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. From: http://www. drugdeliverytech. com/cgi-bin/articles. cgi

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

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. 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
Mean C90-min (mg/L)
Mean AUC (mg/hr/L)
From: Kauffman R et al. J Pediatr 99:963, 1981.

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

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

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

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

13. Deltoid Fat Pad Thickness in Men and Women, and
Implications for Needles Length for Immunizations.
Data from: Poland et al JAMA 277: , 1997.
Women Men
Deltoid fat pad thickness (mm)
Deltoid skin-fold thickness
Percent in whom a standard
16 mm needle would not reach
5 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. Advantages: Disadvantages: D. Subcutaneous
Sites for SC injection
D. Subcutaneous
Advantages:
prompt absorption from aqueous solns
little training necessary
avoid harsh GI tract environment
can be used for suspensions
Disadvantages:
cannot be used for large volumes
potential pain and tissue damage
variability in absorption from various sites

15. Disappearance of I125-insulin from subcutaneous injection
at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980.

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

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

18. Aradigm Intraject® NFI device in protein delivery
Reproduced from:

19. Reproduced from: http://www. drugdeliverytech. com/cgi-bin/articles

20. Reproduced from: http://www. drugdeliverytech. com/cgi-bin/articles

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

41. Dry Powder Inhalers (DPI)
Breath activated
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)

42. Diskus

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

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

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

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

47. IV. TOPICAL
A. Percutaneous

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

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

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

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

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

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

55. Factors that influence ocular drug retention
Technique of application

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

57. Systemic (plasma) concentration range (ng/mL)
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
Pupillary diameter, mm
Phenylephrine 2.5% drop size
From: Lynch et al. Arch Ophthamol 105:1364, 1987)

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

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

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

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

62. Historically utilized only for local effects
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. Intranasal naloxone administration in the field by paramedics
Mucosal Atomizer Device
From:

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

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

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

68. Nasal to brain delivery of drugs
Figure from:

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