Sedatives and hypnotics

sedative and hynpnotics

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

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 4 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 6 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 7 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 9

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 12 • 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 13 • 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 14

16. PHARMACOKINETICS 15 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 16 • 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 17 • 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. T reatment 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 18

22. MECHANISM OF ACTION 19

23. MECANISM OF ACTION 20

24. ADVANTAGES OF BENZODIAPINES OVER BARBITURATES 21 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 22

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