Glutathione | Pharmacology Mentor

Generic Name

Glutathione (GSH)

Mechanism

Free‑radical scavenging: Conjugates reactive oxygen species (ROS) to form glutathione disulfide (GSSG).
Phase II detoxification: Serves as a cofactor for glutathione‑S‑transferases (GST), facilitating conjugation of xenobiotics (acetaminophen, xenobiotics, heavy metals) to GSH for excretion.
Redox buffering: Maintains cellular NADPH/NADP⁺ balance via glutathione reductase, regenerating reduced GSH from GSSG.
Cell signaling: Modulates apoptosis, cytokine production, and neuronal function through redox‑dependent pathways.

Pharmacokinetics

Parameter	Typical Findings
Absorption	Oral bioavailability ≈ 0.5–1 % (first‑pass metabolism, efflux pumps).
Distribution	Widely distributed; peak plasma concentrations after IV ≈ 2–5 µmol/L. CNS penetration limited.
Metabolism	Metabolized by γ‑glutamyl transpeptidase to cysteinyl‑glycine and further by dipeptidases.
Elimination	Primarily renal (≈ 20 % recovered in urine); hepatic metabolism also contributes. Half‑life: 10–20 min IV, ≈ 60 min orally.

Indications

Hepatopurulent disorders (hepatic failure, acetaminophen overdose; *adjunct* to N‑acetylcysteine).
Oxidative‑stress‑related conditions: chronic kidney disease, cardiovascular disease, neurodegenerative disorders.
Oncology: adjunctive therapy to enhance drug penetration, mitigate drug‑induced neurotoxicity.
Allergy and asthma: limited evidence for reduction of airway oxidative stress.
Dermatology: topical GSH in hyperpigmentation, photoprotection.

Contraindications

Hypersensitivity to GSH preparations or excipients.
Renal impairment: risk of accumulation; monitor kidney function.
Sickle‑cell disease: GSH oxidized rapidly; may trigger hemolysis.
Pregnancy/Lactation: Use only if benefits outweigh risks (limited data); GSH considered safe but data are sparse.

Warnings:
• Extravasation of IV infusion may cause tissue necrosis; administer slowly and with caution.
• Respiratory depression reported in high IV doses; monitor in severely ill patients.
• Interaction with alkylating agents: may reduce efficacy; coordinate with oncology pharmacotherapy.

Dosing

Route	Typical Dose	Frequency	Notes
Intravenous (IV)	5–15 mg kg⁻¹ (≈ 250–750 mg) over 60 min	1–3 × day	Preferred for acute hepatic/oxidative injury.
Oral / Sublingual	250–1,000 mg/day (divided)	Daily	Bioavailability low; consider enteric‑coated or liposomal forms.
Inhalational	200–400 µg/d	Daily	Emerging use in COPD/CF; investigational.
Topical	5–15 % solution	Daily	For dermatologic indications.

Adverse Effects

Common: nausea, vomiting, headache, dizziness, flushing, mild hypotension.
Serious: anaphylaxis, bronchospasm, severe hypotension, tissue necrosis from extravasation.
Rare: hemolytic anemia in G6PD deficiency; ocular irritation on topical use.

Monitoring

Serum glutathione & GSSG ratio (baseline and after therapy).
Liver function tests (ALT, AST, ALP, bilirubin).
Renal panel (Cr, BUN).
Complete blood count if used chronically.
Vital signs during IV infusion.
Drug‑specific markers (e.g., acetaminophen serum levels when used as adjunct).

Clinical Pearls

Oral GSH is poorly absorbed; use high‑dose liposomal or enteric‑coated formulas to improve bioavailability.
IV GSH restores hepatic GSH within minutes, making it the gold standard for acute detox scenarios.
Sublingual or buccal administration bypasses first‑pass metabolism and can deliver a measurable rise in plasma GSH.
Concurrent N‑acetylcysteine (NAC) can augment hepatic GSH synthesis; consider dual therapy in acetaminophen overdose.
Topical GSH penetrates epidermal layers ≤ 0.5 mm; combine with 1–2 % tranexamic acid for hyperpigmentation.
Monitor GSH/GSSG ratio > 1.0 post‑infusion to gauge adequacy of oxidative load mitigation.
Patients with G6PD deficiency may experience hemolysis upon high‑dose IV GSH; dose titrate cautiously.
In oncology, GSH may paradoxically contribute to chemoresistance; limit use during alkylating or cross‑linking agents unless protective goals outweigh risk.

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• Key Pharmacology Terms: *antioxidant*, *free radical scavenger*, *detoxification*, *phase II conjugation*, *redox homeostasis*, *glutathione transporters*, *glutathione reductase*.

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