Sedatives_Hypnotics.pptx file for pharmacy

Sedatives_Hypnotics.pptx file for pharmacy

1. Sedatives and Hypnotics 1

2. Basic pharmacology of sedative- hypnotics drug Sedative- hypnotic drug A sedative drug decreases activity, moderates excitement, and calms the recipient A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep This effect is sometimes called hypnosis Sedation is a side effect of many drugs that are not general CNS depressants (e.g., antihistamines and antipsychotic agents) Such agents can intensify the effects of CNS depressants They usually produce more specific therapeutic effects at concentrations far lower than those causing substantial CNS depression 2

3. Although coma may occur at very high doses, neither surgical anesthesia nor fatal intoxication is produced by benzodiazepine (BZP) An important exception is midazolam , which has been associated with decreased tidal volume and respiratory rate The sedative-hypnotic drugs that do not specifically target the BZP receptor cause depression of the CNS in a dose-dependent fashion Progressively producing: calming or drowsiness (sedation) Sleep (pharmacological hypnosis) Unconsciousness Coma Surgical anesthesia Fatal depression of respiration and cardiovascular regulation 3

4. 4 Sedative Hypnotics Amnesia sedation Hypnosis Coma Death Awake Amnesia sedation Hypnosis Coma Death Awake

5. Benzodiazepines Promote the binding of a neurotransmitter GABA to the GABA A subtype of GABA receptors It constitutes the most commonly used group of anxiolytics and sedative–hypnotics Chlordiazepoxide is the first of the member Most of these drugs possess: Anxiolytic Sedative–hypnotic Anticonvulsant properties 5

6. Some of BZP drugs Alprazolam Chlordiazepoxide Clorazepate Clonazepam Diazepam Estazolam Flurazepam Lorazepam Midazolam Oxazepam Quazepam Temazepam Triazolam 6

7. Mechanism of action It potentiates GABAergic neurotransmission in essentially all areas of the CNS This enhancement is thought to occur indirectly at the postsynaptic GABA A receptor complex The increase in chloride conductance mediated by GABA is intensified by the BZPs This facilitation of GABA-induced chloride conductance results in greater hyperpolarization of these cells Therefore, this leads to diminished synaptic transmission 7

8. Fig. A model of the GABA A receptor-chloride ion channel macromolecular complex showing the binding site of BZP and barbiturates 8

9. Pharmacokinetics BZPs are usually given orally and are well absorbed by this route They are weak bases They are less ionized in the alkaline environment of the small intestine Therefore, most of their absorption takes place at this site For emergency treatment of seizures or when used in anesthesia, the BZPs also can be given parenterally Diazepam and lorazepam are available for intravenous administration 9

10. BZP with a greater lipid solubility tend to enter the CNS and produce their effects more quickly Many BZPs do undergo extensive biotransformation by hepatic CYPs, particularly CYPs 3A4 and 2C19 Metabolism takes place both by dealkylation (phase 1) and conjugation (phase 2) reactions Erythromycin, clarithromycin, ritonavir, itraconazole , ketoconazole, nefazodone , and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of BZPs 10

11. Fig. Biotransformation of benzodiazepines. (Boldface, drugs available for clinical use in various countries; *, active metabolite.) 11

12. Effects: Central nervous system effects of BZPs include : Reduction of anxiety and aggression Sedation and induction of sleep Reduction of muscle tone and coordination Anticonvulsant effects CVS When BZPs are given per orally –no effect on HR and BP However, after IV route they cause profound hypotension and cardiac arrest Respiratory system They have little respiratory depression when used alone w/out CNS depressant However, they exacerbate some respiratory disorders such: Hypoventilation and hypoxemia-in patients with COPD Apnea (pause in breathing) 12

13. Clinical uses of BZPs: Insomnia they promote sleep through effect on cortical areas and the sleep-wakefulness clock should be given on an intermittent schedule (3 or 4 days per week) Anxiety - at small doses, used as anxiolytics They reduce anxiety through their effects on the limbic system, a neuronal network associated with emotionality Preoperative medications Eg . Amnesia – resulted from effect on hippocampus and cerebral cortex Acute alcohol withdrawal- alleviate the withdraw syndromes BZPs benefits derived from cross-dependence with alcohol Eg. Chlordiazepoxide , clorazepate , diazepam, and oxazepam are used 13

14. As anticonvulsants inhibit epileptiform activity used for seizures, status epilepticus ( i.v .) Diazepam, lorazepam, clorazepate , clonazepam Chronic muscle spasm and spasticity relaxing the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord and cerebellum Eg. Diazepam 14

15. Adverse effects Hypnotic doses of BZPs can be expected to cause varying degrees of AEs: Light-headedness Lassitude Increased reaction time Motor incoordination Impairment of mental and motor functions Confusion Anterograde amnesia ( inability to form new memories) Cognition appears to be affected less than motor performance All of these effects can greatly impair driving and other psychomotor skills, especially if combined with ethanol 15

16. Other relatively common side effects of BZPs are : Weakness Headache Blurred vision Vertigo Nausea and vomiting Epigastric distress Diarrhea; joint pains, chest pains, and incontinence are much rarer Anticonvulsant benzodiazepines sometimes actually increase the frequency of seizures in patients with epilepsy ( Esp. if the dose is missed or abruptly withdrawn) 16

17. Drug -interactions BZPs interact with: alcohol; cimetidine , ketoconazole , fluvoxamine , fluoxetine , omeprazole ; anticonvulsants; anticholinergics ; rifampicin Contraindications Known hypersensitivity to BZPs Chronic obstructive airways disease with incipient respiratory failure BZPs are not recommended for the primary treatment of psychotic illness BZPs should not be used alone to treat depression or anxiety associated with depression as suicide may occur in such patients Chlordiazepoxide and diazepam have been reported to increase the chance of birth defects when used during the first 3 months of pregnancy During nursing diazepam secret into the breast milk and cause drowsiness and difficulty in feeding of newborn 17

18. Novel benzodiazepine receptor agonists Hypnotics in this class are commonly referred to as "Z compounds“ They include; Zolpidem Zaleplon Zopiclone Eszopiclone which is the S(+) enantiomer of zopiclone The Z compounds are structurally unrelated to each other and to benzodiazepines However, their therapeutic efficacy as hypnotics is due to agonist effects on the BZP site of the GABA A receptor Compared to BZPs, Z compounds are lack the following effects: Anticonvulsants muscle relaxants Anxiolytic This is because Z-compounds do not bind to all BZP receptors, rather they are relative selectivity for GABA A receptors containing the ἀ 1 subunit 18

19. Z compounds have largely replaced BZPs in the treatment of insomnia Like BZPs, based on post-marketing clinical experience with zopiclone and zolpidem, tolerance and physical dependence can be expected The clinical presentation of overdose is similar to that of BZPs Overdose with Z compounds can be treated with the BZPs antagonist flumazenil 19

20. Benzodiazepine receptor antagonist Flumazenil It binds with high affinity to specific sites on the GABA A receptor It competitively antagonizes the binding and allosteric effects of BZPs and other ligands The drug is given intravenously Flumazenil is eliminated almost entirely by hepatic metabolism to inactive products with a t 1/2 of ~1 hour The duration of clinical effects usually is only 30-60 minutes It is used for the management of suspected BZP overdose and the reversal of sedative effects produced by BZPs 20

21. Benzodiazepine overdose May be intentional or secondary to accumulation of doses Symptoms: somnolence, impaired coordination, slurred speech, diminished reflexes, confusion, respiratory depression, hypotension Treatment options Supportive and symptomatic care Gastric lavage (removing poison from GIT) Activated Charcoal (adsorbs poisonous substance) IV hydration and maintain adequate airway IV Flumazenil ( Romazicon ® ): Benzodiazepine antagonist 21

22. Melatonin Congeners Ramelteon It is a synthetic tricyclic analog of melatonin It was approved in the U.S. in 2005 for the treatment of insomnia, specifically sleep onset difficulties It is good for inducing sleep but not for maintaining sleep Mechanism of action Melatonin levels in the suprachiastmatic nucleus rise and fall in a circadian fashion, with concentrations increasing in the evening as an individual prepares for sleep Ultimately decreasing as the night progresses 22

23. Two GPCRs for melatonin, MT 1 and MT 2 , are found in the suprachiasmatic nucleus Each of them playing a different role in sleep Binding of agonists, such as melatonin, to MT 1 receptors promotes the onset of sleep However, melatonin binding to MT 2 receptors shifts the timing of the circadian system 23

24. PKs An 8-mg tablet be taken ~30 minutes before bedtime It is rapidly absorbed from the GI tract In the bloodstream, ~ 80% of ramelteon is protein bound The drug is largely metabolized by the hepatic CYPs 1A2, 2C, and 3A4, with t 1/2 of ~ 2 hours in humans Fluvoxamine , strong inhibitors of Cyp1A2, can increase the levels of ramelteon AE & CIn Very high dose(197 times human dose) causes teratogenic in rat Not recommended for use by nursing mothers 24

25. Barbiturates Once used extensively as sedative-hypnotic drugs They have been largely replaced by the much safer BZPs Mainly because barbiturates induce: Tolerance Induction of drug-metabolizing enzymes Physical dependence Very severe withdrawal symptoms 25

26. They includes: Amobarbital – used for insomnia, pre-operative sedation, emergency management of seizures Butabarbital – used for insomnia, pre-op sedation Mephobarbital –used for Seizure disorders, daytime sedation Methohexital –used for induction and maintenance of anesthesia Pentobarbital –used for insomnia, pre-op sedation, emergency management of seizures 26

27. Phenobarbital- used for seizure disorders, status epilepticus , daytime sedation Secobarbital -used for insomnia, preoperative sedation Thiopental - used for induction/maintenance of anesthesia, pre-op sedation, emergency management of seizures Butabarbital and phenobarbital , are used sometimes to antagonize unwanted CNS-stimulant effects of various drugs, such as ephedrine, dextroamphetamine , and theophylline 27

28. Pharmacological properties The barbiturates reversibly depress the activity of all excitable tissues Sites and mechanisms of action on the CNS Barbiturates act throughout the CNS Enhancement of inhibition occurs primarily at synapses where neurotransmission is mediated by GABA acting at GABA A receptors Barbiturates can produce all degrees of depression of the CNS, ranging from mild sedation to general anesthesia 28

29. Effects on stages of sleep Hypnotic doses increase the total sleep time and alter the stages of sleep in a dose-dependent manner Barbiturates decrease sleep latency, the number of awakenings, and the durations of REM and slow-wave sleep Tolerance Pharmacodynamic (functional) and pharmacokinetic tolerance to barbiturates can occur During repetitive night administration, some tolerance to the effects on sleep occurs within a few days Tolerance rapidly occur to sedation and its hypnotic effects but not to toxic effect 29

30. The effect on total sleep time may be reduced by as much as 50% after 2 weeks of use Discontinuation leads to rebound increases in all the parameters reported to be decreased by barbiturates Pharmacodynamic tolerance to barbiturates confers cross-tolerance to all general CNS-depressant drugs, including ethanol Abuse and dependence Barbiturates are abused, and some individuals develop a dependence on them They may have euphoriant effects 30

31. Respiration The barbiturates: Slightly depress protective reflexes until the degree of intoxication is sufficient to produce severe respiratory depression Coughing, sneezing, and laryngospasm may occur when barbiturates are employed as intravenous anesthetic agents Cardiovascular system When given orally in sedative or hypnotic doses, barbiturates do not produce significant overt cardiovascular effects However they cause a slight decrease in blood pressure and heart rate such as occurs in normal sleep 31

32. Decreased renal and cerebral blood flow with a marked fall in CSF pressure occur with IV thiopental preanesthetic medication GI Tract The oxybarbiturates tend to decrease the tone of the GI musculature and the amplitude of rhythmic contractions A hypnotic dose does not significantly delay gastric emptying in humans The relief of various GI symptoms by sedative doses is probably largely due to the central-depressant action 32

33. Liver Barbiturate causes the microsomal enzyme induction A site at which significant drug-drug interactions can occur Kidney Severe oliguria o r anuria may occur in acute barbiturate poisoning largely as a result of the marked hypotension 33

34. Pharmacokinetics For sedative-hypnotic use, the barbiturates usually are administered orally They are absorbed rapidly and probably completely Na + salts are absorbed more rapidly than the corresponding free acids The onset of action varies from 10-60 minutes, depending on the agent and the formulation High lipid-soluble barbiturates have fast onset of action b/c they rapidly cross BBB and their effect is terminated by redistribution to blood and other tissue from the brain Their absorption is delayed by the presence of food in the stomach The intravenous route usually is reserved for the management of status epilepticus ( phenobarbital sodium) or for the induction and/or maintenance of general anesthesia (e.g., thiopental or methohexital ) 34

35. Barbiturates are readily cross the placenta can injure the developing fetus at 3 rd trimester may cause drug dependence in the infant Except for the less lipid-soluble aprobarbital and phenobarbital Nearly complete metabolism and/or conjugation of barbiturates in the liver precedes their renal excretion (esp. for polar agents) About 25% of phenobarbital and nearly all of aprobarbital are excreted unchanged in the urine Their renal excretion can be increased greatly by osmotic diuresis and/or alkalinization of the urine 35

36. Adverse effect Distortions of mood Impairment of judgment and fine motor skills vertigo, nausea, vomiting, or diarrhea, or sometimes may be manifested as overt excitement Because barbiturates enhance porphyrin synthesis Therefore, they are absolutely contraindicated in patients with acute intermittent porphyria or porphyria variegata Precursors barbiturates stimulates porphyrin Heme Cyp450 By increasing the synthesis of porphyrin , barbiturates increases the production of cyp450 , a key drug-drug interaction 36

37. Hypersensitivity Allergic reactions occur, especially in persons with asthma, urticaria , angioedema , or similar conditions 37

38. Drug interactions Barbiturates combine with other CNS depressants cause severe depression ethanol first-generation antihistamines Isoniazid – decreases metabolism of barbiturates, so it increases CNS effect of barbiturates monoamine oxidase inhibitors- antidepressants have additive effect on CNS-depressant Hepatic enzyme induction enhances metabolism of endogenous steroid hormones, which may cause endocrine disturbances oral contraceptives, which may result in unwanted pregnancy The metabolism of vitamins D and K is accelerated 38

39. Barbiturate poisoning Barbiturate poisoning has declined markedly Because of decreased their use as sedative-hypnotic agents Poisoning with barbiturates is a significant clinical problem Most of the cases are the result of deliberate attempts at suicide, but some are fro m accidental poisonings in children or in drug abusers Severe poisoning is likely to occur when >10 times the full hypnotic dose has been ingested at once 39

40. In severe intoxication, the patient is comatose; respiration is affected early Breathing may be either slow or rapid and shallow Blood pressure falls because of the effect of the drug and of hypoxia on medullary vasomotor centers Depression of cardiac contractility Pulmonary complications (e.g., atelectasis , edema, and bronchopneumonia) and renal failure are likely to be the fatal complications of severe barbiturate poisoning 40

41. The treatment of acute barbiturate intoxication It is based on general supportive measures Hemodialysis or hemoperfusion is necessary only rarely If renal and cardiac functions are satisfactory, and the patient is hydrated forced diuresis and alkalinization of the urine will hasten the excretion of phenobarbital Measures to prevent or treat atelectasis should be taken, and mechanical ventilation should be initiated when indicated the blood pressure can be supported with dopamine In the event of renal failure, hemodialysis should be instituted 41

42. Miscellaneous sedative-hypnotic drugs It includes paraldehyde, chloral hydrate, meprobamate , ethchlorvynol , glutethimide , methyprylon , ethinamate With the exception of ramelteon and meprobamate , the pharmacological actions of these drugs resemble those of the barbiturates All are general CNS depressants that can produce profound hypnosis with little or no analgesia Their effects on the stages of sleep are similar to those of the barbiturates Their chronic use can result in tolerance and physical dependence Meprobamate bear some resemblance to those of the benzodiazepines However, meprobamate has a distinctly higher potential for abuse and has less selective anti-anxiety effects 42

43. Paraldehyde It has a strong odor and a disagreeable taste Orally, it is irritating to the throat and stomach It is not administered parenterally because of its injurious effects on tissues When given rectally as a retention enema, the drug is diluted with olive oil Oral paraldehyde is absorbed rapidly and distributed widely Sleep usually ensues in 10 to 15 minutes after hypnotic doses About 70% to 80% of a dose is metabolized in the liver 43

44. Poisoning with the drug include acidosis, gastritis, and fatty changes in the liver and kidney with toxic hepatitis and nephrosis The clinical uses of paraldehyde include: Treatment of withdrawal reactions Psychiatric states characterized by excitement Convulsions (including status epilepticus ) in children 44

45. Chloral Hydrate It is used for hypnotic effect In addition the drug has been employed in the past for the production of sedation in children undergoing diagnostic, dental, or other potentially uncomfortable procedures It is reduced rapidly to the active compound, trichloroethanol (CCl 3 CH 2 OH), largely by alcohol dehydrogenase in the liver Trichloroethanol is conjugated mainly with glucuronic acid, and the product is excreted mostly into the urine 45

46. It is irritating to the skin and mucous membranes These irritant actions give rise to an unpleasant taste, epigastric distress, nausea, and occasional vomiting (esp. if it is not diluted and taken on empty stomach ) Undesirable CNS effects include lightheadedness, malaise, ataxia, and nightmares Acute poisoning by chloral hydrate may cause jaundice Sudden withdrawal from the use of chloral hydrate may result in delirium and seizures, with a high frequency of death when untreated 46