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Sedative, Hypnotics and Anxiolytics
Sedative, Hypnotic and Anxiolytic Drugs are used to treat anxiety, insomnia and induce sleep. They work by potentiating the action of the inhibitory neurotransmitter GABA in the brain. Benzodiazepines and barbiturates are common classes of these drugs. Benzodiazepines increase the frequency of chloride channel opening, while barbiturates increase the duration. Both classes are used as sedatives, hypnotics and to relieve anxiety. They can cause dependence and tolerance with long term use. Newer non-benzodiazepine drugs like Zolpidem and Zaleplon have fewer side effects.
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Sedative, Hypnotics and Anxiolytics
- 1. Sedative, Hypnotic and AnxiolyticDrugs Prof. Amol B. Deore Department of Pharmacology MVP’s Institute of Pharmaceutical Sciences, Nashik
- 2. Sedative, Hypnotic andAnxiolytic Drugs Drugs that cause sedation and at the same time relieve anxiety (anxiolytics) or can induce sleep. They are used primarily to treat anxiety and insomnia. In general, these drugs will induce sleep when given ill high doses at night and will provide sedation and reduce anxiety then given in low divided doses during the day.
- 6. Sleep disorders • Insomnia •Hyposomnia • Parasomnia • Snoring • Sleep apnea • Narcolepsy
- 8. SLEEP Sleep is anaturally periodic state of mind and body, characterized by altered consciousness, SLEEP CYCLE REM stands for rapid eye movement. During REM sleep, your eyes move quickly in different directions. That doesn't happen during NREM sleep. First comes NREM sleep, followed by a shorter period of REM sleep, and then the cycle starts over again. Dreams typically happen during REM sleep.
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- 12. Sedative Sedative is adrug that produces a calming effect and reduces excitement. It may induce drowsiness without inducing sleep.
- 13. Insomnia Insomnia is asleep disorder in which you have trouble falling and/or staying asleep. Acute insomnia lasts from 1 night to a few weeks. Insomnia is chronic when it happens at least 3 nights a week for 3 months or more.
- 14. Hypnotic Hypnotic is adrug that induces sleep resembling natural sleep. Both sedation and hypnosis may be considered as different grades of CNS depression.
- 15. Anxiety Anxiety is anunpleasant state of tension, apprehension, or uneasiness (a fear that arises from either a known or an unknown source). The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation.
- 16. Anxiolytics This are themedicines which are used to relive the stress, tension, anxiety generated by complex and hectic modern daily life. Because many antianxiety drugs also cause some sedation, they may be used clinically as both anxiolytic and hypnotic (sleep inducing) agents.
- 17. Classification Benzodiazepines (BDZ) • Longacting benzodiazepines • Ex. Diazepam, Flurazepam, Clonazepam, Prazepam • Intermediate acting benzodiazepines • Ex. Nitrazepam, Lorazepam, Oxazepam, Temazepam, Medazepam • Short acting benzodiazepines • Ex. Alprazolam, Triazolam, Oxazolam, Estazolam, Midazolam Barbiturates • Long acting Barbiturates • Ex. Phenobarbital, Mephobarbital, Metharbital. • Intermediate acting Barbiturates • Ex. Amobarbital, Apobarbital, Butabarbital. • Short acting Barbiturates • Ex. Pentobarbital, Secobarbital • Ultra short acting Barbiturates: • Ex. Methohexital, Thiomylol, Thiopental. Newer Non-Benzodiazepine Hypnotics • Ex. Zolpidem, Zopiclone, Eszopiclone, Zaleplon, Buspirone, Doxepin.
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- 20. Mechanism of actionof Benzodiazepines GABA, the most potent inhibitory transmitter in the CNS controls the state of neuronal excitability. It acts by binding to the neuronal GABA receptor and opens the chloride channels.
- 21. The site ofaction of benzodiazepines in the CNS appears to be limbic system, thalamus and reticular activating system (which maintains consciousness, sleep, and alertness). Benzodiazepines act by potentiating the action of neurotransmitter GABA (gama amino butyric acid).
- 23. BDZ bind selectivelyto subunits of the GABA receptors, a site distinct from that of GABA or barbiturates binding site, and is designated as benzodiazepine binding site. Thus, they increase the frequency of chloride channel opening and the chloride ion concentration in the neuron. This causes hyperpolarisation of the neuronal membrane, making it more difficult for the excitatory neurotransmitters to depolarise the cell. so neuronal transmission in brain and spinal cord decreases.
- 24. C E LL M E M B R A N E Mechanism of Benzodiazepine BDZ receptorGABA receptor Chloride ion channel GABA Benzodiazepine Hyperpolarization Chloride ions Chloride ions
- 25. Pharmacological actions ofBenzodiazepine
- 26. • In smallerdose, BDZ cause sedation and relief of anxiety. • In higher dose, BDZ induce sleep (hypnosis). • They shorten the time spent in stage 4 of NREM and REM but increase total sleep time. • Sleep produced by them is more refreshing and with less hangover symptoms. Sedative hypnotic effect • The BDZ exert a specific effect on limbic system and therefore reduce anxiety and thus produce a calming effect without affecting sleep. • Alprazolam has additional antidepressant properties. Antianxiety effect
- 27. • The longacting BDZ Clonazepam produce anticonvulsant effect by raising the seizure threshold in the limbic system by potentiating GABA action • lorazepam and diazepam prevent the spread of seizure in the brain. Anticonvulsant effect: • The BDZ produce relaxation of skeletal muscle by facilitating GABA-nergic transmission in the brainstem and spinal cord. • Hence they used in acute spasm of skeletal muscles caused by trauma or inflammation and muscular rigidity. Skeletal muscle relaxants:
- 28. • Midazolam anddiazepam are used for preanesthetic medications (given IM) and for induction of general anesthesia (given IV). • This action is produce by potentiation of GABA nergic neurotransmission. Anesthetic action • BZDs produce anterograde amnesia, i.e. loss of memory for the events happening after the administration of BZDs. • This property is an advantage when BZDs are used in surgical procedures as the patient does not remember the unpleasant events. Amnesia
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- 30. Therapeutic uses ofBDZ Anxiety disorders • Panic disorder, generalized anxiety disorder (GAD), • Social anxiety disorder, performance anxiety, • Posttraumatic stress disorder, obsessive–compulsive disorder, • Extreme anxiety associated with phobias, such as fear of flying. Sleep disorders • Hypnotic agents, • In the treatment of insomnia Amnesia • Premedication for anxiety-provoking and unpleasant procedures such as endoscopy, dental procedures, and angioplasty
- 31. Seizures • types ofseizures, • status epilepticus, • treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures Muscular disorders • Skeletal muscle spasms, • degenerative disorders, such as multiple sclerosis and cerebral palsy. Therapeutic uses of BDZ
- 32. Adverse drug reactionof BDZ Tolerance and dependence • Both tolerance and dependence liability are less with BZDs as compared to barbiturates. Central nervous system • Confusion, disorientation, agitation, slurred speech, headache, vertigo, depression, vivid dreams, hallucinations and tremors. Gastrointestinal system • Constipation, anorexia, Urinary system • Urinary incontinence, urinary retention Cardiovascular system • Bradycardia, hypotension, palpitation Hematologic • Agranulocytosis, neutropenia
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- 35. Mechanism of actionof barbiturates Barbiturates depress the sensory and motor activity in the cerebral cortex. Barbiturates also act on the “reticular activating system” and elevate firing threshold and depress the firing rate of neurons. Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings.
- 37. Barbiturate bind selectivelyto subunits of the GABA receptors, a site distinct from that of GABA or BDZ binding site, and is designated as Barbiturate binding site. The sedative–hypnotic action of the barbiturates is due to their interaction with GABAA receptors, which potentiate GABAergic transmission. Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings. This causes hyperpolarisation of the neuronal membrane, making it more difficult for the excitatory neurotransmitters to depolarise the cell. In this way, CNS depresses and patient sleeps
- 38. C E LL M E M B R A N E Mechanism of Barbiturates BDZ receptor GABA receptor Chloride ion channel GABA Hyperpolarization of neuron and decreased CNS activity. i.e. CNS depression Chloride ions Chloride ions Barbiturate receptor Barbiturate
- 39. Key Feature Benzodiazepines, increase the frequencyof chloride channel opening and the chloride ion concentration in the neuron. Barbiturates, increase the duration of chloride channel opening and the chloride ion concentration in the neuron.
- 40. Pharmacological actions ofBarbiturates
- 41. Sedation • In lowdoses barbiturates show drowsiness and calmness and a sense well-being (euphoria). • This sedation is due to depression of reticular activating system (RAS) in the brain. Hypnosis: • They induce sleep in a dose 3 to 4 times higher than the sedative dose. • A barbiturates show relief from insomnia by inducing stage 2 of the NREM sleep. General anesthesia: • Ultra short acting barbiturates (methohexital, thiopental) are administered IV for induction of general anesthesia. • They produce reversible loss of consciousness by blocking the impulse generation and transmission from reticular activity system.
- 42. Anticonvulsant action: • TheLong acting Barbiturates (phenobarbital, mephobarbital) showing anticonvulsant action by blocking the excess neuronal firing. • They are indicated in the therapy of grand mal epilepsy and cortical focal seizure. Respiratory depression: • Barbiturates in large doses show respiratory depression by depressing respiratory center in medulla oblongata. Enzyme induction: • Barbiturate especially phenobarbital can increase functioning of hepatic microsomal enzyme activity. This process is called enzyme induction. • This results in increase in the metabolism and hence decreased effectiveness of many drugs.
- 43. Therapeutic use ofBarbiturates
- 44. Adverse Drug Reaction •Due to residual depression of the CNS may be accompanied by headache, nausea, vomiting, vertigo and diarrhea, distortions of mood, impaired judgement etc. Hangover: • Barbiturates, if administered to a woman during labour, may depress the fetal respiration. Depression of fetal respiration:
- 45. • When abarbiturate is employed as a hypnotic, because of confusion and amnesia, a patient may repeatedly take the barbiturate at night and poison himself. Drug automatism: • Repeated administration of barbiturates causes tolerance to their sedative and hypnotic actions.Tolerance: • Repeated ingestion of barbiturates causes drug dependence. Drug dependence: • Urticaria, angioneurotic edema, agranulocytosis and thrombocytopenic purpura. Allergic reactions:
- 46. Acute Barbiturate Poisoning Causes •Used as sleeping pills for suicidal attempt. • Drug automatism (memory loss) Symptoms • CNS depression, particularly the respiratory depression, and a peripheral circulatory collapse. • The frequent and often fatal complications are atelectasis, pulmonary edema and pneumonia. • wheezing, hypotension, hypopyrexia, salivation, coma, and death may occur.
- 47. Management of BarbituratePoisoning Hospitalization Gastric lavage Adequate tissue oxygenation Forced diuresis Intravenous fluids Alkalinisation of the urine Prophylactic antibiotics
- 48. Gastric lavage If thepatient is conscious and less than four hours have elapsed since ingestion, vomiting may be induced with syrup of ipecac or concentrated salt solution. In comatose patients, endotracheal intubation should precede gastric intubation to prevent aspiration.
- 49. Adequate tissue oxygenation Ifthe respiration is not much affected, oxygen can be given by a nasal catheter. Endotracheal intubation is performed when spontaneous respiration is inadequate and also to remove secretions. If assisted ventilation is required for more than 24 hours, tracheostomy is usually performed.
- 50. Forced diuresis Mannitol, anosmotic diuretic, is given IV, initially in the dose of 100-120 ml of 25% solution. Subsequently, a sustained infusion of 5% mannitol alternately in normal saline and a litre of 5% dextrose is administered. Alternatively, furosemide is used in the dose of 20 mg along with 500 ml of 1.2% sodium bicarbonate and one litre of 5% dextrose IV.
- 51. Intravenous fluids Fluids mustbe given in sufficient quantity as an adjuvant to forced diuresis, in order to prevent dehydration and for maintaining the blood volume. Normal saline with dextrose is employed for this purpose. If hypotension does not respond to replacement by fluids, vasopressor agents like dopamine may be used.
- 52. Alkalinisation of theurine • Sodium bicarbonate 50ml of a 7.5% solution may be added to every litre of fluid intended for IV administration. • The urinary pH should be maintained between 7.5 and 8.5. • This increases the excretion of long acting barbiturates, such as phenobarbitone
- 53. Prophylactic antibiotics These shouldnot be used on routinely but may be necessary in those requiring tracheostomy or catheterisation.
- 54. Hemodialysis All are moreeffective in removing long acting barbiturates than short acting ones. In general, peritoneal dialysis is more suitable than forced diuresis in patients who have severe cardiac and renal impairment. Hemodialysis is about forty times more effective than forced diuresis in promoting barbiturate elimination.
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- 56. Zolpidem The hypnotic zolpidemis not structurally related to benzodiazepines, but it selectively binds to the benzodiazepine receptor subtype Zolpidem has no anticonvulsant or muscle-relaxing properties. It shows few withdrawal effects, exhibits minimal rebound insomnia, and little tolerance occurs with prolonged use.
- 57. Zaleplon Zaleplon is anoral nonbenzodiazepine hypnotic similar to zolpidem
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