BENZODIAZEPINES PREOPERATIVE MEDICATIONS

1. BENZODIAZEPINESPREOPERATIVE MEDICATIONS DENNIS STEVENS MSN, CRNA, ARNP OCTOBER 2005 FLORIDA INTERNATIONAL UNIVERSITY PHARMACOLOGY OF ANESTHESIOLOGY NURSING NGR 6173

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. REFERENCES Morgan, G.E., Mikhail, M.S., and Murray, M.J. (2002). Clinical Anesthesiology. (3rd Ed.) New York, NY: McGraw-Hill. Nagelhout, J.J. and Zaglaniczny, K.L. (2005). Nurse Anesthesia. (3rd Ed.) St. Louis, MO: Elsevier-Saunders. Stoelting, R.K. (1999). Pharmacology & Physiology in Anesthetic Practice. (3rd Ed.) Philadelphia, PA: J.B. Lippincott Company.

4. 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

5. 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

6. 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

7. CHEMICAL STRUCTUREDIAZEPAM & LORAZEPAM

8. CHEMICAL STRUCTUREMIDAZOLAM

9. 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)

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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)