Toxicity glucocorticoids

Sapolsky RM (1985) A mechanism for glucocorticoid toxicity in the hippocampns Increased neuronal vulnerability to metabolic insnlts. J Nenrosci 5 1228-1232. 

Proximal muscle weakness in an elderly patient associated with a normal electromyogram (EMG) can be caused by type-2 muscle fiber atrophy, which is diagnosable only on muscle biopsy. One should seek an identifiable cause, such as cachexia, disuse, glucocorticoid toxicity, a "remote" neoplasm, hyperparathyroidism, subtle denervation, or supra-segmental central nervous system (CNS) abnormality. This mainly-sensory nerve neuropathy can cause slowed sensory nerve conductions, if involving large diameter fiber, small diameter ones. 

Unfortunately steroids merely suppress the inflammation while the underlying cause of the disease remains. Another serious concern about steroids is that of toxicity. The abmpt withdrawal of glucocorticoid steroids results in acute adrenal insufficiency. Long term use may induce osteoporosis, peptidic ulcers, the retention of fluid, or an increased susceptibiUty to infections. Because of these problems, steroids are rarely the first line of treatment for any inflammatory condition, and their use in rheumatoid arthritis begins after more conservative therapies have failed. 

Vitamin D withdrawal is an obvious treatment for D toxicity (219). However, because of the 5—7 d half-life of plasma vitamin D and 20—30 d half-life of 25-hydroxy vitamin D, it may not be immediately successful. A prompt reduction in dietary calcium is also indicated to reduce hypercalcemia. Sodium phytate can aid in reducing intestinal calcium transport. Calcitonin glucagon and glucocorticoid therapy have also been reported to reduce semm calcium resulting from D intoxication (210). 

Gl. Gadina, M., Bertini, R., Mengozzi, M., Zandalasini, M., and Ghezzi, P., Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. J. Exp. Med. 173, 1305-1310 (1991). 

Mitotane (o,p-DDD) -adrenocortical cytotoxin -nausea and vomiting -CNS toxicity—lethargy, vertigo, sedation, dizziness -adrenal insufficiency—must use replacement doses of mineralocorticoids and glucocorticoids -diarrhea -fever -wheezing -flushing... 

Glucocorticoids are endogenous compounds that have an effect on carbohydrate, lipid, and protein metabolism, and which exhibit anti-inflammatory, desensitizing, and anti-aUergy action. They are immunodepressants, and they also possess anti-shock and anti-toxic action. 

Glucocorticoids are cautiously employed in various disease states, such as rheumatoid arthritis, although they still should be regarded as adjunctive rather than primary treatment in the overall management scheme. The toxic effects of steroids are severe enough that a number of factors must be considered when their prolonged use is contemplated. 

Interestingly, while peripheral neuroendocrine function appears normal in patients with panic disorder, decreased basal cortisol concentrations have been reported in most studies in PTSD patients. This relative hypocortisolism occurs in the context of increased feedback inhibition of the HPA axis (see Yehuda, 2000). However, a dissociation between central and adrenocortical (re)activity has been found in animal models of severe early-life stress as well as in abused children and women, suggesting that adrenal dysfunction may, at least in part, contribute to hypocortisolism in PTSD. In the face of hypocortisolism, it seems surprising that hippocampal atrophy is one of the most prominent findings in patients with PTSD, including adult survivors of childhood abuse with PTSD (see Newport and Nemeroff, 2000). While increased glucocorticoid sensitivity of hippocampal cells may play a role in the development of hippocampal atrophy, another potential mechanism may involve toxic effects of markedly increased cortisol responses to everyday stress in patients with PTSD. 

BFM and St. Jude protocols, are that on BFM protocols no topoisomerase 11 inhibitors are given in close association with thiopurines and, finally, that on BFM protocols no intrathecal triple therapy (methotrexate, cytarabine, and a glucocorticoid) are given concurrent with cranial radiotherapy and 6-MP. Another important toxicity issue associated with TPMT status relates to the above-described VOD-like symptoms of the liver in childhood ALL patients treated with 6-TG on the British MRC ALL97 trial (209). In this trial, TPMT activity was significantly lower in children in whom VOD developed while no differences in RBC 6-TGN levels were described. This information in association with ongoing research efforts will help to develop a better understanding of 6-TG-associated liver toxicity and may help to identify those individuals upfront who should not be administered 6-TG. 

Another important group of agents is characterized as disease-modifying antirheumatic drugs (DMARDs). They decrease inflammation, usually improve symptoms, and slow the bone damage associated with rheumatoid arthritis. They are thought to affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. They may also be more toxic than those alternative medications. 

Glucocorticoids (corticosteroids) were the first hormonal agents recognized as having lympholytic properties. Administration of any glucocorticoid reduces the size and lymphoid content of the lymph nodes and spleen, although it has no toxic effect on proliferating myeloid or erythroid stem cells in the bone marrow. 

Toxic optic neuropathy can occur and may underlie various reports of sudden blindness in patients taking glucocorticoids. In one case, transient visual loss occurred on several occasions, each time after administration of a glucocorticoid (SEDA-17, 447). In another case, blindness occurred suddenly and paradoxically after glucocorticoid injections into the nasal turbinates (78). Although glucocorticoids are sometimes used successfully to relieve... 

A possible risk of glucocorticoid treatment of ulcerative colitis is the development of toxic megacolon or colonic... 

Glucocorticoids that have been used for local ophthalmic treatment include medrysone, fluorometholone, tetrahy-droxytriamcinolone, and clobetasone. Loteprednol etabo-nate 0.5% increases intraocular pressure less than dexamethasone. Studies on animal models of uveitis and two randomized double-masked trials showed that loteprednol etabonate 0.5% was less potent than dexamethasone, prednisolone acetate 1%, or fluorometholone, which may partly explain the improved toxicity profile of loteprednol etabonate (429). 

The adrenal glands are sensitive to the toxic effects of suramin both glucocorticoid and mineralocorticoid functions can be impaired at doses normally used, necessitating replacement therapy (1081). 

Leukotriene inhibitors are safer than other antiinflammatory agents such as the glucocorticoids. Some hepatic impairment has been reported with these drugs, but cases of severe toxicity are relatively rare. 

---