Oral (Enteral) Versus Parenteral Administration. Often there is a choice of the route by which a therapeutic agent may be administered, and knowledge of the advantages and disadvantages of the different routes of administration is then of primary importance. Some characteristics of the major routes employed for systemic drug effect are compared in Table 2–1.
Oral ingestion is the most common method of drug administration. It also is the safest, most convenient, and most economical. Disadvantages to the oral route include limited absorption of some drugs because of their physical characteristics (e.g., low water solubility or poor membrane permeability), emesis as a result of irritation to the GI mucosa, destruction of some drugs by digestive enzymes or low gastric pH, irregularities in absorption or propulsion in the presence of food or other drugs, and the need for cooperation on the part of the patient. Such cooperation is frequently not forthcoming, since tolerating certain oral medications means accepting unwanted effects, such as GI pain, which may require use of an alternate route of administration (Cosman, 2009). In addition, drugs in the GI tract may be metabolized by the enzymes of the intestinal flora, mucosa, or liver before they gain access to the general circulation.
Parenteral injection of drugs has certain distinct advantages over oral administration. In some instances, parenteral administration is essential for the drug to be delivered in its active form, as in the case of monoclonal antibodies such as infliximab, an antibody directed against tumor necrosis factor α (TNF α) used in the treatment of rheumatoid arthritis. Availability usually is more rapid, extensive, and predictable when a drug is given by injection. The effective dose can therefore be delivered more accurately. In emergency therapy and when a patient is unconscious, uncooperative, or unable to retain anything given by mouth, parenteral therapy may be a necessity. The injection of drugs, however, has its disadvantages: asepsis must be maintained, and this is of particular concern when drugs are given over time, such as in intravenous or intrathecal administration; pain may accompany the injection; and it is sometimes difficult for patients to perform the injections themselves if self-medication is necessary.
Oral Administration. Absorption from the GI tract is governed by factors such as surface area for absorption, blood flow to the site of absorption, the physical state of the drug (solution, suspension, or solid dosage form), its water solubility, and the drug's concentration at the site of absorption. For drugs given in solid form, the rate of dissolution may limit their absorption, especially drugs of low aqueous solubility. Since most drug absorption from the GI tract occurs by passive diffusion, absorption is favored when the drug is in the non-ionized and more lipophilic form. Based on the pH-partition concept (Figure 2–3), one would predict that drugs that are weak acids would be better absorbed from the stomach (pH 1-2) than from the upper intestine (pH 3-6), and vice versa for weak bases. However, the epithelium of the stomach is lined with a thick mucus layer, and its surface area is small; by contrast, the villi of the upper intestine provide an extremely large surface area (~200 m2). Accordingly, the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predominantly ionized in the intestine and largely non-ionized in the stomach. Thus, any factor that accelerates gastric emptying (recumbent position, right side) will be likely to increase the rate of drug absorption (Queckenberg and Fuhr, 2009), whereas any factor that delays gastric emptying is expected to have the opposite effect, regardless of the characteristics of the drug. Gastric motor activity and gastric emptying rate are governed by neural and humoral feedback provided by receptors found in the gastric musculature and proximal small intestine. In healthy individuals, gastric emptying rate is influenced by a variety of factors including the caloric content of food; volume, osmolality, temperature, and pH of ingested fluid; diurnal and inter-individual variation; metabolic state (rest/exercise); and the ambient temperature. Such factors will influence ingested drug absorption. Gastric emptying is influenced in women by the effects of estrogen (i.e., slower than in men for premenopausal women and those taking estrogen replacement therapy).
Drugs that are destroyed by gastric secretions and low pH or that cause gastric irritation sometimes are administered in dosage forms with an enteric coating that prevents dissolution in the acidic gastric contents. These pharmacologically inactive coatings, often of cellulose polymers, have a threshold of dissolution between pH 5 and 6. Enteric coatings are useful for drugs such as aspirin, which can cause significant gastric irritation in many patients, and for presenting a drug such as mesalamine to sites of action in the ileum and colon (Figure 47–4).
Controlled-Release Preparations. The rate of absorption of a drug administered as a tablet or other solid oral dosage form is partly dependent on its rate of dissolution in GI fluids. This is the basis for controlled-release, extended-release, sustained-release, and prolonged-action pharmaceutical preparations that are designed to produce slow, uniform absorption of the drug for 8 hours or longer. Such preparations are offered for medications in all major drug categories. Potential advantages of such preparations are reduction in the frequency of administration of the drug as compared with conventional dosage forms (often with improved compliance by the patient), maintenance of a therapeutic effect overnight, and decreased incidence and/or intensity of both undesired effects (by dampening of the peaks in drug concentration) and nontherapeutic blood levels of the drug (by elimination of troughs in concentration) that often occur after administration of immediate-release dosage forms.
Many controlled-release preparations fulfill these expectations and may be preferred in some therapeutic situations (e.g., therapy for depression [Nemeroff, 2003] and ADHD [Manos et al., 2007]) or treatment with dihydropyridine Ca2+ entry blockers (Chapters 26, 27, 28). However, such products do have drawbacks: variability of the systemic concentration achieved may be greater for controlled-release than for immediate-release dosage forms; the dosage form may fail, and "dose dumping" with resulting toxicity can occur because the total dose of drug in a controlled-release preparation may be several times the amount contained in the conventional preparation, although current regulatory approval requirements generally preclude such occurrences. Controlled-release dosage forms are most appropriate for drugs with short half-lives (t1/2 <4 hours) or in selected patient groups such as those receiving anti-epileptics (Bialer, 2007; Pellock et al., 2004). So-called controlled-release dosage forms are sometimes developed for drugs with long t1/2 values (>12 hours). These usually more expensive products should not be prescribed unless specific advantages have been demonstrated. The availability of controlled-release dosage forms of some drugs can lead to abuse, as in the case of controlled-release oxycodone marketed as oxycontin. Crushing and snorting the delayed-release tablets results in a rapid release of the drug, increased absorption, and high peak serum concentrations (Aquina et al., 2009).
Sublingual Administration. Absorption from the oral mucosa has special significance for certain drugs despite the fact that the surface area available is small. Venous drainage from the mouth is to the superior vena cava, bypassing the portal circulation and thereby protecting the drug from rapid intestinal and hepatic first-pass metabolism. For example, nitroglycerin is effective when retained sublingually because it is non-ionic and has very high lipid solubility. Thus, the drug is absorbed very rapidly. Nitroglycerin also is very potent; absorption of a relatively small amount produces the therapeutic effect ("unloading" of the heart; Chapter 27).
Transdermal Absorption. Not all drugs readily penetrate the intact skin. Absorption of those that do is dependent on the surface area over which they are applied and their lipid solubility because the epidermis behaves as a lipid barrier (Chapter 65). The dermis, however, is freely permeable to many solutes; consequently, systemic absorption of drugs occurs much more readily through abraded, burned, or denuded skin. Inflammation and other conditions that increase cutaneous blood flow also enhance absorption. Toxic effects sometimes are produced by absorption through the skin of highly lipid-soluble substances (e.g., a lipid-soluble insecticide in an organic solvent). Absorption through the skin can be enhanced by suspending the drug in an oily vehicle and rubbing the resulting preparation into the skin. Because hydrated skin is more permeable than dry skin, the dosage form may be modified or an occlusive dressing may be used to facilitate absorption. Controlled-release topical patches have become increasingly available, including nicotine for tobacco-smoking withdrawal, scopolamine for motion sickness, nitroglycerin for angina pectoris, testosterone and estrogen for replacement therapy, various estrogens and progestins for birth control, and fentanyl for pain relief.
Rectal Administration. Approximately 50% of the drug that is absorbed from the rectum will bypass the liver; the potential for hepatic first-pass metabolism thus is less than that for an oral dose; furthermore, a major drug metabolism enzyme, CYP3A4, is present in the upper intestine but not in the lower intestine. However, rectal absorption can be irregular and incomplete, and certain drugs can cause irritation of the rectal mucosa. The use of special mucoadhesive microspheres may increase the number of medications that can be given by the rectal route (Patil and Sawant, 2008).
Parenteral Injection. The major routes of parenteral administration are intravenous, subcutaneous, and intramuscular. Absorption from subcutaneous and intramuscular sites occurs by simple diffusion along the gradient from drug depot to plasma. The rate is limited by the area of the absorbing capillary membranes and by the solubility of the substance in the interstitial fluid. Relatively large aqueous channels in the endothelial membrane account for the indiscriminate diffusion of molecules regardless of their lipid solubility. Larger molecules, such as proteins, slowly gain access to the circulation by way of lymphatic channels.
Drugs administered into the systemic circulation by any route, excluding the intra-arterial route, are subject to possible first-pass elimination in the lung prior to distribution to the rest of the body. The lungs serve as a temporary storage site for a number of agents, especially drugs that are weak bases and are predominantly non-ionized at the blood pH, apparently by their partition into lipid. The lungs also serve as a filter for particulate matter that may be given intravenously, and they provide a route of elimination for volatile substances.
Intravenous. Factors limiting absorption are circumvented by intravenous injection of drugs in aqueous solution because bioavailability is complete and rapid. Also, drug delivery is controlled and achieved with an accuracy and immediacy not possible by any other procedure. In some instances, as in the induction of surgical anesthesia, the dose of a drug is not predetermined but is adjusted to the response of the patient. Also, certain irritating solutions can be given only in this manner because the drug, if injected slowly, is greatly diluted by the blood. There are both advantages and disadvantages to the use of this route of administration. Unfavorable reactions can occur because high concentrations of drug may be attained rapidly in both plasma and tissues. There are therapeutic circumstances where it is advisable to administer a drug by bolus injection (small volume given rapidly, e.g., tissue plasminogen activator immediately following an acute myocardial infarction) and other circumstances where slower administration of drug is advisable, such as the delivery of drugs by intravenous "piggyback" (e.g., antibiotics). Intravenous administration of drugs warrants close monitoring of the patient's response. Furthermore, once the drug is injected, there is often no retreat. Repeated intravenous injections depend on the ability to maintain a patent vein. Drugs in an oily vehicle, those that precipitate blood constituents or hemolyze erythrocytes, and drug combinations that cause precipitates to form must not be given by this route.
Subcutaneous. Injection into a subcutaneous site can be done only with drugs that are not irritating to tissue; otherwise, severe pain, necrosis, and tissue sloughing may occur. The rate of absorption following subcutaneous injection of a drug often is sufficiently constant and slow to provide a sustained effect. Moreover, altering the period over which a drug is absorbed may be varied intentionally, as is accomplished with insulin for injection using particle size, protein complexation, and pH to provide short-acting (3-6 hours), intermediate-acting (10-18 hours), and long-acting (18-24 hours) preparations. The incorporation of a vasoconstrictor agent in a solution of a drug to be injected subcutaneously also retards absorption. Thus, the injectable local anesthetic lidocaine incorporates epinephrine into the dosage form. Absorption of drugs implanted under the skin in a solid pellet form occurs slowly over a period of weeks or months; some hormones (e.g., contraceptives) are administered effectively in this manner, and implantable devices (e.g., a plastic rod delivering etonogestrel) can provide effective contraception for 3 years (Blumenthal et al., 2008).
Intramuscular. Drugs in aqueous solution are absorbed quite rapidly after intramuscular injection depending on the rate of blood flow to the injection site. This may be modulated to some extent by local heating, massage, or exercise. For example, while absorption of insulin generally is more rapid from injection in the arm and abdominal wall than the thigh, jogging may cause a precipitous drop in blood sugar when insulin is injected into the thigh rather than into the arm or abdominal wall because running markedly increases blood flow to the leg. A hot bath accelerates absorption from all these sites owing to vasodilation. Generally, the rate of absorption following injection of an aqueous preparation into the deltoid or vastus lateralis is faster than when the injection is made into the gluteus maximus. The rate is particularly slower for females after injection into the gluteus maximus. This has been attributed to the different distribution of subcutaneous fat in males and females and because fat is relatively poorly perfused. Very obese or emaciated patients may exhibit unusual patterns of absorption following intramuscular or subcutaneous injection. Slow, constant absorption from the intramuscular site results if the drug is injected in solution in oil or suspended in various other repository (depot) vehicles. Antibiotics often are administered in this manner. Substances too irritating to be injected subcutaneously sometimes may be given intramuscularly.
Intra-arterial. Occasionally, a drug is injected directly into an artery to localize its effect in a particular tissue or organ, such as in the treatment of liver tumors and head/neck cancers. Diagnostic agents sometimes are administered by this route (e.g., technetium-labeled human serum albumin). Intra-arterial injection requires great care and should be reserved for experts. The dampening, first-pass, and cleansing effects of the lung are not available when drugs are given by this route.
Intrathecal. The blood-brain barrier and the blood-cerebrospinal fluid (CSF) barrier often preclude or slow the entrance of drugs into the CNS. Therefore, when local and rapid effects of drugs on the meninges or cerebrospinal axis are desired, as in spinal anesthesia or treatment of acute CNS infections, drugs sometimes are injected directly into the spinal subarachnoid space. Brain tumors also may be treated by direct intraventricular drug administration. More recent developments include special targeting of substances to the brain via receptor-mediated transcytosis (Jones and Shusta, 2007) and modulation of tight junctions (Matsuhisa et al., 2009).
Pulmonary Absorption. Provided that they do not cause irritation, gaseous and volatile drugs may be inhaled and absorbed through the pulmonary epithelium and mucous membranes of the respiratory tract. Access to the circulation is rapid by this route because the lung's surface area is large. The principles governing absorption and excretion of anesthetic and other therapeutic gases are discussed in Chapter 19. In addition, solutions of drugs can be atomized and the fine droplets in air (aerosol) inhaled. Advantages are the almost instantaneous absorption of a drug into the blood, avoidance of hepatic first-pass loss, and in the case of pulmonary disease, local application of the drug at the desired site of action. For example, owing to the ability to meter doses and create fine aerosols, drugs can be given in this manner for the treatment of allergic rhinitis or bronchial asthma (Chapter 36). Pulmonary absorption is an important route of entry of certain drugs of abuse and of toxic environmental substances of varied composition and physical states. Both local and systemic reactions to allergens may occur subsequent to inhalation.
Mucous Membranes. Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder primarily for their local effects. Occasionally, as in the application of synthetic anti-diuretic hormone to the nasal mucosa, systemic absorption is the goal. Absorption through mucous membranes occurs readily. In fact, local anesthetics applied for local effect sometimes may be absorbed so rapidly that they produce systemic toxicity.
Eye. Topically applied ophthalmic drugs are used primarily for their local effects (Chapter 64). Systemic absorption that results from drainage through the nasolacrimal canal is usually undesirable. Because drug that is absorbed via drainage is not subject to first-pass intestinal and hepatic metabolism, unwanted systemic pharmacological effects may occur when β adrenergic receptor antagonists or corticosteroids are administered as ophthalmic drops. Local effects usually require absorption of the drug through the cornea; corneal infection or trauma thus may result in more rapid absorption. Ophthalmic delivery systems that provide prolonged duration of action (e.g., suspensions and ointments) are useful additions to ophthalmic therapy. Ocular inserts, such as the use of pilocarpine-containing inserts for the treatment of glaucoma, provide continuous delivery of small amounts of drug. Very little is lost through drainage; hence systemic side effects are minimized.
Novel Methods of Drug Delivery
Drug-eluting stents and other devices are being used to target drugs locally and minimize systemic exposure. The systemic toxicity of potentially important compounds can be decreased significantly by combination with a variety of drug carrier vehicles that modify distribution. For example, linkage of the cytotoxic agent calicheamicin to an antibody directed to an antigen found on the surface of certain leukemic cells can target the drug to its intended site of action, improving the therapeutic index of calicheamicin.
Recent advances in drug delivery include the use of biocompatible polymers with functional monomers attached in such a way as to permit linkage of drug molecules to the polymer. A drug-polymer conjugate can be designed to be a stable, long-circulating prodrug by varying the molecular weight of the polymer and the cleavable linkage between the drug and the polymer. The linkage is designed to keep the drug inactive until it released from the backbone polymer by a disease-specific trigger, typically enzyme activity in the targeted tissue that delivers the active drug at or near the site of pathology. Nanoparticles are offering new opportunities for diagnosis, targeted drug delivery, and imaging of clinical effect (Prestidge et al., 2010; Sajja et al., 2009).
Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration. Two pharmaceutically equivalent drug products are considered to be bioequivalent when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different under suitable test conditions. In the past, dosage forms of a drug from different manufacturers and even different lots of preparations from a single manufacturer sometimes differed in their bioavailability. Such differences were seen primarily among oral dosage forms of poorly soluble, slowly absorbed drugs such as the urinary anti-infective, metronidazole (flagyl). When first introduced, the generic form was not bioequivalent because the generic manufacturer was not able to mimic the proprietary process used to microsize the drug for absorption initially. Differences in crystal form, particle size, or other physical characteristics of the drug that are not rigidly controlled in formulation and manufacture affect disintegration of the dosage form and dissolution of the drug and hence the rate and extent of drug absorption.
The potential non-equivalence of different drug preparations has been a matter of concern (Meredith, 2009). However, no prospective clinical study has shown an FDA-approved generic drug product to yield significantly different therapeutic effects, even when testing published anecdotal reports of non-equivalence. Because of the legitimate concern of clinicians and the financial consequences of generic prescribing, this topic will continue to be actively addressed. Generic versus brand name prescribing is further discussed in connection with drug nomenclature and the choice of drug name in writing prescription orders (Appendix I).