BENZODIAZEPINEeeeeeeeeeeeeeeeePPT 2.pptx

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1. BENZODIAZEPINE PRESENTER-Dr ANJUL SINGH MODERATOR-Dr ARVIND GUPTA

2. Chemical Structure of Benzodiazepines Derivative of 1,4- benzodiazepines. Benzene ring fused to a 7 membered diazepine ring. Chemical structure- 5-aryl-1,4-benzodiazepine

3. PHARMACOKINETIC ASPECTS Well absorbed orally. High plasma protein binding. High lipid solubility cause many of them to accumulate gradually in body fat. Distribution volumes is big. Metabolic transformation in the microsomal enzyme systems P450(CYP3A4) of the liver. Excreted as glucuronide conjugates in the urine.

4. Site and Structure of Action Site of action is the GABA A receptor Structure of GABA A receptor      Comprised of 5 subunits      2 α subunits (to which GABA binds)      2 β subunits (to which barbiturates bind) 1 γ subunit (to which benzodiazepines bind) Benzodiazepines interact with a site located between α and γ subunit of GABA A receptor. γ subunit is required for Benzodiazepins binding. α -1 and α -5 containig receptor for sedation α -2 and α -5 containing receptor for anxiolytic activity.

5. COMMON BENZODIAZIPINES Midazolam Diazepam Lorazepam Oxazepam Alprazolam Clonazepam Flurazepam Temazepam &Triazolam

6. Mechanism of Action Benzodiazepines produce pharmacologic effects by facilitating the actions of γ-aminobutyric acid (GABA ), the principal inhibitory neurotransmitter in the CNS. Benzodiazepines do not activate GABA receptors but rather enhance the affinity of the receptors for GABA. An enhanced opening of chloride gating channels results in increased chloride conductance, thus producing hyperpolarization of the postsynaptic cell membrane and rendering postsynaptic neurons more resistant to EXCITATION . This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.

7. Benzodiazepines  Frequency of openings of gabanergic channels. Agonistic action on gaba may account for the sedative-hypnotic and anesthetic properties

8. Benzodiazepines Augment the Effects of GABA GABA is the main inhibitory neurotransmitter in the brain. GABA neurons are inter-neurons. Benzodiazepines augment the effect of GABA. They exert their action only in the presence of GABA – for this reason they are called positive allosteric modulators (PAMs). Benzodiazepines increase the affinity of the receptor for GABA, and thus increase Cl ­- conductance and hyperpolarizing membrane. Therefore, benzodiazepines are indirect agonists of the GABA receptor.

9. Benzodiazepine Properties The effects of benzodiazepines depend on their properties: Half-life Lipid solubility Receptor affinity

10. Lipid solubility Highly lipophilic benzodiazepines such as diazepam 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.

11. 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.

12. Tolerance and Dependence Tolerance to the sedative and euphoric effects are rapid, but nonexistent to anti-anxiety and antipanic effects. Dependence can develop even following only therapeutic dosages.

13. Pharmacological Actions Sedation. Anxiolytic action. Depression of cognitive and psychomotor function. Anterograde amnesia. Anticonvulsant. Spinal cord mediated skeletal muscle relaxation Diazepam relaxes muscle spasticity by presynaptic inhibition in the spinal cord.

14. Indications 1.Anxiety Short term relief (two to four weeks only) of anxiety that is severe, disabling, or causing the patient unacceptable stress. 2.Insomnia Benzodiazepines should be used to treat insomnia only when it is severe, disabling or causing the patient extreme distress. 3.Chronic Muscle Spasm or spasticity. 4.Status epilepticus 5.Febrile Convulsions 6.Hypnotic (sleep inducing) Withdrawal treatment 7.Panic disorder with anxiety.

15. Clinical uses 1.Pre operative medication Midazolam is the most commonly used. oral midazolam syrup (2 mg/mL) is effective for producing sedation and anxiolysis at a dose of 0.25 mg/kg with minimal effects on ventilation and oxygen saturation. 2. Intravenous Sedation 3. Induction of Anesthesia 4. Maintenance of Anesthesia 5. Postoperative Sedation

16. Clinical uses Paradoxical Vocal Cord Motion It is a cause of nonorganic upper airway obstruction and stridor that may manifest postoperatively Midazolam (0.5 to 1 mg IV) may be an effective treatment for the paradoxical vocal cord motion that may manifest postoperatively.

17. CLASSIFICATION LONG ACTING T1/2 1 FLURAZEPAM 50-100 2 Diazepam 30-60 3 Nitrazepam 30 4 Flunitrazepam 15-25 Short Acting Temazepam 8-12 Triazolam 2-3 Midazolam 2

18. MIDAZOLAM Water soluble and no pain on injection pH-dependent ring-opening phenomenon in which the ring remains open at pH values of less than 4, thus maintaining water solubility of drug. The ring closes at pH values of greater than 4, as when the drug is exposed to physiologic pH, thus converting midazolam to a highly lipid-soluble drug

19. It is helpful in preventing emergence delirium after ketamine administration. The amnestic effects of midazolam are more potent than its sedatives effects Analgesia: when given intrathecally or epidurally acts as an intraoperative as well as postoperative analgesia. DOSE- Intrathecal =0.3 to 2 mg Epidural =50 ug/kg Induction= 0.05-0.15mg/kg Maintenance=0.05mg/kg pm Sedation=0.5-1 mg repeated or0.07mg/kg IM.

20. Central Nervous System Decrease in CMRO2 and cerebral blood flow Induction with midazolam does not prevent increases in ICP associated with direct laryngoscopy for tracheal intubation. No neuroprotective activity Potent anticonvulsant effective in the treatment of status epilepticus. Ventilation Dose-dependent decreases in ventilation COPD patients experience greater depression of ventilation. Transient apnea may occur in the presence of opioid. Depress swallowing reflex and decrease upper airway activity.

21. Cardiovascular System Hemodynamic response to endotracheal intubation is not reliably blunted Midazolam used for induction produces a greater decrease in systemic blood pressure and increase in heart rate Cardiac output is not altered

22. Clinical uses Preoperative Medication Most commonly used oral preoperative medication for children. Oral midazolam syrup (2 mg/mL) is effective for producing sedation and anxiolysis at a dose of 0.25 mg/kg. Intravenous Sedation Sedation during regional anesthesia and for brief therapeutic procedures Induction of Anesthesia Although seldom used for this purpose currently, anesthesia can be induced by administration of midazolam, 0.1 to 0.2 mg/kg IV, over 30 to 60 seconds.

23. Maintenance of Anesthesia May be administered to supplement opioids, propofol, and/or inhaled anesthetics during maintenance of anesthesia Postoperative Sedation Long-term IV administration of midazolam (loading dose 0.5-4 mg IV and maintenance dose 1-7 mg/hour IV) to produce sedation in intubated patients.

24. DIAZEPAM Highly lipid soluble slow hepatic extraction and large Volume of distribution results in long elimination half life of diazepam. Insoluble in water, so formulated in propylene glycol or sod. benzoate , which is very irritating and causes pain and thrombophlebitis on injection.

25. LORAZEPAM More potent Slower onset of action Longer duration of action Formation of glucoronide metabolites of lorazepam is not dependent on hepatic microsomal enzymes so metabolism of lorazepam is not influenced by liver disease ,increasing age, or drugs that inhibit P450 enzyme Prolonged duration due to very high receptor affinity. This limits its usefulness in PAM when rapid awakening at the end of surgery is required.

26. Oxazepam Pharmacologically active metabolite of diazepam and is commercially available. Inactivated by conjugation with glucuronic acid. Oral absorption relatively slow. Not useful in treatment of insomnia characterized by difficulty in falling sleep. Alprazolam Significant anxiety reducing effect in patient with primary anxiety and panic attack. Inhibition of adrenocorticotrophic hormone and cortisol secretion may be prominent than other benzodiazepins .

27. Clonazepam Highly lipid soluble and well absorbed orally. Effective in control and prevention of seizures especially myoclonic and infantile spasms. Flurazepam Used exclusively to treat insomnia. Principal metabolite desalkylflurazepam which is pharmacologically active and manifest as day sedation(hangover).

28. ADVERSE DRUG REACTION Side-effects during therapeutic use: Drowsiness, Fatigue, Confusion, Amnesia, Decreased motor coordination, Impairment of cognitive function Tolerance and dependence : After long term use >6 month, Due to induction of hepatic drug- metabolising enzymes. A change at the receptor level.

29. Drug interactions :- Synergistic effects with other CNS depressants Decreased anesthetic requirements Potentiation of ventilatory depressant effects of opioids Reduced analgesic effects of opioids Suppression of the hypothalamic-pituitary adrenal axis Inhibit platelet aggregation

30. Acute toxicity : Benzodiazepines in acute overdose are considerably less dangerous than other sedative-hypnotic drugs. Clinical presentation-prolonged sleep, Without serious depression of respiration or cardiovascular. Effective antagonist- FLUMAZENIL.

31. Management Flumazenil -1,4 imidazobenzodiazepine derative Antagonist of Bdz . Dose- 0.2 mg IV to reverse CNS effect of Bdz , if required, further 0.1mg IV administered at 60 sec intervals. Total doses of 0.5 -1.0 mg IV completely abolish effect of theraputic dose of Bdz . Infusion dose -.1 to .4 mg/ hr T ½= 30 to 60 min Seizures and cardiac arrhythmias may occur following Flumazenil administration when BDZ are taken with TCAs. Flumazenil is not effective against BARBs overdose.

32. Drug Interactions with BDZs BDZ's have additive effects with other CNS depressants (narcotics), alcohol => have a greatly reduced margin of safety. BDZs reduce the effect of antiepileptic drugs. Combination of anxiolytic drugs should be avoided. Concurrent use with antihistaminic and anticholinergic drugs as well as the consumption of alcohol should be avoided. SSRI’s and oral contraceptives decrease metabolism of BDZs.

33. Increased Effects with Alcohol Analgesics (Fentanyl) Antibacterials (Clarithromycin, Isoniazid) Antifungals ( ketokonazole , itraconazole) Antipsycotics Antivirals Muscle relaxants (baclofen) Decreased Effects with Antibacterial (Rifampicin) Probenecid Theophylline Neoquinolone

34. Effects on Pregnancy Benzodiazepines (and their metabolites) can freely cross the placental barrier and accumulate in fetal circulation Administration during the first trimester can result in fetal abnormalities Administration in third trimester (close to the time of birth) can result in fetal dependence, or “floppy-infant syndrome” Benzodiazepines are also excreted in the breast milk. 

35. Caution with Benzodiazepines Reduce dose with: Elderly or debilitated. Acute alcohol intoxication. Acute angle glaucoma. COPD.

36. Thank you