EFFECT OF ROUTE OF ADMINISTRATION ON XENOBIOTIC DISPOSITION AND ACTION

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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 30152-158, 1975.
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From http//www.drugdeliverytech.com/cgi-bin/arti
cles.cgi?idArticle128
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I. PARENTERAL
A. Intravenous
Advantages

• 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

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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.
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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 De
xamethasone 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) 22.6 27.5 Mean AUC (mg/hr/L)
78 110
From Kauffman R et al. J Pediatr 99963, 1981.
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I. PARENTERAL
A. Intravenous
B. Intra-arterial
C. Intramuscular
Injection sites for IM administration
From Fundamentals of Nursing, 4th edition,
Lippincoitt, Williams Wilkins
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Advantages

• less skill necessary for administration
• can be used to administer oily vehicles
• prompt absorption from aqueous soln

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
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Blood concentration of chlordiazepoxide after
oral (?) or intramuscular (o) administration of
50 mg. Reproduced from Greenblatt DJ, et al.
NEJM 291116-1118, 1974.
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Plasma phenytoin concentrations in patients
during oral and IM administration
oral
IM
oral
Phenytoin Concentration (mcg/mL)
20 40 60
Days
Redrawn from Wilder et al. Clin Pharmacol Ther
16507-513, 1974.
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Effect of administration site on lidocaine
suppression of arrhythmias after intramuscular
injection. Data from Swartz et al. Clin
Pharmacol Ther 1477, 1974.
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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
18215, 1975.
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Deltoid Fat Pad Thickness in Men and Women, and
Implications for Needles Length for
Immunizations. Data from Poland et al JAMA
2771709-1711, 1997.
Women Men Deltoid fat pad thickness (mm)
11.7 8.3 Deltoid skin-fold thickness
34.7 17.2 Percent in whom a standard 16 mm
needle would not reach 5 mm into muscle
48.4 17.0
Needle length recommendation based on above
data All men 25 mm women lt60 kg 16 mm women
60-90 kg 25 mm women gt90 kg 38 mm
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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

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Disappearance of I125-insulin from subcutaneous
injection at different sites. Data from Koivisto
Felig, Ann Intern Med 9259, 1980.
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Postprandial rise in plasma glucose after insulin
injection at different sites. Data from Koivisto
Felig, Ann Intern Med 9259-61, 1980.
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Effect of exposure to a sauna bath on insulin
absorption after subcutaneous adminsitration. From
Koivisto VA. Br Med J 2801411, 1980.
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Aradigm Intraject NFI device in protein delivery
Reproduced from http//www.drugdeliverytech.com/c
gi-bin/articles.cgi?idArticle178
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Reproduced from http//www.drugdeliverytech.com/c
gi-bin/articles.cgi?idArticle178
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Reproduced from http//www.drugdeliverytech.com/c
gi-bin/articles.cgi?idArticle178
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II. ENTERAL
Reproduced from Rowland M, Tozer TN. Clincal
Pharmacokinetics Concepts and Applications, 3rd
edition, Williams Wilkins, 1995, p. 12.
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A. ORAL
Advantages

• 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

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Effect of varying volumes of water on oral drug
absorption
From Shargel L, Yu ABC. Applied Biopharmaceutics
and Pharmacokinetics, 4th edition, 1999, p. 119.
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(No Transcript)
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From Benet LZ, Cummins CL. The
drug-efflux-metabolism alliance biochemical
aspects. Adv Drug Deliv Rev 50S3-S11, 2001.
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Effect of route of administration on
isoproterenol dose response dogs
From Shargel L, Yu ABC. Applied Biopharmaceutics
and Pharmacokinetics, 4th edition, 1999, p. 155.
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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

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Isosorbide concentrations after a 5 mg oral or
sublingual dose. Data from Assinder et al. J
Pharm Sci 66775, 1977.
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Effect of buffer pH on the buccal absorption of
nicotine Adapted from Svensson CK. Clin
Pharmacokinet 1230, 1987.
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http//www.novadel.com/
http//www.vitamist.com/
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C. Rectal
Advantages

• 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

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From Washington N, Washington C, Wilson CG.
Physiological Pharmaceutics, 2nd edition, 2001,
Taylor Francis
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Availability () of lidocaine after IV, oral and
rectal administration Data from de Boer et al.
Clin Pharmacol Ther 26701-709, 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 59 71
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From Washington N, Washington C, Wilson CG.
Physiological Pharmaceutics, 2nd edition, 2001,
Taylor Francis
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III. PULMONARY
Pharmacologic Agents Administered via Inhalation
For Systemic Effects pentamidine halothane ergotam
ine methoxyflurane enflurane isoflurane nitrous
oxide
For Local Effect beclomethasone terbutaline cromol
yn metaproterenol albuterol pirbuterol
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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

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Reproduced from Pliss et al. Ann Emerg Med
10353-355, 1981.
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Forms of pulmonary delivery

• Metered dose inhaler
• Dry powder inhalers
• Nebulizer

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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
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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
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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)

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Diskus
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Nebulizer

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

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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

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From Washington N, Washington C, Wilson CG.
Physiological Pharmaceutics, 2nd edition, 2001,
Taylor Francis
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From Washington N, Washington C, Wilson CG.
Physiological Pharmaceutics, 2nd edition, 2001,
Taylor Francis
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IV. TOPICAL
A. Percutaneous
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Advantages

• 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

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Reproduced from Brown L, Langer R. Ann Rev Med
39221-229, 1988.
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Factors that influence percutaneous absorption

• Site of application
• Condition of skin
• Hydration of skin
• Temperature
• Vehicle

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Adapted from Hansen et al. Heart Lung
8716-720, 1979
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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 60308-315,
1996.
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B. Ocular
From Fundamentals of Nursing, 4th edition,
Lippincoitt, Williams Wilkins
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Types of Ophthalmic Preparations

• Solutions
• Suspensions
• Ointments
• Inserts
• Intraocular solutions

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Factors that influence ocular drug retention

• Technique of application

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Factors that influence ocular drug retention

• Technique of application
• Drop size (volume)
• Formulation (tonicity, viscosity)
• pH of solution

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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 1051364, 1987)
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Adapted from Zimmerman et al. Arch Opthamol
102551, 1984.
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Reproduced from Ellis et al. J Pharm Sci
81219-220, 1992.
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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 26207, 1982
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Aqueous humor concentration of fluorometholone
following various preparations
From Sieg JW, Robinson JR. J Pharm Sci 64931,
1975
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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)
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Intranasal naloxone administration in the field
by paramedics
Mucosal Atomizer Device
From www.ofmaa.org
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Comparison of nicotine concentrations after
administration via smoking, chewing gum, or use
of a nasal solution. Redrawn from Russell et al.
Br Med J 286683, 1983
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Factors that influence absorption from the nasal
mucosa

• pH
• Concentration
• Molecular weight
• Formulation
• Condition of nasal mucosa

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From Washington N, Washington C, Wilson CG.
Physiological Pharmaceutics, 2nd edition, 2001,
Taylor Francis
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Reproduced from Lunell E, et al. Eur J Clin
Pharmacol 4871, 1995.
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Nasal to brain delivery of drugs
Figure from http//www.drugdeliverytech.com/cgi-b
in/articles.cgi?idArticle61
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65.55
Which route is best?
143.11
143.11
41.71