Brukinsa and Hyponatremia: Mechanism Unknown, Not Established as SIADH
The mechanism by which Brukinsa (zanubrutinib) causes hyponatremia is not established in the available evidence, and there is no documentation linking it specifically to SIADH. The provided evidence does not contain any information about Brukinsa/zanubrutinib causing hyponatremia through any mechanism.
What We Know About Drug-Induced Hyponatremia Mechanisms
While the evidence doesn't address Brukinsa specifically, drug-induced hyponatremia generally occurs through two main pathways:
SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)
- Characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), leading to water retention and dilutional hyponatremia 1
- Common culprits include vincristine and ifosfamide, which sustain elevated plasma AVP levels 1
- Other medications like platinum-based chemotherapy, vinca alkaloids, opioids, NSAIDs, anticonvulsants, and antidepressants can cause SIADH 2
NSIAD (Nephrogenic Syndrome of Inappropriate Antidiuresis)
- Characterized by intrarenal activation of water reabsorption with suppressed plasma AVP levels 1
- Antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia through upregulation of aquaporin-2 (AQP2) in collecting ducts 1
- These drugs activate V2R-cAMP-PKA signaling independent of vasopressin 1
Clinical Approach When Brukinsa-Associated Hyponatremia Occurs
If hyponatremia develops in a patient on Brukinsa, evaluate systematically:
Initial Workup
- Assess volume status (orthostatic hypotension, dry mucous membranes, skin turgor for hypovolemia; edema, ascites, JVD for hypervolemia) 3
- Measure serum and urine osmolality, urine sodium, and uric acid 3, 4
- Rule out other causes: adrenal insufficiency, hypothyroidism, renal insufficiency 2
Diagnostic Criteria for SIADH (if present)
- Hypotonic hyponatremia with serum sodium <134 mEq/L 4
- Inappropriately high urine osmolality (>500 mosm/kg) 4
- Urine sodium >20 mEq/L 4
- Clinical euvolemia 4
- Normal thyroid, adrenal, and renal function 4
Management Based on Severity
For severe symptomatic hyponatremia (seizures, altered mental status):
- Administer 3% hypertonic saline with goal to correct 6 mmol/L over 6 hours or until symptoms resolve 4, 5
- Maximum correction must not exceed 8 mmol/L in 24 hours to prevent osmotic demyelination syndrome 3, 4
- Transfer to ICU for monitoring every 2 hours initially 4
For mild-moderate asymptomatic hyponatremia:
- Fluid restriction to 1 L/day is first-line treatment 4, 6
- If ineffective, add oral sodium chloride 100 mEq three times daily 3
- Consider demeclocycline or tolvaptan for refractory cases 4, 6
Critical Caveat
The absence of Brukinsa in the evidence base means the mechanism remains speculative. If hyponatremia occurs with Brukinsa, consider alternative causes including the underlying malignancy (paraneoplastic SIADH is common with certain cancers) 2, concomitant medications 1, 7, or disease-related factors before attributing it to the BTK inhibitor itself.