Dilantin and Adrenal Insufficiency : The Endocrinologist

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00019616-200709000-00003ReportThe EndocrinologistThe Endocrinologist© 2007 Lippincott Williams & Wilkins, Inc.17September 2007 p 246-248Dilantin and Adrenal InsufficiencyCase ReportPrebtani, Ally MD, BScPhm, ABIM, FRCP(C); Rana, Punam MD, BHScFrom the Department of Medicine, Division of Endocrinology and Metabolism.Reprints: Punam Rana, 1253 Main St West, Apt 4, Hamilton, Ontario, Canada, L8S 1C4. E-mail: [email protected] drugs may interact with a corticosteroid, altering its bioavailability. Phenytoin is one example which reduces the bioavailability of a corticosteroid via enzyme induction through the CYP450 system. In this case report, we examine an adrenally insufficient patient on steroid therapy who developed an acute adrenal crisis following phenytoin administration. We list other major drugs that interact with corticosteroids and discuss alternative antiepileptics that have less interaction.A 70-year-old woman presented to hospital with an acute episode of confusion and bilateral leg weakness followed by syncope. Just 2 days prior, the patient was discharged after an overnight admission due to a tonic-clonic seizure. Her past medical history included Parkinson disease, coronary artery disease, hypertension, seizure disorder, and a sellar mass seen on MRI. The patient's blood pressure was 117/82 mm Hg; pulse 78 beats per minute, respiratory rate 18, and she was afebrile. Respiratory, cardiovascular, and abdominal examinations were unremarkable. There was a left-sided facial droop, and the left pupil was observed to be bigger than the right. Both pupils were reactive to light. The rest of the neurologic examination was unremarkable. A CT of the head showed no acute changes from a previous CT. We thought that the patient may have experienced another seizure. On May 29, 2006 she was started on phenytoin 200 mg po daily.The laboratory results on admission included Na+ 122 mmol/L (135–145 mmol/L), TSH 4.7 MU/L (0.3–4.2 MU/L), free T4 7.1 pmol/L (9.1–23.8 pmol/L), prolactin 322 μg/L (<24 μg/L), and a low AM cortisol at 38 nmol/L. At this point, a diagnosis of hypopituitarism was suspected. A pituitary macroadenoma, likely a macroprolactinoma, was originally suspected on an MRI scan of the head done in 2005 (Fig. 1). A cosyntropin stimulation test on May 29 revealed a low cortisol response: 4.5 μg/L after 30 minutes and 42 μg/L after 60 minutes. ACTH levels were low, at <2 pmol/L. A diagnosis of central adrenal insufficiency was made. The patient was started on prednisone 5 mg OD and thyroxine 25 μg OD. Domperidone, a dopaminergic antagonist, was discontinued, and cabergoline, a dopamine agonist, was initiated. Even after stopping domperidone, however, the serum prolactin remained elevated (112 ng/mL) a few days later.JOURNAL/endst/04.03/00019616-200709000-00003/figure1-3/v/2021-02-17T201837Z/r/image-tiff MRI of pituitary macroadenoma medication interaction with corticosteroids. Phenobarbital, phenytoin, and rifampin induce hepatic enzymes to increase clearance of corticosteroids.6 Troleandomycin and ketoconazole inhibit the metabolism of corticosteroids, may cause steroid toxicity. ASA corticosteroids can increase clearance of chronic, high-dose aspirin. Oral anticoagulants: Variable, inconclusive results have been noted. Estrogen: Reduced rate of biotransformation of steroids, resulting in prolonged half-life and residence time.7 Macrolide antibiotics: Inhibition of steroid elimination.8On June 5, the patient developed an acute loss of consciousness. The systolic BP dropped to 70 mm Hg. The chest was clear and oxygen saturation was satisfactory. Jugular venous pressure was low. There was no evidence of blood or fluid loss. Capillary blood sugars were normal and an echocardiogram revealed no ST elevation or depression, nor arrhythmia. A cardiac cause for the syncope was thus excluded.A comprehensive list of medications that the patient was taking daily included prednisone 5 mg, fluticasone 500 mg, enteric coated aspirin 81 mg, atorvastatin 20 mg, levodopa/carbidopa 100/25 (8 tablets), calcium carbonate 500 mg, docusate sodium 200 mg, heparin 10,000 units, and cabergoline 0.25 mg (weekly). There was no history of nausea, vomiting, or diarrhea preceding this episode. It was then suspected that the drop in blood pressure was due to an acute adrenal crisis. We administered intravenous fluids, along with hydrocortisone 50 mg q8 hours. Systolic BP increased to 92 mm Hg and she regained consciousness within minutes. A diagnosis of acute adrenal crisis was confirmed. She remained stable on hydrocortisone 25 mg IV Q8 hours, with a blood pressure of 120/58 mm Hg and a HR 58 beats per minute. Sodium levels improved to 127 mmol/L. The prolactin level, however, remained elevated, at 180 μg/L.The glucocorticoid was switched to 25 mg oral hydrocortisone daily, and neurology consultation was obtained. Phenytoin was discontinued, and the patient was started on levetiracetam (Keppra) 250 mg twice a day for 2 weeks and then maintained on 500 mg twice a day. Shortly thereafter, the hydrocortisone was changed to prednisone, 5 mg daily (Fig. 2).JOURNAL/endst/04.03/00019616-200709000-00003/figure2-3/v/2021-02-17T201837Z/r/image-tiff Patient's daily systolic blood pressure.DISCUSSIONThis case illustrates the potential adverse reactions that can result from pharmacokinetic interactions between oral glucocorticoid therapy and phenytoin, a cytochrome P450 enzyme inducer, in a patient with adrenal insufficiency on a fixed dose of glucocorticoid. The CYP450 system is a group of enzymes responsible for metabolizing various endogenous and exogenous substances, including 40%–50% of all medications.1 These substances are metabolized into more hydrophilic forms, facilitating excretion from the body. Certain drugs are known to cause either inhibition or induction of the P450 enzyme family. Enzyme inhibition occurs when one drug competes for available enzymes, resulting in decreased breakdown of another drug. Enzyme induction, on the other hand, occurs when one drug stimulates P450 enzyme synthesis such that there is increased metabolism and therefore decreased effect of another drug. It is believed that phenytoin affects prednisone via enzyme induction, largely by the CYP4502C9 subfamily of enzymes. The major pathway of phenytoin metabolism is 4′-hydroxylation to form 5-(4-p-hydroxyphenyl)-5-phenylhydantoin (HPPH), which is responsible for 80% of phenytoin elimination.2 Furthermore, chronic phenytoin administration is also associated with increased corticosteroid-binding globulin levels.3Some antiepileptics, including levetiracetam, gabapentin, and vigabatrin, do not increase hepatic metabolism via the cytochrome P450 pathway and are therefore safer to use in conjunction with steroids.4 For example, levetiracetam (Keppra) is one of the newer antiepileptic medications that is gaining popularity due to its superior clinical profile. It has good bioavailability, minimal protein binding, and wide margins of safety, and its major metabolic pathway is not dependent on the hepatic cytochrome P450 system. Since levetiracetam does not inhibit or induce hepatic enzymes, there is minimal risk of interaction with drugs such as prednisone.5CONCLUSIONThis case reveals the importance in considering the potential for drug interaction in patients taking fixed doses of glucocorticoids to avoid such episodes of acute adrenal crisis. Table 1 lists some of the drugs that are known to modulate serum corticosteroid concentrations. Using these drugs concurrently with corticosteroids is not necessarily contraindicated. However, the potential for adverse reactions must be kept at the forefront of the physician's mind during therapy. For example, patients with adrenal insufficiency on steroid replacement may require increased doses of corticosteroids.6 Alternatively, a drug may be sought that does not alter steroid metabolism and thus does not increase the risk for acute adrenal crisis.JOURNAL/endst/04.03/00019616-200709000-00003/table1-3/v/2021-02-17T201837Z/r/image-tiff Steroid-Drug InteractionsREFERENCES1. Rogers JF, Nafziger AN, Bertino JS. Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs. Am J Med. 2002;V113.[Context Link]2. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45:525–538.[Context Link][Full Text][CrossRef][Medline Link]3. Putignano P, Kaltsas GA, Satta MA, et al. The effects of anti-convulsant drugs on adrenal function [review]. Horm Metab Res. 1998;30:389–397.[Context Link][CrossRef][Medline Link]4. Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. 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Phenobarbital, phenytoin, and rifampin induce hepatic enzymes to increase clearance of corticosteroids.6 Troleandomycin and ketoconazole inhibit the metabolism of corticosteroids, may cause steroid toxicity. ASA corticosteroids can increase clearance of chronic, high-dose aspirin. Oral anticoagulants: Variable, inconclusive results have been noted. Estrogen: Reduced rate of biotransformation of steroids, resulting in prolonged half-life and residence time.7 Macrolide antibiotics: Inhibition of steroid elimination.8 Patient's daily systolic blood pressure. Steroid-Drug InteractionsDilantin and Adrenal InsufficiencyPrebtani Ally MD BScPhm ABIM FRCP(C); Rana, Punam MD, BHScCase ReportCase Report517p 246-248