Hydrochlorothiazide

Mechanism

Thiazide diuretics raise allopurinol and oxypurinol metabolite levels, increasing hypersensitivity risk, including allopurinol hypersensitivity syndrome (DRESS).

Symptoms

Rash, fever, facial oedema, lymphadenopathy, abnormal liver function. Reactions develop 2–8 weeks after starting allopurinol, more often in older patients and chronic kidney disease.

Management

On the combination, dose allopurinol by creatinine clearance: if below 60 mL/min, start at 100 mg/day with titration of 100 mg every 4 weeks until target uric acid is reached. In Asian patients (especially Han Chinese and Thai), HLA-B*58:01 testing is recommended before starting allopurinol. Alternatives in hyperuricaemia: febuxostat (if no heart failure), or replace the thiazide with losartan (urocosuric effect).

Mechanism

Additive hypotension and fall risk. No direct pharmacokinetic interaction.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk.

Management

In older patients, check standing and sitting blood pressure 1–2 weeks after start. Alternative anxiolytic: hydroxyzine or a short lorazepam course.

Mechanism

Additive orthostatic hypotension. Older patients: fall and delirium risk with thiazide-induced hypovolaemia.

Symptoms

Postural dizziness, syncope, fatigue. Older patients: fall and fracture risk.

Management

In older patients, check standing and sitting blood pressure and assess fluid and electrolyte balance. For neuropathic pain, alternative: gabapentin or pregabalin.

Mechanism

Standard combination in hypertension – additive antihypertensive effect. Thiazide diuretic causes hypokalaemia.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk. With additional antihypertensives: bradycardia (pulse below 60/min).

Management

Standard combination (fixed-dose product available). Check potassium 2–4 weeks after start and then annually. If potassium drops below 4.0 mmol/L, add a potassium-sparing component.

Mechanism

Thiazide diuretic causes hypokalaemia and hypomagnesaemia, increasing myocardial sensitivity to digoxin. Arrhythmia risk rises, especially ventricular arrhythmias.

Symptoms

Nausea, vomiting, loss of appetite, confusion, yellow-green halos around lights, arrhythmia (bigeminy, AV block). Symptoms appear earlier in older patients and chronic kidney disease.

Management

On the combination, check potassium and magnesium every 2–4 weeks in the first 3 months, then every 3–6 months. If potassium falls below 4 mmol/L, add potassium supplements or a low-dose potassium-sparing diuretic (spironolactone). Thiazide alternatives in hypokalaemia: indapamide with potassium supplementation or a thiazide/potassium-sparing combination.

Mechanism

Additive antihypertensive effect. In the first weeks hydrochlorothiazide increases renin-angiotensin system activity, raising sensitivity to the ACE inhibitor. A standard fixed combination for arterial hypertension.

Symptoms

Symptomatic hypotension on starting: dizziness, weakness, especially on standing. In older patients: fall risk. Potassium monitoring matters — thiazide depletes, ACE inhibitor retains.

Management

On starting the combination, begin enalapril at the lowest dose (2.5 mg) at bedtime. Check creatinine and potassium at 1–2 weeks, then every 6 months. In older patients, take the first dose seated.

Mechanism

Sequential nephron blockade: furosemide acts at the loop of Henle, the thiazide at the distal tubule. Additive diuresis in fluid retention resistant to a single diuretic.

Symptoms

Weakness, dizziness, thirst, reduced urine output, rising creatinine. In older patients, fall risk from orthostatic hypotension. Weakness, muscle cramps, fatigue, palpitations, arrhythmia (particularly dangerous with digoxin). Symptoms appear at potassium below 3.5 mmol/L.

Management

Use only as short courses (3–7 days) with daily weight and creatinine every 1–2 days. Potassium, sodium, magnesium every 2–3 days. When weight loss reaches 1–1.5 kg/day, reduce diuresis pace — return to a single diuretic. For sustained need, consider an SGLT-2 inhibitor or tolvaptan.

Mechanism

Thiazide diuretics reduce glycaemic control via hypokalaemia-driven suppression of insulin secretion. HbA1c may rise by 0.3–0.5%, especially in the first 6 months.

Symptoms

Return of thirst and polyuria, rising fasting glucose, signs of worsening control. Symptoms are typically mild.

Management

Check fasting glucose and HbA1c 3 months after starting hydrochlorothiazide. If HbA1c rises, increase metformin or add another glucose-lowering agent. Potassium every 6 months. In overt diabetes decompensation, alternatives: indapamide (less metabolic effect) or an SGLT-2 inhibitor.

Mechanism

Thiazides are one of the most common drug causes of hyponatraemia in older patients via SIADH-like mechanism and natriuresis. SSRIs (sertraline) add a SIADH-like effect. Additive risk.

Symptoms

Headache, nausea, confusion, drowsiness; severe cases: seizures. Develops slowly over 1–2 weeks and is often missed in older patients.

Management

On the combination, check sodium at 2 and 4 weeks after starting sertraline or the thiazide, then every 6 months. If sodium falls below 130 mmol/L, consider switching sertraline to mirtazapine or agomelatine, or replacing the thiazide with indapamide (lower hyponatraemia risk).

Mechanism

Opposing effects on potassium: thiazide depletes it, spironolactone retains it. Combination in resistant hypertension and ascites. In CKD, hyperkalaemia risk rises.

Symptoms

With a balanced combination, no specific symptoms. Weakness, fatigue, paraesthesias, arrhythmia. Symptoms develop at potassium above 5.5 mmol/L; life-threatening above 6.5 mmol/L.

Management

Check potassium and creatinine at 2 and 4 weeks after starting, then every 3 months. With creatinine clearance below 30 mL/min, do not prescribe spironolactone. In older patients, watch for dehydration, especially in heat or acute illness.