Metabolic acidosis and anaemia associated with dorzolamide in a patient with impaired renal function

Abstract

Topical carbonic anhydrase inhibitors (CAI), used for treatment of glaucoma, are generally regarded as safe and unconnected with systemic side effects. We report an unusual case of fatigue, metabolic acidosis, and normocytic anaemia associated with ocular administration of the CAI, dorzolamide, in a patient with impaired renal function. In chronic kidney disease, where CAI elimination may be decreased, and patients prone to develop metabolic acidosis, systemic absorption of ocular administered CAI could lead to rare, but potentially serious adverse reaction, that are a consequence of inhibition of extraocular carbonic anhydrase isoenzymes.

A 46‐year‐old white man (height 165 cm; weight 50 kg) with moderate renal impairment (Table 1), due to diabetic nephropathy, with bilateral proliferative diabetic retinopathy and neovascular glaucoma in the left eye, was being treated for glaucoma. Glaucoma treatment consisted of the topical carbonic anhydrase inhibitor (CAI), dorzolamide, in the form of a 2% ophthalmic solution (one drop in the left eye, twice daily), and the topical alpha 2 adrenergic agonist, brimonidine, in the form of a 0.2% ophthalmic solution (one drop in the left eye, twice daily). His type 1 diabetes mellitus was treated with analogue insulin. Otherwise, he had no concomitant morbidity, no concomitant medication, no allergies or previous drug sensitivities, and no relevant social, occupational, or family history.

Table 1.

Selected laboratory parameters over time

	Before dorzolamide treatment	Dorzolamide treatment for 2 months	3 months after stop of dorzolamide	8 months after stop of dorzolamide	14 months after stop of dorzolamide
pH	7.36	7.26	7.37	7.39	7.38
BE (mmol l −1 )	−2.1	−9.1	+1.0	+2.1	+3.2
HCO 3 (mmol l−1)	23.3	17.3	26.7	27.5	29.1
Anion gap (mmol l −1 )	18.2	19.6	19.0	17.1	19.1
pCO 2 (kPa)	5.62	5.25	6.32	6.16	6.68
Creatinine (μmol l −1 )	133	130	127	136	132
CrCl; CKD‐EPI equation (ml min −1 1.73 m −2 )	54.8	56.4	58.0	53.4	55.3
CrCl; Cocroft Gault equation (ml min −1 /1.73)	43	44	45	42	44
Na (mmol l −1 )	143	145	143	145	146
K (mmol l −1 )	4.15	6.78	4.02	4.12	4.59
WBC (× 10 9 l −1 )	8.2	8.8	6.1	10.2	9.7
RBC (× 10 12 l −1 )	4.59	3.02	3.9	4.06	4.07
HBG (g l −1 )	127	82	114	119	117
HCT	0.389	0.266	0.34	0.355	0.345
MCV (fl)	84.7	87.2	87.2	87.4	84.8
RTC (× 10 12 l −1 )	−	0.06	0.066	0.078	−
RTC (%)	−	2	1.7	1.9	−
PLT (× 10 9 l −1 )	226	379	322	325	276

BE, base excess; CrCl, creatinine clearance; HBG, haemoglobin; HCT, haematocrit; MCV, mean corpuscular volume; PLT, platelet count; RBC, red blood cell count; RTC, reticulocyte count; WBC, white blood cell count

Two months after starting treatment, the patient was admitted to the internal medicine department complaining of unexplained fatigue. Arterial blood gas analysis (Astrup) revealed normal anion gap metabolic acidosis (NAGMA) (pH 7.26, BE −9.1 mmol l⁻¹, pCO₂ 5.25 kPa) with hyperkalemia (6.78 mmol l⁻¹). A complete blood cell count found isolated normocytic anaemia with a haemoglobin level of 82 g l⁻¹, the number of white blood cells and platelets were within normal range (Table 1). Microscopic evaluation of a bone marrow aspirate smear showed non‐specific cytologic atypia of the erythroid elements, such as abnormal nuclear shape, nuclear fragmentation, internuclear chromatin bridging, and defects in cytoplasmic staining. No primary bone marrow disorder was found.

After excluding other causes of metabolic acidosis (such as worsening of renal function, worsening diabetes compensation, diarrhoea, adrenal insufficiency, other systemic or topical medications, changes in diet or physical activity, and weight loss) and other reasons for the normocytic anaemia (no history of bleeding, no deficiency of erythropoietin, iron, ferritin, and vitamins involved in erythropoiesis, no laboratory signs of haemolysis, normal serum thyrotropin level, normal findings from upper gastrointestinal endoscopy and colonoscopy, normal findings from urinalysis, normal abdominal ultrasound including kidneys and urinary bladder, and normal chest X‐ray), we considered the possibility that both the NAGMA and normocytic anaemia could be a side effect of dorzolamide treatment. The patient denied inappropriate dosing of dorzolamide. Dorzolamide was stopped, and adequate control of intraocular pressure was subsequently established with a combination of topical prostaglandin (bimatoprost) and brimonidine.

To correct the NAGMA and hyperkalemia, the patient was given sodium bicarbonate tablets. The dosing was gradually decreased according to acid–base measurements. At the 3‐month follow‐up (i.e. after discontinuation of dorzolamide), the patient reported no fatigue, the NAGMA had resolved, and the anaemia had improved spontaneously. All improvements persisted through the most recent follow‐up, which was 14 months after dorzolamide was stopped (Table 1). A re‐challenge was not performed, because it was refused by the patient.

To our knowledge, this is the first laboratory documented case report of NAGMA and anaemia stemming from standard treatment with dorzolamide in an adult.

Topical ophthalmic CAIs (dorzolamide and brinzolamide) are generally regarded as safe, especially compared with the earlier oral forms of CAI (such as acetazolamide), which had numerous systemic adverse effects (including NAGMA, nephrolithiasis, blood dyscrasias, and fatigue) 1. Little information exists regarding the possible systemic adverse effects of topical CAIs. However, it is well recognized, that after ophthalmic instillation, some amount of the active drug in eye drops, including dorzolamide, rapidly enters the systemic circulation via absorption from the nasopharyngeal mucosa, or directly via the conjunctival blood vessels 2, 3, 4.

Topical ophthalmic CAI functions by inhibiting the type II isoenzyme of carbonic anhydrase (CA‐II) in the ciliary epithelium of the eye, thereby decreasing aqueous humour production and reducing intraocular pressure 3. Potential systemic effects of CAI are based on its ability to inhibit carbonic anhydrase isoenzymes (mainly CA‐II), which are present in most tissues, cells, and organs, including erythrocytes and kidneys 3, 5, 6. CA‐II is a major non‐haemoglobin protein in erythrocytes 3. In red blood cells, CA‐II links blood O₂ delivery to metabolic CO₂ production in tissues. In the kidney, inhibition of renal tubular CA‐II leads to significant bicarbonate excretion into the renal tubules, which can lead to NAGMA 1, 3, 7, 8. Several case reports have described NAGMA in neonates resulting from the systemic effects of topical dorzolamide 9, 10. In adults, indirect evidence of metabolic acidosis (i.e. lethargy, bad taste in the mouth, and supposedly increased acidity of sweat leading to a black discoloration/oxidation of silver chain and medallion, which the patient wore around his neck), secondary to topical brinzolamide use, has also been reported 11. Importantly, dorzolamide is likely capable of inducing a state of alkaline urine via excretion of bicarbonate by acting on renal tubular CA‐II enzyme. Alkaline urine is low in citrate and magnesium, which may favour crystallization of calcium salts in tubular fluid and urine. Three cases of dorzolamide‐induced nephrolithiasis have been published 12. After entering into the systemic circulation, 90% of dorzolamide is absorbed into red blood cells and bound to the CA‐II enzyme. Dorzolamide is slowly metabolized to N‐de‐ethyldorzolamide, which is stored in erythrocytes. Plasma concentrations of dorzolamide can reach 11 μg l⁻¹ 3. Both, dorzolamide and its metabolite have a long half‐life (˃4 months), are metabolized in liver, and slowly eliminated via the kidneys 3. The possibility of adverse effects is therefore enhanced in patients with decreased glomerular filtration 1, as seen this case report.

To our knowledge, no information about dorzolamide‐induced anaemia has been published to date. In this reported case of dorzolamide‐induced anaemia, we very probably see a condition that ties in with a variety of blood disorders (such as aplastic anaemia, non‐aplastic anaemias, pancytopenia, agranulocytosis, thrombocytopenia, eosinophilia, or mild leukopenia) reported to be associated with orally administered CAIs 13, 14, 15, 16, 17. Additionally, several reports have also described dorzolamide‐induced thrombocytopenia 18, 19. However, the real causes of anaemia and other blood dyscrasias associated with CAI are unknown 1.

In the setting of evidence‐based medicine, case reports describing unusual adverse drug reactions are often undervalued and regarded as non‐convincing or providing poor evidence. However, according to Aronson et al. 20, even single reports describing a mechanism of injury that is related to the pharmacological properties of a drug, or describing a drug‐related physiological dysfunction, which can be demonstrated with physicochemical testing, should be classified as evidence of an adverse reaction to the drug. The chronological coincidence of NAGMA with anaemia, together with resolution of both findings (NAGMA and anaemia) after discontinuation of dorzolamide, provides some likelihood of a causal association between dorzolamide administration and both side effects.

In conclusion, the purpose of this report is to increase awareness of systemic absorption of dorzolamide eye drops and to remind that the topically administered CAIs may cause (although rarely) systemic side effects. This is especially true in patients with chronic kidney disease, where CAI elimination may be compromised (leading to an accumulation of CAI and its metabolite), and patients prone to develop acidosis. In such patients, these drugs should be prescribed with caution. Moreover, patients treated with topical CAI should be warned of these rare, but potentially serious, systemic adverse effects, i.e. fatigue, pallor, bleeding, purpura, and/or infection. Patients on CAIs should be told to immediately contact their physician if they experience any changes in their physical condition.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 21, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 22, 23.

Competing Interests

There are no competing interests to declare.

Hoffmanová, I. , and Sánchez, D. (2018) Metabolic acidosis and anaemia associated with dorzolamide in a patient with impaired renal function. Br J Clin Pharmacol, 84: 796–799. doi: 10.1111/bcp.13499.