Subcutaneous injection sites, absorption

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). 

Pharmacokinetics Insulin glargine is characterized by slow absorption from the subcutaneous injection site and a fiat plasma insulin profile. Absorption patterns are similar after subcutaneous injection into the arm, abdomen, or thigh. A study in patients with type 1 diabetes found that the median time between injection and the end... 

In a study involving 11 insulin-dependent diabetic subjects, leg exercise accelerated insulin absorption from a subcutaneous injection site in the leg, whereas it had no effect on insulin absorption from the arm and reduced it from the abdomen (Koivisto and Felig, 1978). Most exercise involved many muscle groups, and increased absorption was still likely. Patients who developed hypoglycaemia were advised to take extra carbohydrate before exercise rather than decrease the insulin dose (Zinman et al., 1978). Studies in five subjects suggested that absorption was increased by exercise (Koivisto, 1980a). 

Studies in eight insulin-dependent diabetic men indicated that a sauna accelerated insulin absorption from the subcutaneous injection site and that, 2 h after the sauna, mean blood glucose concentration was significantly lower than on the control day (Dandona etal., 1978 Cuppers et al., 1980 Koivisto, 1980b). Hypoglycaemia and seizures were observed in one patient after the use of a sunbed (Husband and Gill, 1984). 

Possible advantages of intraperitoneal versus subcutaneous insulin include the avoidance of erratic absorption (both rate and extent of absorption), convenience, avoidance of subcutaneous injection site-related complications, and prevention of peripheral hyperinsulinemia. Insulin appears to be cleared into the systemic compartment by an active transport process, or via the peritoneal lymphatics. A number of studies have demonstrated the bioavailability of intraperitoneal insufin to be about 25% to 30%, although none clearly compares the clinical effectiveness of intraperitoneal versus subcutaneous insufin in diabetes control. Insufin requirements for PD patients may be greater than in hemodialysis patients because of the continued absorption of dextrose from the peritoneal cavity. Furthermore, because of adsorption of insufin to the polyvinyl chloride bag and administration set, the intraperitoneal dose of insufin often needs to be two to three times the subcutaneous maintenance dose. 

Linde, B., 1986, Dissociation of insulin absorption and blood flow during massage of a subcutaneous injection site. Diabetes Care 9 570-574. 

IFN s pharmacokinetic characteristics limit its therapeutic efficacy. IFN is rapidly absorbed from the subcutaneous injection site, and peak semm concentrations occur 3 to 8 hours after dosing. IFN is rapidly cleared by renal filtration, reabsorption and catabolism in the kidney . The rapid absorption and avid renal clearance of IFN produce the large fluctuations in IFN semm concentrations that are seen after each dose (Figure 1). UN s therapeutic efficacy is Mmited by its relatively brief residence time in a patient s circulation. Indeed, the amount of IFN left in the body after 24 hours is so insignificant that the three times weekly regimen is unlikely to maintain semm levels that are required for adequate antiviral or immunomodulatory activity. 

It is not surprising that intramuscular injection of epinephrine into the vastus lateralis produces a prompt peak plasma epinephrine concentration, because of the large size and excellent vascularization of this muscle. It is also not surprising that subcutaneous injection of epinephrine potentially leads to delayed absorption, because of the potent Ui-adrenergic agonist vasoconstrictor effects in the skin and subcutaneous tissue, as evidenced by skin blanching at the injection site [19, 20]. 

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

Organophosphate Ester Hydraulic Fluids. Absorption rates of TOCP were measured in chickens after subcutaneous injection by measuring the apparent disappearance of TOCP from the site of injection with 31P NMR spectroscopy (Carrington et al. 1988). Five chickens were injected with single,... 

The rate of absorption from an SC injection site may be retarded by immobilization of the limb, local cooling to cause vasoconstriction, or application of a tourniquet proximal to the injection site to block the superficial venous drainage and lymphatic flow. In small amounts, adrenergic stimulants, such as epinephrine, will constrict the local blood vessels and, therefore, slow systemic absorption. Conversely, cholinergic stimulants (such as methacholine) will induce very rapid systemic absorption subcutaneously. Other agents may also alter their own rate of absorption by affecting local blood supply or capillary permeability. 

TVpes of preparations (B). As a peptide, insulin is unsuitable for oral administration (destruction by gastrointestinal proteases) and thus needs to be given parenterally. Usually, insulin preparations are injected subcutaneously. The duration of action depends on the rate of absorption from the injection site. 

Even when administered by intramuscular or subcutaneous injection the rate of absorption of drugs from their site of administration varies, not only from individual to individual, but from site to site in the same subject (B13). For the few drugs studied in this way absorption and distribution was quicker and higher blood levels achieved when injections were given into upper rather than lower limbs and proximal to the trunk than distally. 

Each pramlintide dose should be administered subcutaneously into the abdomen or thigh (administration into the arm is not recommended because of variable absorption). Injection sites should be rotated so that the same site is not used repeatedly. The injection site selected should also be distinct from the site chosen for any concomitant insulin injection. Patients should always use a new syringe and needle to give pramlintide and insulin injections. 

Native human insulin self-associates to hexameric unit, which limits its absorption rate from injection sites (e.g., subcutaneous or intramuscular space). Based on the... 

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). 

Absorption of orally administered cefquinome is poor, but absorption following intramuscular or subcutaneous administration proceeds relatively quickly. A small fraction of the intramammarily administered cefquinome is absorbed systemically. Distribution of cefquinome is not extensive following parenteral administration of radiolabeled cefquinome the highest activities were found in injection-site tissues, kidney, and liver. Excretion of parenterally administered cefquinome is predominantly renal, while intramammarily administered cefquinome is excreted mainly in milk. Cefquinome is metabolically quite stable. 

After subcutaneous or intramuscular injection of netobimin into cattle, absorption was rapid but plasma levels of radioactivity were lower than those achieved following oral administration. This indicates that absorption occurred prior to the conversion to albendazole since high levels of parent drug were found in plasma and milk soon after the injection. On the other hand, at 12 h after the injection the parent drug could not be detected at the injection site or in liver. 

Figure 3.8 Blood flow and resulting distribution of a foreign compound from the three major sites of absorption or routes of injection. Abbreviations, i.v., intravenous injection s.c., subcutaneous injection i.m., intramuscular injection i.p., intraperitoneal injection.

Intramuscular and subcutaneous administration involves absorption from the injection site into the circulation by passive diffusion. The rate of absorption is limited by the size of the capillary bed at the injection site and by the solubility of the drug in the interstitial fluid.3 If blood flow is increased at the administration site, absorption will be increased. Conversely, if blood pressure is decreased for any reason (such as cardiogenic shock) absorption will be prolonged. 

The effects of insulin are modified by various factors. The speed and extent of absorption of insulin depends, for example, on the site of injection (1), the depth of the subcutaneous injection, skin temperature (2), the presence of lipodystrophy, and variation in the extent of inactivation of injected insulin. The disposal of insulin depends on many factors. Exercise and hard work lower the blood glucose and thereby increase the effect of insulin. Infections and obesity reduce its effect. The timing of food intake and the composition of meals are also related to the action of insulin. A thin layer of fat, as sometimes occurs in the upper arm or in the thighs of thin men, can result in intramuscular injection, leading to faster absorption of long-acting insulins. This can reduce the absorption time by half (3). The major factors that affect the fate of injected insulin (and thereby also its risks) are listed in Table 1 (4). 

The absorption of drugs in solution from intramuscular and subcutaneous sites of injection is limited by the perfusion rate. Failure to recognize this important concept has resulted in patient death. For example, morphine sulfate is often administered subcutaneously in a dose of 10 mg per 70 kg of body weight. This dose is sufficient to produce analgesia in 70% of patients with moderate to severe pain. However, in the setting of circulatory collapse and shock (e.g., septic shock in bacteremia due to release of endotoxin) in which the peripheral circulation may be impaired, morphine is not absorbed. Cases have been reported in which the lack of analgesia prompted the additional injection of morphine, all of which remained at the injection site and in the subcutaneous capillary bed. When the peripheral circulation improved, the massive amount of morphine that had collected became absorbed and death ensued, which was primarily due to respiratory depression. 

Jain and coworkers showed that polysialylation significantly changes the PK/PD profile of insulin, prolonging the hypoglycemic activity after subcutaneous (SC) administration to T/O mice. Slight differences were observed between derivatives obtained with 22 kDa and 39 kDa polysialic acid these were attributed to the slower hormone absorption obtained with the latter polymer, which favors hormone degradation at the injection site and hinders the interaction with the receptor more efficiently than the former polymer [11]. 

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