Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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3. Midazolam 3.2 Pharmacologic effects, metabolism and elimination 2 The pharmacologic effects of midazolam, an imidazobenzodiazepine, are basically the classic effects of all benzodiazepines. Midazolam has sedative and sleep-inducing effects of pronounced intensity. It also exerts anxiolytic, anticonvulsant, and muscle-relaxant effects. Anterograde amnesia 3 of short duration is reported, especially for administrations providing fast rising plasma concentrations (e.g., i.v. or i.m. injection). Midazolam stands out against the other benzodiazepines because of its rapid onset of clinical effects and shorter duration of action because of fast metabolic transformation as well as low activity and short half-life of the main active metabolite (αhydroxymidazolam). The pharmacologic effects of benzodiazepines results from a reversible interaction with the gamma-amino butyric acid (GABA) receptor. GABA is the major inhibitory neurotransmitter in the central nervous system. The benzodiazepine receptor antagonist, flumazenil, readily reverses the action of midazolam. Midazolam is mainly metabolized by CYP 3A4 isoenzyme to major metabolite α-hydroxymidazolam, see Figure 3-2. The unconjugated metabolite α- hydroxymidazolam is pharmacologically active, and contributes about 10% to the pharmacological effect of midazolam. The glucuroconjugated α-hydroxymidazolam is excreted in urine (60-80% of injected midazolam). Less than 1% of the injected midazolam dose is recovered in urine as unchanged drug. The terminal elimination halflife of α-hydroxymidazolam is about 1 hour. Due to the almost exclusive metabolism mediated by CYP3A4 isoenzyme, especially co-administration of CYP3A4 inhibitors and inducers result in pharmacokinetic interactions. Because of changed pharmacokinetics resulting in prolonged elimination half-life, in neonates, children, elderly, obese, patients with hepatic or renal impairment, critically ill patients, and patients with cardiac insufficiency, midazolam application is to be performed with caution. glucuronide midazolam 4-hydroxymidazolam α-hydroxymidazolam α-4-hydroxymidazolam glucuronide glucuronide Figure 3-2: Metabolism of midazolam. CYP 3A4 metabolizes midazolam to the main metabolite α- hydroxymidazolam, 4-hydroxymidazolam, and to α-4-hydroxymidazolam. All metabolites are urinary excreted as glucuronides. 2 [Documed 2006] 3 The patient does not remember events that occurred during the maximal activity of the compound. Katja Suter-Zimmermann Page 24 of 188 University of Basel, 2008
3. Midazolam 3.2.1 Indications and doses The short-acting and sleep-inducing properties of midazolam facilitate the use of midazolam for different therapeutic indications. The Committee for Proprietary Medical Products (CPMP) of the EMEA summarizes the indications and doses of midazolam as displayed in Table 3-1. Table 3-1: Therapeutic indication and dosage of midazolam, published by the Committee for Proprietary Medical Products (CPMP) of the EMEA Adults Indication Children < 60 years ≥ 60 years / debilitated or chronically ill Conscious sedation before and during diagnostic or therapeutic procedures with or without local anesthesia Anesthesia premedication 6 months to 5 years (i.v.) - initial: 0.05-0.1 mg/kg - total: < 6 mg 6 to 12 years (i.v.) - initial: 0.025-0.05 mg/kg - total: 6 months (rectal) - 0.3-0.5 mg/kg 1-15 years (i.m.) - 0.05-0.15 mg/kg >6 months (rectal) - 0.3-0.5 mg/kg 1-15 years (i.m.) - 0.08-0.2 mg/kg i.v. - initial: 2-2.5 mg - titration: 1 mg - total:
Page 1: TRANSMUCOSAL NASAL DRUG DELIVERY Sy
Page 5 and 6: Acknowledgments At the Hospital Pha
Page 7: Index EXPERIMENTAL SECTION 5 Projec
Page 11 and 12: Summary Summary Transmucosal nasal
Page 13: Summary Project III: In this random
Page 17: THEORETICAL SECTION
Page 20 and 21: 1. Nasal drug delivery 1.2 Transmuc
Page 22 and 23: 1. Nasal drug delivery 1.3 Challeng
Page 25 and 26: 2. Impact of anatomy and physiology
Page 31: 3. Midazolam 3 Midazolam 3.1 Physic
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Page 39 and 40: 4. Compounding of nasal midazolam p
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6. Project II: Pharmacokinetic of t
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7. Project III: Transmucosal nasal
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8 Overall discussion pharmacokineti
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8 Overall discussion considered as
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Appendix
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10 Appendix 10.2 Project I 10.2.1 R
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10 Appendix 10.2.4 Specification: M
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10 Appendix 10.2.6 Specification: C
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10 Appendix Katja Suter-Zimmermann
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10 Appendix 10.2.9 Specification: C
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10 Appendix 10.3.2 Case report form
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10 Appendix Frequency 10.3.5 Intens
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10 Appendix 10.3.7 Serumconcentrati
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10 Appendix Identification midazola
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10 Appendix 10.3.8 Midazolam serum
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10 Appendix 10.3.10 Nasal delivery
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10 Appendix 10.4.3 Flowchart: multi
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11 References 11 References Abrams,
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11 References Erjefalt, J.S., I. Er
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11 References Irie, T. and K. Uekam
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11 References Malinovsky, J.M., C.
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11 References Scheepers, M., B. Sch
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12 Curriculum vitae 12 Curriculum v
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