NS Pharma Intro & Sedative Hypnotics Drugs ppt.pptx

Thus document contains several CNS affecting drugs

1. PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM (CNS) AFFECTING DRUGs 10/3/2025 1

2. Introduction: CNS drugs are agents that act on the brain and spinal cord. They are used widely for medical and nonmedical purposes. Their Medical applications include: Treatment of psychiatric disorders, Suppression of seizures, relief of pain, and Production of anesthesia Non-medically CNS drugs used for their - Stimulant, depressant, euphoriant, and other “mind-altering” abilities. 10/3/2025 2

3. Chemical Neurotransmitters in Brain: Acetylcholine(Ach): Ach is an excitatory NT in the mammalian CNS Has effects on arousal, learning, and short-term memory Dementia and parkinsonism are associated with Ach Decreased in certain cognitive disorders(Alzheimer’s disease) Aminobutyric Acid (GABA): Is an inhibitory neurotransmitter in CNS Act on GABA A- and GABA B-receptors GABA agonists are anticonvulsants and GABA antagonists are convulsants , 10/3/2025 3

4. Glycine : Is another inhibitory CNS neurotransmitter Found predominantly in the spinal cord Few drugs ( strychnine ) are known to interact with glycine 5-HT(Serotonin): Physiological functions include: Feeding behaviour , behavioural response (hallucinatory behaviour ), Control of mood and emotion, Control of body temperature and vomiting, Sleep, pain perception, depression, sexual activity 10/3/2025 4

5. Dopamine: Is the most important of the biogenic amine NT in the CNS Appears to be an inhibitory neurotransmitter D1- and D2-receptors are the most studied groups Blocks certain calcium channels, and opens certain potassium channels Nor epinephrine: Has many functions including: A role in affective disorders, In learning and memory, and In sleep–wake cycle regulation 10/3/2025 5

6. Glutamic Acid and Aspartic Acid: Are excitatory amino acids (EAAs) Widely distributed throughout the mammalian CNS Their administration leads to rapid depolarization of neurons and an increase in firing rate 10/3/2025 6

7. Pharmacological agents can either increase or decrease neurotransmission Increase the amount of transmitter at the synaps an exaggerated effect. This can be accomplished by: Increasing the rate of transmitter synthesis, Increasing the rate of transmitter release, or Prolonging the time the transmitter is in the synapse 10/3/2025 7

8. Can produce a diminished response by: Decreasing synthesis of transmitter, Increasing transmitter metabolism, Promoting an increased neuronal uptake, or Blocking access of the transmitter to its receptor 10/3/2025 8

9. SEDATIVE & HYPNOTICS 10/3/2025 9

10. Sedative & Hypnotics Drugs Sedative : Drugs that clam the patient and reduce anxiety without inducing normal sleep. Hypnotics: Drugs that initiate and maintain the normal sleep. The sedative-hypnotics produce dose-dependent CNS depressant effects. 10/3/2025 10

11. 10/3/2025 11 Fig. CNS depression: dose-response curve Barbiturates Benzodiazepines

12. Sedative-Hypnotics- Classification Benzodiazepines Barbiturates Miscellaneous agents Short Ultra acting short Intermediate Short Intermediate Buspirone acting Chloral hydrate Long Long Zaleplon acting action Zolpidem

13. Sedative-Hypnotic Drugs common properties Lipid soluble Absorbed well from the GIT Good distribution to the brain Metabolized before elimination from the body by hepatic enzymes

14. I. Benzodiazepines (BDZs): Classifications: According to Duration of Action: Short acting: (3-5 hours)- Triazolam Intermediate: (6-24 hours)- Alprazolam, Lorazepam , Estazolam, Oxazepam, Temazepam Long acting: ( 24-72 hours)- Chlorazepate , Chlordiazepoxide, Diazepam ,Flurazepam,Quazepam, Prazepam,Nitrazepam 10/3/2025 14

15. According to uses- Sedative (Anxiolytics)- Alprazolam ,Chlordiazepoxide , Diazepam, Prazepam Hypnotics – Triazolam, Lorazepam, Estazolam, Temazepam , Flurazepam , Nitrazepam , Quazepam Preanesthetics- Diazepam, Midazolam 10/3/2025 15

16. Mechanism of Action: Bzs binding to BZ receptors (BZ1 or BZ2) to facilitate GABA-induced chloride channels hyperpolarization GABA-mediated inhibitory neurotransmission. Increase GABA-mediated inhibition in: Spinal cord, cerebellum, brain stem, hippocampus, neocortex 10/3/2025 16

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18. Bzs  facilitation of GABA action on GABA receptors Chloride channels opening C hloride influx to the cell Cell membrane hyperpolarization Inhibition of propagation of action potential Inhibitory effect on different sites of the brain especially: Motor cortex, and limbic system. 10/3/2025 18

19. BDZs Pharmacokinetics: Most of them are well absorbed orally, Rapid absorption- E.g . Triazolam , Alprazolam, Diazepam & Chlorazepate Slow Absorption- E.g. Lorazepam, Oxazepam, &Temazepam Chlorazepate is a prodrug converted by acid hydrolysis in stomach to form nordiazepam (desmethyldiazepam). BDZs can be given parenterally – Diazepam & Chlordiazepoxide (IV only not IM – errattic BA) Midazolam & Lorazepam (IV or IM) 10/3/2025 19

20. Bzs are lipid soluble and widely distributed Redistribution from CNS to skeletal muscles, adipose tissue (termination of action). Cross placental barrier during pregnancy and are excreted in milk (Fetal & neonatal depression). Highly bound to plasma protein All BDZs are metabolized in the liver Phase I: ( liver microsomal system) Phase II: glucouronide conjugation and excreted in the urine. 10/3/2025 20

21. Diazepam: Mean half-life 20-80 hrs (desmethyldiazepam) Metabolites have long half-life Lorazepam- Mean half-life 10-20 hrs, Rapid oral absorption, Disposition not altered appreciably by liver disease, aging or inhibitors of drug metabolism 10/3/2025 21

22. Oxazepam - Mean half-life 10-20 h, slower absorption than lorazepam, disposition not altered appreciably by liver disease, aging or inhibitors of drug metabolism Triazolam - Mean half life 2-3 h, rapid absorption, disposition not altered appreciably by liver disease, aging or drugs 10/3/2025 22

23. BDZs Pharmacological Actions: Anxiolytic action- affects the hippocampus and nucleus amygdalae- Relief of anxiety and tension , Emotional calming, Drowsiness (tolerance), Motor incoordination(tolerance) Depression of cognitive and psychomotor function Anterograde amnesia 10/3/2025 23

24. Hypnotic actions- At higher dose, BDZs change sleep pattern- Induction of normal sleep (latency of sleep is reduced). Increase non REM sleep (stage 2). Decrease REM sleep & slow waves sleep ( 3,4 stages).  Usage for more than 2 weeks  tolerance to their effect on sleep patterns. 10/3/2025 24

25. Anticonvulsant effect: especially diazepam, lorazepam, clorazepate , clonazepam, nitrazepam . Central skeletal muscle relaxant effect E.g. Diazepam relaxes muscle spasticity by presynaptic inhibition in the spinal cord. CVS and respiratory system: Minimal depressant effects in therapeutic doses & in normal patients. Usually insignificant Preexisting respiratory failure can be aggravated by any hypnotic sedative drug 25

26. Major Therapeutic Uses: Generalized anxiety disorder Atypical anxiety disorder Anticipatory anxiety Post-traumatic anxiety Disorders of initiation and maintenance of sleep (insomnia) Convulsive disorders Chronic alcoholism Neuromuscular disorders Miscelaneous – Balanced anesthesia, sedation for various procedures 10/3/2025 26

27. Adverse Effects: 1. Ataxia (motor incoordination), cognitive impairment. 2.Hangover - Sleep tendency, drowsiness, confusion especially in long acting drugs. 3. Physical and Psychological dependence 4. Withdrawal symptoms Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion. 5. Increase in appetite, Skin rash Teratogenic effect 10/3/2025 27

28. Drug Interaction:- Synergistic effect with other CNS depressants Enzyme Modulators – Rifampicin (decreases t1/2 ) Cimetidine, estrogen, disulfiram, isoniazid (increases half life) 10/3/2025 28

29. Dose reduction in Liver disease Old people Contraindication : Combined with Alcohol and other CNS depressants, Antihistaminics Pregnant mothers   10/3/2025 29

30. Flumazenil: A selective competitive antagonist of BZD receptors (Bz1). Blocks action of benzodiazepines, but not other sedative /hypnotics. Blocks psychomotor, cognitive and memory impairment of BZs. 10/3/2025 30

31. Pharmacokinetics: Has short duration of action T 1 /2 = 1 hour Absorbed orally Undergoes extensive first pass metabolism No active metabolites Should be used IV (Repeated doses are necessary). 10/3/2025 31

32. Therapeutic Uses: 1.  Acute BZD toxicity (comatose patients). 2. Reversal of BZD sedation after endoscopy, dentistry. Side Effects  Nausea Dizziness Precipitate withdrawal symptoms. 10/3/2025 32

33. II. Barbiturates: Are derivatives of barbituric acid Second choice as sedative – hypnotic Members end with the suffix ( barbital or barbitone) Thiobarbiturates are highly lipid soluble. 10/3/2025 33

34. 10/3/2025 34 Fig. Chemical structures of some barbiturates and other sedative-hypnotics.

35. Mechanism of Action: 1.  Facilitation of GABA action on the brain. Potentiate GABAergic inhibition by increasing the lifetime of Cl¯ channel opening but in large dose, They can directly activate chloride channels (GABA-mimetic action - not through BZD receptors). 2. Depress excitatory neurotransmitter actions 3. Interfere with Na & K transport across cell membranes (reticular activating system inhibition). 10/3/2025 35

36. 10/3/2025 36 Pharmacokinetics: 1.   All barbiturates are weak acids Are lipid soluble (high rate of entry into CNS- very brief onset of action). Absorbed orally Distribute throughout the body Redistribute in the body from the brain to skeletal muscles- adipose tissues. Metabolized in the liver to inactive metabolites

37. 7. Excreted in the urine Alkalinization(NaHCO3) increases excretion 8. Cross the placenta ( pregnancy) 10/3/2025 37

38. Pharmacological Actions: 1. CNS depression: In a dose-dependent fashion Sedative  Hypnotic Anesthesia in large dose A nticonvulsant action Coma and death. 2. Respiratory depression : Is dose –related S uppress hypoxic and chemoreceptor response to CO2 Large doses - Respiratory depression & death. 10/3/2025 38

39. 3. CVS depressions: Healthy patient: A t low doses, they have insignificant effects. Hypovolemic states, CHF, normal doses may cause cardiovascular collapse. Large dose  circulatory collapse due to medullary vasomotor depression  direct vasodilatation , Ganglionic blockade and direct decrease in cardiac contractility. 10/3/2025 39

40. 4. Enzyme induction- CYP-450 microsomal enzymes inducers (Tolerance - drug interaction). Increase activity of hepatic gamma amino levulinic acid synthetase ALA  synthesis of porphyrin ( porphyria). 5. Smooth muscles- Tone and motility of bowel is decreased slightly by hypnotic doses; More profound during intoxication. Action on bronchial, ureteric, vesical and uterine muscles is not significant. Kidney- T end to reduce urine flow by decreasing BP and increasing ADH release. Oliguria attends barbiturate intoxication. 40

41. Uses : Anticonvulsants: (Phenobarbitone) Tonic-clonic seizures, status epilepticus and febrile convulsion. Induction of anesthesia (thiopental, methohexital). Hypnotic (pentobarbital) Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl transferase activity). 10/3/2025 41

42. Adverse effects: 1.   Respiratory depression 2. Hangover: Residual sedation after awakening 3. Tolerance 4. Withdrawal symptoms 5. Precipitation of acute attack of porphyria 6. Many drug interactions 7. Allergic reaction: urticaria and skin rash 10/3/2025 42

43. Toxicity: Respiratory depression, Cardiovascular collapse, coma and death Contraindications: 1.   Acute intermittent porphria 2.   Respiratory obstruction 3.   Liver & kidney diseases 4.   Shock 5.   Old people ( mental confusion) 6.   Pregnancy 7.   Hypersensitivity to barbiturates 43

44. Drug interactions: 1. Other CNS depressants: Ethanol 2. MAOI: potentiate CNS depression 3. Phenytoin, warfarin, and dicumarol: Their metabolism is increased 10/3/2025 44

45. Advantages of BZD over Barbiturates; Selective: Minimal respiratory and cardiovascular depression 2. High therapeutic index 3. Less hangover 4. Not enzyme inducer 5. Less dependence with minimal withdrawal symptoms 6. Has specific antagonist 10/3/2025 45

46. 10/3/2025 46 Benzodiazepines vs. Barbiturates Criteria BZ Barb. Relative Safety High Low Maximal CNS depression Low High Respiratory Depression Low High Suicide Potential Low High Abuse Potential Low High Antagonist Available? Yes No