Anxiety and BDZ at undergraduate level especially

How BZD can be used for Anxiety. Especially for undergraduates

1. Anxiety disorders and Insomnia

2. Anxiety disorders Anxiety disorder is characterized by apprehension, worry, irritability, inability to concentrate, hypervigilance and insomnia. Tachycardia, Hypertension, Headache and Hyperacidity may be present. In Generalized anxiety disorder these symptoms persist on most days for atleast 6 months. In acute anxiety state s – Benzodiazepines and β blocker are effective. For chronic anxiety states – SNRIs, SSRIs, 5HT 1A partial agonist and sometimes atypical antidepressants are used.

3. Benzodiazepines Benzodiazepines are effective in management of both acute and chronic anxiety disorders. Alprazolam has antidepressant property also. Benzodiazepines commonly used in anxiety disorder Daily Dose in mg Diazepam 5 – 30 Lorazepam 1 – 4 Oxazepam 10 – 60 Clonazepam 1 – 10 Chlodiazepoxide 10 – 100 Alprazolam 0.5 – 4

4. Benzodiazepines Benzodiazepines are not preferred for long term use because of : Risk of dependence and abuse. Negative effect on cognition and memory. Decreased alertness and slow reaction time may lead to accidents. Potentiate the effect of other sedatives and alcohol. Abrupt withdrawal may cause anxiety and seizures and therefore withdrawal should be gradual.

5. β blockers When a person is exposed to anxiety provoking situations, β blockers effectively control anxiety manifestations and panic symptoms. β blockers manage tachycardia, palpitation, tremors and nervousness associated with anxiety. Prophylactic use of β blocker calms the person before public speech and may also improve performance like of musicians. Anxiety disorders respond very well to Lipophilic β blockers like Propranolol (40 – 160 mg/day).

6. Chronic Anxiety disorder SNRIs and SSRIs are considered the first line drugs in this condition. 5HT 1A partial agonists are also effective in this condition. Sometimes in refractory cases, the atypical antidepressants like Trazodone , Nefazodone or Mirtazepine can be used. H 1 blocker – Hydroxyzine can be used when Benzodiazepines cannot be used because of drug / alcohol abuse. Pregablin and Tiagabine are also tried in chronic anxiety disorder.

7. Selective Inhibitors of Reuptake of both NA & 5-HT (SNRIs) Drug Oral d aily dose in mg Venlafaxine 150-225 Desvenlafaxine 50-100 Milnacepran 100-200 Levomilnacepran 40-120 Duloxetine 40-60

8. Selective Serotonin Reuptake Inhibitors (SSRIs) Drug Oral d aily dose in mg Fluoxetine 5-80 Paroxetine 20-50 Fluvoxamine 100-300 Sertraline 50-200 Citolapram 20-40 Escitolapram 10-20

9. 5-HT 1A partial agonists These drugs are specifically effective in anxiety disorder. Buspirone Ipsapirone Gepirone Trospirone Buspirone is used in management of chronic anxiety in the dose 10-60 mg/day.

10. Does not cause sedation, so no cognitive or psychomotor impairment. Dose not potentiate CNS depressant effect of other drugs. Does not have Myorelaxant and Anticonvulsant effect. No significant risk of dependence and abuse liability. Buspirone differs from BDZ in following respect -

11. Delayed onset of action (2 weeks). Therefore, not used in acute severe anxiety, panic attacks and alcohol withdrawal syndrome. Antianxiety potential is weaker than BDZ. Effectiveness of Buspirone may be less in patients who were on long term BDZ therapy. Buspirone differs from BDZ in following respect -

12. Sedative & Hypnotic Drugs Sedative drug - is a drug which calms the patient, decreases alertness and responsiveness. Hypnotic drug - is a drug which induces sleep.

13. These are classified as:- Short acting Triazolam , Midazolam , Oxazepam Intermediate acting Lorazepam , Temazepam , Estazolam Alprazolam , Nitrazepam Long acting Diazepam, Flurazepam , Clonazepam Chlodiazepoxide BENZODIAZEPINES

14. BDZ : Pharmacological actions Sedation Hypnotic action – stage 2 NREM sleep stage 1, 3 & 4 NREM sleep Sleep latency is reduced. No rebound increase in REM sleep on withdrawal. Patients wake up with feeling of refreshing sleep. The sleep induced is beneficial in conditions like sleep walking, nightmares, endogenous depression and nocturnal enuresis but sleep apnea may worsen.

15. BDZ : Pharmacological actions Anticonvulsant effect – Clonazepam , Clobazam and Midazolam are used for this purpose. Myorelaxant effect (Skeletal muscle relaxation). Analgesic effect, coronary vasodilation and hypotension are observed with I/V Diazepam.

16. BDZ : Mechanism of action GABA is an inhibitory neurotransmitter in brain. Benzodiazepines bind at the site near GABA receptor and intensify the interaction of GABA with its receptor leading to increased frequency of opening of chloride ( Cl - ) channel leading to hyperpolarization .

17. BDZ : Pharmacokinetics Most of the Benzodiazepines have active metabolite and therefore, biological effect half life is more than plasma half life. Estazolam , Oxazepam and Lorazepam do not have any active metabolite. Oxazepam , Temazepam , Lorazepam are preferred in elderly patients and in presence of hepatic disease. Absorption of Diazepam on I/M administration is erratic. Lorazepam and Midazolam have reliable absorption on I/M administration.

18. BDZ : Adverse effects Drowsiness, lethargy, confusion, fatigue, Increased reaction time Impairment of psychomotor skills Disorientation Dysarthia Ataxia Anterograde amensia (inability to form new memories) Tolerance – mild Drug dependence – less marked in comparison to Barbiturates.

19. BDZ : Adverse effects There are reports of fetal craniofacial defects when Benzodiazepines used during first trimester of pregnancy. Use of Benzodiazepines near labor may cause hypotonia and hypothermia in newborn baby. The new born baby may be unresponsive and may develop withdrawal syndrome.

20. BDZ : Drug interaction Benzodiazepines potentiate CNS depressant effect of Alcohol and other CNS depression drugs. Aminophylline reduces effect of Benzodiazepines. Antacid reduce absorption of Benzodiazepines. INH, Clarithromycin potentiate the effect of BDZ.

21. BDZ - ANTAGONIST FLUMAZENIL Specific antagonist at BZ 1 and BZ 2 receptors. Does not antagonize the effect of Alcohol, Barbiturates, Opioids and General anaesthetics . It is used in overdose toxicity / reverse the effect of Benzodiazepines. Dose: 0.2 – 1 mg every minute till improvement to the total dose 5 mg.

22. FLUMAZENIL The drug has been tried in Hepatic encephalopathy. (Transient improvement in mental status in 30% cases) Drug should not be used in preexisting seizure disorder, Benzodiazepine addicts and in overdose toxicity of Tricyclic antidepressant. (risk of seizure)

23. BENZODIAZEPINES : Therapeutic uses Insomnia Anxiety disorder Characterized by apprehension, worry, irritability, inability to concentrate, hypervigilance and insomnia. Tachycardia, Hypertension, Headache and Hyperacidity may be present. Benzodiazepines commonly used in anxiety disorder Daily Dose in mg Diazepam 5 – 30 Lorazepam 1 – 4 Oxazepam 10 – 60 Clonazepam 1 – 10 Chlodiazepoxide 10 – 100 Alprazolam 0.5 – 4

24. BDZ : Indications Epilepsy and other convulsive disorders Clonazepam is used in petitmal epilepsy (absences) in the dose 0.04 - 0.2 mg/kg BW in two divided dose. However, tolerance develops in three months. Clobazam is used in refectory epilepsy. Lorazepam (4 mg) or Diazepam (10 mg) is used I/V (at a rate 2 mg/min.) in status epileptics and if convulsions are not controlled then repeated after 10 minutes. Phenytoin or Fosphenytoin is administered simultaneously. Midazolam as I/V infusion has been tried in refractory cases of status epilepticus . Diazepam ( per rectum) is used to prevent febrile convulsions.

25. BDZ : Indications 4. As Myorelaxant – In conditions like Tetanus Strychnine poisoning Prior to ECT Upper motor neuron spasticity (multiple sclerosis, cerebral palsy etc.) 5. In preanaesthetic medication 6. For short surgical or diagnostic procedures - Short acting like Midazolam is used. 7. Endogenous depression – Alprazolam is used in dose 0.5 – 6 mg/day. 8. Acute attack of mania– Clonazepam is used in dose 1 – 2 mg 4-6 hrly .

26. BDZ : Indications 9. Alcohol withdrawal syndrome Drugs like Diazepam, Oxazepam and Chlodiazepoxide have been tried. 10. Barbiturate dependence Benzodiazepines have been tried as substitution therapy because of their low addiction potential. 11. Anticipatory vomiting – When chemotherapy in cancer patient is started for first time, the patient develops severe vomiting due to cytotoxic drugs. When chemotherapy is planned for second dose / subsequent doses, the patient starts vomiting even before the administration of drug. This is the vomiting of psychic origin and may respond to prior use of Benzodiazepines.

27. BENZODIAZEPINES Midazolam + Hydromorphone combination is used for judicial execution in USA. Flunitrazepam is a tasteless BDZ. It is misused because of its sedative and amnestic property (which obliterates memory of events) like in sexual assault (date rape) and theft during journey.

28. Normal person spends one third of his life in sleep. Adult needs 7 hrs sleep for optimum health. While falling asleep one passes through stage 1, 2, 3, 4 NREM sleep followed by REM sleep. REM sleep constitute 20-25% of total sleep. Slow wave sleep (stage 3 & 4 of NREM) is important for physical restorative process while REM sleep aid in consolidation of memory. Sleep

29. I nability to fall or stay asleep. Reduction in total sleep time. Frequent awakening. Disturbed sleep by nightmares. Sleep does not refresh. Early morning awakening. Insomnia

30. Inadequate sleep leads to decreased day time functioning, fatigue, irritability, malaise and lowered mood. Insomnia is associated with enhanced risk of Diabetes mellitus, obesity, metabolic syndrome, atherosclerosis, cognitive impairment, cardiac disease, impaired immune response, Alzheimer’s disease and stroke. Sleep loss can heighten pain perception. An unmet public health problem. Insomnia

31. Revolves around two issues – Pharmacological versus nonpharmacological measures. Use of short acting versus long acting hypnotic drug Management of Insomnia

32. Non-pharmacological measures are the mainstay in treatment of insomnia. Management of Insomnia

33. Non-pharmacological measures Day time activity is to be increased (this may increase stage 4 NREM sleep). Sleep restriction therapy – sleep 30-60 minutes less than usual duration.

34. Non-pharmacological measures (Stimulus Control Therapy) Avoid day time naps. Go to bed only when feeling sleepy. Bed should be used only for sleep and not for eating, reading and watching television. Avoid sleep distracters (TV, Computer, Radio, Smartphone, Videogames, thinking about anything which is stressful – problems with relationship/work).

35. Non-pharmacological measures (Stimulus Control Therapy) If cannot fall asleep in 20 minutes, get out of bed and read or listen music in dim light and return to bed only when feel sleepy. Observe regular bed time and wake time. Get up at same time in morning regardless of amount of sleep in night. Avoid vigorous exercise 2-3 hour before sleep. 30 minutes before bed time person must have relaxing routine like warm bath, listening music, meditation etc.

36. Non-pharmacological measures Setting of bedroom should be comfortable and temperature room should be kept on cooler side. Avoid Tea, Coffee, Alcohol & Tobacco in evening hours. Elderly should restrict fluids in evening hours to decrease Nocturia . A glass of warm milk may be helpful as Tryptophan present in milk quickens the onset of sleep.

37. Non-pharmacological measures Relaxation Exercises, Yoga and Meditation will also help in management of insomnia.

38. Transient Insomnia Insomnia lasts for < 3 days. It is caused by unusual pattern of work, Jet-leg, new place, overnight train journey and in shift workers. Short acting hypnotic drug is used for 2-3 days.

39. Short Term Insomnia Insomnia lasts for 3 days to 3 weeks. It is caused by personal stressful situation like grief, illness and job problems. Long acting hypnotic drug is used 2-4 times a week for not more than 3 weeks. Skip the dose after 1-2 night of good sleep.

40. Long Term Insomnia Insomnia lasting for > 3 weeks. It is due to underline disease or personality disorder. Long acting hypnotic drug every 3rd night for 3-6 months and then gradually discontinued.

41. Benzodiazepines Facilitates GABAergic transmission in brain. Decrease sleep latency. Increase total sleep time. Decrease number of awakenings . Produces refreshing sleep. Effective in sleep terror.

42. Drugs Hypnotic Dose (in mg.) Triazolam * 0.125 – 0.25 Temazepam * 15 – 30 Quazepam ** 7.5 –15 Flurazepam ** 15 – 30 Estazolam ** 1 – 2 Nitrazepam ** 5 – 10 Lorazepam ** 0.5 Benzodiazepines * Short acting - Onset of action is quick . Preferred in Transient insomnia. ** Long acting – Preferred in short term, long term insomnia and day time anxiety.

43. Benzodiazepines Short acting drugs may cause morning insomnia and anxiety. Long acting drugs may cause day time cognitive impairment, hangover and amnesia. Dose is to be reduced in elderly patients. Dose should be tapered if used for >2 wks. Rebound insomnia on discontinuation of therapy . Significant risk of tolerance and dependence.

44. Benzodiazepines Benzodiazepines are effective in sleep terror – a disorder of arousal from slow wave sleep Benzodiazepines are not used in sleep apnea because these drugs may decrease the upper airway muscle tone while decreasing the arousal response to hypoxia.

45. Z – Drugs Drugs Hypnotic Dose (in mg.) Zolpidem * (O) 5 – 10 (S/L) 3.5 man, 1.75 woman Zaleplon ** 5 –10 Zopiclone 7.5 Eszopiclone * 2 – 3 * Long acting. Reduce sleep latency and increase total sleep time. Preferred in all the types of insomnia. * * Short acting. Reduce sleep latency only. Preferred in mid of the night awakening with difficulty in falling back to sleep

46. Z - Drugs No Anticonvulsant and Myorelaxant effect. No significant problem of: - Day time sedation and amnesia. - Respiratory depression. - Rebound insomnia on discontinuation. - Tolerance and dependence. Suppress REM sleep less than BDZ.

47. Z - Drugs Late night administration of Zolpidam may cause morning sedation, delayed reaction time and anterograde amnesia and therefore exercise caution while use in elderly. Zolpidem in hypnotic dose increases hypoxia and hypercarbia .

48. Melatonin Agonists Drugs Hypnotic Dose (in mg.) Melatonin 3 Ramelteon 8 Tasimelteon 20 Melatonin is released from pineal gland during darkness (starts increasing in evening). Melatonin interact with MT 1 receptor and promotes onset of sleep and by binding the M 2 receptor shifts the timing of circadian system.

49. Melatonin Agonists Metatonin is used to manage insomnia in jet leg, shift change worker Ramelteon – MT 1 and MT 2 agonists. More efficacious than Melatonin but less efficacious than BDZ it is used in transient and chronic insomnia. There is no risk of tolerance, abuse liability and rebound insomnia on withdrawal.

50. Tasimelteon Tasimelteon – it is a selective agonist at MT 1 and MT 2 receptors. It is used for treatment of non-24 hrs sleep wake syndrome in totally blind patient experiencing circadian rhythm disorder. Later on the use is extended to non blind persons also. Tasimelteon is also used to manage sleep disturbances in Smith- magenis syndrome which is a rare neuro -developmental disorder involving reversed circadian rhythm that makes nighttime sleep difficult. On discontinuation of Tasimelteon , the sleep pattern returns to baseline in one month.

51. Orexin receptor antagonist Orexin neuropeptide – released from hypothalamus and promote wakefulness. Suvorexant – Orexin receptor antagonist is used in dose of 10-20 mg 30 min before bed time. Do not produce anterograde amnesia which is seen with BDZ and Z compounds. There is a risk of day time somnolence and worsening of depression or suicidal ideation.

52. Orexin receptor antagonist Lemborexant is used in the dose of 2.5-10 mg for management of insomnia with minimal next morning drowsiness. Moderate risk of drug dependence is found with Orexin receptor antagonist. These are expensive drugs.

53. Insomnia Clinical condition Preferred Drug Restless leg syndrome Gabapentine Insomnia during pregnancy Diphenhydramine , Doxylamine Depression with insomnia Trazodone , Amitriptyline , Doxepin , Mirtazepine Insomnia due to pain Analgesic drug (may not required sedative hypnotic drug) Depressed patient responding to SSRIs but having insomnia Trazodone (evening dose)

54. Non-pharmacological measures are the mainstay in treatment of insomnia. Treat the underlying cause of insomnia – Asthma, COPD, GERD, Painful condition, Dementia, Parkinsonism, Menopause, Cystic fibrosis. Weigh the side effect of hypnotic drugs against the sequelae of chronic insomnia which includes 4 fold increase in serious accidents. On treatment patient feel more energetic, less day time fatigue, improved cognition and may improve comorbid condition. Insomnia

55. Medication for insomnia may cause injurious fall and confusion in elderly and therefore, drug is prescribed in lowest effective dose. Morning sedation may interfere with driving and judgment. Insomnia

56. With BDZ there is a risk of abuse. Hypnotic drugs will worsen sleep apnea. High dose of hypnotic may cause sleep walking and sleep eating. Insomnia

57. Is a common problem encountered by family physician. Non pharmacological measures remain mainstay in the management. Pharmacotherapy is started when insomnia is severe, disabling and subjecting the individual to extreme distress. Long term use of hypnotic drug is irrational and hazardous. Insomnia

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59. Thanks for kind attention