EFFECT OF ROUTE OF
ADMINISTRATION ON XENOBIOTIC
DISPOSITION AND ACTION
70
% exhibiting 60
50
desired
effect
40
30
20
10
0
20 40 60 90
oral
im, thigh Time (min)
im, buttock
Influence of route of administration on the clinical action of diazepam.
Data from Assaf et al. Anaesthesia 30:152-158, 1975 . 1
2
From: http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=128
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
3
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.
4
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) 22.6 27.5
Mean AUC (mg/hr/L) 78 110
5
From: Kauffman R et al. J Pediatr 99:963, 1981.
I. PARENTERAL
A. Intravenous
B. Intra-arterial
C. Intramuscular
Injection sites for IM
administration
From: Fundamentals of Nursing, 4th edition,
Lippincoitt, Williams & Wilkins
6
Advantages: •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
7
Reproduced from: Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rd
edition, 1994, p. 39.
8
Blood concentration of chlordiazepoxide after oral () or intramuscular (o)
administration of 50 mg. Reproduced from Greenblatt DJ, et al. NEJM
29:1116-1118, 1974.
9
Plasma phenytoin concentrations in patients during
oral and IM administration
Phenytoin Concentration oral IM oral
(mcg/mL)
20 40 60
Days
10
Redrawn from: Wilder et al. Clin Pharmacol Ther 16:507-513, 1974.
Deltoid Vastus Lateralis
18
16
14
12
VEBs/min
10
8
6
4
2
0
0 2 4 6
TIME(hr)
Effect of administration site on lidocaine suppression
of arrhythmias after intramuscular injection. Data from:
Swartz et al. Clin Pharmacol Ther 14:77, 1974. 11
Peak plasma cephradine concentrations
(mcg/mL) after IM administration to
different sites in male and female subjects
Injection site Males Females
deltoid 11.7 10.2
vastus lateralis 9.8 9.4
gluteus maximus 11.1 4.3
Data from: Vukovich et al. Clin Pharmacol Ther 18:215, 1975. 12
Deltoid Fat Pad Thickness in Men and Women, and
Implications for Needles Length for Immunizations.
Data from: Poland et al JAMA 277:1709-1711, 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 90 kg: 38 mm
13
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 14
Disappearance of I125-insulin from subcutaneous injection
at different sites. Data from Koivisto & Felig, Ann Intern Med 92:59, 1980.
110
100
90
% of initial counts
80
70
60
Abdomen 50
Arm
40
Leg
0 30 60 90 120
Time (minutes)
15
Postprandial rise in plasma glucose after insulin injection at
different sites. Data from: Koivisto & Felig, Ann Intern Med 92:59-61, 1980.
Abdomen Arm Leg
Rise in plasma glucose (mg/dl)
120
100
80
60
40
20
0
0 50 100 150
Time (min)
16
Effect of exposure to a sauna bath on insulin absorption after subcutaneous adminsitration.
From Koivisto VA. Br Med J 280:1411, 1980. 17
Aradigm Intraject®
NFI device in
protein delivery
Reproduced from: http://www.drugdeliverytech.com/cgi-
bin/articles.cgi?idArticle=178 18
Reproduced from: http://www.drugdeliverytech.com/cgi-
bin/articles.cgi?idArticle=178 19
Reproduced from: http://www.drugdeliverytech.com/cgi- 20
bin/articles.cgi?idArticle=178
II. ENTERAL
Reproduced from: Rowland M, Tozer TN.
Clincal Pharmacokinetics – Concepts and
Applications, 3rd edition, Williams & Wilkins,
1995, p. 12.
21
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
22
Effect of varying
volumes of water
on oral drug
absorption
From: Shargel L, Yu ABC.
Applied Biopharmaceutics
and Pharmacokinetics, 4th
edition, 1999, p. 119.
23
24
From: Benet LZ, Cummins CL. The drug-efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 50:S3-S11, 2001.
25
Effect of route of administration on isoproterenol dose response dogs
From: Shargel L, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 4th edition,
26
1999, p. 155.
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
27
Isosorbide concentrations after a 5 mg oral or sublingual dose.
Data from: Assinder et al. J Pharm Sci 66:775, 1977.
14
Isosorbide Conc (ng/ml)
12
10
8
6
Sublingual
4
2
Oral
0
5 15 30 45 60 90 120
Time (min)
28
Effect of buffer pH on the buccal absorption of nicotine
Adapted from: Svensson CK. Clin Pharmacokinet 12:30, 1987.
35
30
% Absorbed
25
20
15
10
5
0
5 5.5 6 6.5 7 7.5 8 9
Buffer pH
29
http://www.novadel.com/
http://www.vitamist.com/
30
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
31
32
From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis
Availability (%) of lidocaine after IV, oral and
rectal administration
Data from: de Boer et al. Clin Pharmacol Ther 26:701-709, 1979.
Subject IV Oral Rectal
1 100 17 59
2 100 49 87
3 100 53 80
4 100 13 31
5 100 35 100
6 100 37 59
100 34 71
33
34
From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis
III. PULMONARY
Pharmacologic Agents Administered
via Inhalation
For Systemic Effects For Local Effect
pentamidine beclomethasone
halothane terbutaline
ergotamine cromolyn
methoxyflurane metaproterenol
enflurane albuterol
isoflurane pirbuterol
nitrous oxide
35
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
36
Reproduced from: Pliss et al. Ann Emerg Med 10:353-355, 1981. 37
Forms of pulmonary delivery
• Metered dose inhaler
• Dry powder inhalers
• Nebulizer
38
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
typical MDI
• Flavoring agent (e.g., menthol)
39
Techniques for use of MDI devices:
Two finger width Use of space or Placement of
from mouth holding chamber inhaler in mouth
(not for use with
Patient must steroids)
coordinate
inhalation and
actuation of
device
40
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)
41
Diskus
42
Nebulizer
• Device produces small droplets from a
suspension or solution through an air jet
or ultrasonic atomization (quieter, but
more expensive)
43
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
44
45
From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis
46
From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis
IV. TOPICAL
A. Percutaneous
47
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
48
Reproduced from: Brown L, Langer R. Ann Rev Med 39:221-229, 1988.
49
Factors that influence
percutaneous absorption
• Site of application
• Condition of skin
• Hydration of skin
• Temperature
• Vehicle
50
Effect of Nitroglycerin on Systolic Blood Pressure When
Adminisitered Percutaneously at Different Sites
Change in Mean SBP (mmHg)
5
0 Forehead
Chest
-5 0 50 100 150 200
Ankle
-10
-15
Adapted from: Hansen et al. Heart & Lung 8:716-720, 1979
51
30
Plasma Nicotine Concentration (ng/ml)
25 C o n tro l
S a u n a b a th
20
15
10
5
S a u n a b a th
0
0 1 2 3
T im e (h o u r s)
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.
52
B. Ocular
From: Fundamentals of Nursing, 4th edition, Lippincoitt, Williams & Wilkins 53
Types of Ophthalmic
Preparations
• Solutions
• Suspensions
• Ointments
• Inserts
• Intraocular solutions
54
Factors that influence ocular drug
retention
• Technique of application
55
Factors that influence ocular drug
retention
• Technique of application
• Drop size (volume)
• Formulation (tonicity, viscosity)
• pH of solution
56
Effect of drop size on effect and systemic
availability of phenylephrine in infants
Pupillary diameter, mm
5
Systemic (plasma)
concentration range
4
(ng/mL)
3
8 uL: 0 – 1.8
2
30 uL: 0.6 – 3.2
1
0
8 uL 30 uL
Phenylephrine 2.5% drop size
From: Lynch et al. Arch Ophthamol 105:1364, 1987) 57
Systemic Absorption of Timolol
1 hour after instillation
1.5
Timolol, ng/ml
1
0.5
0
No NLO NLO Eyelid
Closure
Adapted from Zimmerman et al. Arch Opthamol 102:551, 1984.
58
Reproduced from: Ellis et al. J Pharm Sci 81:219-220, 1992.
59
3
Change in pupillary diameter, mm
2.5
2
1.5
1
0.5
0
A B C
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
60
From: Shell JW. Surv Ophthamol 26:207, 1982
Aqueous humor concentration of
fluorometholone following
various preparations
Steroid Concentration (mg/ml)
0.1
0.01
0.05 mL Saturated Solution
0.05 mL 0.1% suspension
50 mg dose of ointment
0.001
100 200 300 400
Time, min
From: Sieg JW, Robinson JR. J Pharm Sci 64:931, 1975
61
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
62
(nicotine)
Intranasal naloxone
administration in
the field by
paramedics
Mucosal Atomizer Device
63
From: www.ofmaa.org
180
160
Nicotine Concentration (nmole/ml)
140
120
100 C ig a r e tte
N a s a l S o lu tio n
80 C h e w in g G u m
60
40
20
0
0 10 20 30 40 50 60
T im e (m in u te s )
N a s a l s o l'n
N ic o tin e g u m
C ig a r e tte
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
64
Factors that influence absorption
from the nasal mucosa
• pH
• Concentration
• Molecular weight
• Formulation
• Condition of nasal mucosa
65
66
From: Washington N, Washington C, Wilson CG. Physiological Pharmaceutics, 2nd edition, 2001, Taylor & Francis
Reproduced from: Lunell E, et al. Eur J Clin Pharmacol 48:71, 1995. 67
Nasal to brain delivery of drugs
68
Figure from: http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=61
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69