Mohammad Shariful Alam (Shohan)

SEDATIVE AND HYPNOTICS

**Hypnotic: A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep. **Sedative: Sedatives are the agents which reduce anxiety and exert a calming effect on motor or mental function. [Graded dose depression of central nervous system is a characteristic of sedative hypnotic Sedation Hypnosis General anaesthesia Coma Death

*Classification of sedative and hypnotics: A. Benzodiazepines: Duration i. Short acting (t1/2 < 6 hrs) ii. Intermediate acting (t1/2 6-24 hrs) iii. Long acting (t1/2 > 24 hrs) Hypnotic Midazolam Temazepam Alprazolam Clonazepam Flurazepam Sedative Triazolam Clorazepate (inactive) Lorazepam Oxazepam Diazepam Nitrazepam

B. Barbiturates: 1. Ultra short acting (< 15 min): Thiopental Na+ 2. Short acting (1-3 hrs): Secobarbitone, Pentobarbitone, Hexobarbital 3. Intermediate acting (4-6 hrs): Amylobarbitone, Butobarbitone 4. Long acting (> 6 hrs): Phenobarbitone, Barbital C. Miscellaneous: o o o o

Chloralhydrate Ethanol Zolpidem Buspirone.

Mohammad Shariful Alam (Shohan)

BENZODIAZEPINES

Chemistry: Benzodiazepines contain a carboxamide group in the 7-membered heterocyclic ring structure. A substitute in the 7 position, such as a halogen or a nitro group, is required for sedative hypnotic activity. The structure of triazolam and alprazolam include the addition of a triazole ring at the 1, 2 position. Pharmacokinetics:

Route of administration: Usually given orally or I/V Absorption: Oral absorption of triazolam is extremely rapid Distribution: Diazepam and triazolam are more lipids soluble, so CNS activity is rapid. Redistribution: It is an important feature of the biodisposition of sedative hypnotics. Thus constitute to the termination of their major CNS effect. - All sedative hypnotics cross placental barrier during pregnancy - They are also detectable in breast milk - They are extremely plasma protein bound drug
Biotransformation: Phase I: Oxidation (Hydroxylation and dealkylation) Phase II: Glucoronidation (Conjugation) Chlordiazepoxide Desmethylchlordiazepoxide Demoxipam Diazepam Prazepam Clorazepate (inactive)

Desmethyldiazepam Oxazepam

Alprazolam and triazolam Alpha hydroxy metabolites

Hydroxyethylflurazepam Flurazemap Desalkylflurazepam Conjugation Lorazepam

URINARY EXCRETION

Mohammad Shariful Alam (Shohan)

Characteristics of phase-I metabolites:

Name: Desmethyldiazepam Hydroxyethylflurazepam Desalkyl flurazepam Characteristics: As active as parent drug Long half life (80-120 hours) Suitable for anxiolytic effect Responsible for cumulative effect.

Excretion: Mainly through kidney.

Mechanism of benzodiazepine action (pharmacodynamics): GABA receptors: Subtype: i. GABAA: Located in neuronal membranes in the central nervous system ii. GABAB: Located in postsynaptic nerve endings. GABAA: The GABAA receptor has a pentameric structure assembled from five subunits (each with four transmembrane spanning domains) selected from multiple polypeptide classes (, , , , , , etc.). Different subunits of several of these classes have been characterized, e.g., six , four , and three . Function: This ionotropic receptor functions as a chloride channel, which is activated by inhibitory neurotransmitter GABA. **M/A: Benzodiazepines Enhances GABAs effect without directly activating GABA receptor or opening the associated chloride channels Potentiate GABAergic inhibition GABA binds with , subunit of GABAA receptor Increase in the frequency of Cl- channel opening Enhancement of chloride conductance Hyperpolarization of cell Inhibition of neuronal firing

Mohammad Shariful Alam (Shohan)

CNS depression [GABA= Gamma amino-butyric acid] Benzodiazepine receptor ligands: Three types of ligand-benzodiazepine receptor interactions have been recorded-

(1)
(2) (3)

Agonist: Facilitates GABA action e.g., Zolpidem and related imidazolpyridine Antagonists: e.g., Flumazenil (as it has high affinity for the benzodiazepine receptor act as competitive antagonists; so used to overcome benzodiazepine toxicity). Inverse agonists: e.g., - carbolines

**Organ level effects/pharmacological effects: A. Sedation: Suppression of responsiveness to a constant level of stimulation with decreased spontaneous activity and ideation. These behavioral changes occur at a lowest effective dose of the commonly used sedative hypnotic. B. Hypnosis: All of the sedative hypnotic will induce sleep if high enough doses are given.
[Normal sleep has two componentsi. Non rapid eye movement sleep (NREM) ii. Rapid eye movement sleep (REM) REM and NREM sleep occurs cyclically over 90 minutes interval]

C. Anaesthesia: Certain sedative and hypnotic in high doses will depress the CNS to the point known as stage III of GA. Ex- Thiopental, Methohexital. D. Anticonvulsant effect: Certain drugs can exert anticonvulsant effect without marked CNS depression. So that mental and physiologic activity is unaffected. Ex- Clonazepam, Nitrazepam, Lorazepam, and Diazepam. E. Muscle relaxation: Some sedative hypnotic exert inhibitory effect on polysynaptic reflex and intracranial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Ex- Carbamate and Benzodiazepine group. F. Effect on respiration and cardiovascular function: Sedative hypnotics even at therapeutic doses can produce significant respiratory depression in patient with pulmonary disease.

Mohammad Shariful Alam (Shohan)

[Effect on respiration is dose related and depression of the medullar respiratory center is the usual cause of death due to overdose of sedative and hypnotics.] Indication/clinical use of Benzodiazepines: 1. For relief of anxiety 2. For insomnia 3. For sedation and amnesia before medical and surgical procedures such as endoscopy, brochoscopy 4. For treatment of epilepsy and seizure states 5. As a component of balanced anaesthesia (intravenous administration) 6. For control of ethanol or other sedative hypnotic withdrawal states 7. For muscle relaxation in specific neuromuscular disorders 8. As diagnostic aids or for treatment in psychiatry. Toxicity: A. Adverse effects due to CNS action: In low doses: Drowsiness Impaired judgment Diminished motor skills Significant impact on driving ability, job performance and personal relationship Hangover At higher doses: Lethargy A state of exhaustion In lethal dose: Respiratory depression from central action of the drug Loss of brain stem vasomotor control Direct myocardial depression B. Others: Drug interactions: Hypersensitivity reaction including skin rash Teratogenicity leading to foetal deformation On I/V injection- thromboembolism.

Sedative hypnotics + alcoholic beverage/opioid analgesics/anticonvulsants/ Phenothiazine = Additive effects. Sedative hypnotics + antihistamines, antihypertensive agents, tricyclic antidepressant drugs = Enhanced CNS depression. Barbiturate + decumarol/ phenytoin/ digitalis/ griseofulvin = Increase rate of metabolism of mentioned drugs. Cimetidine + Diazepam = Doubles the elimination half life of diazepam as cimetidine inhibits the metabolism of Diazepam.

Mohammad Shariful Alam (Shohan)

Chloralhydrate + Warferin = Displace warferin from plasma proteins thus enhance anticoagulant effect.

Disadvantage of barbiturates as hypnotics: Drug of social abuse Low therapeutic index Physical dependence occur with withdrawal syndrome Induce hepatic microsomal enzyme Generalized CNS depression. Advantages of benzodiazepines over barbiturates: High TI. Hypnotic dose does not affect cardio-respiratory function. Lower abuse liability Physical dependence and withdrawal syndrome are less marked A specific benzodiazepine antagonist- flumazenil is available in poisoning cases. Q. Compare Benzodiazepines and Barbiturates as hypnotics. Benzodiazepines i) High therapeutic index, so safety margin is high. ii) Doesnt induce hepatic microsomal enzyme. iii) Doesnt alter normal sleeping patterns iv) Less tolerance and dependence v) Less chance of cardiorespiratory failure, it requires extremely large dose vi) Has specific antidote- flumazenil vii) Slower elimination, so it has efficacy viii) Withdrawal syndrome less severe Barbiturate i) Low therapeutic index, so safety margin is narrow. ii) Induce hepatic microsomal enzymes iii) Alter normal sleeping patterns v) More tolerance and dependence v) More chance of cardiorespiratory failure vi) Has no specific antidote vii) Rapid elimination, so it has low efficacy viii) More severe withdrawal syndrome

*Sedation: It is a state of drowsiness, calmness and quietness without producing actual sleep. *Hypnosis: It is a state of CNS depression resembling normal/physiological sleep from which an individual can be aroused by ordinary stimulus.

Q. Define hypnotic & sedative. Mention the indication of benzodiazepines.

Q. Compare Benzodiazepines and Barbiturates as hypnotics. Q. What are Benzodiazepines? How Benzodiazepines act? Q. Discuss the pharmacological effects of benzodiazepines/diazepam. Q. What are the adverse effects of diazepam? Q. Explain the advantages of Benzodiazepines over barbiturates.