April 01, 2004
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Hypoglycemia and quinine use in a non-diabetic with end-stage renal disease

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Quinine therapy is commonly used for benign nocturnal leg cramps and for cramps associated with hemodialysis. Originally developed as an antimalarial, quinine has been repeatedly associated with hypoglycemia in patients with Falciparum malariae disease.1,2 Quinine is widely prescribed for the treatment of leg cramps, and often regarded, wrongly, as a safe medication.

There is at least one reported case of insulin-mediated hypoglycemia in an otherwise healthy adult who was being treated with oral quinine sulfate for leg cramps.3 Apart from that, however, little has been written about quinine-mediated hypoglycemia independent of malaria treatment.

We present a case of quinine-mediated hypoglycemia in a non-diabetic patient with end-stage renal disease (ESRD) and congestive heart failure, with a brief review of the literature exploring the possible mechanisms of hypoglycemia associated with the use of quinine.

Case history

A 54-year-old woman with ESRD secondary to adult polycystic kidney disease who, while receiving hemodialysis, became unresponsive and had a grand mal seizure in association with a blood glucose of 18 mg/dL. Neither the patient nor any family member had been treated with or had access to insulin or oral hypoglycemic agents.

The patient’s medical history included hypertension, coronary artery disease and cardiomyopathy with a left ventricular (LV) ejection fraction of 25% associated with global LV hypokinesis, mitral and tricuspid regurgitation.

Past surgical history included bilateral nephrectomy, hysterectomy and left brachial arteriovenous access placement for dialysis. The patient had a 60-pack-year smoking history.

Her medications included quinine sulfate 325 mg three times per week, isosorbide nitrate 30 mg q.d., lansoprazole 30 mg b.i.d, metoprolol 12.5 mg b.i.d, valsartan 80 mgq.d., aspirin 81 mg q.d., conjugated estrogen 0.625 mg q.d. and calcium acetate1 tablet b.i.d.

At the time of endocrine consultation, 24 hours after the hypoglycemic event, the patient appeared in no distress. Her blood pressure was 105/60 mm Hg and her pulse rate was 85 beats per minute.

A summation gallop and displaced PMI were noted along with a 3/6 pansystolic murmur at the apex that radiated to the axilla and a holosystolic murmur along the left lower sternal border that increased with inspiration. The patient had 2+ pitting leg edema and discoloration of the legs consistent with venous insufficiency. Otherwise, her physical examination was normal.

An electrocardiogram identified supraventricular bigeminy with a ventricular rate of 97 and nonspecific t wave abnormalities.

Labs

Because of the pathophysiology of the diseased kidney, patients with renal impairment are at particular risk of toxicity, particularly severe life-threatening hypoglycemia.

The patient’s laboratory results (during dialysis) were as follows:

Hemoglobin and hematocrit were 10.7 gm/dL and 31.8%.

Sodium was 140 mEq/L; potassium 2.4 mEq/L; bicarbonate 34 mEq/L; blood urea 14 mg/dL; creatinine 4.1 mg/dL; alkaline phosphatase 185 U/L; and albumin was 3.2 gm/dL.

Alanine and aspartate transferase, serum calcium and TSH were normal; serum phosphorus was low at 1.0 mg/dL.

Cardiac enzymes were normal.

B-type natriuretic peptide was 2,930 pg/mL (secondary to intravascular volume overload and chronic congestive heart failure).

Insulin level was 612.77 mcunit/mL (normal, 2-110 mcU/mL).

C-peptide was 2.498 pmol/mL (normal, 0.22-1.20). Random serum cortisol was 13.3 µg/dL.

Sulfonylurea screen was negative.

She received seven ampules of 50% dextrose intravenously over four hours, and then received a continuous 10% dextrose I.V. infusion at 200 cc/hr for 20 hours to maintain serum glucose > 100 mg/dL.

After discontinuation of quinine, the patient was discharged to home. She has had no further documented episodes of hypoglycemia over the ensuing year.

Quinine sulfate has been used as an antimalarial agent for the last 350 years.4

It is the chief alkaloid of cinchona, the bark of the South American cinchona tree, otherwise known as Peruvian, Jesuit’s or Cardinal’s bark.5,6 Its primary use as an antimalarial agent is well known, but its use in preventing leg cramps stems from the 1930s when anecdotal data suggested benefits in persons with myotonic dystrophy.7

Quinine has analgesic and muscle-relaxant properties and has been shown to decrease the excitability of the motor end plate to nerve stimulation and increase the muscle refractory period. 6 This latter property has led to the widespread use of quinine in the treatment of muscle cramps.

Leg cramps occur in 70% of elderly persons8 and are a common complication of hemodialysis (prevalence of 335).9

Other conditions that are associated with cramps include venous stasis, pregnancy, thyroid disease, diuretic use, fluid and electrolyte imbalance, and uremia.10 Most cases are idiopathic. Quinine sulfate has been the most widely-used pharmacologic agent for the prevention and treatment of leg cramps to date.11

Does not reduce leg cramps

In a meta-analysis of eight randomized, double-blinded, placebo-controlled trials, Man-Son-Hing et al concluded that quinine sulfate does reduce the frequency of leg cramps, but does not improve the severity or duration.12

In 1995 the FDA said quinine should not be recognized as safe and effective for this indication, and in February of that year marketing of over-the-counter quinine-based preparations used for the treatment and prevention of leg cramps was banned.13

Despite its dubious efficacy and the warnings regarding its use for this purpose, quinine continues to be frequently prescribed for the treatment of leg cramps in hemodialysis patients.

Despite its dubious efficacy and the warnings regarding its use for this purpose, quinine continues to be frequently prescribed for the treatment of leg cramps in hemodialysis patients.

Adverse effects associated with quinine sulfate include hypersensitivity reactions, cinchonism, high-frequency hearing loss, impaired vision including blindness, nausea, vomiting, epigastric pain, thrombocytopenia, granulomatous hepatitis, cardiovascular effects including cardiac conduction abnormalities, vascular instability with postural hypotension, and hyperinsulinemia with hypoglycemia.14

These can occur in healthy fasting volunteers, patients with malaria and patients with deliberate overdose.15 Patients with chronic renal failure have a significant risk of developing toxic manifestations, as do those with congestive heart failure.16

Absorption

Quinine is readily absorbed from the small intestine, with peak plasma levels occurring one to three hours after ingestion. About 70% is bound to plasma proteins, hence, low albumin levels in renal failure patients may lead to higher blood levels of the free drug. Elimination is unusually slow in patients with hepatic insufficiency because it is metabolized in the liver.

Normally, about 20% of an administered dose is excreted unaltered in the urine. In patients with reduced glomerular filtration rate, unmetabolized quinine is reabsorbed in the distal renal tubule by passive back diffusion, potentially resulting in a dangerously high tissue and serum level of quinine.6

The etiology of hypoglycemia in patients taking quinine is probably multifactorial. Insulin release from isolated pancreatic islets of Langerhans stimulated by quinine in vitro has been demonstrated.17

Quinine augments the insulinotropic effect of glucose and also stimulates the release of insulin at low glucose concentrations, through the activation of voltage-sensitive calcium channels by inhibition of potassium conductance.18

Quinine acts on the Kir component of the KATP channel. The SUR subunit of the KATP channel on the beta cell may serve as a chaperone protein for Kir and there is evidence that the reverse may be true also.19 Quinine mediated hypoglycemia in renal patients has also been ascribed to loss of gluconeogenetic substrate in the form of alanine normally released from the kidney.20 As stated earlier, quinine is often regarded, wrongly, as a safe medication. Because of the pathophysiology of the diseased kidney, patients with renal impairment are at particular risk of toxicity, particularly severe life-threatening hypoglycemia. We suggest that the hypoglycemia observed in our patient was due to ESRD-mediated quinine accumulation, therefore caution should be exercised with the use of quinine in patients with kidney disease.

For more information:
  1. Agbenyega T, Angus B, Bedu-Addo G, et al. Glucose and Lactate Kinetics in Children with Severe Malaria. J Clin Endocrinol Metab. 2000;85:1569-1576.
  2. English M, Wale S, Binns G, et al. Hypoglycemia on and after admission in Kenyan children with severe malaria. QJM. 1998;91:191-197.
  3. Limburg P, Katz H, Grant C, et al. Quinine-Induced Hypoglycemia. Ann of Intern Med. 1993;119:218-219.
  4. Warrell D, Molyneux M, Beales P (eds). Severe and complicated Malaria. Trans Roy Soc trop. Med Hyg. 1990;84(suppl.):1-65.
  5. Goldenberg A, Wexler L. Quinine Overdose: Review of Toxicity and Treatment. Clin. Cardiol. 1988;11:716-718.
  6. Chemotherapy of Parasitic Infections. In: Gilman AG, Rall TW, Nies AS, et al, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 10th edition. New York: Pergamon Press, year: 1086-1089.
  7. Leclerc K, Landry F.Benign Nocturnal Leg Cramps. Current controversies over use of quinine. Postgraduate Medicine 1996;99: 177-184.
  8. Kanaan N, Sawaya R. Nocturnal leg cramps. Clinically mysterious and painful-but manageable.Geriatrics. 2001;56:34-42.
  9. Mandal A, Abernathy T, Nelluri S, et al. Is Quinine Effective and Safe in Leg Cramps? J Clin Pharmacol. 1995;35:588-593.
  10. Riley J, Antony S, Leg cramps: Differential diagnosis and management. Am Fam Physician. 1995; 52: 1794-8.
  11. Wilson M. Commentary on “Quinine is effective for preventing nocturnal leg cramps.” ACP J Club. 1995 Nov/Dec;123:11.
  12. Man-Son-Hing M, Wells G, Lau A. Qunine for Nocturnal Leg Cramps. A Meta-Analysis Including Unpublished Data. J Gen Intern Med. 1998;13:600-606.
  13. US Department of Health and Human Services. Drug products for the treatment and/or prevention of nocturnal leg muscle cramps for over-the-counter human use. Federal Register. Aug 22, 1994;59(161):43234-52.
  14. Jaeger A, Sauder P, Kopferschmitt J, et al. Clinical features and management of poisoning due to antimalarial drugs. Med Toxicol. 1987: 2: 242-273.
  15. Davis T, Karbwang J, looareesuwan S, et al. Comparative effects of quinine and quinidine on glucose metabolism in healthy volunteers. Br J Clin Pharmac. 1990; 30: 397-403.
  16. Garber AJ, Vier D, Cryer P, et al. Hypoglycemia in compensated chronic renal insufficiency. Diabetes. 1974; 23: 982-6.
  17. Henquin J, Horemans B, Nenquin M, et al. Quinine induced modifications of insulin release and glucose metabolism by isolated pancreatic islets. FEBS Lett 1975;57:280-284.
  18. Herchuelz A, Lebrun P, Carpinelli A, et al. Regulation of calcium fluxes in rat pancreatic islets: quinine mimics the dual effect of glucose on calcium movements, Biochem Biophys Acta. 1981;640:16-30.
  19. Doyle ME and Egan JM. Pharmacological Agents That Directly Modulate Insulin Secretion. Pharmacological Reviews. 2003;55:105-131.
  20. Mayes PA. Gluconeogenesis and Control of the Blood Glucose. In: Murray, RK, Granner DK, Mayes PA, et al, eds. Harper’s Biochemistry, 25th edition. New York: The McGraw-Hill Companies/Appleton & Lange, 1999: 208-218.