1

EFFECT OF ROUTE OF EFFECT OF ROUTE OF ADMINISTRATION ON ADMINISTRATION ON

XENOBIOTIC DISPOSITION AND XENOBIOTIC DISPOSITION AND ACTIONACTION

010203040506070

% e

xhib

itin

g de

sire

d ef

fect

20 40 60 90

Time (min)

oral

im, thigh

im, buttock

Influence of route of administration on the clinical action of diazepam.

Data from Assaf et al. Anaesthesia 30:152-158, 1975.

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

3

A. Intravenous

AdvantagesAdvantages:•rapid achievement of concentrationrapid achievement of concentration•precise delivery of dosageprecise delivery of dosage•easy to titrate doseeasy to titrate dose

DisadvantagesDisadvantages:•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. PARENTERALI. PARENTERAL

4

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

5

While it is generally viewed that 100% of drug While it is generally viewed that 100% of drug administered intravenously is bioavailable, administered intravenously is bioavailable,

prodrug administration via this route may result prodrug administration via this route may result in less than 100% bioavailability.in less than 100% bioavailability.

DrugDrug BioavailabilityBioavailabilityChloramphenicol succinateChloramphenicol succinate ~70%~70%Dexamethasone phosphateDexamethasone phosphate ~90%~90%Dexamethasone sulfateDexamethasone sulfate ~40%~40%Prednisolone phosphatePrednisolone phosphate ~90%~90%Prednisolone phthalatePrednisolone phthalate ~50%~50%

Comparative bioavailability of IV chloramphenicol Comparative bioavailability of IV chloramphenicol succinate and oral chloramphencol palmitatesuccinate and oral chloramphencol palmitate

IVIV POPOMean CMean C90-min90-min (mg/L) (mg/L) 22.622.6 27.527.5

Mean AUC (mg/hr/L) Mean AUC (mg/hr/L) 7878 110110From: Kauffman R et al. J Pediatr 99:963, 1981.

6

I. PARENTERALI. PARENTERALA. IntravenousA. Intravenous

B. Intra-arterialB. Intra-arterial

C. IntramuscularC. Intramuscular

Injection sites for IM administration

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

7

Advantages: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:Disadvantages:•painfulpainful•cannot be used in presence of cannot be used in presence of abnormal clotting timeabnormal clotting time•drug may ppt at the site of drug may ppt at the site of administrationadministration•variability in bioavailabilityvariability in bioavailability

Z-track method for IM injections

8

Reproduced from: Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications, 3rdedition, 1994, p. 39.

9

Blood concentration of chlordiazepoxide after oral () or intramuscular (o) administration of 50 mg. Reproduced from Greenblatt DJ, et al. NEJM29:1116-1118, 1974.

10

Days

20 40 60

Ph

enyt

oin

Co

nce

ntr

atio

n

(

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

0

2

4

6

8

10

12

14

16

18

0 2 4 6

TIME (hr)

VE

Bs/

min

Deltoid Vastus Lateralis

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

12

Injection siteInjection site deltoiddeltoidvastus lateralisvastus lateralisgluteus maximusgluteus maximus

MalesMales11.711.7 9.89.811.111.1

FemalesFemales 10.210.2 9.49.4 4.34.3

Data from: Vukovich et al. Data from: Vukovich et al. Clin Pharmacol TherClin Pharmacol Ther 18:215, 1975. 18:215, 1975.

Peak plasma cephradine concentrations Peak plasma cephradine concentrations (mcg/mL) after IM administration to (mcg/mL) after IM administration to

different sites in male and female subjectsdifferent sites in male and female subjects

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 Data from: Poland et al JAMAJAMA 277:1709-1711, 1997. 277:1709-1711, 1997.

WomenWomen MenMenDeltoid fat pad thickness (mm)Deltoid fat pad thickness (mm) 11.7 11.7 8.3 8.3Deltoid skin-fold thicknessDeltoid skin-fold thickness 34.7 34.7 17.217.2Percent in whom a standard Percent in whom a standard 16 mm needle would not reach 16 mm needle would not reach 5 mm into muscle5 mm into muscle 48.4 48.4 17.017.0

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 mmwomen >90 kg: 38 mm

14

D. D. SubcutaneousSubcutaneous

Advantages: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: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

40

50

60

70

80

90

100

110

0 30 60 90 120

Time (minutes)

% o

f ini

tial

cou

nts

Abdomen

Arm

Leg

Disappearance of IDisappearance of I125125-insulin from subcutaneous injection-insulin from subcutaneous injectionat different sites. at different sites. Data from Koivisto & Felig, Data from Koivisto & Felig, Ann Intern MedAnn Intern Med 92:59, 1980. 92:59, 1980.

16

0

20

40

60

80

100

120

0 50 100 150

Time (min)

Ris

e in

pla

sma

gluc

ose

(mg/

dl)

Abdomen Arm Leg

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

18Reproduced from: http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=178

Aradigm Intraject® NFI device in protein delivery

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

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

21

Reproduced from: Rowland M, Tozer TN. Reproduced from: Rowland M, Tozer TN. Clincal Pharmacokinetics – Concepts and Clincal Pharmacokinetics – Concepts and ApplicationsApplications, 3, 3rdrd edition, Williams & Wilkins, edition, Williams & Wilkins, 1995, p. 12.1995, p. 12.

II. ENTERALII. ENTERAL

22

A. ORALA. ORAL

Advantages: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: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-increased sources of drug-drug and drug-nutrient intxnsnutrient intxns•many drugs degrade in GI environmentmany drugs degrade in GI environment•exposes drugs to first-pass effectexposes drugs to first-pass effect

23

Effect of Effect of varying varying

volumes of volumes of water on oral water on oral

drug absorptiondrug absorption

From: Shargel L, Yu ABC. From: Shargel L, Yu ABC. Applied Biopharmaceutics Applied Biopharmaceutics and Pharmacokineticsand Pharmacokinetics, 4, 4thth edition, 1999, p. 119.edition, 1999, p. 119.

24

25From: 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 dogsEffect of route of administration on isoproterenol dose response dogs From: Shargel L, Yu ABC. From: Shargel L, Yu ABC. Applied Biopharmaceutics and PharmacokineticsApplied Biopharmaceutics and Pharmacokinetics, 4, 4thth edition, edition, 1999, p. 155.1999, p. 155.

27

B. Sublingual/BuccalB. Sublingual/Buccal

Advantages:Advantages:

•rapid onsetrapid onset•avoids first-pass effectavoids first-pass effect•ability to swallow is not requiredability to swallow is not required

Disadvantages:Disadvantages:

•few drugs adequately absorbedfew drugs adequately absorbed•patients must avoid swallowingpatients must avoid swallowing•compliance difficultcompliance difficult

28

Oral

Sublingual

0

2

4

6

8

10

12

14

5 15 30 45 60 90 120

Time (min)

Iso

sorb

ide

Co

nc

(ng

/ml)

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

29

05

101520253035

5 5.5 6 6.5 7 7.5 8 9

Buffer pH

% A

bsor

bed

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

30

http://www.novadel.com/

http://www.vitamist.com/

31

C. RectalC. Rectal

Advantages: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•maymay avoid first-pass metabolism avoid first-pass metabolism

Disadvantages: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

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

33

Availability (%) of lidocaine after IV, Availability (%) of lidocaine after IV, oral and rectal administrationoral and rectal administration

Data from: de Boer et al. Data from: de Boer et al. Clin Pharmacol TherClin Pharmacol Ther 26:701-709, 1979. 26:701-709, 1979.

SubjectSubject IVIV 11 100100 22 100100 33 100100 44 100100 55 100100 66 100100

100100

OralOral1717494953531313353537373434

RectalRectal595987878080313110010059597171

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

35

Pharmacologic Agents Administered Pharmacologic Agents Administered via Inhalationvia Inhalation

For Systemic EffectsFor Systemic Effectspentamidinepentamidinehalothanehalothaneergotamineergotaminemethoxyfluranemethoxyfluraneenfluraneenfluraneisofluraneisofluranenitrous oxidenitrous oxide

For Local EffectFor Local Effectbeclomethasonebeclomethasoneterbutalineterbutalinecromolyncromolynmetaproterenolmetaproterenolalbuterolalbuterolpirbuterolpirbuterol

III. PULMONARYIII. PULMONARY

36

III. PULMONARYIII. PULMONARY

Advantages:Advantages:

•easy to titrate doseeasy to titrate dose•rapid onsetrapid onset•for local effect, maximize for local effect, maximize benefit/minimize side effectsbenefit/minimize side effects

DisadvantagesDisadvantages::•takes significant degree of coordinationtakes significant degree of coordination

•patients with lung disease may be able patients with lung disease may be able to inhale adequatelyto inhale adequately•variability in deliveryvariability in delivery

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

38

Forms of pulmonary Forms of pulmonary deliverydelivery

• Metered dose inhalerMetered dose inhaler• Dry powder inhalersDry powder inhalers• NebulizerNebulizer

39

Metered Dose Inhaler Metered Dose Inhaler (MDI)(MDI)• Propellant basedPropellant based

• Most common delivery Most common delivery system in tx of asthmasystem in tx of asthma

• Chlorofluorocarbons vs Chlorofluorocarbons vs hydrofluoroalkaneshydrofluoroalkanes

• Products contain a Products contain a surfactant or dispersing surfactant or dispersing agent (e.g., oleic acid)agent (e.g., oleic acid)

• Co-solvent (e.g., ethanol) – Co-solvent (e.g., ethanol) – especially needed with use especially needed with use of HFAof HFA

• Flavoring agent (e.g., Flavoring agent (e.g., menthol)menthol)

typical MDItypical MDI

40

Techniques for use of MDI devices:Techniques for use of MDI devices:

Two finger widthTwo finger widthfrom mouthfrom mouth

Use of space orUse of space orholding chamberholding chamber

Placement of Placement of inhaler in mouthinhaler in mouth(not for use with(not for use withsteroids)steroids)Patient must Patient must

coordinate coordinate inhalation and inhalation and actuation of actuation of devicedevice

41

Dry Powder Inhalers Dry Powder Inhalers (DPI)(DPI)

• Breath activatedBreath activated• Micronized drug particles Micronized drug particles

blended with an excipient blended with an excipient (e.g., glucose or lactose)(e.g., glucose or lactose)

• Physical properties of Physical properties of drug and excipient drug and excipient critical (i.e., particle size, critical (i.e., particle size, shape, surface shape, surface morphology, etc)morphology, etc)

42

DiskusDiskus

43

NebulizerNebulizer• Device produces small droplets Device produces small droplets

from a suspension or solution from a suspension or solution through an air jet or ultrasonic through an air jet or ultrasonic atomization (quieter, but more atomization (quieter, but more expensive)expensive)

44

Factors that influence Factors that influence deposition of particles in the deposition of particles in the

lunglung• Physicochemical propertiesPhysicochemical properties• FormulationFormulation• Technique (depth of Technique (depth of

inspiration, pause prior to inspiration, pause prior to exhalation, coordination of exhalation, coordination of inhalation)inhalation)

• Pulmonary diseasePulmonary disease

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

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

47

IV. TOPICALIV. TOPICAL

A. PercutaneousA. Percutaneous

48

AdvantagesAdvantages::

•when used for local effects, minimize when used for local effects, minimize systemic side effectssystemic side effects•for systemic use, may mimic IV for systemic use, may mimic IV infusion (i.e., zero-order)infusion (i.e., zero-order)•avoid first-pass effectavoid first-pass effect

DisadvantagesDisadvantages::

•cosmetically unappealingcosmetically unappealing•may display erratic absorptionmay display erratic absorption

49

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

50

Factors that influence Factors that influence percutaneous absorptionpercutaneous absorption

• Site of applicationSite of application• Condition of skinCondition of skin• Hydration of skinHydration of skin• TemperatureTemperature• VehicleVehicle

51

Effect of Nitroglycerin on Systolic Blood Pressure When Adminisitered Percutaneously at Different Sites

-15

-10

-5

0

5

0 50 100 150 200

Chan

ge in

Mea

n SBP

(mmH

g) Forehead

Chest

Ankle

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

52

Time (hours)

0 1 2 3

Pla

sma

Nic

otin

e C

once

ntr

atio

n (ng/

ml)

0

5

10

15

20

25

30

Sauna bath

Control

Sauna bath

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

B. OcularB. Ocular

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

54

Types of Ophthalmic Types of Ophthalmic PreparationsPreparations

• SolutionsSolutions• SuspensionsSuspensions• OintmentsOintments• InsertsInserts• Intraocular solutionsIntraocular solutions

55

Factors that influence ocular Factors that influence ocular drug retentiondrug retention

• Technique of application

56

Factors that influence ocular Factors that influence ocular drug retentiondrug retention

• Technique of applicationTechnique of application• Drop size (volume)Drop size (volume)• Formulation (tonicity, Formulation (tonicity,

viscosity)viscosity)• pH of solutionpH of solution

57

0

1

2

3

4

5

8 uL 30 uLPu

pil

lary

dia

met

er,

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 infantsSystemic (plasma)

concentration range (ng/mL)

8 uL: 0 – 1.8

30 uL: 0.6 – 3.2

58

Systemic Absorption of Timolol 1 hour after instillation

0

0.5

1

1.5

No NLO NLO EyelidClosure

Tim

olol

, ng/

ml

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

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

60

0

0.5

1

1.5

2

2.5

3

A B CCh

ang

e in

pu

pil

lary

dia

met

er,

mm

Ch

ang

e in

pu

pil

lary

dia

met

er,

mm

Treatments:A – 25 L pilocarpineB – 25 L pilocarpine followed 2-min later by saline dropC – 25 L pilocarpine followed 30-sec later by saline drop

From: Shell JW. Surv Ophthamol 26:207, 1982

61

Time, min

100 200 300 400

Ste

roid

Co

nce

ntr

atio

n (

g/m

l)

0.001

0.01

0.1

0.05 mL Saturated Solution0.05 mL 0.1% suspension50 mg dose of ointment

Aqueous humor concentration of

fluorometholone following various preparations

From: Sieg JW, Robinson JR. J Pharm Sci 64:931, 1975

62

C. NasalC. 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

Mucosal Atomizer Device

From: www.ofmaa.org

Intranasal naloxone administration in the field by paramedics

64

Time (minutes)0 10 20 30 40 50 60

Nic

otin

e C

once

ntr

atio

n (nm

ole/

ml)

0

20

40

60

80

100

120

140

160

180

Cigarette

Nasal Solution

Chewing Gum

Nicotine gum

Cigarette

Nasal sol'n

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 mucosa

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

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

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

68Figure from: http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=61

Nasal to brain delivery of drugsNasal to brain delivery of drugs

69

Which route is best?Which route is best?

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