Par 5
`E531
`Second Edition, Revised and Expanded
`
`Edited by
`
`Kenneth E. Avis
`
`The University of Tennessee
`Memphis, Tennessee
`
`Herbert A. Lieberman
`
`H.H. Lieberman Associates, Inc.
`Consultant Services
`
`Livingston, New Jersey
`
`leon lachmnn
`
`Lachman Consultant Services
`
`Westbury, New York
`
`Marcel Dekker, Inc.
`
`New York 0 Basel 0 Hong Kong
`ALKERMES EXH. 2006
`ALKERMES EXH. 2006
`Luye v. Alkermes
`Luye v. Alkermes
`|PR2016—1095 & |PR2016—1096
`IPR2016-1095 & IPR2016-1096
`
`

`
`Library of Congress Cataloging- in- Publication Data
`
`Pharmaceutical dosage forms, parenteral medications / edited by
`Kenneth E. Avis, Herbert A. Lieberman, and Leon Lachman.
`rev. and expanded.
`p.
`cm.
`
`-— 2nd ed. ,
`
`Includes bibliographical references and index.
`ISBN 0-8247-8576-2 (V. 1 : alk. paper)
`1. Parenteral solutions.
`2'. Pharmaceutical technology.
`Kenneth E.
`II. Lieberman, Herbert A.
`III. Lachman, Leon.
`
`I. Avis,
`
`[DNLM: 1. Infusions, Parenteral.
`WB 354 P536]
`RS201.P37P48 1992
`615'. 19--dc20
`DNLM/DLC
`
`for Library of Congress
`
`.
`
`2. Technology, Pharmaceutical.
`
`91 '33053
`CIP
`
`This book is printed on acid—free paper.
`
`Copyright © 1992 by MARCEL DEKKER, INC. An Rights Reserved
`
`Neither this book nor any part may be reproduced or transmitted in any form
`or by any means, electronic or mechanical, including photocopying, micro-
`filming, and recording, or by any information storage and retrieval system,
`without permission in writing from the publisher.
`
`MARCEL DEKKER, INC.
`270 Madison Avenue, New York, New York 10016
`
`Current printing (last digit):
`10 9 8 7 6 5 4 3 2 1
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`

`
`
`
`Contents
`
`Preface
`Contributors
`
`Parenteral Medications,
`Contents of Pharmaceutical Dosage Forms:
`Second Edition, Revised and Expanded, Volumes 2 and 3
`Tablets, Second Edition ,
`Contents of Pharmaceutical Dosage Forms:
`Revised and Expanded, Volumes 1-3
`Disperse Systems,
`Contents of Pharmaceutical Dosage Forms:
`Volumes 1 and 2
`
`Chapter 1
`
`The Parenteral Dosage Form and Its Historical Development
`Kenneth E. Avis
`
`I. The Dosage Form
`11. History of Parenteral Medications
`Appendix A: Glossary of Terms
`Appendix B: Highlights in the History of
`Parenteral Medications
`References
`
`Chapter 42
`
`Parenteral Drug Administration: Routes, Precautions,
`Problems, Complications, and Drug Delivery Systems
`
`Richard J. Duma, Michael J. Akers,” and
`Salvatore J. Turco
`
`Introduction
`I. General Indications for Parenteral
`
`11.
`
`Administration of Drugs
`Pharmaceutical Factors Affecting Parenteral
`Administration
`Specific Routes of Administration
`111.
`IV. Distribution of Parenterally Administered Agents
`
`iii
`xi
`
`xiii
`
`XV
`
`xvii
`
`Lb
`
`14
`15
`
`17
`
`17
`
`18
`
`19
`21
`39
`
`vii
`
`

`
`viii
`
`Contents
`
`V. Precautions, Problems, Hazards, and
`Complications Associated with Parenteral Drug
`Administration
`
`VI. Methods and Devices for Drug Delivery Systems
`VII.
`Summary
`References
`
`Chapter 3
`
`Biopharmaceutics of Injectable Medications
`Sol Motola
`
`I .
`
`II.
`
`Introduction
`
`Physicochemical and Physiological Factors
`Affecting Drug Absorption by Injection: An
`Overview
`
`III. Application of Pharmacokinetics to Biopharma—
`ceutic Investigations: Pharmacokinetic Models
`IV. Examples of Biopharmaceutic/Pharmacokinetic
`Principles
`V. Regulatory Considerations for Bioequivalence
`Studies
`
`VI. Bioequivalence Study of Two Injectable Forms
`of the Same Drug
`Summary
`References
`
`VII.
`
`Chapter 4
`
`Preformulation Research of Parenteral Medications
`
`Sol Motola and Shr-eeram N. Agharkar
`I .
`Introduction
`
`II. Drug Substance Physicochemical Properties
`III. Accelerated Stability Evaluation
`IV. General Modes of Drug Degradation
`V.
`Preformulation Studies for Proteins and Peptides
`VI.
`Preformulation Screening of Parenteral
`Packaging Components
`Summary
`Preformulation Worksheet
`References
`
`VII.
`VIII.
`
`Chapter 5
`
`Formulation of Small Volume Parenterals
`
`Patrick P. DeLuca and James C. Boylan
`I.
`Introduction
`
`Formulation Principles
`II.
`III. Container Effects on Formulation
`IV.
`Stability Evaluation
`V. Process Effects
`References
`
`41
`49
`56
`57
`
`59
`
`59
`
`60
`
`77
`
`98
`
`108
`
`109
`111
`112
`
`115
`
`115
`116
`140
`150
`154
`
`158
`163
`163
`169
`
`173
`
`173
`174
`227
`234
`244
`245
`
`

`
`Contents
`
`ix
`
`Chapter 6
`
`Formulation of Large Volume Parenterals
`
`Levit J. Demorest and Jeffrey G. Hamilton
`I.
`Introduction
`II.
`III.
`IV.
`V.
`
`Concepts of Formulation
`Formulation Development
`Solution Quality
`Summary
`References
`
`Chapter 7
`
`Parenteral Products of Peptides and Proteins
`
`Yu-Chang John Wang
`1.
`Introduction
`II.
`III.
`IV.
`
`Characteristics of Proteins and Peptides
`Formulation Principles
`Compatibility with Packaging Components and
`Infusion Sets
`Formulation of Market Products
`References
`
`Chapter 8
`
`V.
`
`Sterile
`
`Leif E.
`I.
`II.
`III.
`IV.
`V.
`VI.
`VII.
`
`Diagnostics
`Olsen
`
`Introduction
`
`Diagnostic Products Defined
`Sterile Diagnostics
`Definitions
`
`.
`
`Aseptic Manufacturing Considerations
`Validation Program
`Conclusion
`References
`
`Chapter 9
`
`Glass Containers for Parenterals
`
`R. Paul Abendroth and Robert N. Clark
`
`I.
`II.
`III.
`
`IV.
`V.
`VI.
`VII.
`VIII.
`
`Introduction
`The Nature of Glass
`
`United States Pharmacopeia Glassware
`Classifications
`The Manufacture of Glass Containers
`Chemical Performance
`Mechanical Performance
`
`The Container and Closure as a System
`Quality Assurance
`References
`
`249
`
`249
`250
`273
`280
`281
`281
`
`283
`
`283
`284
`302
`
`310
`312
`317
`
`321
`
`321
`321
`322
`325
`330
`351
`359
`359
`
`361
`
`361
`361
`
`362
`369
`375
`380
`380
`382
`384
`
`

`
`ac
`
`Contents
`
`Chapter 10 Use of Plastics for Parenteral Packaging
`
`John M. Anes, Robert S. Nose, and
`Charles H. White
`
`I.
`II.
`III.
`IV.
`V.
`VI.
`
`Introduction
`Fundamentals
`Fabrication Processes
`
`Important Criteria for Selection of Plastics
`Plastics Used in Parenteral Packaging
`Quality Assurance of Parenteral Containers
`References
`
`Chapter 11 Elastomeric Closures for Parenterals
`
`Edward J. Smith and Robert J. Nash
`
`I.
`
`II .
`III.
`IV .
`V .
`VI.
`VII.
`VIII.
`IX .
`X .
`
`XI.
`
`Elastomeric Parenteral Packaging Components:
`A Physical Description
`Physical Description of Rubber
`Types of Rubber Used in Parenteral Packaging
`Closure Design
`Rubber Compounding
`Vulcanization Process
`Closure Manufacture and Control
`
`Closure Design Qualification
`Regulatory Considerations
`Interaction of Drug Formulations with
`Rubber Closures
`
`Contemporary Closure—Related Issues
`References
`
`Chapter 12 Parenteral Products in Hospital and Home Care
`Pharmacy Practice
`
`John W. Levchuk
`
`I.
`II.
`
`III.
`IV.
`
`V.
`VI.
`VII.
`
`Introduction
`
`The Preparation of Sterile Dosage Forms in the
`Hospital and in Home Care
`Dispensing and Compounding Processes
`Technology of Sterile Compounding in the
`Hospital Pharmacy
`Clinical Supply and Use of Sterile Products
`Quality Assurance
`Conclusion
`
`Appendix: Abbreviated Sequence for Preparing a‘
`Series of Extemporaneously Compounded I.V.
`Admixtures
`References
`
`Index
`
`387
`
`387
`389
`398
`407
`422
`439
`443
`
`445
`
`445
`450
`451
`462
`463
`470
`477
`494
`503
`
`505
`507
`508
`
`513
`
`513
`
`513
`524
`
`532
`547
`552
`562
`
`563
`566
`
`569
`
`

`
`2 P
`
`arenteral Drug Administration: Routes,
`Precautions, Problems, Complications,
`and Drug Delivery Systems
`
`Richard J. Duma
`
`Medical College of Virginia, Virginia Commonwealth University, Richmond,
`Virginia
`
`Michael J. Akers
`
`Eli Lilly and Company, Indianapolis, Indiana
`
`Salvatore J. Turco
`
`Temple University, Philadelphia, Pennsylvania
`
`Parenteral, from para enteron (Greek), meaning "to avoid the intestines,"
`includes in its broadest sense, any drug (or fluid) whose delivery does not
`utilize the alimentary canal for entry into body tissues. Although drugs ap-
`plied topically to the eye, ear, and skin, or even inhaled, may be broadly
`interpreted as parenterals, medical and pharmaceutical health care deliveries
`generally limit the definition to those drugs injected or infused directly into
`tissues, tissue spaces, vessels, or body compartments.
`The development of techniques for administering parenterals, coupled
`with innovative designs of new devices to achieve and monitor their delivery,
`occur almost daily and are enabling therapeutics to approach an exact science.
`In addition, parenteral therapy is not restricted to hospitals or clinics but is
`being increasingly employed, even in its most invasive forms of delivery (e.g. ,
`intravenous), to manage patients at home and in the work place. Most pa-
`tients readily accept or easily adapt to almost every form of parenteral ther-
`apy, and many self-administer their own drugs, even when the route of de-
`livery is intravenous (e.g. , home infusion programs).
`Parenteral administration offers many advantages over therapy given by
`nonparenteral routes. Most notably, therapeutists can reliably predict with
`considerable accuracy the pharmacokinetics and pharmacology of the agents
`they prescribe; they can quickly interdict a rapidly progressive lethal pro-
`cess or disease; and, even though the physiology and pathology of patients
`may be complicated, they can "fine tune," stratify and quantitate results.
`However, despite these advantages, parenteral administration is not without
`
`17
`
`

`
`18
`
`_
`
`Duma et al.
`
`certain, measurable risks and limitations that the professional must intelligent-
`ly weigh in terms of risks, benefits, and costs.
`This chapter will attempt to review and update the usage of parenteral
`administration in today's practice of medicine. However, since the subject is
`dynamic and the technology is growing, the reader must appreciate that some
`of the material contained herein may become quickly outdated.
`
`I. GENERAL INDICATIONS FOR PARENTERAL
`ADMINISTRATION OF DRUGS
`
`The parenteral routes of drug administration are indicated for one or more
`of the following reasons:
`
`1. To ensure delivery of adequate concentrations of the drug in ques-
`tion to diseased tissues or target areas of the body, especially when
`inadequate or marginal transport of that drug into the tissues or tar-
`get areas is anticipated. Example: Direct intraventricular injection
`of drugs (e.g. , antibiotics such as the aminoglycosides) which cross
`the "blood-brain-meninges barrier" poorly may be used in certain
`patients with bacterial or fungal meningitis and /or ventriculitis.
`2. To permit the user to exert direct control over certain pharmacologic
`parameters, such as the time of drug onset, serum peak and trough
`levels, tissue concentrations, and rate of elimination of the drug from
`the body. Example:
`Intravenous or direct cardiointraventricular
`routes may be desirable to achieve immediate effects in emergencies
`such as might occur in the control of life-threatening hypotension,
`hypertension, or arrhythmias; or intramuscular routes may be desir-
`able to obtain protracted or sustained effects, such as the use of
`benzathine penicillin G in the treatment of infections.
`3. To allow the therapist, when outpatient management is desirable, to
`guarantee dosage and drug compliance, especially when the patient
`cannot be relied upon to self-medicate. Example: The use of long-
`acting (monthly) intramuscular penicillins may be used to manage
`children prophylactically for rheumatic heart disease in order to pre-
`vent Group A streptococcal pharyngitis.
`4. To deliver a biologic effect that cannot be achieved through oral ad-
`ministration, perhaps because of nonabsorbance from the alimentary
`canal or degradation by gastric acidity. Example: Therapeutic pep- ,
`tides and proteins such as insulin, human growth hormone, other
`products from recombinant DNA technology, and polyene antibiotics
`(such as the antifungal agent amphotericin B).
`5. To administer a drug when the desired route (e.g. , oral) may not be
`available. Example:
`In patients who are aspirating or who have had
`the upper gastrointestinal tract stream diverted or removed (e.g. ,
`because of a carcinoma) a parenteral route may be necessary.
`6. To provide a local effect when it is desirable to minimize or avoid sys-
`temic toxic effects or reactions. Example: Methotrexate may be given
`intrathecally to patients with leukemia and leukemic involvement of
`the meninges to avoid the systemic, toxic effects that would occur if
`an intravenous route was employed.
`
`

`
`Parenteral Drug Administration
`
`19
`
`7. To administer drugs to the unconscious, uncooperative, or uncon-
`trollable patient. Example: Patients with uncontrollable grand mal
`seizures often will not cooperate in the oral administration of drugs
`or will be at risk to aspirate if compelled to take medicines by mouth.
`Similarly, patients unconscious from narcotic abuse, anesthetic usage,
`or trauma, or uncooperative patients such as those suffering delerium
`tremens or a psychosis, may be satisfactorily managed by using paren-
`teral routes.
`
`8. To permit rapid correction of fluid and electrolyte imbalances and to
`supply short- or long-term nutritional needs (hyperalimentation or
`parenteral feeding). Example: Patients suffering severe dehydration
`or electrolyte depletion for a variety of reasons (e.g'. , heat stroke)
`can be rapidly corrected with intravenous electrolyte solutions; and
`patients whose intestinal tracts have been resected for one reason
`or another may be intravenously "fed" a complete diet of all the neces-
`sary amino acids, glucose, minerals, and vitamins for prolonged and
`indefinite periods of time.
`9. To achieve a desired local effect. Example: Local anesthetics for
`tooth extractions or local anti-inflammatory agents for inflamed joints
`may be injected directly into the site in question to avoid systemic
`effects or "systemic" dosages.
`
`II. PHARMACEUTICAL FACTORS AFFECTING
`PARENTERAL ADMINISTRATION
`
`Certain pharmaceutical characteristics dictate the method or route of paren-
`teral administration, and once the dosage form is injected or infused, influ-
`ence the rate and extent of drug availability. These characteristics will be
`reviewed briefly in this section, but the reader is also referred to Chapter 3
`for a more detailed treatment of the biopharmaceutical factors affecting paren-
`teral drug availability.
`
`A. Solubility of the Drug and Volume of the Injection
`
`A drug must be completely solubilized, preferably in water, before it can be
`administered by intravenous injection. Both the extent of drug solubility in
`its intended vehicle and the dose required for the desired therapeutic effect
`will determine the volume of the injection. Parenteral routes other than the
`intravenous one have limitations regarding the maximum volume of medication
`administered (e.g. , intradermal, intramuscular, intraocular, intraventricular,
`and intrathecal, to name a few).
`
`B . Vehicle Characteristics
`
`Drugs in aqueous vehicles may be administered by any parenteral route,
`whereas drugs in nonaqueous vehicles, which may or may not be water mis-
`cible, are administered most frequently by the intramuscular route. The in-
`travenous route may be used for a few drugs in mixed solvent systems (e.g. ,
`diazepam, digoxin, and phenytoin) , but precautions must be applied in adjust-
`ing the rate of drug infusion to avoid drug‘ precipitation at the site of infusion.
`
`

`
`20
`
`Duma et al.
`
`Large volume parenteral fat emulsions are also available by the intravenous
`route. Nonaqueous vehicles that are more viscous than water vehicles will
`affect the rate of injection through a small—gauge needle and the rate of ab-
`sorption from the injection site.
`
`C.
`
`pH and Osmolality of lnjectable Solutions
`
`Ideally, administered injections should be formulated at a pH and osmolality
`similar to that of biological fluids. Unfortunately, this is not possible for
`many parenteral dosage forms, as many parenteral drugs are unstable at neu-
`tral pH. Therefore, such drugs are formulated at the pH at which they are
`most stable. For example, diazoxide (a nondiuretic benzothiadiazine deriva-
`tive) is formulated at a pH of 11.6, the pH at which it is most stable. Many
`parenteral drugs are salt forms of weak bases. Thus the pH of a dosage form
`containing the salt of a weak base may be as low as 2.0 (e.g. , tetracycline
`hydrochloride), or the pH of a dosage form containing the salt of a weak acid
`may be as high as 12.0 (e.g. , Dilantin) in order to maintain the active in-
`gredient in solution. Although dosage forms with extreme pH values may be
`administered by any parenteral route, the rate and volume of injection must
`be controlled to minimize pain and irritation to the patient and damage to the
`surrounding tissues.
`Certain parenteral formulations are hyperosmotic with biological fluids
`and contain a relatively high dose of active ingredient(s) in order to achieve
`a desired level of biological activity. For example, water-soluble contrast
`media, spinal anesthetics, ophthalmic sodium sulfacetamide, diazoxide, and
`osmotic diuretics are a few hypertonic parenteral formulations containing high
`drug concentrations to achieve an appropriate biological action(s) . Products
`of parenteral nutrition are formulated or admixed with high concentrations
`of amino acids, dextrose, and other essential ingredients, resulting in very
`hypertonic solutions. These solutions, called hyperalimentation solutions,
`are so hypertonic that they must be administered via a large vein such as the
`subclavian. The blood in this vein enters directly into the heart, which allows
`the hypertonic solution to be rapidly diluted by a still larger volume of blood.
`Generally, hypertonic parenteral dosage forms are contraindicated for
`subcutaneous or intramuscular injections. Whereas the vitreous humor, can
`tolerate only very narrow ranges of osmotic values from an injected medication.
`Therefore, although stability and solubility problems may prevent dosage forms
`from being formulated at physiological pH, they should be formulated with
`solute contents approximately equal to those of biological fluids.
`
`D. Type of Dosage Form
`
`Parenteral dosage forms include solutions, suspensions, and sterile solids
`for reconstitution.
`If the dosage form is a suspension, it may be administered
`only by the intramuscular or subcutaneous route. Particles should not be
`present in dosage forms administered intravenously or by other parenteral
`routes in which the medication enters directly into a biological fluid or sensi-
`tive tissue (e.g. , brain or eye). Reconstituted solids should be completely
`dissolved in the reconstituting diluent before they are administered intraven-
`ously.
`T
`
`

`
`Parenteral Drug Administration
`
`21
`
`E . Formulation I ngredients
`
`As discussed in Chapter 5, parenteral formulations may contain various active
`and inactive excipients other than the main therapeutic agent, for a variety
`of reasons. For multidose parenterals, antimicrobial agents are added to the
`formulation for the preservation of sterility. However, these agents may be
`contraindicated in medications to be administered into the cerebrospinal fluid
`or intraocular fluid because of the toxicity they may produce. Several paren-
`teral formulations contain surface-active agents (such as polysorbate 80) to
`maintain drug solubility in the solution vehicle. Surface—active agents are
`known to alter membrane permeability, so their presence must be recognized
`when administering such dosage forms by the subcutaneous or intramuscular
`routes.
`
`The expanding field of sustained and prolonged release of drug delivery
`employs various formulations and additives that at times aid in achieving the
`desired duration of drug action. These additives are primarily high-molecular-
`weight polymers or oily solvents. Formulations containing these macromole-
`cules are administered by the subcutaneous or intramuscular routes to permit
`the delayed release of the active ingredient within deeper tissues of the body.
`
`III. SPECIFIC ROUTES OF ADMINISTRATION
`
`Three primary routes of parenteral administration are commonly employed:
`intramuscular, intravenous, and subcutaneous. These three routes satisfy
`to a large extent the four principal reasons for administering parenterals:
`(1) for therapy (definitive or palliative), (2) for prevention, (3) for diagnosis,
`and (4) for temporarily altering tissue function(s) in order to facilitate other
`forms of therapy. Besides these three primary routes, additional ones are
`utilized under special circumstances:
`for example, _subconjunctival, intra-
`ocular, intrathecal, intra-articular, and so on.
`In the sections to follow ,
`the primary and special routes of parenteral administration are reviewed in
`alphabetical order. Each review will include four subheadings: description,
`indications, precautions, and method of drug or fluid delivery.
`
`A . Primary Routes
`Intramuscular
`
`Description.
`
`Injection directly into the body of a relaxed muscle.
`
`Indications. The intramuscular (i.m.) route is one of the most popular
`and convenient routes available, both for the administrator and for the patient
`[1], especially for a child [2]. Therefore, whenever it is possible and prac-
`ticable, the intramuscular route is used. The intramuscular route provides
`a means for prolonged release of drugs formulated as aqueous or oily solutions
`or suspensions. The intramuscular route is preferred over the subcutaneous
`route when a rapid rate of absorption is desired and over the intravenous
`route when for one reason or another the drug cannot be administered direct-
`ly into the vascular compartment.
`Many factors affect the rate of drug absorption from an intramuscular
`injection [2]; they will be discussed later in this chapter. Drugs commonly
`
`

`
`22
`
`—
`
`Duma et al.
`
`injected by intramuscular administration include lidocaine, cephalosporins,
`aminoglycosides, diazepam, insoluble salts of penicillin G (procane penicillin
`G), corticosteroids, narcotics, narcotic antagonists, and contraceptive steroids,
`to name a few.
`
`I Precautions. Although intramuscular injections are much easier to ad-
`minister than other injections, the main precaution is to avoid entering a blood
`vessel (especially an artery), which might lead to infusion of a toxic agent
`or a toxic Vehicle directly to an organ or tissue. This can be prevented usu-
`ally by pulling back on the plunger of the syringe; if blood does not appear,
`the needle is probably not in a vessel. Also, the accidental striking of or
`injection into a peripheral nerve may result in a peripheral nerve palsy with
`or without sensory damage. Occasionally, when a large bolus of drug is in-
`jected into the muscle, local damage or muscle infarction may result, leading
`to a sterile abscess or to elevation of serum levels of muscle enzymes. The
`latter complication may present confusing diagnostic problems, especially in
`patients under suspicion of having a myocardial infarction or hepatitis.
`If materials contaminated with microorganisms are injected, a septic abscess
`may result. Therefore, appropriate precautions must be taken to ensure ster-
`ility prior to injection.
`In patients with poor hygiene or skin care, microorga-
`nisms from the skin flora may be punched in by the needle at the time of in-
`jection, resulting in staphylococcal or streptococcal abscesses; and rarely in
`such situations as gas gangrene [3] (especially if epinephrine is injected)
`or tetanus [4].
`the intramuscular route should never be
`An important note of caution:
`employed in patients with significant heart failure or shock, when uptake into
`the vascular compartment may be expectantly poor. This caution should be
`followed especially if immediately high serum or plasma concentrations of the
`drug are desired or if rapid distribution to a distal organ is mandatory.
`
`Method. Various muscle sites are available for delivery (Fig. 1), includ-
`ing the gluteal, deltoid, triceps, pectoral, and vastus lateralis muscles.
`In
`adults the site of choice often is the gluteal muscle, because large volumes
`of drug may be injected and tolerated. However, the vastus lateralis of the
`thigh may also be used because it not only tolerates large volumes of medica-
`tion, but it is also away from any major vessels or nerves. For rapid absorp-
`tion and small volumes (<2 ml), the deltoid muscle is preferred, as some stud-
`ies suggest that blood flow in the deltoid muscle is 7% greater than that of
`the vastus lateralis and 17% greater than that of the gluteus maximus [5].
`For this reason, in adults the deltoid is the preferred site for vaccine admin-
`istration.
`In infants and small children, the vastus lateralis of the thigh is
`often preferred because it is better developed than other muscle groups, de-
`pending on the site selected. The skin is first cleaned with alcohol or a suit-
`able disinfectant, and the plunger on the syringe is always retracted prior
`to injeciton to be sure that the needle is not in a vessel. For deep intramus-
`cular injections, as might be used for irritating medications such as iron prep-
`arations, a "z-track" injection method is employed.
`
`Intravenous
`
`Description.
`
`Injections or infusions directly into a vein.
`
`

`
`Parenteral Drug Administration
`
`23
`
`Figure 1 Some common sites employed for intramuscular injections. Upper
`left: posterior gluteal, located in the outer upper quadrant about 2 in. below
`the iliac crest. Upper right: deltoid located about 2 in. below the acromion
`process. Lower left: ventrogluteal, located in the triangle formed by one
`finger on the anterior superior iliac spine and the other on the iliac crest.
`Lower right: vastus lateralis, located along the middle third and lateral as-
`pect of the thigh. The "bull's-eye" indicates the approximate site of injection.
`
`Intravenous (i.v.) administration of drugs, fluids, and/or
`Indications.
`electrolytes is one of the most common parenteral routes employed in hospitals
`today.
`It is especially convenient for rapidly infusing large volumes of fluid.
`The most common indication for use of this route are:
`( 1) to guarantee de-
`livery and distribution when hypotension or shock exists; (2) to restore rapid-
`ly electrolyte and fluid balance; (3) to achieve an immediate pharmacologic
`effect, especially in emergencies, such as the treatment of certain arrythmias
`or of seizures; (4) to treat serious, life-threatening infections or conditions;
`(5) to provide continuous nutrition (hyperalimentation) when patients are
`unable to be fed by mouth; and (6) to avoid complications which might result
`if other administration routes were employed (e.g. , hematomas at the site of
`intramuscular injections in a patient with a bleeding diathesis) .
`In addition,
`the intravenous route may be used for a variety of other purposes, such as
`plasmapheresis, blood transfusion, and hemodynamic monitoring, to name a few.
`
`

`
`24
`
`Duma et al.
`
`Precautions. A large number and variety of complications may occur us-
`ing the intravenous route. A few of these are:
`(1) thrombosis with or with-
`out complicating infection at the site of injection or infusion; (2) injection of
`microorganisms, toxins, particulate matter, or air; (3) the occurrence of phys-
`ical or chemical incompatibilities between agents prior to or at the time of in-
`jection; (4) uncontrolled or excessive administration of drugs or fluids; and
`(5) extravasation of injections or infusions at the site of administration. When
`indwelling catheters are utilized, rarely the catheter tip may break off and
`lodge in a major vessel, in the heart, or in the lung.
`
`Method. The upper extremities are chosen whenever possible for the
`site of injection or infusion. As many venous sites as possible should be pre-
`served for future use; thus the most peripheral veins (e.g. , those over the
`hand) are selected for initial use. When arm sites are no longer available,
`the leg veins (femoral and saphenous) or dorsal foot veins may be utilized;
`and in small children the scalp veins.
`Selection of a vein depends on the size of the needle or catheter intended
`for use, type of fluids to be infused, flow rate anticipated, volume to be re-
`ceived, concomitant medications to be given, degree of patient mobility de-
`sired, and of course the skill of the person performing the venipuncture or
`catheterization. The veins in the ante-cubital fossa are among the most com-
`monly chosen, because they are large and readily punctured. Other veins
`utilized commonly are basilic, cephalic, radial at the wrist, and the metacarpal
`and dorsal venons plexuses.
`Although the risk of infection appears to be less with needles than with
`indwelling intravenous catheters [6], an 8—in. long intravenous, plastic cathe-
`ter is commonly used for delivery of fluids via peripheral veins. Such cathe-
`ters reduce the risk of infiltration considerably, thus providing more comfort
`to the patient, reducing time and labor costs of nursing in managing the in-
`fusion, rendering pharmacokinetic predictions more reliable, and avoiding
`If
`adverse side effects, such as cellulitis and occasionally tissue sloughing.
`peripheral insertion sites become exhausted, surgical cut-downs of deep veins
`with implantation of indwelling catheters may be performed. When long-term ,
`repeated, or prolonged usage is anticipated, the subclavian or internal jugu-
`lar (central) veins in the upper chest may be utilized. These Veins are es-
`pecially useful if hyperosmolar fluids are to be infused, as physicochemical
`irritation and venospasm produced by the hyperosmolarity or chemical formu-
`lation of the fluids may be reduced or negated.
`In such instances, silastic
`tunnelled, implanted, central venous access catheters (e.g. , Broviac, Hick-
`man, Groshong, Port-A-Cath) tailored to each patient so that the tip of the
`catheter rests just above the right atrium, are often utilized. These devices
`are designed so that they can remain in place and be maintained indefinitely
`for the life of the patient.
`If needles are to be used for intravenous infusion, at 1- to 2—in. long,
`beveled, 18 to 22 gauge (Table 1), stainless steel needle is commonly used.
`Whether using a catheter or needle, the device is inserted percutaneously
`into the vein only after thoroughly cleaning the skin-insertion site and pre-
`paring it aseptically. Since infections appear to be more commonly associated
`with indwelling intravenous catheters than with needles, more time and care
`needs to be given to skin preparation with catheter use than with needle in-
`sertion. Such aseptic practices are especially important when "long-term"
`
`

`
`Parenteral Drug Administration
`
`Table I Needle Selection
`
`25
`
`Injection site
`
`Length range (in. )
`
`Gauge range
`
`Intra-abdominal
`
`Intra— articular
`
`Intracardiac
`
`Intradermal
`
`Intraocular
`Anterior chamber
`Intravitreal
`Retrobulbar
`Subconjunctial
`
`Intrapleural
`Intrathecal
`Adult
`Pediatric
`N eonatal
`
`Intravenous
`Metal needle
`
`Winged needle
`Plastic needle
`Intracatheter
`
`In—lying catheter
`Silastic catheter
`
`Hypodermoclysis
`Adult
`Pediatric
`
`Subcutaneous
`
`4-6
`
`1-3
`
`4-6
`
`1/4-5/8
`
`U1I-*I-‘P‘l—‘Iupn|.nIIO3CA303
`
`&lT*OOI-‘P-‘U1M.‘
`
`1-1%
`
`1/4-5/8
`
`14-18
`
`19- 22
`
`18-21
`
`24-26
`
`25
`25
`25
`25
`
`13-18
`
`20-22
`25
`27
`
`15-25
`16-23
`15-21
`15-21
`14, 15
`12-19
`
`19
`20-22
`
`24-25
`
`silastic catheters inserted into the subclavian vein or vena cava are utilized
`(vide supra). The mechanics of insertion usually involve a tourniquet being
`applied proximal to the site of insertion in order to Congest the vein (thus,
`If a catheter
`expanding the vein) , so that the device may be easily inserted.
`Afterwards,
`is used, it is inserted over a needle used for the initial puncture.
`the needle is removed, and the catheter is left in place.
`The indwelling cathe-
`ter or needle, whichever is utilized, is anchored to the extremity or body
`by means of appropriate, sterile occlusive or nonocclusive dressings, often
`impregnated with antibiotic ointments to reduce the risk of a complicating in-
`fection .
`Indwelling catheters often contain heparin locks to ensure against
`clotting and loss of patency from venous thrombosis.
`
`Subcutaneous
`
`Description .
`the skin (dermis).
`
`Injection into the loose connective and adipose tissue beneath
`
`

`
`26
`
`Duma et al.
`
`Indications. This route may be utilized if drugs cannot be administered
`orally because of lack of absorption from or inactivation by the contents of
`the gastrointestinal tract, if the patient is unable to ingest medications by
`mouth or if self-medication of parenterals (e.g. , insulin) is desired. Drugs
`are more rapidly and more predictably absorbed by this route than by the
`oral one, but absorption is slower and less predictable than by the intramus-
`cular route. Medications commonly administered subcutaneously (s.c.) include
`insulin, vaccines, narcotics, epinephrine, and vitamin B12. As with the intra-
`muscular route, if heart failure, shock, or vascular collapse exists, this route
`should not be depended upon.
`Hypoder-moclysis (see Sec. III.B) is a special form of subcutaneous admin-
`istration, namely, the infusion of large amounts of fluid into the subcutaneous
`tissues when intravenous sites are not available. This form of administration
`is rarely (if ever) used today but in the recent past was a common mode of
`replenishment of fluid and electrolytes in infants and elderly patients.
`
`Precautions. Medications that are highly acidic, alkaline