sedative and hynpnotics

1. PREPARED BY : SONAL. V. PANDE
M PHARM
DEPARTMENT : PHARMACOLOGY
SEDATIVES AND HYPNOTICS

2. 2
OVERVIEW
• INTRODUCTION
• BASIC PHARMACOLOGY OF SEDATIVE- HYPNOTICS.
• CLASSIFICATION
• PHARMACOKINETIC ASPECTS
• ADVERSE DRUG REACTION
• MECHANISM OF ACTION
• ADVANTAGES

3. 3
INTRODUCTION
• Normal sleep consists of distinct stages, based on three physiologic measures: the
electroencephalogram, the electromyogram, and the electronystagmogram.
Sleep is divided into 2 categories that is :
• Rapid Eye moment sleep
• Non rapid eye moment sleep
NORMAL SLEEP

4. STAGES OF SLEEP
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There are 4 stages of sleep :-
• Stage 1 is light sleep where you drift in and out of sleep and can be
awakened easily. In this stage, the eyes move slowly and muscle activity
slows. During this stage, many people experience sudden muscle
contractions preceded by a sensation of falling.
• In stage 2, eye movement stops and brain waves become slower with only
an occasional burst of rapid brain waves. The body begins to prepare for
deep sleep, as the body temprature begins to drop and the heart rates
slows.
• When a person enters stage 3, extremely slow brain waves called delta
waves are interspersed with smaller, faster waves. This is deep sleep. It is
during this stage that a person may experience sleepwalking, night terrors,
talking during one’s sleep, and bedwetting. These behaviors are known
as parasomnias, and tend to occur during the transitions between non-REM
and REM sleep.

5. STAGES OF SLEEP conti…
5
• In stage 4, deep sleep continues as the brain produces delta waves almost exclusively. People roused from
this state feel disoriented for a few minutes.

6. SEDATIVE - HYPNOTICS
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SEDATIVES
• A drug that reduce excitement, calms the
patient and induces sleep.
• Sedatives in therapeutic doses are anxiolytic
agents.
• Most sedative in larger dose produces
hypnosis.
• Site of action is on limbic system which
regulates thought and mental function.
HYPNOTICS
• A drug which produces sleep.
• They are used for initiation and /or maintenance of
sleep.
• Hypnotics in higher dose produce general
anesthesia.
• Site of action is on the mid brain.

7. CLASSIFICATION
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SEDATIVES AND HYPNOTICS
Benzodiazepines Barbiturates Miscellaneous
agents
Short
action
Interme-
diate
action
Long
action
Ultra
short
action
Short
action
Long
action

8. Benzodiazepines
 The first benzodiazepine, chlordiazepoxide, was synthesized by accident in 1961.
8

9. Benzodiazepines
• Barbiturates are substituted derivatives of barbituric acid
(malonyl urea).
• Barbituric acid as such is not a hypnotic but compounds with
alkyl or aryl substitution on C5 are.
• Replacement of O with S at C2 yields thiobarbiturates which are
more lipid-soluble and more potent.
• Barbiturates have variable lipid solubility, the more soluble
ones are more potent and shorter acting.
• They are insoluble in water but their sodium salts dissolve
yielding highly alkaline solution.

10. Benzodiazapines
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Triozolam Oxazepam
Nitrazepam Midazolam
SHORT
ACTING
Alprazolam Lorazepam
Temazepam Estazolam
INTERMEDIATE
ACTING
Diazepam Flurazepam
Clonazepam Chlordiazepoxide
LONG
ACTING

11. PHARMACOLOGICAL EFFECTS OF
BENZODIAZEPINES
1. Reduction of anxiety and aggression :
Affects the hippocampus and nucleus amygdalae
2. Sedation and induction of sleep:
(1) the latency of sleep onset is decreased;
(2) the duration of stage 2 is increased;
(3) the duration of slow-wave sleep is decreased.
3. Anticonvulsant and antiseizure
They are highly effective against chemically induced convulsions caused by leptazol, bicuculline and similar drugs
but less so against electrically induced convulsions.
The can enhance GABA-mediated synaptic systems and inhibit excitatory transmission.
10

12. PHARMACOLOGICAL EFFECTS OF
BENZODIAZEPINES CONTI…
11
4. Muscle relaxation
Relax contracted muscle in joint disease or muscle Spasm.
5. Other effects
Lead to temporary amnesia decrease the dosage of anesthetic; depress respiratory and
cardiovascular function.

13. PHARMACOKINETIC ASPECTS
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• Well absorbed when given orally;
• They bind strongly to plasma protein, and their high lipid solubility cause many of them to accumulate
gradually in body fat. Distribution volumes is big.
• Metabolic transformation in the microsomal drug-metabolizing enzyme systems of the liver, eventually
excreted as glucuronide conjugates in the urine.

14. ADVERSE DRUG REACTION
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• Acute toxicity: Benzodiazepines in acute overdose are considerably less dangerous than other sedative-
hypnotic drugs. Cause prolonged sleep, without serious depression of respiration or cardiovascular. The
availability of an effective antagonist, flumazenil.
• Side-effects during therapeutic use: drowsiness, confusion, amnesia, impaired coordination. Main
disadvantages are interaction with alcohol, long-lasting hangover and the development of dependence.
• Tolerance and dependence: induction of hepatic drug-metabolising enzymes; a change at the receptor
level.

15. BARBITURATES
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Thiopentone Methohexitone
ULTRA
SHORT
ACTING
Butobarbitone. Pentobarbitone.
SHORT
ACTING
Pheno
barbitone
LONG
ACTING

16. PHARMACOKINETICS
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• Well absorbed after administration and distribute throughout the body.
• 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. Alkalization of the urine expedites the
excretion n of barbiturates. Treatment of acute overdosage: Sodium bicarbonate.
• More lipid soluble hence fast onset and short duration of action.
• All barbiturates redistribute from the brain to the splanchnic, to skeletal muscle and finally to adipose tissue.
• Readily cross the placenta and depress the fetus.
• Metabolized in liver and inactive metabolites are excreted in urine.

17. Therapeutic uses
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• Sedative-hypnotic agents
• Used in the treatment of amnesia and seizures.
• 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.
ACTIONS
• At low dose produce SEDATION (have a calming effect and reduce excitement).
• At higher dose cause hypnosis, followed by anesthesia and finally coma and death.
• Large dose cause circularly collapse due to medullary vasomoter depression and direct vasodilation.

18. ADVERSE EFFECTS
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• 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.
• Dependence: including psychologic 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

19. Barbiturate poisoning
• Acute barbiturate poisoning: Mostly suicidal, sometimes accidental.
It is infrequently encountered now due to inavailability of barbiturates.
However, the principles of treatment apply to any CNS depressant poisoning.
• Manifestations are due to excessive CNS depression— patient is flabby and
comatose with shallow and failing respiration, fall in BP and cardiovascular
collapse, renal shut down, pulmonary complications, bullous eruptions.
• Lethal dose depends on lipid solubility.
• It is 2–3 g for the more lipid-soluble agents (short-acting barbiturates) and 5–
10 g for less lipid-soluble phenobarbitone.

20. Treatment
1. Gastric lavage; leave a suspension of activated charcoal in the stomach to
prevent absorption of the drug from intestines.
2. Supportive measures: such as, patent airway, assisted respiration, oxygen,
maintenance of blood volume by fluid infusion and use of vasopressors—
dopamine may be preferred for its renal vasodilating action.
3. Alkaline diuresis: with sodium bicarbonate 1 mEq/kg i.v. with or without
mannitol is helpful only in the case of longacting barbiturates which are
eliminated primarily by renal excretion.
4. Haemodialysis and haemoperfusion (through a column of activated
charcoal or other adsorbants) is highly effective in removing long-acting as
well as short-acting barbiturates.

21. Miscellaneous agents
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Zolpidem Zopiclone
Ramelteon Zaleplon
Miscellaneous
agents

22. MECHANISM OF ACTION
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23. MECANISM OF ACTION
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24. ADVANTAGES OF BENZODIAPINES OVER
BARBITURATES
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BENZODIAPINES BARBITURATES
• Less neuronal depression.
• High therapeutic index.
• More neuronal depression.
• No anesthesia even at high dose.
• Patient can be aroused.
• Loss of consciousness .
• Low margin of safety.
• No effect on respiration or
cardiovascular functions at hypnotic
doses.
• Cause respiratory and cardiac
depression.
• No effect on REM sleep. • Suppression of REM.
• Abuse liability is very low • Tolerance
• Dependence.
• Amnesia without Automatism • Amnesia with automatism.
• Loss of short term memory.

25. OTHERS
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26. THANK YOU