Influence of Route of Administration on Diazepam Action

1. 1 EFFECT OF ROUTE OF ADMINISTRATION ON XENOBIOTIC DISPOSITION AND ACTION EFFECT OF ROUTE OF ADMINISTRATION ON XENOBIOTIC DISPOSITION AND ACTION Influence of route of administration on the clinical action of diazepam. Data from Assaf et al. Anaesthesia 30:152-158, 1975 .

2. 2 From: http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=128

3. 3 A. Intravenous Advantages Advantages : rapid achievement of concentration rapid achievement of concentration precise delivery of dosage precise delivery of dosage easy to titrate dose easy to titrate dose Disadvantages Disadvantages : high initial concentration - toxicity high initial concentration - toxicity invasive - risk of infection invasive - risk of infection requires a certain level of skill requires a certain level of skill I. PARENTERAL I. PARENTERAL

4. 4 There are some preparations that, due to poor solubility of the drug, contain solvents that may produce rate-related toxicity. For example, diazepam injection USP contains 40% propylene glycol, among other solvents. Injected rapidly, diazepam may induce hypotension or arrhythmias. For this reason, it is recommended that IV injections of diazepam be given no more rapidly than 1 mL/min. There are some preparations that, due to poor solubility of the drug, contain solvents that may produce rate-related toxicity. For example, diazepam injection USP contains 40% propylene glycol, among other solvents. Injected rapidly, diazepam may induce hypotension or arrhythmias. For this reason, it is recommended that IV injections of diazepam be given no more rapidly than 1 mL/min.

5. 5 While it is generally viewed that 100% of drug administered intravenously is bioavailable, prodrug administration via this route may result in less than 100% bioavailability. While it is generally viewed that 100% of drug administered intravenously is bioavailable, prodrug administration via this route may result in less than 100% bioavailability. Drug Bioavailability Drug Bioavailability Chloramphenicol succinate ~70% Chloramphenicol succinate ~70% Dexamethasone phosphate ~90% Dexamethasone phosphate ~90% Dexamethasone sulfate ~40% Dexamethasone sulfate ~40% Prednisolone phosphate ~90% Prednisolone phosphate ~90% Prednisolone phthalate ~50% Prednisolone phthalate ~50% Comparative bioavailability of IV chloramphenicol succinate and oral chloramphencol palmitate Comparative bioavailability of IV chloramphenicol succinate and oral chloramphencol palmitate IV PO IV PO Mean C 90-min (mg/L) 22.6 27.5 Mean C 90-min (mg/L) 22.6 27.5 Mean AUC (mg/hr/L) 78 110 Mean AUC (mg/hr/L) 78 110 From: Kauffman R et al. J Pediatr 99:963, 1981.

6. 6 I. PARENTERAL I. PARENTERAL A. Intravenous A. Intravenous B. Intra-arterial B. Intra-arterial C. Intramuscular C. Intramuscular Injection sites for IM administration From: Fundamentals of Nursing, 4th edition, Lippincoitt, Williams & Wilkins

7. 7 Advantages: Advantages: less skill necessary for administration less skill necessary for administration can be used to administer oily vehicles can be used to administer oily vehicles prompt absorption from aqueous soln prompt absorption from aqueous soln Disadvantages: Disadvantages: painful painful cannot be used in presence of abnormal clotting time cannot be used in presence of abnormal clotting time drug may ppt at the site of administration drug may ppt at the site of administration variability in bioavailability variability in bioavailability Z-track method for IM injections

8. 8

9. 9 Blood concentration of chlordiazepoxide after oral ( ) or intramuscular (o) administration of 50 mg. Reproduced from Greenblatt DJ, et al. NEJM 29:1116-1118, 1974.

10. 10 Days 20 40 60 Phenytoin Concentration (mcg/mL) oral IM oral Redrawn from: Wilder et al. Clin Pharmacol Ther 16:507-513, 1974. Plasma phenytoin concentrations in patients during oral and IM administration

11. 11 Effect of administration site on lidocaine suppression of arrhythmias after intramuscular injection. Data from: Swartz et al. Clin Pharmacol Ther 14:77, 1974.

12. 12 Injection site Injection site deltoid deltoid vastus lateralis vastus lateralis gluteus maximus gluteus maximus Males Males 11.7 11.7 9.8 9.8 11.1 11.1 Females Females 10.2 10.2 9.4 9.4 4.3 4.3 Data from: Vukovich et al. Clin Pharmacol Ther 18:215, 1975. Data from: Vukovich et al. Clin Pharmacol Ther 18:215, 1975. Peak plasma cephradine concentrations (mcg/mL) after IM administration to different sites in male and female subjects Peak plasma cephradine concentrations (mcg/mL) after IM administration to different sites in male and female subjects

13. 13 Deltoid Fat Pad Thickness in Men and Women, and Deltoid Fat Pad Thickness in Men and Women, and Implications for Needles Length for Immunizations. Implications for Needles Length for Immunizations. Data from: Poland et al JAMA 277:1709-1711, 1997. Data from: Poland et al JAMA 277:1709-1711, 1997. Women Men Women Men Deltoid fat pad thickness (mm) 11.7 8.3 Deltoid fat pad thickness (mm) 11.7 8.3 Deltoid skin-fold thickness 34.7 17.2 Deltoid skin-fold thickness 34.7 17.2 Percent in whom a standard Percent in whom a standard 16 mm needle would not reach 16 mm needle would not reach 5 mm into muscle 48.4 17.0 5 mm into muscle 48.4 17.0 Needle length recommendation based on above data: Needle length recommendation based on above data: All men: 25 mm; women <60 kg: 16 mm; women 60-90 kg: 25 mm; All men: 25 mm; women <60 kg: 16 mm; women 60-90 kg: 25 mm; women >90 kg: 38 mm women >90 kg: 38 mm

14. 14 D. Subcutaneous D. Subcutaneous Advantages: Advantages: prompt absorption from aqueous solns prompt absorption from aqueous solns little training necessary little training necessary avoid harsh GI tract environment avoid harsh GI tract environment can be used for suspensions can be used for suspensions Disadvantages: Disadvantages: cannot be used for large volumes cannot be used for large volumes potential pain and tissue damage potential pain and tissue damage variability in absorption from various sites variability in absorption from various sites Sites for SC injection

15. 15 Disappearance of I 125 -insulin from subcutaneous injection Disappearance of I 125 -insulin from subcutaneous injection at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980. at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980.

16. 16 Postprandial rise in plasma glucose after insulin injection at Postprandial rise in plasma glucose after insulin injection at different sites. Data from: Koivisto & Felig, Ann Intern Med 92:59-61, 1980. different sites. Data from: Koivisto & Felig, Ann Intern Med 92:59-61, 1980.

17. 17 Effect of exposure to a sauna bath on insulin absorption after subcutaneous adminsitration. From Koivisto VA. Br Med J 280:1411, 1980.

18. 18 Reproduced from: http://www.drugdeliverytech.com/cgi- bin/articles.cgi?idArticle=178 Aradigm Intraject NFI device in protein delivery

19. 19 Reproduced from: http://www.drugdeliverytech.com/cgi- bin/articles.cgi?idArticle=178

20. 20 Reproduced from: http://www.drugdeliverytech.com/cgi- bin/articles.cgi?idArticle=178

21. 21 Reproduced from: Rowland M, Tozer TN. Clincal Pharmacokinetics Concepts and Applications , 3 rd edition, Williams & Wilkins, 1995, p. 12. Reproduced from: Rowland M, Tozer TN. Clincal Pharmacokinetics Concepts and Applications , 3 rd edition, Williams & Wilkins, 1995, p. 12. II. ENTERAL II. ENTERAL

22. 22 A. ORAL A. ORAL Advantages: Advantages: Convenient (storage, portability, pre-measured dose) Convenient (storage, portability, pre-measured dose) economical economical non-invasive, often safer route non-invasive, often safer route requires no special training requires no special training Disadvantages: Disadvantages: drug delivery is often erratic and incomplete drug delivery is often erratic and incomplete highly dependent upon patient compliance highly dependent upon patient compliance increased sources of drug-drug and drug-nutrient intxns increased sources of drug-drug and drug-nutrient intxns many drugs degrade in GI environment many drugs degrade in GI environment exposes drugs to first-pass effect exposes drugs to first-pass effect

23. 23 Effect of varying volumes of water on oral drug absorption Effect of varying volumes of water on oral drug absorption From: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics , 4 th edition, 1999, p. 119. From: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics , 4 th edition, 1999, p. 119.

24. 24

25. 25 From: Benet LZ, Cummins CL. The drug-efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 50:S3-S11, 2001.

26. 26 Effect of route of administration on isoproterenol dose response dogs Effect of route of administration on isoproterenol dose response dogs From: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics , 4 th edition, 1999, p. 155. From: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics , 4 th edition, 1999, p. 155.

27. 27 B. Sublingual/Buccal B. Sublingual/Buccal Advantages: Advantages: rapid onset rapid onset avoids first-pass effect avoids first-pass effect ability to swallow is not required ability to swallow is not required Disadvantages: Disadvantages: few drugs adequately absorbed few drugs adequately absorbed patients must avoid swallowing patients must avoid swallowing compliance difficult compliance difficult

28. 28 Isosorbide concentrations after a 5 mg oral or sublingual dose. Data from: Assinder et al. J Pharm Sci 66:775, 1977.

29. 29 Effect of buffer pH on the buccal absorption of nicotine Adapted from: Svensson CK. Clin Pharmacokinet 12:30, 1987.

30. 30 http://www.novadel.com/ http://www.vitamist.com/

31. 31 C. Rectal C. Rectal Advantages: Advantages: can be used when patients cannot take oral meds can be used when patients cannot take oral meds good option in pediatric population good option in pediatric population may avoid first-pass metabolism may avoid first-pass metabolism Disadvantages: Disadvantages: absorption from solid dosage forms erratic absorption from solid dosage forms erratic many patients have an aversion to rectal administration many patients have an aversion to rectal administration

32. 32 From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2 nd edition, 2001, Taylor & Francis

33. 33 Availability (%) of lidocaine after IV, oral and rectal administration Availability (%) of lidocaine after IV, oral and rectal administration Data from: de Boer et al. Clin Pharmacol Ther 26:701-709, 1979. Data from: de Boer et al. Clin Pharmacol Ther 26:701-709, 1979. Subject IV Subject IV 1 100 1 100 2 100 2 100 3 100 3 100 4 100 4 100 5 100 5 100 6 100 6 100 100 100 Oral Oral 17 17 49 49 53 53 13 13 35 35 37 37 34 34 Rectal Rectal 59 59 87 87 80 80 31 31 100 100 59 59 71 71

34. 34 From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2 nd edition, 2001, Taylor & Francis

35. 35 Pharmacologic Agents Administered Pharmacologic Agents Administered via Inhalation via Inhalation For Systemic Effects For Systemic Effects pentamidine pentamidine halothane halothane ergotamine ergotamine methoxyflurane methoxyflurane enflurane enflurane isoflurane isoflurane nitrous oxide nitrous oxide For Local Effect For Local Effect beclomethasone beclomethasone terbutaline terbutaline cromolyn cromolyn metaproterenol metaproterenol albuterol albuterol pirbuterol pirbuterol III. PULMONARY III. PULMONARY

36. 36 III. PULMONARY III. PULMONARY Advantages: Advantages: easy to titrate dose easy to titrate dose rapid onset rapid onset for local effect, maximize benefit/minimize side effects for local effect, maximize benefit/minimize side effects Disadvantages: Disadvantages: takes significant degree of coordination takes significant degree of coordination patients with lung disease may be able to inhale adequately patients with lung disease may be able to inhale adequately variability in delivery variability in delivery

37. 37 Reproduced from: Pliss et al. Ann Emerg Med 10:353-355, 1981.

38. 38 Forms of pulmonary delivery Forms of pulmonary delivery Metered dose inhaler Metered dose inhaler Dry powder inhalers Dry powder inhalers Nebulizer Nebulizer

39. 39 Metered Dose Inhaler (MDI) Metered Dose Inhaler (MDI) Propellant based Propellant based Most common delivery system in tx of asthma Most common delivery system in tx of asthma Chlorofluorocarbons vs hydrofluoroalkanes Chlorofluorocarbons vs hydrofluoroalkanes Products contain a surfactant or dispersing agent (e.g., oleic acid) Products contain a surfactant or dispersing agent (e.g., oleic acid) Co-solvent (e.g., ethanol) especially needed with use of HFA Co-solvent (e.g., ethanol) especially needed with use of HFA Flavoring agent (e.g., menthol) Flavoring agent (e.g., menthol) typical MDI typical MDI

40. 40 Techniques for use of MDI devices: Techniques for use of MDI devices: Two finger width Two finger width from mouth from mouth Use of space or Use of space or holding chamber holding chamber Placement of Placement of inhaler in mouth inhaler in mouth (not for use with (not for use with steroids) steroids) Patient must coordinate inhalation and actuation of device Patient must coordinate inhalation and actuation of device

41. 41 Dry Powder Inhalers (DPI) Dry Powder Inhalers (DPI) Breath activated Breath activated Micronized drug particles blended with an excipient (e.g., glucose or lactose) Micronized drug particles blended with an excipient (e.g., glucose or lactose) Physical properties of drug and excipient critical (i.e., particle size, shape, surface morphology, etc) Physical properties of drug and excipient critical (i.e., particle size, shape, surface morphology, etc)

42. 42 Diskus Diskus

43. 43 Nebulizer Nebulizer Device produces small droplets from a suspension or solution through an air jet or ultrasonic atomization (quieter, but more expensive) Device produces small droplets from a suspension or solution through an air jet or ultrasonic atomization (quieter, but more expensive)

44. 44 Factors that influence deposition of particles in the lung Factors that influence deposition of particles in the lung Physicochemical properties Physicochemical properties Formulation Formulation Technique (depth of inspiration, pause prior to exhalation, coordination of inhalation) Technique (depth of inspiration, pause prior to exhalation, coordination of inhalation) Pulmonary disease Pulmonary disease

45. 45 From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis

46. 46 From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis

47. 47 IV. TOPICAL IV. TOPICAL A. Percutaneous A. Percutaneous

48. 48 Advantages : Advantages : when used for local effects, minimize systemic side effects when used for local effects, minimize systemic side effects for systemic use, may mimic IV infusion (i.e., zero-order) for systemic use, may mimic IV infusion (i.e., zero-order) avoid first-pass effect avoid first-pass effect Disadvantages : Disadvantages : cosmetically unappealing cosmetically unappealing may display erratic absorption may display erratic absorption

49. 49 Reproduced from: Brown L, Langer R. Ann Rev Med 39:221-229, 1988.

50. 50 Factors that influence percutaneous absorption Factors that influence percutaneous absorption Site of application Site of application Condition of skin Condition of skin Hydration of skin Hydration of skin Temperature Temperature Vehicle Vehicle

51. 51 Adapted from: Hansen et al. Heart & Lung 8:716-720, 1979

52. 52 Plasma nicotine concentration in subjects wearing nicotine patches exposed (squares) or not exposed (diamonds) to three 10 min sauna bath sessions over 1 hr. Figure adapted from: Vanakoski et al Clin Pharmacol Ther 60:308-315, 1996.

53. 53 B. Ocular B. Ocular From: Fundamentals of Nursing, 4 th edition, Lippincoitt, Williams & Wilkins

54. 54 Types of Ophthalmic Preparations Types of Ophthalmic Preparations Solutions Solutions Suspensions Suspensions Ointments Ointments Inserts Inserts Intraocular solutions Intraocular solutions

55. 55 Factors that influence ocular drug retention Factors that influence ocular drug retention Technique of application Technique of application

56. 56 Factors that influence ocular drug retention Factors that influence ocular drug retention Technique of application Technique of application Drop size (volume) Drop size (volume) Formulation (tonicity, viscosity) Formulation (tonicity, viscosity) pH of solution pH of solution

57. 57 Pupillary diameter, mm Phenylephrine 2.5% drop size From: Lynch et al. Arch Ophthamol 105:1364, 1987) Effect of drop size on effect and systemic availability of phenylephrine in infants Systemic (plasma) concentration range (ng/mL) 8 uL: 0 1.8 30 uL: 0.6 3.2

58. 58 Adapted from Zimmerman et al. Arch Opthamol 102:551, 1984.

59. 59 Reproduced from: Ellis et al. J Pharm Sci 81:219-220, 1992.

60. 60 Change in pupillary diameter, mm Change in pupillary diameter, mm Treatments: A 25 L pilocarpine B 25 L pilocarpine followed 2-min later by saline drop C 25 L pilocarpine followed 30-sec later by saline drop From: Shell JW. Surv Ophthamol 26:207, 1982

61. 61 Aqueous humor concentration of fluorometholone following various preparations From: Sieg JW, Robinson JR. J Pharm Sci 64:931, 1975

62. 62 C. Nasal C. Nasal Historically utilized only for local effects Growing number of compounds administered intranasally that are intended for systemic effects For drugs that are destroyed in the GI environment (or first-pass effect) As an alternative to intravenous administration better safety and patient acceptance Drugs include anticonvulsants (midazolam), narcotic antagonists (naloxone), peptides (calcitonin, insulin), and smoking cessation agents (nicotine)

63. 63 Mucosal Atomizer Device From: www.ofmaa.org Intranasal naloxone administration in the field by paramedics

64. 64 Comparison of nicotine concentrations after administration via smoking, chewing gum, or use of a nasal solution. Redrawn from Russell et al. Br Med J 286:683, 1983

65. 65 Factors that influence absorption from the nasal mucosa pH Concentration Molecular weight Formulation Condition of nasal mucosa

66. 66 From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis

67. 67 Reproduced from: Lunell E, et al. Eur J Clin Pharmacol 48:71, 1995.

68. 68 Figure from: http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=61 Nasal to brain delivery of drugs Nasal to brain delivery of drugs

69. 69 Which route is best? Which route is best? $41.71 $41.71 $143.11 $143.11 $65.55