Generic Name

Hydrochlorothiazide

Mechanism

• Hydrochlorothiazide: inhibits the Na⁺/Cl⁻ co‑transporter in the early distal convoluted tubule, causing natriuresis, diuresis, and a modest diuretic‑induced BP fall.
• Valsartan: blocks the angiotensin‑II type 1 (AT₁) receptors in the vasculature and kidney, preventing angiotensin‑mediated vasoconstriction, aldosterone release, and sympathetic activation.
• Combination yields additive antihypertensive effects, lowers intraglomerular pressure, and mitigates diuretic‑induced potassium loss.

Pharmacokinetics

• Hydrochlorothiazide
• *Absorption*: >90 % after oral dosing; peak plasma 0.5‑1 h.
• *Metabolism*: minimal hepatic oxidation; mostly unchanged.
• *Distribution*: volume ≈ 1 L/kg; protein binding 30‑40 %.
• *Elimination*: almost entirely renal; half‑life 6‑15 h.
• Valsartan
• *Absorption*: ~50 % oral bioavailability; peak 1‑3 h.
• *Metabolism*: hepatic octanoyl‑CoA intermediates; minor CYP3A4 involvement.
• *Distribution*: volume ≈ 17 L/kg; protein binding 90‑95 %.
• *Elimination*: renal excretion 50 % unchanged; half‑life ≈ 6‑9 h.
• Drug‑Drug Interaction
• NSAIDs, diuretics, potassium‑sparing agents, or ACE inhibitors may enhance hyperkalaemia or renal impairment.

Indications

• Primary: uncontrolled essential hypertension.
• Adjunctive:
• Hypertensive patients with diabetes or chronic kidney disease (CKD) for additional renal protection.
• Congestive heart failure with mild–moderate edema when diuretics fail to control BP.
• Sodium‑water overload in patients intolerant to diuretics alone.

Contraindications

• Contraindications
• Anuria, severe renal impairment (CrCl < 15 mL/min).
• Known hypersensitivity to thiazides or valsartan.
• Pregnancy (contraindicated; safe only with risk–benefit assessment).
• Warnings
• Hyperkalaemia: especially when combined with ACE inhibitors or potassium supplements.
• Dehydration / electrolyte disturbance: risk of hyponatremia, hypochloremia.
• Gout and hyperuricaemia: potential trigger during therapy.
• Angioedema: rare but serious; monitor for swelling.
• Renal dysfunction: increased risk of AKI in volume‑depleted states.

Dosing

• Start HCTZ 12.5‑25 mg + Valsartan 80 mg once daily, preferably in the morning.
• Titrate upward in 2‑week intervals:
• HCTZ: 25 → 50 mg.
• Valsartan: 80 → 160 mg.
• Max doses: HCTZ 50 mg + Valsartan 160 mg.
• Adjust downward in CKD or if hyperkalaemia develops.
• Take with food to reduce GI upset.

Adverse Effects

• Common
• Dizziness, orthostatic hypotension, headache.
• Electrolyte shifts: hypokalemia, hyponatremia.
• Increased serum uric acid → gout flares.
• Hyperglycemia, mild dyslipidemia.
• Rash or pruritus.
• Serious
• Severe hyperkalaemia (esp. with ACE inhibitors).
• Acute kidney injury or chronic renal failure.
• Angioedema.
• Severe rash (Stevens–Johnson syndrome).
• Hypovolemic shock in volume‑depleted patients.

Monitoring

Clinical Pearls

1. Synergistic BP lowering – The diuretic load of HCTZ is amplified when paired with valsartan; a 2‑dose regimen can be more effective than high‑dose monotherapy.

2. Hyperkalaemia Check – Before starting, verify potassium‑sparing agents or ACE inhibitor overlap. If creatinine rises > 30 % or K⁺ > 5.5 mEq/L, hold the combination.

3. CKD Dosing – For CrCl 30‑59 mL/min, start at the lowest dose (12.5/80 mg) and titrate slowly; 160 mg valsartan permissible only if creatinine  1.5 in women.

4. Gout Screens – Patients with prior gout episodes benefit from baseline uric acid measurement; consider prophylactic allopurinol if urate is high.

5. NSAIDs caution – NSAIDs blunt diuretic efficacy and may precipitate renal dysfunction. Counsel patients to report NSAID use.

6. Educate on orthostatic hypotension – Advise patients to rise slowly, especially during dose escalation, and to maintain adequate hydration.

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• *References are available upon request, including peer‑reviewed pharmacology texts and current hypertension guidelines.*