1. Anxiolytics-Sedatives -Hypnotics

2. Definitions Anxiolytics: are drugs which reduce anxiety. Sedatives: A drug that reduces a person’s response to most external stimuli and causes drowsiness Hypnotics: drugs that induce state like sleep. General anesthetic: A drug that causes loss of consciousness associated with absence of response to painful stimuli

3. Classification They are : 1.Benzodiazepine. 2.Barbiturate. 3.Miscellaneous.

4. A. Benzodiazepine 1.Short acting: e.g. Triazolam. 2.Intermediate acting: e.g. Alprazolam. 3.Long acting: e.g. Flurazepam, Diazepam.

5. B. Barabiturates 1.Ultra short action: thiopental. 2.Short action: e.g. secobabital. 3.Long action: e.g. phenobarbital.

6. C. Miscellaneous 1.Buspirone. 2.Zolpidem. 3.Ezopiclone. 4.Chloralhydrate.

7. A. Benzodiazepines Mechanism of action: BDZ potentiate GABAergic inhibition at all levels of CNS. They bind to receptors located at the interface between alpha and gamma subunits of the GABA-A receptor. The binding increases the affinity of the GABA-A receptor for GABA, which in turn causes an increased frequency of chloride channel opening Since BDZ need GABA for their activity, a ceiling effect occurs with high doses.

9. Benzodiazepines Pharmacological effects All BDZ produce a dose-dependent but limited depression of the CNS. This leads to the following four actions: 1.Anxiolytic. 2.Sedative-hypnotic. 3.Anticonvulsant. 4.Muscle relaxant.

10. Dose-response relationship Increasing sedative-hypnotic dose Sedation, disinhibition, anxiolysis Possible selective anticonvulsant and muscle-relaxing activity Hypnosis Anesthesia Medullary depression Coma Central Nervous System effects Barbiturates Benzodiazepines

11. Pharmacokinetics and Administration Very good oral bioavailability. Distribution in all tissues. Redistribution contributes to the termination of CNS effects. Extensive biotransformation in the liver. Many metabolites are active (so increasing the duration of drug action). Half-lives vary widely (4 – 100 hours) Administered PO or IV.

12. Benzodiazepines Adverse Effects 1. CNS Drowsiness, dizziness, sedation. Impaired motor skills. Impaired concentration and judgment. Paradoxical effects. Lethargy, medullary depression (with very high doses) Rebound effects (insomnia, restlessness, etc.) after abrupt discontinuation of 2-3 weeks of treatment. Tolerance and dependence develop after long-term use of high doses.

13. Benzodiazepines Respiratory system: Respiration can be depressed by high doses, or when BDZ are used together with other CNS depressants, or in persons with pulmonary diseases. Cardiovascular system: Hypotension (mainly in the elderly). Pregnancy: BDZ are included in pregnancy category D by FDA because exposure has been associated with malformations (mainly cleft lip/palate).

14. Benzodiazepines Therapeutic Uses Situational stress (short term use) Anxiety disorders (second choice drugs) Sleep disorders Seizure disorders Muscle spasms. Induction of ‘conscious sedation” and amnesia. Induction of general anesthesia.

15. Benzodiazepines Contraindications and Precautions Contraindications / PrecautionsExplanations When the CNS is already depressed (e.g. due to drugs, coma, shock, etc.) CNS depression can worsen Major depressive illnessDepression can worsen if these drugs are used Bipolar disorderMania and hypomania can ensue Parkinson’s diseaseImpaired cognition and psychosis can worsen Myasthenia Gravis, muscular dystrophiesThese condition can be exacerbated States of respiratory depression (COPD, asthma, sleep apnea, etc.) Ventilatory failure can ensue History of substance abuseBenzodiazepine can cause dependence Closed-angle glaucoma An acute attack of glaucoma can start (mechanism unknown) ElderlyCNS effects are more pronounced Pregnancy Benzodiazepines are classified as FDA category D

16. Benzodiazepines : ( Inverse agonists and antagonists) Inverse agonists Beta-carboline derivatives act as inverse agonists at BDZ receptors (an inverse agonist is a drug that decreases the response of an effector system below its basal level). Their effects are opposite to those of BDZ. Antagonists Flumazenil is a competitive BDZ receptor antagonist that can block both the effects of BDZ and those of beta- carboline derivatives. It is used clinically to counteract excessive effects of BDZ.

18. B. Barbiturates Mechanism of action: Barbiturates(BRB) bind to specific binding site of the GABA A receptor. The binding increases the affinity of the GABA A receptor for GABA, which in turn causes an increased duration of chloride channel opening, which cause post synaptic hyperpolarization and inhibition.

19. Barbiturates Pharmacological effects: 1. CNS 1.After low doses: reduction of anxiety with pronounced sedation and sleep induction 2.After intermediate doses: euphoria disinhibition, impaired judgment, emotional instability, loss of self-control. 3.After high doses: induction of general anesthesia.

20. Dose-response relationship Increasing sedative-hypnotic dose Sedation, disinhibition, anxiolysis Possible selective anticonvulsant and muscle-relaxing activity Hypnosis Anesthesia Medullary depression Coma Central Nervous System effects Barbiturates Benzodiazepines

21. 2. Other effects C.V.S: Large dose: can cause hypotension Endocrine: Increase A.D.H. release. Liver: hepatic microsomal enzyme induction.

22. Barbiturates Pharmacokinetics and administration. Good oral bioavailability. Redistribution is the main factor for the termination of CNS effects of lipid-soluble compounds. Variable biotransformation in the liver. Half-lives vary widely Administered PO, IM or IV.

23. Barbiturates Adverse Effects CNS Dose-dependent CNS depression Euphoria and behavioral disinhibition Increased pain perception Hangover effects Confusional states Paradoxical effects (1-5% of patients) Lethargy, medullary depression (with high doses) Tolerance and dependence (not with phenobarbital) Respiratory system Dose-dependent depression of respiration.

24. Barbiturates Cardiovascular system Hypotension. Cardiovascular collapse (when given IV). Hypersensitivity reactions Idiosyncratic reactions Exacerbation of acute intermittent porphyria (due to increase porphyrin biosynthesis). Pregnancy BRB are included in pregnancy category D by FDA. Hepatic microsomal enzyme induction.

25. Barbiturates Contraindications and Precautions: Absence, myoclonic and atonic seizures Porphyria Previous history of serious allergic reactions to BRB. Major depression. Serious respiratory, liver or kidney diseases Patients with severe pain (BRB may cause excitement and even delirium in patients with pain). Elderly Pregnancy

26. Therapeutic Uses: Induction of general anesthesia (thiopental). Seizure disorders (phenobarbital). Sleep disorders (very rarely used). Psychiatric procedures Neonatal jaundice (phenobarbital, rarely used today).

27. C. Miscellaneous 1. Buspirone Mechanism of action The drug acts as a partial agonist at 5-HT 1A receptors Pharmacological effect: Selective anxiolytic actions Advantages Negligible sedative, hypnotic,amnesic effects, anticonvulsant and muscle relaxant effects. No abuse liability. No cross tolerance with benzodiazepines.

28. Adverse effects Most common (up to 10%): dizziness, drowsiness. Therapeutic uses To treat anxiety disorders that have not responded to SSRIs/SNRIs. (The drug is ineffective in severe anxiety, panic disorders and acute anxiety attack)

29. 2. Newer Hypnotic Drugs; Zolpidem. Mechanism of action: They bind selectively to alpha1 subunit of the GABA receptor chloride channel complex. Pharmacological effects: Selective hypnotic actions Pharmacokinetics Zolpidem: oral bioavailability 70%; t 1/2 2-3 hs Adverse effects Most common (>5%): dizziness, drowsiness. Therapeutic uses Sleep-onset insomnia. Nocturnal insomnia.

30. Good Luck