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Home , Drug interaction, Propranolol

CASE REPORT East J Med 23(2): 124-127, 2018 DOI: 10.5505/ejm.2018.43434

Elevated blood concentration following concomitant lithium and therapy: A case report

Emine Füsun Akyüz Çim1* and Hülya Çeçen2

1Van District Training and Research Hospital Department of Psychiatry, Van, Turkey 2Tatvan State Hospital Department of Psychiatry, Bitlis, Turkey

ABSTRACT Lithium is used in the treatment for many psychiatric disorders, like bipolar disorder, schizoaffective disorder and depression. Lithium has a very narrow therapeutic range and there are many reasons that increase the blood levels of lithium. Combining lithium with other medications with the aim of reducing side effects or supporting the therapy may result in substantial elevations in lithium concentrations and may lead to signs of int oxication. This study presents increased blood lithium concentration after the initiation of the concomitant therapy of lithium and propranolol, which is a beta-blocker drug, due to the complaint of causing functional impairment. Key Words: Lithium, beta-blocker, propranolol, drug

Introduction clonus, seizure and even coma have been well described in the literature. Tremor is the most Lithium is used in the treatment for many common neurological caused by the psychiatric disorders, like bipolar disorder, use of lithium (2). schizoaffective disorder and depression. Lithium Different treatment options are available for the is absorbed by gastrointestinal tract. Afterwards treatment of tremor related to lithium, such as absorbing lithium is distributed in extracellular reduction of lithium dose, addition of beta fluid initially. In principally kidneys eliminates blocker. For Lithium-induced tremor treatment, in lithium. one of the most frequently used β-blocker agent is Lithium has a very narrow therapeutic range and propranolol. Because of the presentation of there are many reasons that increase the blood tremor, we added propranolol to the lithium levels of lithium. Combining lithium with other therapy. Propronolol is non selective medications with the aim of reducing side effects with a hepatic or supporting the therapy may result in substantial elimination. Also, propronolol is the drug that is elevations in lithium concentrations and may lead not expected to interact with lithium. to signs of intoxication. of lithium In this study, we present a patient who had been with several nonsteroidal anti-inflammatory drugs on lithium therapy for the last one year due to the (NSAIDs), thiazide , and angiotensin- diagnosis of bipolar disorder and was presented converting (ACE) inhibitors have been with increased blood lithium concentration after commonly reported. Additionally, the initiation of the concomitant therapy of insipidus, low salt diet, over 50 years old, lithium and propranolol, which is a beta-blocker hypothyroidism and deterioration in renal drug, due to the complaint of tremor causing function could be risk factors for lithium functional impairment. intoxication (1). With lithium treatment side effects in many organ Case report systems could be seen. One of them is neurological system. Neurotoxic side-effects such A 32-year-old male patient had been followed up as nystagmus, ataxia, tremor, fasciculation, due to the diagnosis of bipolar disorder for the

*Corresponding Author: Emine Füsun Akyüz Çim, MD, Van District Training and Research Hospital Department of Psychiatry, Van, Turkey, Tel: +90 (505) 397 10 82, E-mail: [email protected] Received: 16.10.2016, Accepted: 07.02.2018

Çim and Çeçen / Increased blood lithium concentration

last 9 years. He was married, unemployed, had the patient had a history of several manic three children. He lived with his family in a small episodes, we did not reduce the dosage of lithium town very near to city center. For daily activity, he due to the risk of repeated manic episodes and could help child care, do shopping, occasionally added propranolol with the lithium therapy. deal with gardening. He had good self-care and Second week of combined lithium and sociability. Last one year, he had come to the propranolol treatment, neurotoxic signs was regular monthly psychiatric out patients clinic for defined related with lithium blood level rising. follow-up. Increase in blood levels of lithium in our case The patient had been treated by various physicians occurred independently from the oral lithium with numerous pharmacotherapeutic agents and dose intake. This shows that, a problem which had been receiving a monotherapy with lithium relating to renal of lithium could be. 1200 mg/day for the last one year. Patient history Reduction of excretion of lithium could be due to revealed that the patient had several manic two reasons; the function is damaged or episodes due to the reduction or cessation of drug another drug that affect renal excretion is used. use over the last one year. He came to psychiatric Chemical tests showed that the physiological polyclinic with his brother. In the psychiatric limits of the parameters such as kidney function physical exam; he was oriented to place, time and tests that could lead to rising of lithium blood person. No delusion was described. His speech level. The rise in the blood level of lithium in was organized and his mood was euthymic. clinical evaluation was linked to possible drug Biochemical analysis revealed a blood lithium level interactions between lithium and propranolol. of 0.76 mEq/L. The patient was present with A large part of the lithium is excreted through the tremor that caused functional impairment in both kidneys (3). Lithium is filtered through the kidney hands, which was also detected during the physical glomeruli and absorbed back from proximal examination. Also, no neurotoxic side-effects such tubules. Approximately 80% of the lithium filtered as nystagmus, ataxia, fasciculation were definied is reabsorbed by the glomerulus and the remainder but tremor. Due to the presentation of tremor, is excreted as urine (4). Increased intake or propranolol was added to the lithium therapy in a decreased excretion from kidney is responsible of divided dosage of 40 mg/day. Two weeks later, lithium toxicity (5). the patient presented to the polyclinic with the Nonsteroidal anti-inflammatory drugs (NSAIDs), complaints of dizziness, , exhaustion, and thiazide diuretics, and angiotensin-converting weakness. The blood lithium level was elevated to enzyme (ACE) inhibitors are the drugs which 1.6 mEq/Lit. No pathology was detected in could changed lithium dosage. Also, diabetes electrocardiography (ECG). Laboratory tests insipidus, low salt diet, being over 50 years old revealed that hemogram, blood biochemical and deterioration in renal function could be risk parameters (glucose, urea, creatinine, AST, and factors for lithium intoxication (1). As seen, the ALT), thyroid hormone levels, and parathyroid common features, drugs and situations which hormone levels were in normal range. Serum change lithium serum levels are effective on electrolyte levels were determined as: Sodium: 137 kidney cell and ion. mmol/L, : 3.7 mmol/L, : 1.9 In our case possible mechanisms which may cause mEq/L, Phosphate: 1.1 mmol/L. high blood lithium levels are: Considering the risk of , the -Changes in the concentration of sodium ions propranolol therapy was terminated and the blood lithium levels were followed up every other day. -Lithium and propranolol's effect on the renin All the symptoms were completely removed angiotensin aldosterone system within the first week and the blood lithium level -Lithium and propranolol on the cell signaling progressively decreased to 0.78 mEq/L in 10 days. system. Lithium blood levels could be changed by sodium Discussion ion concentration. The most sensitive to lithium- induced alterations is renal collecting tubule Tremor is the most common neurological side .Lithium is reabsorbed into the collecting duct effect caused by the use of lithium (2). In patients cells from . Also, lithium is used with side effects such as tremor, if reduction or like sodium in proximal tubules (4). Lithium cessation of the use of lithium is not considered, a reduce water and salt reabsorption. Therefore beta-blocker drug such as propranolol should be possible changes on ion sodium levels may affect added to the lithium therapy. In our patient, since the de lithium serum levels.

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Çim and Çeçen / Increased blood lithium concentration

Another structure on the kidney, that can lead to suppressed on many cell types including kidney potential changes for lithium and sodium ion is epithelial cells by lithium (6). On the other hand Renin-Angiotensin-Aldosterone-System (RAAS). the effects of propranolol on the cAMP pathway In the kidney juxtaglomerular cells secrete renin, are in inhibitory features (7). when blood pressure falls and the sodium chloride As shown, likewise both drugs (propranolol and reaching the cell juxtaglomerular level falls. The lithium) may make adenylate cyclase inhibition. enzyme renin stimulates angiotensin complex. End For these two drugs with the same mechanism on of circulation the hormone system, aldosterone is intracellular system may occur released from adrenal kortex. Aldosterone with the possible drug interactions. increases water and sodium retention in blood. In conclusion, Propranolol is a sympatholytic agent A possible explanation may be drug interactions at with a hepatic elimination and is not likely to interact the molecular level intracellular cell signaling with lithium. In our patient, the blood lithium level system. Lithium and propranolol is effective on was elevated, likely because of the concomitant adenylate cyclase (6,7). Effect of the drugs lithium and propranolol therapy. Hypothetically, the (lithium and propranolol) on adenylate cyclase elevation in lithium concentration may be associated activities could bring interactions together. with the lowering effect of propranolol on glomerular In our case we have added propranolol for the filtration, inhibiting renin release on kidney by treatment of tremor induced lithium which is non propranolol, the interaction of lithium and selective sympatholytic beta blocker propranolol, propranolol with the adenylate cyclase activities, or an commonly used in the treatment of lithium- unknown drug interaction. The case presented in this induced tremor. Although, propranolol is highly study indicates that concomitant lithium and extracted in the (8), propranolol has effects propranolol therapy may lead to toxic levels of on glomerular filtration and the enzyme of renin. lithium concentration in blood. The clinicians should Propranolol's effect on the kidneys could bring be awakened about this possible drug interactions. the lithium blood level changes possible. Propranolol inhibits renin release on kidney like References other beta blocker drugs (9). With prevention of renin enzyme, aldosteron 1. Shine B, McKnight RF, Leaver L, Geddes JR. blood level decreases. So that, sodium ion Long-term effects of lithium on renal, thyroid, concentration in water volume could decrease too. and parathyroid function: a retrospective As a result; the inhibited renin enzyme by analysis of laboratory data. Lancet 2015; 386: propronolol could changed lithium serum level 461-468. 2. Morgan JC, Sethi KD. Drug-induced . because of the decreasing of sodium concentration Lancet Neurol 2005; 4: 866-876. and water volume. 3. Timmer RT, Sands JM. Lityum intoxication. J Another factor may affect on blood levels of Am Soc Nephrol 1999; 10: 666-674. lithium is glomerular filtration. Removing excess 4. Psikiyatride Güncel Yaklaşımlar-Current wastes and fluids is the processes by glomerular Approaches in Psychiatry 2011; 3(3):426-445 © filtration. Glomerular filtration is the first stage 2011, eISSN:1309-0674 pISSN:1309-0658. for excretion of lithium from the body by kidney. 5. Aral H, Vecchio-Sadus A. Toxicity of lithium to humans and the environment- A literature Propranolol could cause lowering effect on review. Ecotoxicol Environ Saf 2008; 70: 349- glomerular filtration (10), so that lithium blood 356. levels may increase by glomerular filtration 6. Lenox RH, McNamara RK, Papke RL, Manji reduction. HK. Neurobiology of lithium: An update. J Clin Additionally, propranolol and lithium are effective Psychiatry 1998; 58: 37-47. on adenylate cyclase activities. cAMP is a second 7. Conley D, Coyne M, Chung A, Bonorris G, messenger, used for intracellular signal Schoenfield L. Propranolol inhibits adenylate transduction and is synthesized from ATP by cyclase and secretion stimulated by deoxycholic in the rabbit colon. Gastroenterology 1976; adenylate cyclase and involved in the regulation of 71: 72-75. certain renal function such as the provision of the 8. Shand DG. of propranolol: a normal fluid balance. review. Postgrad Med J 1976; 52: 22-25. Lithium is effective on pathways 9. Laragh JH, Bühler FR. Propranolol, renin and and gene expression. Transferring genetic : a review. Postgrad Med J 1976; information pathway of cAMP is the main target 52: 109-115. for intracellular effects of lithium. cAMP is 10. Bahalı K, Gülçelik G, Fettahoğlu Ç, et al. (Çev). Duygudurum Düzenleyiciler. Avcı A, Yolga

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