Benzodiazepines.

1. Benzodiazepines. Florida International University Nurse Anesthetist Program Pharmacology of Anesthesiology Nursing I Linda Wunder MSN,CRNA

2. OBJECTIVES Discuss the principal pharmacologic effects of benzodiazepines. Explain mechanism of action associated with benzodiazepines and their interaction with the CNS. Compare the unique chemical structure of midazolam and how it differs at various pH levels. Discuss the pharmacokinetic properties specific to benzodiazepines. Explain the effects on organ systems of benzodiazepines. State the clinical indications of midazolam and diazepam. Discuss the action and dosing regime of flumazenil.

3. CLINICAL CONSIDERATIONS Benzodiazepines exert five principal pharmacologic effects: Sedation Anxiolysis Anticonvulsant actions Spinal cord-mediated skeletal muscle relaxation Anterograde amnesia Benzodiazepines have replaced barbiturates for preoperative medication and production of sedation during monitored anesthesia care

4. MECHANISM OF ACTION Benzodiazepines interact with specific receptors in the central nervous system Benzodiazepine-receptor binding enhances the inhibitory effects of various neurotransmitters Facilitates GABA receptor binding which increases the membrane conductance of chloride ions Causes a change in membrane polarization that inhibits normal neuronal function Receptor occupancy Receptor subtypes

5. STRUCTURE-ACTIVITY RELATIONSHIPS Benzodiazepines are similar structurally and share many active metabolites Benzodiazepine refers to the portion of the chemical structured composed of a benzene ring fused to a seven-membered diazepine ring Substitutions at various positions on these rings affect potency and biotransformation Benzodiazepines differ markedly in speed that they are metabolized and eliminated

6. CHEMICAL STRUCTUREDIAZEPAM & LORAZEPAM

7. CHEMICAL STRUCTUREMIDAZOLAM

8. PHARMACOKINETICS Absorption: Commonly administered orally, intramuscularly, and intravenously Diazepam and lorazepam are well absorbed from the GI tract, peak plasma levels usually achieved in 1 and 2 hours IM injection of diazepam is painful and unreliable Oral midazolam popular for pediatric premedication Intranasal: (0.2-0.3 mg/Kg) Buccal: (0.07 mg/Kg) Sublingual: (0.1 mg/Kg) Premedication IM: (0.07-0.15 mg/Kg) Sedation IV: (0.01-0.1 mg/Kg)

9. PHARMACOKINETICS Distribution: Diazepam quite lipid-soluble and rapidly penetrates the blood brain barrier Midazolam water-soluble at low pH and at physiologic pH increase in its lipid solubility Moderate lipid solubility of lorazepam Redistribution fairly rapid for the benzodiazepines Benzodiazepines highly protein-bound

10. BIOTRANSFORMATION AND EXCRETION Rely on the liver for biotransformation into water-soluble glucuronide end products Phase I metabolites of diazepam are pharmacologically active Elimination half-life: time necessary to eliminate 50% of a drug from the body after its rapid IV injection Long elimination half-life for diazepam Lorazepam shorter elimination half-life Midazolam shortest elimination half-life Metabolites of benzodiazepine biotransformation are excreted chiefly in the urine

11. EFFECTS ON ORGAN SYSTEMS Cardiovascular: Minimal cardiovascular depressant effects Arterial blood pressure, cardiac output, and peripheral vascular resistance usually decline slightly and heart rate sometimes rises Midazolam tends to reduce blood pressure and peripheral vascular resistance more than diazepam

12. EFFECTS ON ORGAN SYSTEMS Respiratory: Benzodiazepines depress the ventilatory response to CO2 Ventilation must be monitored in all patients receiving IV medications Cerebral: Reduce CMRO2, cerebral blood flow, and intracranial pressure Effective in preventing and controlling grand mal seizures Provides antianxiety, amnesic, and sedative effects Possesses mild muscle-relaxant properties No direct analgesic properties

13. DRUG INTERACTIONS Cimetadine binds to cytochrome P-450 and reduces the metabolism of diazepam Erythromycin inhibits midazolam metabolism and causes prolongation and intensification of its effects Heparin displaces diazepam from protein-binding sites and increases free drug concentration Combination of opioids and diazepam markedly reduces arterial blood pressure and peripheral vascular resistance MAC of volatile anesthetics reduced as much as 30% Ethanol, barbiturates, and other CNS depressants potentiate sedative effects

14. MIDAZOLAM: CLINICAL USES Most commonly used benzodiazepine for preoperative medication and IV sedation Provides amnesia Potent anticonvulsant for the treatment of grand mal seizures Administration: PO: 0.5 mg/Kg IV: 0.01-0.1 mg/Kg IM: 0.05-0.10 mg/Kg Doses of 1.0-2.5 mg IV effective for sedation during regional anesthesia and brief therapeutic procedures Administered as a supplement for maintenance of anesthesia

15. DIAZEPAM: CLINICAL USES Diazepam dissolved in organic solvents and is associated with pain on injection and thrombophlebitis Popular drug for preoperative medication of adults, management of delirium tremens, and treatment of local anesthetic-induced seizures Produces anterograde amnesia Skeletal muscle relaxant Preoperative: PO 10-15 mg Extensively bound to plasma protein

16. FLUMAZENIL An imidazobenzodiazepine, specific and competitive antagonist of benzodiazepines at benzodiazepine receptors Useful in the reversal of sedation and overdose Prompt onset (< 1 minute) Slow titration of 0.2 mg doses IV (up to 1 mg)