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Sodium-lowering

• ↓ serum Na⁺ → nausea, confusion, falls
• Seizures and coma if severe or fast
• SIADH-like: ↑ ADH release or renal ADH sensitivity (carbamazepine family, cyclophosphamide, vincristine; SRIs mildly)
• Direct V2 agonism (desmopressin, oxytocin at high infusion rates)
• Renal salt wasting (thiazides, cisplatin)
• Correct slowly: ≤ 8–10 mmol/L per 24 h to avoid osmotic demyelination

What hyponatremia is and why it matters

Sodium below 135 mmol/L — a water problem more often than a salt problem

• Serum Na⁺ < 135 mmol/L; severe below about 120, or any level with neurological symptoms¹²
• Most drug-induced cases are dilutional: the body holds water it should have excreted, and the sodium is diluted, not lost³
• Chronic and mild: nausea, unsteady gait, falls, inattention, fractures — easy to miss in an older patient¹
• Acute or severe: brain swelling → headache, vomiting, seizures, coma, death; the brain has had no time to adapt¹²
• The paradox of treatment: raising sodium too fast after the brain has adapted causes osmotic demyelination (the pons first)¹²

How the body holds sodium steady

ADH, thirst and the kidney — and where drugs break in

• Antidiuretic hormone (vasopressin) from the posterior pituitary acts on renal V2 receptors → aquaporin-2 → water is reabsorbed, urine concentrates
• A falling plasma osmolality should switch ADH off and let dilute urine carry the excess water away
• SIADH: ADH keeps acting when it should not — concentrated urine despite low plasma osmolality, normal volume, normal adrenal and thyroid function¹²
• Four ways a drug lowers sodium: mimic or release ADH (SIADH-like), stimulate V2 directly, waste salt through the kidney, or drive water in faster than the kidney can excrete it³

Route 1 — SIADH-like: the carbamazepine family

The antiseizure drugs with the biggest sodium effect

• Carbamazepine, oxcarbazepine and eslicarbazepine increase the renal response to ADH and probably ADH release; the effect is dose-related³⁴
• Oxcarbazepine is the worst of the three: sodium < 125 mmol/L in 2.5% of patients in its controlled trials, and any hyponatremia in about half of long-term users in a large epilepsy cohort⁴⁵
• Carbamazepine: about a quarter of long-term users in the same cohort, severe in a minority⁴
• Eslicarbazepine: a dose-related label warning; less than oxcarbazepine at comparable doses — the same active molecule, less of it as the R-enantiomer and a flatter curve⁶
• Risk multiplies with age, thiazides, other sodium-lowering drugs and high doses; check sodium before and within the first weeks⁴⁵

Route 1 — SIADH-like: the serotonergic and other drugs

Why the SRIs are not pegged

• SSRIs and SNRIs raise ADH release; reported incidence varies enormously with the definition used, and the risk sits in older patients, in the first weeks, and with concurrent diuretics³⁷
• The effect is mild and common to the whole class — it comes with SERT binding — so it is described on the SERT card rather than pegged on every SRI ballicule
• Mirtazapine, bupropion and agomelatine carry less risk than the SRIs⁷
• Cyclophosphamide (high-dose IV) and vincristine cause SIADH; the forced hydration given with cyclophosphamide compounds it³¹²
• Ifosfamide: SIADH and proximal tubular injury¹²

Route 2 — direct V2 agonism

The drug is the antidiuretic hormone

• Desmopressin is a V2-selective vasopressin analog: each dose produces antidiuresis, preventing excretion of additional water⁹
• The nocturia products carry a boxed warning for hyponatremia; sodium is checked before starting and within the first week⁹
• Oxytocin shares enough structure to act on V2 at high infusion rates — water intoxication with prolonged infusion, worse with hypotonic fluids¹⁰

Route 3 — renal salt wasting: the thiazides

The commonest drug cause of hyponatremia

• Thiazides block the distal NCC cotransporter: sodium is lost while the kidney keeps its ability to concentrate urine, so water is retained on top of the salt loss³⁸
• Loop diuretics rarely do this — they wash out the medullary gradient, so the kidney cannot hold water either³
• Onset is usually within the first weeks; older women, low body weight and higher doses carry the risk; it recurs on rechallenge⁸
• Chlorthalidone and indapamide are longer-acting than hydrochlorothiazide and are implicated at least as often⁸
• Cisplatin: renal salt wasting from tubular injury, plus SIADH¹²

Route 4 — intake exceeds water excretion

MDMA and polydipsia

• MDMA releases ADH and drives thirst at the same time; dancing, heat and deliberate water-loading finish the job — the classic fatal hyponatremia of a young woman at a party¹¹
• Psychogenic polydipsia in schizophrenia: intake outruns even a normal kidney; antipsychotics are the context, not the cause
• Beer potomania and "tea and toast": too little solute to excrete free water — a diet problem that drugs can unmask

Who is at risk, and what to check

The same patient keeps appearing

• Older age, female sex, low body weight, and any second sodium-lowering drug — the thiazide plus SSRI plus oxcarbazepine combination is the one to notice³⁸
• Check sodium before starting and within the first two to four weeks for thiazides, oxcarbazepine or eslicarbazepine, desmopressin, and SRIs in the elderly⁵⁸⁹
• Symptoms are non-specific: a confused, unsteady older patient on a new drug has hyponatremia until proven otherwise

Treatment — and the speed limit

Stop the drug, restrict water, and go slowly

• Mild and chronic: stop or reduce the drug; restrict fluid; add solute (salt tablets, urea) if needed¹²
• Severe symptoms (seizure, coma): hypertonic 3% saline in small boluses until symptoms settle, then stop¹²
• Limit the rise to about 8–10 mmol/L in the first 24 hours; slower still when the risk of osmotic demyelination is high (sodium ≤ 105, hypokalemia, alcoholism, malnutrition, liver disease)¹²
• Vaptans (V2 antagonists) treat SIADH by making the kidney excrete water — never for hypovolemic hyponatremia, and never with fluid restriction in the first day¹²

How the peg is sized

Editorial magnitude, not a measurement

• Full size: chlorthalidone and desmopressin — a boxed warning or the commonest cause
• Large: the other thiazides and oxcarbazepine
• Middle: cyclophosphamide, MDMA, carbamazepine, eslicarbazepine, oxytocin, ifosfamide, vincristine, cisplatin
• Not pegged: SRIs, TCAs, mirtazapine, antipsychotics, NSAIDs, opioids, loop and potassium-sparing diuretics, lamotrigine, valproate, levetiracetam, ACE inhibitors — at or below the SRI level

References

Numbered as cited on the slides

• [1] Verbalis JG, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med 2013;126(10 Suppl 1):S1–S42
• [2] Spasovski G, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 2014;170:G1–G47
• [3] Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis 2008;52:144–153
• [4] Berghuis B, et al. Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy. Epilepsia 2017;58:1227–1233
• [5] Oxcarbazepine (TRILEPTAL) prescribing information: clinically significant hyponatremia (sodium <125 mmol/L) in 2.5% of treated patients in controlled trials
• [6] Eslicarbazepine acetate (APTIOM) prescribing information: dose-related hyponatremia; warnings and precautions
• [7] De Picker L, et al. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics 2014;55:536–547
• [8] Barber J, et al. A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation? Br J Clin Pharmacol 2015;79:566–577
• [9] Desmopressin nasal spray for nocturia (NOCTIVA) prescribing information: boxed warning for hyponatremia
• [10] Oxytocin (PITOCIN) prescribing information: water intoxication with prolonged infusion and hypotonic fluids
• [11] Hall AP, Henry JA. Acute toxic effects of "Ecstasy" (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth 2006;96:678–685
• [12] Cyclophosphamide, vincristine, cisplatin and ifosfamide prescribing information: hyponatremia / SIADH / renal salt wasting in warnings and adverse reactions

Drugs with this mechanism (19)

• Carbamazepine — Anticonvulsant/mood stabilizer and potent autoinducer; HLA-B*1502 rash risk.
• Carbamazepine ER capsules — Bead-filled extended-release carbamazepine capsule; can be opened and sprinkled.
• Chlorothiazide — The original thiazide diuretic; the only one available in an intravenous form.
• Chlorthalidone — Long-acting thiazide-like diuretic; preferred for hypertension outcomes.
• Cisplatin — Platinum DNA-crosslinking chemotherapy; nephro-, oto-, and neurotoxic.
• Cyclophosphamide — DNA-alkylating chemotherapy and immunosuppressant; hemorrhagic cystitis.
• Desmopressin — Vasopressin V2 analog for diabetes insipidus, enuresis, and bleeding.
• Carbamazepine ER (Equetro) — Carbamazepine ER capsule - the only carbamazepine approved for acute bipolar mania.
• Eslicarbazepine — Once-daily sodium-channel anticonvulsant related to oxcarbazepine.
• Hydrochlorothiazide — The most-prescribed thiazide diuretic for hypertension.
• Ifosfamide — Alkylating chemotherapy; neurotoxic, needs mesna for cystitis.
• Indapamide — Thiazide-like diuretic antihypertensive.
• Midomafetamine — Serotonin-predominant monoamine releaser (empathogen) under study for PTSD.
• Metolazone — Thiazide-like diuretic that works even in renal impairment; adds to loop diuretics.
• Oxcarbazepine — Prodrug of licarbazepine; carbamazepine analog with less enzyme induction and more hyponatremia.
• Oxcarbazepine XR — Extended-release oxcarbazepine for focal seizures; hyponatremia and enzyme induction complicate use.
• Oxytocin — Uterotonic hormone used to induce labor and control postpartum hemorrhage.
• Carbamazepine XR — Extended-release carbamazepine for seizures and trigeminal neuralgia; potent enzyme inducer.
• Vincristine — Vinca-alkaloid chemotherapy; dose-limiting peripheral neuropathy, fatal if intrathecal.

Self-check

• Why correct drug-induced hyponatremia slowly?
  To avoid osmotic demyelination.
• Which drugs can cause hyponatremia through renal salt wasting?
  Thiazides and cisplatin.

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