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1 EFFECT OF ROUTE OF ADMINISTRATION ON XENOBIOTIC DISPOSITION AND ACTION Influence of route of administration on the clinical action of diazepam. Data.

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Presentation on theme: "1 EFFECT OF ROUTE OF ADMINISTRATION ON XENOBIOTIC DISPOSITION AND ACTION Influence of route of administration on the clinical action of diazepam. Data."— Presentation transcript:

1 1 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: , 1975.

2 2 From:

3 3 A. Intravenous Advantages Advantages: rapid achievement of concentrationrapid achievement of concentration precise delivery of dosageprecise delivery of dosage easy to titrate doseeasy to titrate dose Disadvantages Disadvantages : high initial concentration - toxicityhigh initial concentration - toxicity invasive - risk of infectioninvasive - risk of infection requires a certain level of skillrequires a certain level of skill 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.

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. Drug Bioavailability Chloramphenicol succinate~70% Dexamethasone phosphate~90% Dexamethasone sulfate~40% Prednisolone phosphate~90% Prednisolone phthalate~50% Comparative bioavailability of IV chloramphenicol succinate and oral chloramphencol palmitate IV PO IV PO Mean C 90-min (mg/L) Mean AUC (mg/hr/L) From: Kauffman R et al. J Pediatr 99:963, 1981.

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

7 7 Advantages: less skill necessary for administrationless skill necessary for administration can be used to administer oily vehiclescan be used to administer oily vehicles prompt absorption from aqueous sol’nprompt absorption from aqueous sol’n Disadvantages: painfulpainful cannot be used in presence of abnormal clotting timecannot be used in presence of abnormal clotting time drug may ppt at the site of administrationdrug may ppt at the site of administration variability in bioavailabilityvariability 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: , 1974.

10 10 Days Phenytoin Concentration (mcg/mL) oralIMoral Redrawn from: Wilder et al. Clin Pharmacol Ther 16: , 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 deltoid deltoid vastus lateralis gluteus maximus Males Females Data from: Vukovich et al. Clin Pharmacol Ther 18:215, 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 Implications for Needles Length for Immunizations. Data from: Poland et al JAMA 277: , WomenMen Deltoid fat pad thickness (mm) Deltoid skin-fold thickness Percent in whom a standard 16 mm needle would not reach 16 mm needle would not reach 5 mm into muscle mm into muscle Needle length recommendation based on above data: All men: 25 mm; women <60 kg: 16 mm; women kg: 25 mm; women >90 kg: 38 mm

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

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

16 16 Postprandial rise in plasma glucose after insulin injection at 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: bin/articles.cgi?idArticle=178 Aradigm Intraject® NFI device in protein delivery

19 19 Reproduced from: bin/articles.cgi?idArticle=178

20 20 Reproduced from: 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. II. ENTERAL

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

23 23 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.

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 From: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 4 th edition, 1999, p. 155.

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

31 31 C. Rectal Advantages: can be used when patients cannot take oral medscan be used when patients cannot take oral meds good option in pediatric populationgood option in pediatric population may avoid first-pass metabolismmay avoid first-pass metabolism Disadvantages: absorption from solid dosage forms erraticabsorption from solid dosage forms erratic many patients have an aversion to rectal administrationmany 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 Data from: de Boer et al. Clin Pharmacol Ther 26: , SubjectIV Oral Rectal

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

35 35 Pharmacologic Agents Administered via Inhalation For Systemic Effects pentamidinehalothaneergotaminemethoxyfluraneenfluraneisoflurane nitrous oxide For Local Effect beclomethasoneterbutalinecromolynmetaproterenolalbuterolpirbuterol III. PULMONARY

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

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

38 38 Forms of pulmonary delivery Metered dose inhalerMetered dose inhaler Dry powder inhalersDry powder inhalers NebulizerNebulizer

39 39 Metered Dose Inhaler (MDI) Propellant basedPropellant based Most common delivery system in tx of asthmaMost common delivery system in tx of asthma Chlorofluorocarbons vs hydrofluoroalkanesChlorofluorocarbons 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 HFACo-solvent (e.g., ethanol) – especially needed with use of HFA Flavoring agent (e.g., menthol)Flavoring agent (e.g., menthol) typical MDI

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

41 41 Dry Powder Inhalers (DPI) Breath activatedBreath 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

43 43 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 Physicochemical propertiesPhysicochemical properties FormulationFormulation Technique (depth of inspiration, pause prior to exhalation, coordination of inhalation)Technique (depth of inspiration, pause prior to exhalation, coordination of inhalation) Pulmonary diseasePulmonary 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 A. Percutaneous

48 48 Advantages : when used for local effects, minimize systemic side effectswhen 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 effectavoid first-pass effect Disadvantages : cosmetically unappealingcosmetically unappealing may display erratic absorptionmay display erratic absorption

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

50 50 Factors that influence percutaneous absorption Site of applicationSite of application Condition of skinCondition of skin Hydration of skinHydration of skin TemperatureTemperature VehicleVehicle

51 51 Adapted from: Hansen et al. Heart & Lung 8: , 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: , 1996.

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

54 54 Types of Ophthalmic Preparations SolutionsSolutions SuspensionsSuspensions OintmentsOintments InsertsInserts Intraocular solutionsIntraocular solutions

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

56 56 Factors that influence ocular drug retention Technique of applicationTechnique of application Drop size (volume)Drop size (volume) Formulation (tonicity, viscosity)Formulation (tonicity, viscosity) pH of solutionpH 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 – 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: , 1992.

60 60 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 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: 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: Nasal to brain delivery of drugs

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


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