that may produce acute
• muscle spasm
Aldehyde
Chloral hydrate is 2,2,2 trichloroacetaldehyde.
(1) relatively safe hypnotic, inducing sleep in a
half hour and lasting about 6h.
(2) used mainly in children and the elder, and the
patients when failed to other drug.