For medications that do not require an immediate onset of action or would benefit from sustained, constant blood concentrations without requiring constant infusion, administration can be accomplished using superficial, nonvascular injections. Typically, the sites utilized are the large muscles (intramuscular) or subcutaneous tissue spaces. The muscles, and to a somewhat lesser extent, the subcutaneous tissues are well perfused by the vascular system, thus, both of these sites are frequently used for systemic administration. The peritoneal cavity can also be used for the administration of large volumes of drug solution for systemic or local therapies.
Other parenteral delivery sites include the dermis, a region just below the skin (intradermal); the spinal column (intrathecal, intralumbar, or epidural); the joint spaces (intra-articular or intrasynovial); and the eye (intravitreal, subconjunctival).
The administration of relatively small volumes (<2-5 mL) of concentrated drug solutions or suspensions into large muscles (deltoid, vastus lateralis, gluteus maximus) can result in therapeutic systemic concentrations of drug. The injected volumes spread within the interstitial spaces of the muscle tissue bringing the drug into close proximity with the muscle capillary network. When aqueous drug solutions are administered, absorption into the systemic circulation is quite rapid, and drug distribution patterns are similar to those observed after IV administration of the same drug, often with only a slight delay due to the necessary absorption step. More prolonged action can be obtained using a lipophilic form of drug dissolved in an oil-based vehicle (e.g., sesame oil). Drug absorption is slowed by the necessity for drug partitioning from the oily vehicle into the aqueous-like ISF prior to systemic absorption.
There is the possibility that the drug may not be entirely absorbed from the administration site or it may be metabolized by the enzymes present within the cells or ISF. For example, Doluisio et al. (6) found that only 77% to 78% of an intramuscular injection of ampicillin sodium was absorbed systemically. The remaining * 12% was likely chemically or enzymatically changed to an inactive form.
Drug suspensions, either in oily or in aqueous vehicles, can also be administered intramuscularly, and their absorption is much slower than that of drug solutions. The solid drug must first dissolve in the vehicle and then mix with or partition into the ISF. Since the ISF volume is low, this dissolution step may be quite slow and can result in the continuous absorption of small amounts of drug for extended periods (days, weeks, months) of time. If this small amount of drug results in a therapeutic concentration at the target site, then an intramuscular injection provides an excellent mode of drug delivery. Unfortunately, there are only a limited number of drugs that are suitable for extended delivery following intramuscular injection because of the limited volumes that can be utilized for these injections and the need for a highly potent drug to achieve therapeutic blood levels following the absorption of the small amounts of drug that can be dissolved in the muscle fluids.
Because of the need to accommodate the volume of fluid contained in an intramuscular injection, the large muscles of the upper arm, thigh, abdomen, or buttocks are typically used as sites of administration. While these tissues are quite similar and would be expected to show similar absorption patterns, it has been shown that significant differences in the rate of absorption of lidocaine hydrochloride (7-9) are observed when different muscle sites are utilized, and the absorption differences can be attributed to the differences in regional blood flow to these muscles. Among the deltoid, vastus lateralis, and gluteus maximus muscles, the blood flow is greatest to the deltoid and least to the gluteus maximus; the magnitude of the lidocaine blood concentrations following administration to these muscles was shown to follow the same pattern (Fig. 3). As lidocaine partitions into the blood vessels, the increased perfusion of the deltoid muscle allows the more rapid removal of lidocaine from this muscle, and this results in a higher drug concentration in the blood. If, instead, a slower, more sustained blood concentration is desired, especially for longer-acting dosage forms, it would be best to administer these in the gluteus maximus because of the lower perfusion of this muscle. As one might also expect, the degree of muscle movement may directly impact absorption because of increases or decreases in blood flow. This effect can be directly observed in geriatric patients whose more sedentary nature can lead to poor and erratic absorption of intramuscular dosage forms.
The subcutaneous tissues are composed of adipose and connective tissues and are only moderately perfused by the vascular system. As a result, drug absorption following subcutaneous administration is typically slower than that following intramuscular administration, and it may be somewhat erratic, depending on the amount of adipose tissue present at the site. Lipophilic drug compounds, in particular, may partition into the adipose tissue and remain at the delivery site for an extended period of time. The subcutaneous tissues, however, are more loosely arranged than the muscle tissues, and this enables aqueous-based subcutaneous formulations to readily mix with the ISF and allows for rapid systemic absorption of water-soluble compounds. Aqueous-based suspensions can also be administered subcutaneously. Similar to the behavior of suspensions administered intramuscularly, the dissolution step of the solid drug into the ISF can be quite slow, resulting in an extended duration of the effect following administration.
The significant population of lymphatic vessels present within the subcutaneous tissues also influences the resulting systemic distribution pattern of drugs administered subcutaneously. Since systemic bioavailability is typically estimated by measuring the concentration of the drug in the blood following administration, drugs that distribute into
05 15 30 60 90 120 180 240
05 15 30 60 90 120 180 240
Figure 3 Differences in blood concentration of lidocaine following the intramuscular injection of 6 mg/kg lidocaine (10%) into either the deltoid or the gluteal muscle. Absorption from the deltoid muscle was more rapid than from the gluteus, and higher blood concentrations were obtained from the intradeltoid injection. Source: From Ref. 8
the lymph may appear to have lower systemic bioavailabilities while still retaining pharmacologic efficacy. The distribution of drug within the lymph system and its subsequent entry into the vascular system are difficult to precisely control because of the slower flow velocities of the lymph and the dependence of lymphatic clearance on nearby muscle movement. An enhanced effectiveness of a drug whose pharmacologic target is within or associated with the lymphatics may be accomplished using subcutaneous administration.
The peritoneal cavity can accommodate large volumes of fluid and contains a large vascular surface area from the peritoneum, the membrane that defines the cavity. Perhaps the best-known use of the peritoneal cavity is for peritoneal dialysis in the treatment of renal failure. In this case, large volumes of fluids are placed into the peritoneal cavity, and small polar molecules, those typically cleared by the kidneys, equilibrate with the fluids and are thus removed from the body when the peritoneal fluids are evacuated from the cavity. Drugs can also be added to the fluids placed into the peritoneal cavity and can be absorbed into the surrounding vasculature and tissues for systemic delivery. Peritoneal delivery can also be used to administer drugs to the organs of the peritoneal cavity in an effort to limit systemic side effects. A good example of this is the increased survival rate of patients receiving paclitaxel intraperitoneally in addition to IV therapy in the treatment of ovarian cancer (10).
While limited to highly specialized therapies, the ability to deliver drugs directly via injection to some otherwise poorly perfused or difficult-to-reach tissue sites can enable the local treatment of symptoms or diseases that cannot otherwise be accomplished through systemic administration. Since the drug concentration at any site within the body that is distant from the site of administration is the direct result of the concentration gradient between the blood and adjacent tissue, extremely high blood concentrations are required to reach therapeutic tissue concentrations at many sites. These elevated blood concentrations, however, can lead to numerous unwanted effects of the drug at other sites. Yet, if a tissue site is somewhat isolated or distinct from other nearby structures, it may be possible to inject drug directly into the tissue allowing a local therapeutic concentration to be reached. Since most of these sites receive only a small fraction of the total vascular volume, only small amounts of drug are transferred into the systemic vasculature, and any amounts that are transferred are diluted into the systemic volume of distribution. This typically results in low systemic concentrations of drug and potentially prolonged effective concentrations at the site of administration. Some of the more frequently accessed sites are listed in Table 2.
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