Download Tranquilizers and Sedative-Hypnotics

Tranquilizers
and Sedative-Hypnotics
Barbiturates
Prof. Farsi T.Abachi
PHD Pharmacy
2015
Barbiturates
• All derivatives of Barbituric acid
• Produce a wide spectrum of central nervous system
depression, from mild sedation to coma.
• Nonspecific depressant.
• In moderate amounts, these drugs produce a state of
intoxication that is remarkably similar to alcohol intoxication.
Symptoms include:
1- Slurred speech
2- loss of motor coordination
3-Impaired judgment.
• Barbiturates were widely diverted from medical use and used
on the street in the 60s where they were called “downers” and
sold under a variety of different names.
History
Barbituric acid was first created in 1864 by a German •
scientist named Adolf von Baeyer. It was a combination
of urea from animals and malonic acid from apples.
Its first derivative utilized as medicine was used to put •
dogs to sleep but was soon
produced by Bayer as a sleep aid in 1903 called Veronal•
Phenobarbital was soon discovered and marketed as •
well as many other barbituric acid derivatives
Prescribed as sedatives, anesthetics, anxiolytics, and •
anti-convulsants
Also popular and abused in pop culture because of their •
alcohol like effects
Classification of ba
1- long acting BA over 6h •
E.g. Phenobarbital •
2- Intermediate acting BA 3-6h •
Eg. Butabarbital •
3- Short acting BA 0,5-3h •
E.g. Cyclobarbital •
4-Ultrashort acting BA less than 30 min. •
E.g. Thiapental •
Synthesis of BA.
Malonic Acid
Urea
Barbituric Acid
Barbituric acid is synthesized by a condensation reaction that results in the release of H2O
(dehydration) and the heterocyclic pyrimidine
Further substitution of side chains on the ring produce the pharmacologically active barbiturates
General SAR of Barbiturates
5,5 dihydrogen BA is unactive •
5,5dihydrogen thio BA is unactive •
1,3 di substituted BA is not active •
1,3 disubstituted thio BA is not active •
1,3,5,5 tetra substituted BA is not active •
1,3,5,5 tetra substituted thio BA is not active •
Only 5,5 disubstituted is active •
- 5,5 disubstituted with R2 & R3 for maxiumum activity •
- R= C5—C6 long chain for good activity, and enhance potency . C9 •
increase lipophlicity.
- Branching of R , cyclic or uncaturated C=C •
Enhanced short duration of action •
- N-methyl decrease activity of BA •
-Replace ( S ) in position 2 ( thiopental) on set of action •
Replace phenyl group increase duration e.g. phenbarbital. •
•
Barbiturate products
1- phenobarbital ( Luminal ) •
5-ethyl 5-phenyl BA •
2- Butabarbital •
5-ethyl5( 1methyl butyl)BA •
3- Thiopental •
5-ethyl5(1-methyl pentyl)BA •
•
Metabolism of BA
1- Ring hydroxylation •
2- Omega & Omega -1 oxidation •
3- Desulfuration •
4- Ring Closure ( Opening ) •
Uses:
• Sedatives, hypnotics, anesthetics and anticonvulsants.
• The primary differences among many of these products are how fast
they produce an effect and how long those effects last. Barbiturates are
classified as ultrashort, short, intermediate, and long-acting.
• The ultrashort-acting barbiturates produce anesthesia within about one
minute after intravenous administration.
• Those in current medical methohexital (Brevital®), thiamyl (Surital®)
and thiopental (Pentothal®).
• Barbiturate abusers prefer short-acting and intermediate-acting
barbiturates that include
• Amobarbital (Amytal®), pentobarbitalts (Nembutal®),
secobarbital(Seconal®), and Tuinal (an amobarbital/secobarbital
combination product).
• After oral administration, the onset of action is from 15 to 40 minutes,
and the effects last up to six hours. These drugs are primarily used for
insomnia and preoperative sedation. Veterinarians use pentobarbital
for anesthesia and euthanasia.
• Long-acting barbiturates include phenobarbital (Luminal®) and
mephobarbital (Mebaral®), Effects of these drugs are realized in about
one hour and last for about 12 hours, and are used primarily for
daytime sedation and the treatment of seizure disorders.
How are Barbiturates Consumed?
• Orally – In pill, tablet or
liquid form
• Injection –
•Into the blood stream
•Into muscle tissue
•Directly under the skin
• Inserted into the body via
suppository.
Short term effects
• Small doses relieve tension; large doses produce drowsiness,
staggering, blurred vision, impaired thinking, slurred speech,
impaired perception of time and space, slowed reflexes and
breathing, and reduced sensitivity to pain.
• Overdoses can cause unconsciousness, coma and death.
Long-Term Effects
• Long-term, high-dose use may result in effects similar to chronic
intoxication (impaired vision, memory and judgment, and slurred
speech), as well as depression or mood swings. Changes in liver
function may result in faster metabolism of other drugs. Babies of
chronic users may have difficulty in breathing and feeding, disturbed
sleep patterns, sweating, irritability and fever.
dependence
• Regular use induces tolerance, making
increased doses necessary to produce the
desired effect.
• The margin between an effective dose and a
lethal dose gradually narrows. Psychological
dependence can occur with regular use, as
can physical dependence. Withdrawal
symptoms including restlessness, anxiety,
insomnia, delirium, seizures and may result in
death.
Marilyn Monroe
died of barbiturate
overdose in 1962
3- miscellenous sedative-hypnotics
There are many types of sedative non-BA •
1-Imides •
2-Amides •
3-Alcohols •
These types are similar in structure , characteristics, and chemical •
properties.
1- Imides •
3- ethyl -3-phenyl glutaimide •
It is effective as sedative-hypnotic •
At high doses will be toxic •
2- Amides ( Carbamate ) •
2-Methyl2- propyl 1,3 propandiol dicarbamate •
A carbamate with hypnotic, sedative, and some muscle relaxant •
properties, although in therapeutic doses reduction of anxiety rather
than a direct effect may be responsible for muscle relaxation.
Meprobamate has been reported to have anticonvulsant actions
against petit mal seizures, but not against grand mal seizures .
3- Alcohol •
Ethchlorvynol •
Ethchlorvynol is a sedative and hypnotic drug. It has been used to •
treat insomnia. 1-chloro-3-ethyl -1-propene- 4-yne-3-ol.
Another example for alcohol is chlorohydrate •
Trichloro gem diol ( Two OH at same c atom) •