Routes of Drug Administration☆

Gordon T Bolger, Nucro-Technics, Scarborough, ON, Canada

© 2018 Elsevier Inc. All rights reserved.

This is an update of Lester Sultatos, Routes of Drug Administration, In xPharm: The Comprehensive Pharmacology Reference, Elsevier, New York, 2007,
Pages 1–3.

Enteral 1
Oral Route 1
Sublingual/Buccal and Rectal Suppositories 1
Parenteral 2
Intravenous 2
Intramuscular 2
Intraperitoneal 2
Subcutaneous 2
Topical Transdermal and Intradermal 2
Pulmonary and Intranasal 3
Intravaginal 3
Epidural and Intrathecal 3
References 3

In preclinical and clinical drug development studies and in therapeutic use, drugs may be given by a variety of routes of
administration. The selection of a route of is dependent on, ease of administration, compliance, the therapeutic target, study
being considered, the dosage form and the toxicological properties of the drug. To be discussed are the two major routes of drug
administration, enteral (via the gastrointestinal tract) and parenteral (outside of the gastrointestinal tract). In addition the impact of
physical–chemical properties of the drug, dose presentation, injection volume and metabolic barriers as they pertain to each route
of administration will be briefly discussed where appropriate.

Enteral
Oral Route
Administration (by mouth, per os, PO) is the most common route of administration for therapeutic drugs and the least invasive.
The dosage forms for PO administration include tablets, capsules containing liquids (oils) and solids and liquid preparations
(aqueous and oil). PO administration can be used for drugs with widely ranging solubilities, molecular weights and formulations
(ideal pH 3.0–9.0). Systemic levels of drugs achieved after oral administration are dependent on absorption through the brush-
border membrane of the gastrointestinal tract (GIT) lumen (Wilkinson, 2001), and display species specificity (Toutain et al., 2010).
Drug formulation is also influential as the composition of the formulation (pH, presence of solubility and permeation enhancers)
can greatly impact absorption (Strickley, 2004; Gad et al., 2006). Barriers to PO drug absorption include the molecular size and
charge of the drug, being substrates for GIT brush border efflux pumps, enzymatic stability and sequestration by the liver for
metabolism (first-pass effect). Facilitators of PO drug absorption include uptake transporters, bile salt emulsification and absorp-
tion via the lymphatic system, a route for larger drugs and drug-lipid complexes. Appropriately designed drug formulations can
control both the site of absorption (i.e., enteric coating) and rate of absorption (i.e., sustained release capsules). More recently,
nanoparticle (i.e., liposomes) drug preparation forms (liquid or solid) are being investigated to increase oral absorption. For
preclinical toxicological studies, the oral route of drug administration is preferred providing good systemic absorption is obtained.

Sublingual/Buccal and Rectal Suppositories

These routes can be used for the rapid absorption of drugs (re: sublingual/buccal, nitroglycerin (Takx et al., 2015) or when oral
administration is not possible due to vomiting or unconsciousness (re: rectal suppositories, tacrolimus (Stifft et al., 2014)). Many
drug formulations are tolerated by these routes. An additional advantage is avoidance of the “first-pass effect” for drugs that are
rapidly sequestered by the liver resulting in an increase in their systemic exposure. Drawbacks to the use of rectal suppositories
include patient compliance and interference with defication. In addition, the plasma levels of drugs attained following rectal
administration are usually lower than oral. Examples of drugs administered as rectal suppositories are valium, promethazine, and
morphine.

☆
Change History: March 2018. Gordon T Bolger Jan 2018 update the text references and figures.

Reference Module in Biomedical Sciences https://doi.org/10.1016/B978-0-12-801238-3.11099-2 1

2 Routes of Drug Administration

Parenteral

Parenteral routes available for drug administration may include intravenous, intramuscular, subcutaneous, dermal and subdermal,
pulmonary and intranasal, intraperitoneal, ocular, otic, intravaginal, epidural, and intrathecal. Parenteral compared to PO admin-
istration is employed under circumstances: (i) where an drug is subjected to limited bioavailability (poor absorption); (ii) for a
patient who is vomiting or unconscious; (iii) when drugs must be applied directly to, or in the vicinity of, the target site (i.e., ocular,
medicated eye drops; otic, medicated ear drops; intranasal, nasal decongestants; intravaginal, medicated vaginal suppositories;
penile, suppositories for erectile dysfunction), (iv) when drugs are irritating to the gastrointestinal tract; (v) when drugs, such as
some general anesthetics, are gases or vapors at room temperature and pressure; (vi) when an immediate effect is required. Water
solubility as well as solubility in the drug vehicle and the rate of blood flow are important factors for the non-intravenous routes as
absorption into the systemic circulation usually occurs by passive diffusion. Parenteral routes of dosing are discussed in more detail
below.

Intravenous
Intravenous (IV) administration avoids the first-pass drug effect resulting in direct entry of drug into the systemic circulation and
consequently an immediate drug effect. Intravenously administered drugs are given either as a “bolus” (within 1–30 min) or an
infusion over a period of many hours. Bolus IV administration is rarely used and is restricted to emergency situations where a critical
rapid, but restricted duration of drug action is required. The anesthesia inducing agent thiopental is an example of a short acting
bolus IV injected drug. Administration of drugs via IV infusion is necessary when longer/continuous systemic exposures are required
to elicit a therapeutic effect. Examples of drug classes that are administered by IV infusion are cancer chemotherapeutics, antibiotics,
antifungals, and antinociceptive drugs. Critical factors for IV dosing include, injection volume, pH, tonicity, and drug presentation
(only soluble, emulsion, nanoparticle forms tolerated) of the formulation administered to avoid cardiopulmonary side effects.

Intramuscular
Intramuscular (IM) administration is by injection into the striated muscle (Hopkins and Arias, 2013). The sites most commonly
used for IM injection are the deltoid, dorsogluteal, rectus femoris, vastus lateralis, and ventrogluteal muscles. The choice of a site
depends on the volume to be injected. Striated muscle is rich in vasculature and IM injected drug diffuses into the systemic
circulation rapidly. Water soluble drugs (i.e., insulin for diabetes and epinephrine for anaphylactic shock) diffuse quicker whereas
drugs dissolved in an oil based vehicle diffuse slower. Bioavailability via the IM route of administration is 100% as the first-pass
effect of the liver is avoided. Dosing by the IM route is restricted by the small volume of administration (0.05–0.5 mL/kg in
preclinical species, 2–5 mL in human). The rate of administration should be slow (to avoid muscle damage) and the drug
formulation should be non-irritating.

Intraperitoneal
The injection of substances by this route is commonly used in rodents in preclinical studies (Turner et al., 2011) and is rarely used in
larger mammals and humans. Injection volumes up to 10 mL/kg are well tolerated and should be from formulations that are
isotonic and non-irritating. The absorption of drug occurs through the mesenteric vessels and is similar to oral drug administration.

Subcutaneous
Subcutaneous (SC) injection is similar to intramuscular administration of drugs. Volumes administered are restricted (human
1.5–3.5 mL, preclinical species 1–10 mL/kg) to minimize pain at the injection site. As with intramuscular injection, it can be utilized
to circumvent drug inactivation or patient noncompliance. In some cases vasoconstrictors are included in the drug formulation
reduce systemic absorption (i.e., local anesthetics). SC drug administration may be utilized when intramuscular administration
might damage the tissue at the site of injection or for the slow release of drug into the systemic circulation. Biopharmaceuticals (i.e.,
trastuzumab, rituximab, bortezomib), are examples of drugs administered by the SC route (Jin et al., 2015).

Topical Transdermal and Intradermal

The skin forms an effective barrier to most drugs, large drug molecule are less likely to be absorbed transdermally (TD). Other critical
factors for TD drug absorption include drug lipophilicity, formulation (presence of penetration enhancers) and the hydration state
of the skin (hydrated skin is more absorptive). TD delivery systems both hydrate the skin and serve as a reservoir to deliver drug by
passive diffusion over a longer period of time. Estradiol, is an example of such a drug. TD absorption is slow but continuous
circumventing possible toxicity to the gastrointestinal tract and the liver and can deliver drug for both systemic and local activity.
Diclofenac is too toxic for oral administration, but can be applied topically to the skin to reduce the pain associated with local
inflammation. Intradermal (ID) injection is restricted to small volumes (0.05–0.1 mL) and dependent on the thickness of the skin.
 Routes of Drug Administration 3

Diffusion from the ID injection site is slow and the use of this route is restricted to local anesthetics and for assessing immune,
inflammatory or sensitization response (Diehl et al., 2001).

Pulmonary and Intranasal

Pulmonary administration (PA) of drugs is by either nasal or oral inhalation for treating chronic pulmonary diseases and can be
used for the systemic delivery of drugs (Patil and Sarasija, 2012). Intratracheal instillation directly into the lung is most commonly
used in preclinical research. Devices for PA drug delivery by inhalation include aerosolized/nebulized liquids, nanoparticles, and
dry powders. Particle size dictates where the inhaled drug will go in the lungs and produce a therapeutic effect. The alveoli provides
little or no barrier to drugs and thus, general anesthetics such as halothane and nitrous oxide will readily traverse them, resulting in
the rapid anesthesia of the CNS. Aerosols may penetrate the alveoli, although most aerosols will be trapped in the upper respiratory
tract. Examples of PA drugs include glucocorticoids to treat COPD and anti-tubercular drugs. Preclinical studies have indicated the
potential for the systemic administration of insulin by PA. The rich blood vessel vasculature of the nasal mucosa, is a target for either
local administration (i.e., vaccinations, decongestant sprays) or the rapid systemic delivery of substances (i.e., migraine drugs,
nicotine replacement, hormone therapy).

Intravaginal
Absorption systemically of drugs via these routes is through the mucosal membrane, is for specific applications, is limited and drug
activity depends on their potency and how rapidly they are metabolized. Drugs are administered as a suppository (i.e., pills and
creams) and may either be for local or systemic application depending the therapeutic target. Thus antifungal and antibacterial
preparations for intravaginal administration are formulated for a more local action, while potent hormones such as estrogens and
progestins are administered intravaginally for their systemic actions.

Epidural and Intrathecal

These routes of administration are for the precise administration of drugs by needle into the cerebrospinal tissues or meninges, thus
avoiding potential absorption problems due to the blood-brain barrier (Turner et al., 2011). It is most commonly used for spinal
anesthesia and for the administration of contrast medium to visualize vertebral bodies. This route of administration requires
anesthesia and is technically challenging.

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