Intramuscular and subcutaneous injection

Where differences in bioavailability between i.m., s.c and oral or i.v. delivery occur, the clinical importance is most marked when the route of administrahon is changed from one to the other, and, of course, such changes are most important in dmgs with a low therapeutic index such as digoxin and phenytoin. 

If it is assumed that dmg absorption proceeds by passive diffusion of the dmg, it can he considered to be a first-order process. Thus the rate of absorption is proportional to the concentration, C, of dmg remaining at the injection site  

Drug absorption is 90% complete when a time equivalent to three times the half-life has elapsed. 

Both dissolution and diffusion are important parameters in defining bioavailability of species by the i.m. or s.c. routes. Soluble neutral compounds disperse from intramuscular sites according to size Table 9.7 shows that mannitol, a small molecule, rapidly diffuses from the site of injection insulin 

Drawing modified after David S. Quackenbush, in E. W. Martin, Techniques of Medication, Lippincott, Philadelphia, 1969. 

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Some types of injections must be made iso-osmotic with blood serum. This applies particularly to large-volume intravenous infusions if at all possible hypotonic solutions cause lysis of red blood corpuscles and thus must not be used for this purpose. Conversely, hypertonic solutions can be employed these induce shrinkage, but not lysis, of red cells which recover their shape later. Intraspinal injections must also be isotonic, and to reduce pain at the site of injection so should intramuscular and subcutaneous injections. Adjustment to isotonicity can be determined by the following methods. 

Intramuscular and subcutaneous injections are by far the most common means of parenteral drug administration. Because of the high tissue blood flow and the ability of the injected solution to diffuse laterally, drug absorption generally is more rapid after intramuscular than after subcutaneous injection. Drug absorption from intramuscular and subcutaneous sites depends on the quantity and composition of the connective tissue, the capillary density, and the rate of vascular perfusion of the area. These factors can be influenced by the coinjection of agents that alter local blood flow (e.g., vasoconstrictors or vasodilators) or by substances that decrease tissue resistance to lateral diffusion (e.g., hyaluronidase). 

The rates of absorption, clearance, and elimination of penicillin G are further influenced by the route of administration. Intramuscular and subcutaneous injections provide drug to the bloodstream more slowly, but maintain concentrations longer than the intravenous administration. Absorption of penicillin G from intramuscular or subcutaneous sites can be further slowed down by the use of the relatively insoluble procaine salt. When equivalent dosages of penicillin G and procaine penicillin G were injected parenterally, peak residues concentration in blood occurred after 2 h and the drug had cleared the blood by 8 following penicillin G administration. With the procaine penicillin G, peak residues concentration appeared 5 h after injection and the drug cleared the plasma 24 h after administration (57). 

L Kaartinen, M Salonen, L Alii, S Pyorala. Pharmacokinetics of enrofloxacin after single intravenous, intramuscular and subcutaneous injections in lactating cows. J Vet Pharmacol Ther 18 357— 362, 1995. 

Historically, the administration of crystalline APIs has mainly found use in parenteral applications associated with intramuscular and subcutaneous injections as well as topical applications of suspensions containing micronized APIs. Commercially marketed pharmaceuticals categorized as suspensions for parenteral administration are illustrated in Table 17.3. Many of these products utilize drug substance size reduction in order to promote dissolution following administration. The degree... 

Howard JR, Hadgraft J. The clearance of oily vehicles following intramuscular and subcutaneous injections in rabbits. Int J Pharm 1983 16 31-39. 

Sesame oil is mainly used in intramuscular and subcutaneous injections it should not be administered intravenously. It is also used in topical pharmaceutical formulations and consumed as an edible oil. 

The steroids as a group tend to be poorly soluble in water. Their complex stmcture makes prediction of solubility somewhat difficult, but one can generally rationalise, post hoc, the solubility values of related steroids. Table 5.6 gives solubility data for 14 steroids. As examples, the substitution of an ethinyl group has conferred increased solubility on the estradiol molecule, as would be expected. Estradiol benzoate with its 3-OH substituent is much less soluble than the parent estradiol because of the loss of the hydroxyl and its substitution with a hydrophobic group. The same relationships are seen in testosterone and testosterone propionate. As both estradiol benzoate and testosterone propionate are oil soluble, they are used as solutions in castor oil and sesame oil for intramuscular and subcutaneous injection (see Chapter 9). 

In Equation 17.22, the body is considered as a single homogeneous pool of body fluids as described above for digoxin. For most drugs, however, two or three distinct pools of distribution space appear to exist. This condition results in a time-dependent decrease in the measurable blood or plasma concentration, which reflects distribution into other bod pools independent of the body s ability to eliminate the drug. Figure 17.3 describes mean serum IFN-a concentrations after a 40-min intravenous infusion as well as after intramuscular and subcutaneous injections of the same dose. Note the logarithmic biphasic nature of the mean plasma concentration-time curve after the intravenous infusion. This biphasic nature represents both the distribution and elimination processes. 

Papich MG, Korsrud GO, Boison JO, Yates WD, MacNeil JD, Janzen ED, Cohen RD, Landry DA, A study of the disposition of procaine penicillin G in feedlot steers following intramuscular and subcutaneous injection, J. Vet. Pharmacol. Then. 1993 16 317-327. 

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