Intramuscular irritation

Intramuscular irritation is evaluated as follows Rabbits are sacrificed by lethal dose of barbiturate approximately 24 and 72 h after dosing. The left and right lateral vastus muscles of each rabbit are excised. The reaction resulting from injection is scored for muscle irritation using the scale shown here. 

USP (1985). Intramuscular irritation test. United States Pharmacopeia. USP Convention, Rockville, Maryland, pp. 1180-1183. 

Ethyl oleate is generally considered to be of low toxicity but ingestion should be avoided. Ethyl oleate has been found to cause minimal tissue irritation. No reports of intramuscular irritation during use have been recorded. 

TABLE I. Some physicochemical properties of test solutions used in the intramuscular irritation studies... 

TABLE II. Evaluation scores of the intramuscular irritation produced by CPZ (j IJmol) in the absence and presence of B-CyD ik ymol)... 

Other adverse reactions associated with penicillin are hematopoietic changes such as anemia, thrombocytopenia (low platelet count), leukopenia (low white blood cell count), and bone marrow depression. When penicillin is given orally, glossitis (inflammation of the tongue), stomatitis (inflammation of die mouth), dry mouth, gastritis, nausea, vomiting, and abdominal pain occur. When penicillin is given intramuscularly (IM), there may be pain at die injection site Irritation of the vein and phlebitis (inflammation of a vein) may occur witii intravenous (IV) administration. 

Heparin may be given by intermittent IV administration, continuous IV infusion, and the SC route. Intramuscular administration is avoided because of die possibility of the development of local irritation, pain, or hematoma (a collection of blood in die tissue). A solution of dilute heparin may be used to maintain patency of an IV site used for intermittent administration of any drug given by die IV route ... 

Iron salts occasionally cause gastrointestinal irritation, nausea, vomiting, constipation, diarrhea, headache, backache, and allergic reactions. The stools usually appear darker (black). Iron dextran is given by the parenteral route Hypersensitivity reactions, including fatal anaphylactic reactions, have been reported with the use of this form of iron. Additional adverse reactions include soreness, inflammation, and sterile abscesses at the intramuscular (IM) injection site Intravenous (IV) administration may result in phlebitis at the injection site When iron is administered via the IM route, a brownish discoloration of tlie skin may occur. Fhtients with rheumatoid arthritis may experience an acute exacerbation of joint pain, and swelling may occur when iron dextran is administered. 

The USP usually does not specify an oil, but states that a suitable vegetable oil can be used. The main use of such oils is with the steroids, with which they yield products that produce a sustained-release effect. Sesame oil has also been used to obtain slow release of fluphenazine esters given intramuscularly [14], Excessive unsaturation of an oil can produce tissue irritation. The use of injections in oil has diminished... 

Acute Intravenous Irritation in the Male Rabbit. The design here is similar to the intramuscular assay, except that injections are made into the veins in specific muscle masses. 

Shintani, S., Yamazaki, M., Nakamura, M. and Nakayama, I. (1967). A new method to determine the irritation of drugs after intramuscular injection in rabbits. Tox. Appl. Pharm. 11 293-301. 

The parenteral routes include three major ones IV (intravenous), IM (intramuscular), and SC (subcutaneous) and a number of minor routes (such as intraarterial) that are not considered here. Administration by the parenteral routes raises a number of special safety concerns in addition to the usual systemic safety questions. These include irritation (vascular, muscular, or subcutaneous), pyrogenicity, blood compatibility, and sterility (Avis, 1985 Ballard, 1968). The background of each of these, along with the underlying mechanisms and factors that influence the level of occurrence of such an effect, are discussed in Chapter 11. 

Intramuscular Route. The IM route is frequently used for drugs dissolved in oily vehicles or for those in a microcrystalline formulation that are poorly soluble in water (e.g., procaine or penicillin G). Advantages include rapid absorption (often in under 30 min), the opportunity to inject a relatively large amount of solution, and a reduction in pain and local irritation compared with SC injections. Potential comphcations include infections and nerve damage. The latter usually results from the choice of an incorrect site for injection. 

Solubility/miscibility Generally very soluble or miscible in water. Soluble in ethanol, com oil, and olive oil. Insoluble in mineral oil Biological considerations Surfactant. May cause micelle formation, with incumbent effects on bioavailability if included at concentrations of 1% or higher. May be associated with irritation if given intravenously or intramuscularly. Dogs have the peculiarity that Tweens injected parenterally induce the spontaneous systemic release of histamine. This response is particularly striking with IV injection, and therefore Tweens should not be used as components of IV vehicles in dogs... 

Heparin is prescribed on a unit (lU) rather than milligram basis. Tlie dose must be determined on an individual basis. Heparin is not absorbed after oral administration and therefore must be given parenterally. Intravenous administration results in an almost immediate anticoagulant effect. There is an approximate 2-hour delay in onset of drug action after subcutaneous administration. Intramuscular injection of heparin is to be avoided because of unpredictable absorption rates, local bleeding, and irritation. Heparin is not bound to plasma proteins or secreted into breast mUk, and it does not cross the placenta. 

Botulinum toxin is used clinically in the treatment of blepharospasm, writer s cramp, spasticities of various origins, and rigidity due to extrapyramidal disorders. It is also used to treat gustatory sweating and cosmetically to decrease facial wrinkles. Botulinum toxin A Botox, Oculinum) injected intramuscularly produces functional denervation that lasts about 3 months. Clinical benefit is seen within 1 to 3 days. Adverse effects range from diplopia and irritation with blepharospasm to muscle weakness with dystonias. 

Antimonials are irritating to the intestinal mucosa and therefore are administered by intramuscular or slow intravenous injection. Peak blood concentrations occur in 2 hours. These drugs bind to cells, including erythrocytes, and are found in high concentrations in the liver and spleen. As compared with the trivalent antimonials, which are no longer used, the pentavalent antimonials bind to tissue less strongly. This results in higher blood levels, more rapid excretion, and lowered toxicity. Pentavalent antimonials are rapidly excreted in the urine, with up to one-half of the administered dose excreted in 24 hours. 

Obidaxlme has been stated not to have any local irritant action when injected intramuscularly it did produce facial paresthesia, headache, a sensation of coolness in the mouth, generalized weakness, nausea and vomiting, pallor, pyrosis, and sore throat in 13 of 24 subjects given tablets of IV in doses of 1.84-7.36 g. Administration of IV in tablets with enteric coatings probably did not alter the incidence of side reactions—only four subjects and two doses of the oxime were used in this part of the study. 

Local irritation can produce severe pain after intramuscular injection and thrombophlebitis after intravenous injection. Renal toxicity, including interstitial nephritis and even tubular necrosis, has been demonstrated and has caused the withdrawal of cephaloridine from clinical use. 

Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided. 

Intramuscular and subcutaneous routes deliver the drug promptly, if water-based solutions are used, or slowly, if other types of solutions are used. They are better for larger volumes of material although local irritation can result. 

Oleandomycin is a macrolide antibiotic produced by Streptomyces antibi-oticus. Oleandomycin and its triacetylated form, troleandomycin, are less effective than erythromycin against staphylococcal infections. They are usually administered orally or intravenously intramuscular administration is avoided because of the pain and tissue irritation it induces. Oleandomycin is also used in intramammary treatments and as a feed additive for growth promotion purposes. 

The persistence of residues at intramuscular injection sites may be due in part to the irritant response produced in the muscle (52). Chloramphenicol, tylosin, penicillins, dihydrostreptomycin, and oxytetracycline have been shown to produce local irritation at the site of injection, leading to residue persistence this may be exacerbated by the solvent used. However, residues do not persist with proper injection of drugs and use of formulations that do not cause severe irritation (52), as has been demonstrated with one oxytetracycline product that produced little irritation (53-55). 

In a randomized, placebo-controlled study in women who received leuprolide acetate depot 11.25 mg intramuscularly with tibolone 2.5 mg/day (n = 36), leuprolide acetate depot 11.25 mg with placebo (n = 37), or a placebo injection with placebo tablets (n = 39), irritable bowel syndrome related to the menstrual cycle improved in those who received leuprolide (5). There were hot flushes in those who took leuprolide compared with placebo no data were given about the frequency of hot flushes, but there were no withdrawals because of this symptom. Amenorrhea also occurred. Both flushing and amenorrhea are expected adverse effects of leuprolide. 

In 20 women (mean age 67 years) who received intramuscular triptorelin 3.75 mg 6-weekly for endometriosis, nine developed mood disturbance after the second injection and appeared to be cumulative, since the symptoms only started after the second injection and worsened with successive injections (32). One woman withdrew after the third injection because of severe irritability. 

---