Chlorthalidone
Chlorthalidone
Generic Name
Chlorthalidone
Mechanism
- Inhibition of sodium‑chloride cotransporter (Na⁺/Cl⁻) in the distal convoluted tubule
- ↓ Na⁺ reabsorption → ↑ Na⁺ & water excretion
- Resultant natriuresis and diuresis
- Reduced intravascular volume → decreased cardiac output & peripheral resistance
- Secondary renal effects
- ↓ K⁺ secretion → mild potassium‑sparing action
- ↓ Cl⁻ recycling → diminished “loop” activity
- Long half‑life (∼40–70 h) creates sustained BP control even with once‑daily dosing.
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Pharmacokinetics
| Parameter | Approximate Value | Notes |
| Absorption | 92–98 % | Oral bioavailability unaffected by meals |
| Onset | 2–4 h | Diuretic effect evident within 4 h |
| Peak plasma | 4–6 h | Corresponds to maximal diuresis |
| Half‑life | 40–70 h | Allows once‑daily dosing |
| Protein binding | 99 % | Mainly bound to albumin |
| Elimination | Renal (45 %) & hepatic (40 %) | Metabolized by glucuronidation and sulfation |
| Clearance | 14–27 L/h | Reduced in renal impairment |
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Indications
- Primary hypertension
- Hypertension resistant to other agents
- Congestive heart failure (approved secondary use) – improves fluid balance and symptoms
- Edema associated with renal, hepatic, or cardiac disease
- Benign prostatic hyperplasia (BP‑directed)
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Contraindications
| Category | Detail |
| Absolute | Hypersensitivity to chlorthalidone or sulfonamides; severe renal insufficiency (CrCl < 15 mL/min) |
| Relative | Pregnancy – Category C; contraceptive considerations; pregnancy planning needed |
| Caution | Diabetes mellitus (risk of hypoglycemia), electrolyte disturbances, hepatic disease, gout, sarcoidosis, liver dysfunction, severe hypovolemia |
| Drug Interactions | ACE inhibitors/ARBs, potassium‑sparing diuretics, NSAIDs (renal risk), lithium (increased serum levels) |
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Dosing
| Indication | Starting Dose | Maintenance | Titration | Notes |
| Hypertension | 12.5 mg PO once daily | 25–50 mg PO | Increase by 25 mg increments up to 50 mg | Initiate at lowest dose in elderly or CKD |
| CHF Edema | 25 mg PO once daily | 25–50 mg PO | Same as hypertension | Use with caution in advanced HF |
| Renal‑Edema | 12.5 mg PO once daily | 25–50 mg PO | Same | Monitor serum creatinine |
• Administration: Taken in morning; leads to nocturia if taken late.
• Repeat or hold: If serum creatinine rises by >30 % or potassium falls <3 mmol/L, reduce dose or discontinue.
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Monitoring
| Parameter | Frequency | Rationale |
| Serum creatinine & BUN | Initially, then every 1–2 weeks (first 3 months), monthly thereafter | Detect renal impairment |
| Serum electrolytes (K⁺, Na⁺, Cl⁻, Mg²⁺) | Initially, then every 1–2 weeks (first 3 months) | Monitor electrolyte balance |
| Blood pressure | Clinic visits (every 2–4 weeks initially) | Assess therapeutic response |
| Urinalysis | As indicated (if hematuria, proteinuria) | Detect nephropathy |
| Fasting glucose; HbA1c | Baseline; every 3 months for diabetics | Monitor glycemic impact |
| Lipid profile | Baseline; annually | Assess metabolic effects |
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Clinical Pearls
- Once‑daily dosing advantage: The long half‑life of chlorthalidone (≈60 h) means you can treat hypertension reliably with a single morning dose, reducing patient non‑adherence compared to shorter‑acting diuretics.
- Screen for sulfonamide allergy: Even though chlorthalidone is not a sulfonamide, it has a sulfonamide moiety and can precipitate cross‑reactivity in patients with sulfonamide drug hypersensitivity.
- Electrolyte rebound: When discontinuing chlorthalidone, serum potassium can rebound low rapidly; check electrolytes within 48 h.
- Combination therapy: Adding a potassium‑sparing diuretic (e.g., spironolactone) may mitigate hypokalemia, but keep an eye on serum potassium and BUN/Cr to avoid hyperkalemia.
- Gout awareness: Patients with a history of gout should be counselled; therapy may trigger flares, especially in the initial weeks, so prophylactic colchicine can be considered.
- Timing relative to food: Take chlorthalidone at least 30 min before food to avoid slight delays in absorption; otherwise, it is food‑independent.
- Cytotoxicity context: In oncology, chlorthalidone can help mitigate radiation‑mediated edema, but monitoring of renal function is critical due to cumulative nephrotoxicity.
- Drug holiday counseling: In long‑term use, an intermittent “drug holiday” may reduce the risk of electrolyte disturbances without significantly affecting BP control because of the drug’s prolonged action; however, individualized assessment is essential.
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• Key Take‑away:
Chlorthalidone’s unique pharmacokinetic profile enables it to achieve effective antihypertensive and diuretic effects with once‑daily dosing, making it a favorite among clinicians for both hypertension and edema management—provided careful monitoring of renal function, electrolytes, and potential metabolic effects.