Benzodiazepine poisoning

Benzodiazepine

1. Benzodiazepine poisoning dR.vivek benjamin,md

2. Benzodiazepines  ( BZD ,  BDZ ,  BZs ), sometimes called " benzos ", are a class of  psychoactive drugs  whose core chemical structure is the fusion of a  benzene  ring and a  diazepine  ring. The first such drug,  chlordiazepoxide  (Librium), was  discovered accidentally  by  Leo Sternbach  in 1955, and made available in 1960 by  Hoffmann–La Roche ,. In 1977 benzodiazepines were globally the most prescribed medications. They are in the family of drugs commonly known as  minor tranquilizers . HISTORY

3. TYPES Benzodiazepines Hypnotic Antianxiety Anticonvulsant Diazepam Diazepam Diazepam Flurazepam Chlordiazepoxide Lorazepam Nitrazepam Oxazepam Clonazepam Alprazolam Lorazepam Clobazam Temazepam Alprazolam Triazolam

4. The Interest in Benzodiazepines Increased over the Past Decade SELECTIVITY: For different GABA neurons For different receptor subtypes For the tonic GABA firing

5. ANXIOLYTIC EFFECT: Benzodiazepines inhibit the activation of amygdala , by binding at GABA- A receptors in the amygdala . HYPNOTIC EFFECT : Benzodiazepines promote sleep by binding at GABA-A receptors in the VLPO , causing sleepiness. Traumatic memories stored in the hippocampus can activate the amygdala, causing the amygdala in turn to activate the hippocampus and generate a fear response, REEXPERIENCING (PTSD).

6. Hypnotic Effect of Benzodiazepines Benzodiazepines are also hypnotic drugs. The hypothalamus contains the sleep and wakefulness promoters: VLPO (sleep promoter) TMN (wakefulness promoter).

7. Tuberomammilary Nucleus (TMN) of Hypothalamus is the Wakefulness Promoter (the coffee- house of the brain) TMN of hypothalamus contains histamine producing neurons that are activated by glutamate and inhibited by GABA and Benzodiazepines. These neurons are the wakefulness promoter. *Lateral hypothalamus contains orexin/hypocretin neurons that promote weight loss in addition to wakefulness .

8. Ventro-Lateral Preoptic Nucleus of the Hypothalamus(VLPO) - the Sleep Promoter VLPO nucleus contains GABA neurons that inhibit TMN and thus promote sleep. Benzodiazepines augment the action of GABA in VLPO nucleus.

9. The Balance of Sleep and Wakefulness TM N SCN V L PO INTERNAL CLOCK: Suprachiasmatic nucleus of the hypothalamus – THE SWITCH (activated by light, melatonin). It can promote either sleep or wakefulness. WAKE PROMOTER : Tuberomammillary nucleus –TMN-of the hypothalamus promotes wakefulness( produces histamine ) SLEEP P R O M O T E R: Ventrolateral preoptic area – VLPO-of the hypothalamus promotes sleep (produces GABA )

10. Benzodiazepines – FDA Indications In addition to anxiety, benzodiazepines are indicated for muscle tension, insomnia, status epilepticus(diazepam), myoclonic epilepsy(clonazepam), preoperative anesthesia, and alcohol witdhrawal. Two benzodiazepines: alprazolam and lorazepam have FDA indication for anxiety associated with depression. Clonazepam and Alprazolam are indicated in the treatment of panic disorder .

11. Benzodiazepines – Adverse Effects Sedation Lethargy Dependency/Withdrawal Respiratory depression Possible cognitive impairment. Safe in overdose: up to 30 times the normal daily dose. Usual symptoms of overdose include sedation, drowsiness, ataxia, and slurred speech. May result in respiratory depression in combination with other CNS depressants. Management includes gastric lavage, forced emesis, and assisted ventilation. Drug interactions: drugs that increase benzodiazepine levels include P4503A4 inhibitors, ketoconazole, fluconazole, nefazodone. drugs that decrease benzodiazepine levels include P4503A4 inducers such as carbamazepine.

12. Benzodiazepines - Subclasses keto (chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, prazepam, and flurazepam). The 2-keto drugs and their active metabolites are oxidized in the liver, and because this process is relatively slow, these compounds have relatively long half-lives. hydroxy (lorazepam, oxazepam, temazepam) The 3-hydroxy compounds are metabolized via direct conjugation with a glucuronide radical, a process that is more rapid than oxidation and does not involve the formation of active metabolites . Triazolo (alprazolam, adinazolam, estazolam, and triazolam) The triazolo compounds are also oxidized, however they have a more limited active metabolites and thus shorter half-lives.

13. Benzodiazepine Properties The effects of benzodiazepines depend on their properties: 1. half-life 2. liposolubility 3. receptor affinity

14. Five benzodiazepines are FDA approved for insomnia are : flurazepam and quazepam, (ultra-long half-lives); triazolam (ultra-short half-life) estazolam and temazepam (moderate half-lives). FDA Approved Benzodoazepine Hypnotics

15. Liposolubility Hi g h l y li p o p hil i c ben z od i a z ep i ne s such as dia z epam enter the brain more quickly, “turning on” the effect promptly, but “turning off” the effect more quickly as well as they disappear into body fat. Less lipophilic compounds such as lorazepam produce clinical effects more slowly, but may provide more sustained relief in spite of shorter half life.

16. Relative Receptor Affinity The higher their affinity for GABA-A receptors, the more intense withdrawal symptoms they cause. High potency benzodiazepines such as lorazepam and alprazolam have high receptor affinity – intense withdrawal symptoms. Oxazepam has low receptor affinity – fewer withdrawal symptoms.

17. Memory Impairment (fact or myth) Lucki et al. (1986) conducted a study on long-term benzodiazepine treatment. It failed to show significant cognitive impairment on psychometric tests. The most recent controlled study in this area failed to find significant long-term cognitive effects for alprazolam XR in panic disorder patients (Gladsjo et al. 2001). In spite of these studies some investigators believe that cognitive impairment can occur, particularly in elderly patients.

18. Benzodiazepines Might Cause Memory Impairment in Elderly

19. How Addictive are Benzodiazepines? How long does one have to take a benzodiazepine before withdrawal is seen with discontinuation? Studies in animals have indicated that benzodiazepines can reinforce use and can produce physical dependence and tolerance. Available data seem to reveal that benzodiazepines are rarely sought after or craved in the sense that heroin or cocaine are. Rather, they are used as part of a polysubstance abuse pattern to modulate the effects of primary drug of abuse(e.g. cocaine) or as a backup drug when more euphoriant drugs are not available.

20. Benzodiazepines Potentiate the Effect of Alcohol

21. Adverse Effects ■ Weakness, headache, amnesia, vertigo, diplopia, nausea, diarrhoea, and rarely chest pain. ■ Paradoxical effects (disinhibition or dyscontrol reaction) may sometimes occur characterised by restlessness, agitation, and hallucinations. ■ Flurazepam has been associated with nightmares and hallucinations. ■ Allergic, hepatotoxic, and haematological reactions are rare.

22. Clinical (Toxic) Features Benzodiazepines are remarkably safe drugs and rarely produce serious toxic effects even with substantial ingestion. Death is uncommon unless other synergistic drugs have also been ingested. However, newer benzodiazepines such as alprazolam,triazolam , and temazepam are associated with fatalities.

23. Acute Poisoning: a. Mild—Drowsiness, ataxia, weakness. b. Moderate to Severe— – Vertigo, slurred speech, nystagmus, partial ptosis, lethargy, coma. – Hypotension and respiratory depression. – Analysis of acute benzodiazepine overdoses in relation to the incidence of coma indicate that short acting benzodiazepines (midazolam and triazolam) and intermediate acting (flunitrazepam) have a higher acute toxicity, as compared to diazepam, lorazepam and nitrazepam. –memory impairment/ amnesia in a significant number of patients (TRIAZOLAM). Clinical (Toxic) Features

24. – Administration of benzodiazepines to a pregnant woman prior to delivery may produce signs of poisoning in the neonate.A condition called “floppy infant syndrome”, characterised by hypotonia that may last several days, may occur following maternal diazepam use.

25. Chronic Poisoning: Long-term use of benzodiazepines is associated with the development of tolerance. Abrupt cessation provokes a mild withdrawal reaction characterised by anxiety, insomnia,headache,tremor , and paraesthesia . Restlessness, encephalopathy, and hallucinations may occur after abrupt withdrawal from high daily doses. Convulsions may occur after a lapse of 3 to 10 days.

26. Diagnosis Estimation of plasma levels of benzodiazepines is usually not necessary. Qualitative testing for presence of benzodiazepine is helpful to confirm presence, especially when overdose history is sketchy. Quantitative levels are not usually clinically useful. Blisters of skin (bullae) can occur following overdose with nitrazepam, oxazepam, and temazepam.

27. Treatment 1.Monitor CBC, serum electrolytes, glucose, blood urea nitrogen,creatinine , and urine myoglobin in patients with significant intoxication. 2. Gastric lavage (preferably with a large-bore, double-lumen tube), can be done with benefit upto 12 to 24 hours postingestion . 3. Multiple dose activated charcoal has been shown to be effective. 4. Establish clear airway. Oxygen and assisted ventilation are often necessary. 5. IV fluids (Ringer’s lactate at a rate of 150 ml/hr for adults). 6. Correction of hypotension: Begin by infusing 10 to 20 ml/kg of isotonic fluid, and place patient in Trendelenburg position. If hypotension persists, administer dopamine or noradrenaline. Consider central venous pressure monitoring to guide further fluid therapy. 7. Forced diuresis and haemodialysis are ineffective.

28. ■ – Flumazenil is effective in reversing the coma induced by benzodiazepines as well as zolpidem. The mode of action is competitive antagonism. – In practice, most patients achieve complete reversal of benzodiazepine effect with a total slow IV dose of just 1 mg. Some investigators suggest that flumazenil is better administered in a series of smaller doses in an incremental manner beginning with 0.2 mg and progressively increasing by 0.1 to 0.2 mg every minute until a cumulative total dose of 3.5 mg is reached. However, resedation occurs within ½ hour to 2 hours (depending on the nature and dose of benzodiazepine ingested), and therefore patients must be carefully monitored and subsequent doses of flumazenil should be administered as needed. The use of continuous flumazenil maintenance infusion over 5 to 24 hours seems of therapeutic value in the event of resedation after initial response.

29. – Flumazenil has also been reported to reverse cardiovascular depression secondary to benzodiazepine use. – Flumazenil does not reverse respiratory depression very well and hence fundamental procedures such as supplemental oxygen, endotracheal intubation, and ventilation must not be neglected. – Flumazenil is contraindicated in mixed ingestions involving tricyclic antidepressants and drugs which induce seizures, e.g. theophylline, carbamazepine, chloroquine, etc. But there are indications that it may be beneficial in hepatic encephalopathy and ethanol overdose. – Flumazenil may cause the following adverse effects: fatigue, nausea, vomiting, hypertension, tachycardia, anxiety, confusion, restlessness, aggression, and rarely convulsions and cardiac arrhythmias. .

30. Forensic Issues ■ Ever since the introduction of benzodiazepines in the 1960s, they have become progressively more popular as anxiolytic agents and sedatives, displacing the barbiturates from their previously held top spot. In spite of extensive use worldwide, there have been only a few cases reported involving fatalities, demonstrating the wide margin of safety of benzodiazepines. Deaths have been reported in some recent cases even from unexpectedly low doses of certain benzodiazepines. There are also indications that some of the newer benzodiazepines have a slightly smaller margin of safety. This is particularly true with reference to paediatric and geriatric patients who are more susceptible to the toxicity of these drugs.

31. ■ An area of concern with long-term benzodiazepine use is the possibility of behavioural disinhibition which may induce a person to hostile acts, aggressive behaviour, and verbal indecency. ■ Yet another important issue is with reference to the use of benzodiazepines to deliberately induce amnesia in certain individuals in order to accomplish an immoral act (e.g. date rape). Many of these drugs, particularly flunitrazepam, are capable of causing retrograde amnesia. Flunitrazepam (Rohypnol®; “Roofies”) has become popular as a drug of abuse, often combined with alcohol, marijuana, or cocaine to produce an intense “high”. It has been used as a “date rape” drug, both for its properties of lowering inhibitions and because it can cause retrograde amnesia.

32. ■ Severe dysmorphism, malformations, intrauterine and extrauterine growth retardation, and central nervous system dysfunction have been described in infants born of mothers who used benzodiazepines during pregnancy.

33. Case Report: A 37 year old married female, with history of psychiatric problems, Presentation-unconscious state. Alleged history of ingestion of 60 tablets of alprozolam ( Alprax - Rx) tablets 3 hour back, with the intention of suicide. The relatives of the patient showed us all the empty packs, containing the tablets, found near her body. There were about 60, 1mg tablets of alprazolam that had been ingested by her. Further, her relatives gave history that patient had been suffering from panic disorder, since last five years, for which she had been on medication off and on, as advised by a psychiatrist. Her medications included alprazolam and fluoxetine.

34. Off late, she was also under stress, as she could not conceive in last four years of her marriage, and was pursuing infertility treatments, without any success. On general examination mild cyanosis and pallor was present. Patient’s vitals on admission were as follows-- pulse -100/min feeble, blood pressure-80/mm hg systolic, respiratory rate 30/min regular, temperature - 36.8 C. Neurological examination showed deep coma, bilateral constricted pupils , which reacted minimally to light, diminished tendon reflexes and retention of urine, and plantar reflexes were not illicitable bilaterally. There was no response to painful stimuli. Her Glasgow coma scale (GCS) was 3. Respiratory system examination was within normal limits. On cardiovascular system (CVS) examination tachycardia was noted, and ECG showed sinus tachycardia. Routine Biochemical and hematological tests were normal.

35. As suggested by the evidences above, probability diagnosis of alprazolam over dosage was made. Patient was admitted in ICU. A nasogastric tube was placed and catheterization was done. Patient’s gastric lavage returned no pill fragments. She was urgently intubated and kept on mechanical ventilation with continuous oxygen administration and parenteral fluids. Rest of her treatment was symptomatic. Flumazenil, which is the antidote of alprazolam poisoning was used. Patient showed improvement after few hours and was extubated. Patient got recovered and discharged.

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