3 I. PARENTERAL A. Intravenous Advantages: Disadvantages: rapid achievement of concentrationprecise delivery of dosageeasy to titrate doseDisadvantages:high initial concentration - toxicityinvasive - risk of infectionrequires 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 BioavailabilityChloramphenicol succinate ~70%Dexamethasone phosphate ~90%Dexamethasone sulfate ~40%Prednisolone phosphate ~90%Prednisolone phthalate ~50%Comparative bioavailability of IV chloramphenicol succinate and oral chloramphencol palmitateIV POMean 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 administrationFrom: Fundamentals of Nursing, 4th edition, Lippincoitt, Williams & Wilkins
7 Advantages: Disadvantages: less skill necessary for administration can be used to administer oily vehiclesprompt absorption from aqueous sol’nDisadvantages:painfulcannot be used in presence of abnormal clotting timedrug may ppt at the site of administrationvariability in bioavailabilityZ-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. NEJM29: , 1974.
10 Days Plasma phenytoin concentrations in patients during oral and IM administrationoralIMoralPhenytoin Concentration(mcg/mL)DaysRedrawn 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 subjectsInjection sitedeltoidvastus lateralisgluteus maximusMales11.79.811.1Females10.29.44.3Data 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 MenDeltoid fat pad thickness (mm)Deltoid skin-fold thicknessPercent in whom a standard16 mm needle would not reach5 mm into muscleNeedle 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 injectionD. SubcutaneousAdvantages:prompt absorption from aqueous solnslittle training necessaryavoid harsh GI tract environmentcan be used for suspensionsDisadvantages:cannot be used for large volumespotential pain and tissue damagevariability 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:
21 II. ENTERALReproduced 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)economicalnon-invasive, often safer routerequires no special trainingDisadvantages:drug delivery is often erratic and incompletehighly dependent upon patient complianceincreased sources of drug-drug and drug-nutrient intxnsmany drugs degrade in GI environmentexposes 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.
31 C. Rectal Advantages: Disadvantages: can be used when patients cannot take oral medsgood option in pediatric populationmay avoid first-pass metabolismDisadvantages:absorption from solid dosage forms erraticmany 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 IV1 1002 1003 1004 1005 1006 100100Oral17495313353734Rectal5987803110071
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. PULMONARYPharmacologic Agents Administeredvia InhalationFor Systemic Effectspentamidinehalothaneergotaminemethoxyfluraneenfluraneisofluranenitrous oxideFor Local Effectbeclomethasoneterbutalinecromolynmetaproterenolalbuterolpirbuterol
36 III. PULMONARY Advantages: easy to titrate dose rapid onset for local effect, maximize benefit/minimize side effectsDisadvantages:takes significant degree of coordinationpatients with lung disease may be able to inhale adequatelyvariability in delivery
37 Reproduced from: Pliss et al. Ann Emerg Med 10:353-355, 1981.
38 Forms of pulmonary delivery Metered dose inhalerDry powder inhalersNebulizer
39 Metered Dose Inhaler (MDI) Propellant basedMost common delivery system in tx of asthmaChlorofluorocarbons vs hydrofluoroalkanesProducts contain a surfactant or dispersing agent (e.g., oleic acid)Co-solvent (e.g., ethanol) – especially needed with use of HFAFlavoring agent (e.g., menthol)typical MDI
40 Techniques for use of MDI devices: Use of space orholding chamberPlacement ofinhaler in mouth(not for use withsteroids)Two finger widthfrom mouthPatient must coordinate inhalation and actuation of device
41 Dry Powder Inhalers (DPI) Breath activatedMicronized 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)
43 NebulizerDevice 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 propertiesFormulationTechnique (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
48 Advantages: Disadvantages: when used for local effects, minimize systemic side effectsfor systemic use, may mimic IV infusion (i.e., zero-order)avoid first-pass effectDisadvantages:cosmetically unappealingmay 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 applicationCondition of skinHydration of skinTemperatureVehicle
52 Plasma nicotine concentration in subjects wearing nicotine patches exposed (squares) or not exposed (diamonds) to three 10 min sauna bath sessionsover 1 hr. Figure adapted from: Vanakoski et al Clin Pharmacol Ther 60: , 1996.
53 B. OcularFrom: Fundamentals of Nursing, 4th edition, Lippincoitt, Williams & Wilkins
54 Types of Ophthalmic Preparations SolutionsSuspensionsOintmentsInsertsIntraocular solutions
55 Factors that influence ocular drug retention Technique of application
56 Factors that influence ocular drug retention Technique of applicationDrop 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 infantsSystemic (plasma) concentration range (ng/mL)8 uL: 0 – 1.830 uL: 0.6 – 3.2Pupillary diameter, mmPhenylephrine 2.5% drop sizeFrom: Lynch et al. Arch Ophthamol 105:1364, 1987)
58 Adapted from Zimmerman et al. Arch Opthamol 102:551, 1984.
60 Change in pupillary diameter, mm Treatments:A – 25 mL pilocarpineB – 25 mL pilocarpine followed 2-min later by saline dropC – 25 mL pilocarpine followed 30-sec later by saline dropFrom: 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. NasalHistorically utilized only for local effectsGrowing number of compounds administered intranasally that are intended for systemic effectsFor drugs that are destroyed in the GI environment (or first-pass effect)As an alternative to intravenous administration – better safety and patient acceptanceDrugs 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 DeviceFrom:
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 mucosa pHConcentrationMolecular weightFormulationCondition 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.