Anxiolytic and Hypnotic Drugs

1. Anxiolytic and Hypnotic Drugs

2. Anxiety Neurotransmitters implicated in Anxiety GABA Norepinephrine Serotonin

3. Anxiety • Anxiety disorders includes - • Generalized Anxiety Disorder (GAD) • Phobia / Panic Disorder • Obsessive Compulsive Disorder (OCD) • Post traumatic Stress Disorder (PTSD)

4. Anxiety • A psychological and physiological state characterized by the following components: • cognitive • somatic • emotional • behavioral • These components combine to create an unpleasant feeling that is typically associated with uneasiness, fear, or worry.

5. Cognitive component: expectation of a diffuse and uncertain danger. • Somatically the body prepares the organism to deal with threat (fight or flight reaction): • blood pressure and heart rate are increased • sweating is increased • Blood flow to the major muscle groups is increased • immune and digestive system functions are inhibited.

6. Externally, somatic signs of anxiety may include: • pale skin • sweating • trembling • pupillary dilation

8. Emotionally, anxiety causes a sense of dread or panic and physically causes nausea, and chills. • Behaviorally, both voluntary and involuntary behaviors may arise directed at escaping or avoiding the source of anxiety. • These behaviors are frequent and often maladaptive, being most extreme in anxiety disorders.

9. Generalized anxiety disorder (GAD) • a chronic disorder characterized by: • long-lasting anxiety • not focused on any one object or situation. • Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters

10. Panic disorder • A person suffers from brief attacks of intense terror and apprehension, often marked by: • trembling • shaking • confusion • dizziness • nausea • difficulty breathing • Chest pain or discomfort • Dizziness or faintness • Fear of dying • Acute panic attacks: • defined by fear or discomfort that abruptly arises and peaks in less than ten minutes • can last for several hours • can be triggered by stress, fear, or even exercise

11. Phobias • The largest category of anxiety disorders • Fear and anxiety is triggered by a specific stimulus or situation. • Sufferers typically anticipate terrifying consequences from encountering the object of their fear, which can be anything from an animals to a location to a body fluid.

12. Agoraphobia • Agoraphobia is the specific anxiety about being in a place or situation where escape is difficult or embarrassing. • A common manifestation involves needing to be in constant view of a door or other escape route.

13. Social anxiety disorder (Social phobia) • An intense fear of negative public scrutiny or of public embarrassment or humiliation. • This fear can be specific to particular social situations (such as public speaking) or, more typically, is experienced in most (or all) social interactions. • Social anxiety often manifests specific physical symptoms • blushing • sweating • difficulty speaking

14. Obsessive-compulsive disorder (OCD) • Characterized by : • repetitive obsessions (distressing, persistent, and intrusive thoughts or images) • compulsions (urges to perform specific acts or rituals). • The OCD thought pattern may be likened to superstitions in so far as it involves a belief in a causative relationship where, in reality, one does not exist.

16. Post-traumatic stress disorder • An anxiety disorder which results from a traumatic experience. • Can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. • Common symptoms include • flashbacks • avoidant behaviors • depression

17. Anxiolytics and Hypnotics

18. Anxiolytics and Hypnotics • Benzodiazepines: • High therapeutic index • Cannot induce a state of surgical anesthesia • Dependence liability low • Specific antidote – Flumazenil • Does not induce cytochrome P450

21. Duration of Action of Benzodiazepines

22. Molecular target of Benzodiazepines: • BZD act selectively on GABA A receptor. • BZD acts by binding at a site distinct from GABA binding site on the receptor. • BZD increase the frequencyof channel opening. • BZD is GABA facilitatory in nature.

24. Bzs facilitation of 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, and limbic system.

26. CNS actions of BZD Anti-anxiety Hypnotic activity Anterograde amnesia:the individual is severely impaired in learning new information(temporary) Muscle relaxation Anticonvulsant action Respiration: suppression at high dose. GIT: decrease nocturnal gastric secretion.

27. Pharmacokinetics ofBZD • BZD are lipophilic and cross placental barrier and secreted in the milk. • Most of them are metabolized by CYP450 enzyme system to active compounds. • Lorazepam, Oxazepam, Temazepam do not have active metabolites

28. Adverse effects, contraindications, and drug interactions of BZD • Benzodiazepines commonly produce: • daytime drowsiness • Sedation • Ataxia (Loss of the ability to coordinate muscular movement.)

29. Adverse effects…….. • rebound insomnia on discontinuation. • In the elderly, benzodiazepines infrequently cause reversible confusion and amnesia as well as blurred vision, hypotension, tremor, and constipation. • May depress respiration at higher than hypnotic doses

30. Adverse effects…….. • When given intravenously, may decrease blood pressure and decrease heart rate in patients with impaired cardiovascular function. • These drugs cause rareparadoxical excitement. • They enhance CNS depression when taken in combination with other drugs that depress the CNS, most notably alcohol. • Drugs and grapefruit juice that inhibit CYP3A4 can extend the duration of benzodiazepine action.

31. Tolerance, abuse, and dependence • With long-term administration, tolerance develops to: • the sedative–hypnotic and anti-convulsantactions of benzodiazepines • but not to their anxiolytic action. • patients exhibit cross-tolerance with other sedative–hypnotic agents, including alcohol and barbiturates. • The abuse potential of benzodiazepines is low compared with that of other classes of sedative–hypnotic drugs except when there is already a history of substance abuse.

32. Withdrawal: • Abrupt discontinuation after long-term benzodiazepine use (3–4 months) • Signs of withdrawal may include: • anxiety and insomnia • gastrointestinal disturbances • headache • tremor • Withdrawal occurs sooner and is more severe after abrupt discontinuation of shorter-acting benzodiazepines • Withdrawal symptoms can be minimized by: • tapering the dose • substituting longer-acting benzodiazepines such as diazepam.

33. Therapeutic uses of Benzodiazepines • Short-term treatment of anxiety disorders: • Generalized anxiety disorders • Situational anxiety disorders (SADs; e.g., frightening medical or dental procedures) • Panic disorders. Because of its apparent greater specificity, alprazolam is widely used for urgent care. • Social anxiety disorder

34. Insomnia: • Widely used benzodiazepines: (e.g., triazolam, triazepam, flurazepam). • agents with • a rapid onset • sufficient duration • minimal “hangover”

35. Seizures: • Benzodiazepines elevate the seizure threshold. • Lorazepam (and diazepam), given by intravenous (IV) infusion, is preferred for initial treatment of: • status epilepticus • drug- or toxin-induced seizures. • Clonazepam and clorazepateare used as adjuncts for: • Absence • Myoclonic • atonic seizures. Cannot be used for long-term treatment of seizures: due to tolerance

36. Preanesthetic and short medical/surgical procedures. • Shorter-acting benzodiazepines (e.g., midazolam) are preferred for their anxiolytic, sedative, and amnestic actions prior to and during surgery, endoscopy, or bronchoscopy. • These drugs do not produce full surgical anesthesia. • Muscle relaxation. • Diazepam is used to treat spontaneous muscle spasms, spasms associated with endoscopy, and the spasticity of cerebral palsy.

37. Treatment of agitation (physical and psychological restlessness) in acute mania of bipolar disorder • Physical dependence. • Long-acting benzodiazepines, such as diazepam and chlordiazepoxide, are used to reduce the withdrawal symptoms of physical dependence associated with the: • long-term use of shorter-acting benzodiazepines • other sedative–hypnotic drugs, including alcohol and the barbiturates

38. BENZODIAZEPINE ANTAGONIST Flumazenil: • Competitive antagonist of BZD. • Not given orally because of high first pass metabolism in liver (only IV). • Half life ~1 hr. • It precipitates withdrawal symptoms in BZD dependent patients. • Used in BZD and zolpidem intoxication.

39. B. Barbiturates Duration of Action of Barbiturates

40. Classification and Indications of Barbiturates Drug and classification Indications Intravenous general anesthesia Preanesthetic medication and regional anesthesia; sedation and hypnosis (largely replaced by benzodiazepines) Seizure disorders; withdrawal syndrome from sedative–hypnotics; congenital hyperbilirubinemia, and neonatal jaundice (enhance bilirubin metabolism by induction of microsomal enzymes) • Ultra-short acting • Thiopental [Pentothal] • Methohexital [Brevital] • Thiamylal [Surital] • Intermediate acting • Amobarbital [Amytal] • Pentobarbital [Nembutal] • Secobarbital [Seconal] • Long acting • Phenobarbital [Luminal] • Mephobarbital [Mebaral]

41. Barbiturates :Mechanism of action • Can act on GABA A receptor even without GABA – GABA mimetic. • Increase the duration of opening of the chloride channel. • AMPA (Glutamate) receptor are blocked at high dose. • High dose can block Na channel.

43. Actions of Barbiturates : • Conc. Dependent CNS Depression: • At low doses, the barbiturates produce sedation (have a calming effect and reduce excitement). • At higher doses, the drugs cause hypnosis • followed by anesthesia (loss of feeling or sensation) • finally, coma and death. • Chronic use leads to tolerance. • Respiratory depression: • Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and overdosage is followed by respiratory depression and death.

44. 3. Enzyme induction: Barbiturates induce cytochrome P450 (CYP450) microsomal enzymes in the liver.

45. Therapeutic uses of Barbiturates • Anesthesia: • The ultrashort-acting barbiturates, such as thiopental, are used intravenously to induce anesthesia • Anticonvulsant: • Phenobarbital is used in: • long-term management of: • tonic-clonic seizures • status epilepticus • eclampsia. • the drug of choice for treatment of young children with recurrent febrile seizures. • should be used cautiously in children, because phenobarbital can depress cognitive performance

46. Anxiety: • Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. • When used as hypnotics, they suppress REM sleep more than other stages. • Most have been replaced by the benzodiazepines.

47. Pharmacokinetics of barbiturates • Absorbed orally • Distributed widely throughout the body. • Barbiturates readily cross the placenta and can depress the fetus. • These agents are metabolized in the liver • Inactive metabolites are excreted in urine.

48. Barbiturates :Adverse effects: • Hangover: may lead to impaired ability to function normally for many hours after waking. • Drowsiness and impairment of fine motor skills. • Distortion of mood and judgments. • Behavioral disturbances after long term treatment. • Tolerance and dependence – severe.

49. C. OTHER ANXIOLYTIC AGENTS A. Antidepressants • Used in managing the long-term symptoms of chronic anxiety disorders especially in patients with concerns for addiction or dependence or a history of addiction or dependence to other substances. • Selective serotonin reuptake inhibitors (SSRIs, such a escitalopram), or

50. Selective serotonin and norepinephrine reuptake inhibitors (SNRIs, such as venlafaxine) may be used alone, or prescribed in combination with a low dose of a benzodiazepine during the first weeks of treatment. • After four to six weeks, when the antidepressant begins to produce an anxiolytic effect, the benzodiazepine dose can be tapered.