Hydrochlorothiazide and losartan
Hydrochlorothiazide
Generic Name
Hydrochlorothiazide
Mechanism
- Hydrochlorothiazide
- Thiazide‑type diuretic. Blocks the Na⁺‑Cl⁻ co‑transporters in the distal convoluted tubule → ↑ sodium, chloride excretion → ↓ plasma volume → ↓ systemic blood pressure.
- Secondary effects: ↓ angiotensin‑II release; ↑ renin release; mild vasodilation.
- Losartan
- Selective AT1 receptor antagonist. Prevents angiotensin‑II‑mediated vasoconstriction, aldosterone release, and sympathetic activation.
- Increases natriuresis, improves endothelial function, and reduces progressive renal damage in diabetic nephropathy.
Combined therapy exploits complementary actions: diuretic‑induced volume reduction + ARB‑mediated vasodilation → synergistic BP control and organ protection.
---
Pharmacokinetics
| Parameter | Hydrochlorothiazide | Losartan |
| Absorption | Oral, >70 % bioavailability; peak 30–120 min. | Oral, 99 % bioavailability; Tmax ~1 h. |
| Metabolism | Mainly hepatic, glucuronidation (Phase II). | Hepatic CYP2C9 → losartan → active metabolite (EXP3174) (CYP2C9, CYP3A4). |
| Elimination | Renal (urinary excretion) → half‑life ~6 h. | Renal excretion (urine, feces). Losartan half‑life ~2 h; metabolite ~6–9 h. |
| Protein binding | ~35 % | ~98 % (metabolite ~70 %). |
| Dose‑adjustment | Reduce in CKD GFR < 30 mL/min. | Reduce in severe CKD (eGFR < 30 mL/min). |
| Food effect | No significant effect. | No significant effect. |
--
•
Indications
- Hypertension – first‑line in combination or monotherapy.
- Heart Failure – adjunct to diuretic and ACE/ARB therapy.
- Diabetic Nephropathy – losartan for renoprotection; hydrochlorothiazide for BP control.
- Edema – secondary to renal disease or heart failure (especially early stages).
- Combination Tablets (e.g., HCTZ/Losartan) – for patients needing both diuretic and ARB effects with simplified dosing.
---
Contraindications
- Contraindications
- Severe renal insufficiency (eGFR < 15 mL/min).
- Advanced liver disease.
- Known hypersensitivity to sulfonamides (hydrochlorothiazide) or ARBs.
- Pregnancy – both are category D: avoid, especially first trimester.
- Breastfeeding – avoid; losartan excreted in milk.
- Warnings
- Hyperkalemia: risk increased when combined with other potassium‑sparing agents, ACE inhibitors, ARBs, or high‑potassium diet.
- Hypotension & Dizziness: especially in volume‑depleted states.
- Metabolic disturbances: hyperglycemia, hyperuricemia, hypomagnesemia (hydrochlorothiazide).
- Cushing‑like features or adrenal suppression: rare with high‑dose losartan.
- Drug‑drug interactions: NSAIDs → ↓ diuretic efficacy; potassium‑sparing diuretics ↑ hyperkalemia; ACE inhibitors/ARBs plus diuretic → AKI risk in volume depletion.
---
Dosing
| Drug | Typical Starting Dose | Titration | Max Dose | Administration Notes |
| Hydrochlorothiazide | 12.5–25 mg QD | 25 mg increments up to 50 mg | 50 mg QD (50 mg BID if needed) | Take in morning; avoid nocturia. |
| Losartan | 25 mg QD | 25 mg increments up to 100 mg | 100 mg QD | May be split into twice daily for rapid onset. |
Combination Tablet (e.g., Losartan 50 mg/HCTZ 12.5 mg)
• Start 1 tablet daily; titrate up to 2 tablets (losartan 100 mg HCTZ 25 mg) as needed.
• Administer in the morning; consistent timing reduces diuretic‑induced nocturia.
--
•
Monitoring
| Parameter | Frequency | Rationale |
| Blood pressure & heart rate | Before first dose, day 3, week 1, then monthly | Verify efficacy & tolerance. |
| Serum electrolytes (Na⁺, K⁺, Cl⁻, HCO₃⁻, Mg²⁺, Ca²⁺) | At baseline, day 7, week 4, then every 3 months | Detect hyponatremia, hyperkalemia, hypomagnesemia. |
| Serum creatinine & eGFR | Baseline, 1 week, 1 month, 3 months | Monitor renal function. |
| Urinalysis (protein, glucose, ketones) | Baseline and every 6 months | Detect nephropathy progression. |
| Blood glucose | Every 3 months in diabetes | Thiazides can worsen glycemic control. |
| LFTs | Occasionally in patients with hepatic disease | Losartan metabolism in liver. |
--
•
Clinical Pearls
- Volume‑First Strategy: In uncomplicated hypertension, start with a thiazide diuretic and titrate up; if inadequate, add losartan to exploit vasodilatory synergy.
- Combination Tablet Advantage: Improves adherence; reduces cost; maintains consistent pharmacodynamic profile.
- Avoid Rapid Volume Removal: In patients with pre‑existing CKD or heart failure, start at the low end (12.5 mg HCTZ); monitor creatinine closely to preclude AKI.
- Hyperkalemia Check: Losartan’s ARB effect can counteract potassium loss from HCTZ, but in practice, the additive effect may still produce hyperkalemia; monitor serum K⁺ every 2 weeks initially.
- Photoprotection: Patients on HCTZ should use broad‑spectrum sunscreen and wear hats; increased photosensitivity is common.
- Pregnancy Considerations: Use only if clearly therapeutic need outweighs risk; most clinicians opt for ACE inhibitors or calcium channel blockers instead.
- Drug Interactions: Concurrent NSAIDs blunt HCTZ diuresis and can precipitate AKI; advise patients to limit NSAID use or monitor renal function.
- Renal Protective Edge: Losartan’s ERPs reduce intraglomerular pressure; HCTZ keeps intravascular volume low, balancing hypertensive renal damage mitigation.
--
• Reference‑friendly:
• *Katzung & Trevor’s Pharmacology: The Pathophysiologic Basis of Drug Therapy*
• *American Heart Association Guidelines 2024 – Hypertension*
• *FDA Label Summaries for Hydrophysol 12.5 mg & Losartan HCTZ 50 mg*
Ensure adherence to local prescribing guidelines and patient-specific factors when selecting dose and monitoring schedule.