Sedative & Hypnotics

1. Sedative & Hypnotics Prof. Hanan Hagar Pharmacology Department Medical College King Saud University

2. Sedative & Hypnotics Anxiolytics : Drugs that clam the patient and reduce anxiety without inducing normal sleep. Hypnotics : Drugs that initiate and maintain the normal sleep.

3. Classification of hypnotic drugs 1. Benzodiazepines ( BDZ ) 2. Barbiturates 3. Miscellaneous ( non BDZ non barbiturate drugs). Zolpidem Zaleplon

4. BenzodiazepinesNomenclature End with suffix azolam or azepam Alprazolam Estazolam Triazolam Lorazepam Diazepam Oxazepam Temazepam Nitrazepam

5. Classification of benzodiazepines According to duration of action : - Short acting: (3-5 hours). Triazolam -  Intermediate: (6-24 hours) (LEOTAN). Lorazepam Estazolam Oxazepam Temazepam Alprazolam Nitrazepam

6. - Long acting: ( 24-72 hours) Chlorazepate Chlordiazepoxide Diazepam Flurazepam Quazepam Prazepam According to uses Anxiolytics Lorazepam Oxazepam Alprazolam Chlordiazepoxide Diazepam Prazepam Clonazepam

7. Hypnotics short:Triazolam Intermediate: Lorazepam , Estazolam Temazepam Nitrazepam Long: Flurazepam, Quazepam Preanesthetics   Diazepam - Midazolam

9. Mechanism of Action By binding to BZ receptors (BZ1 or BZ2). Bzs facilitate GABA-induced chloride channels hyperpolarization = GABA-mediated inhibitory neurotansmission

10. Mechanism of Action Benzodiazepines combine with BZ receptors increase GABA action on GABA receptors chloride channels opening   chloride influx to the cell  cell membrane hyperpolarization  inhibition of propagation of action potential  inhibitory effect on different sites of the brain especially motor cortex & limbic system.

12. Pharmacokinetics of benzodiazepines Bzs are lipid soluble, well absorbed orally, Rapid absorption e.g. triazolam & diazepam & chlorazepate (chlorazepate is prodrug converted by acid hydrolysis in stomach to form nordiazepam (desmethyldiazepam). Slower absorption e.g. lorazepam & oxazepam, temazepam (LOT)

13. Can be given parenterally Chlordiazepoxide - Diazepam (IV only NOT IM) Lorazepam - Midazolam (IV or IM) Bzs are widely distributed. Cross placental barrier during pregnancy and are excreted in milk (Fetal & neonatal depression). Redistribution from CNS to skeletal muscles, adipose tissue) (termination of action).

14. All benzodiazepines are metabolized in the liver to active compounds EXCEPTNo active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam

15. Metabolism occurs in two phases Phase I: ( liver microsomal system) Phase II: glucouronide conjugation excreted in the urine. Many of Phase I metabolites are active  elimination half life of the parent comp. cumulative effect with multiple doses

18. Pharmacological Actions Anxiolytic action. Depression of cognitive and psychomotor function. Sedative & hypnotic actions: At higher dose, benzodiazepines change sleep pattern Induction of normal sleep ( reduce latency of sleep). Increase non REM sleep (stage II). Decrease REM sleep & slow waves sleep (3,4 stages). 

21. Anterograde amnesia Some have anticonvulsant effect: diazepam, lorazepam, clonazepam, clorazepate. Some have central skeletal muscle relaxant effect e. g. Diazepam (relax muscle spasticity by increasing presynaptic inhibition in the spinal cord). CVS and respiratory system: Minimal depressant effects in therapeutic doses & in normal patients.

22. Therapeutic Uses Anxiety disorders:   short term relief of severe anxiety General anxiety disorder major depressive disorders Obsessive compulsive disorder Panic attack with depression Alprazolam since it has (antidepressant effect).

23. Sleep disorders (Insomnia) Triazolam: initiate sleep (tolerance & rebound insomnia) Estazolam - Lorazepam - temazepam: (sustain sleep) Flurazepam – Quazepam (hangover). Usage for 1-2 weeks tolerance to their effect on sleep patterns Drug withdrawal anxiety, irritability, restlessness, increase in REM sleep, rebound insomnia

24. Treatment of epilepsy Diazepam – Lorazepam Clonazepam -Clorazepate Muscle relaxation: in spastic states (Diazepam) As cerebral palsy and multiple sclerosis. To control withdrawal symptoms of alcohols diazepam- chlordiazepoxide

25. In anesthesia Preanesthetic medication e.g. diazepam Induction of balanced anesthesia (Midazolam) Adjunct therapy during minor surgery (endoscopy, bronchoscopy, dental surgery).

27. ADVERSE EFFECTS Ataxia (motor incoordination), Cognitive impairment. Hangover: Sleep tendency, drowsiness, confusion especially in long acting drugs. Tolerance Dependence: Physical and Psychological Skin rash and teratogenic effect. Respiratory & cardiovascular depression (Toxic effects).

28. Withdrawal symptoms: Rebound insomnia, anorexia, anxiety, agitation, tremors and convulsion.

29. Drug Interactions

30. Dose should be reduced in Liver disease Old people. Precautions Not for pregnant women or breast-feeding. Not for people over 65. Used for limited time (2 weeks)

31. FLUMAZENIL a selective competitive antagonist of BZD receptors. Blocks action of benzodiazepines, zolpidem, & zaleplon but not other sedative/hypnotics. Blocks psychomotor, cognitive and memory impairment of BZs.

32. 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).

33. Therapeutic Uses 1.  Acute BZD toxicity (comatose patients). 2. Reversal of BZD sedation after endoscopy, dentistry. Side Effects Nausea Dizziness Precipitate withdrawal symptoms.

34. Zolpidem (Ambien) Imidazopyridine derivative. Acts on benzodiazepine receptors (BZ 1) & facilitate GABA mediated neuronal inhibition. Its action is antagonized by flumazenil. Rapidly absorbed from GIT and metabolized to inactive metabolites via liver CYT P450. Short duration of action ( 2- 4 h).

35. has no muscle relaxant effect. has no anticonvulsant effect. Minimal psychomotor dysfunction Minimal tolerance & dependence. Minimal rebound insomnia. Its efficacy is similar to benzodiazepines. Minor effect on sleep pattern, but high dosessuppress REM. Respiratory depression occur at high doses in combination with other CNS depressant as ethanol.

36. Adverse Effects Dizziness GIT upset Drowsiness Uses a hypnotic drug for short term treatment of insomnia.

37. Drug Interactions Inducers Rifampicin, phenytoin, carbamazepine Inhibitors Cimetidine, erythromycin

38. Zaleplon Binds to BZs receptors and facilitate GABA actions. Rapid absorption Short onset of action Short duration of action (1 hr) Metabolized by liver microsomal enzymes CYP3A4 Metabolism is inhibited by cimetidine.

39. Decreases sleep latency Little effect on sleep pattern Potentiates action of other CNS depressants (alcohol). Dose reduction as before. Used as hypnotic drug Advantages Less impairment of pyschomotor and cognitive functions than BZs or zolpidem.

40. Barbiturates are second choice as sedative - hypnotic Mechanism of Action are less selective in action than BZD. Facilitation of GABA action on the brain. increase the duration of the GABA gated channel opening but in large dose, they can directly activating chloride channels. (not through BZD receptors). depress excitatory neurotransmitters action. Interfere with Na & K transport across cell membranes (reticular activating system inhibition).

41. Classification of barbiturates: Long acting( 24-28 h): Phenobarbitone Intermediate (8-24h): Amylobarbitone Short-acting(3-8h): Pentobarbitone Secobarbitone Amobarbital Ultrashort acting (25 minutes): thiopental

42. Pharmacokinetics All barbiturates are weak acids Are absorbed orally. Distribute throughout the body depending on lipid solubility e.g. thiobarbiturates are very lipid soluble with high rate of entry into CNS. Redistribute in the body from the brain to skeletal muscles - adipose tissues.

43. Metabolized in the liver to inactive metabolites Excreted in the urine. Alkalinization increases excretion ( NaHCO3 ). Cross the placenta ( # pregnancy).

44. Pharmacological actions 1. CNS depression : a dose-dependent fashion. Sedative & hypnotic anesthesia in large dose Anticonvulsant action Coma and death. 2. Respiratory depression: is dose –related. suppress hypoxic and chemoreceptor response to CO2 Large doses respiratory depression & death.

45. 3. CVS depressions Healthy patient: at 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.

46. 4. Enzyme induction. CYT P-450 microsomal enzymes inducers (Tolerance - drug interaction). Increase activity of hepatic gamma amino levulinic acid synthetase (ALA) synthesis of porphyrin (# porphyria).

47. Uses : Anticonvulsants: (Phenobarbitone) Phenobarbital is indicated in the treatment of all types of seizures except absence seizures. Tonic-clonic seizures, status epilepticus Eclampsia and febrile convulsion. Induction of anesthesia (thiopental, methohexital). Hypnotic (pentobarbital) Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl transferase activity).

48. 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.

49. Toxicity Respiratory depression, cardiovascular collapse, comaand 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.

50. Drug interactions 1. Other CNS depressants: Ethanol 2. MAOI: potentiate CNS depression 3. Phenytoin, warfarin, and dicumarol: their metabolism is increased.