Sclerosing agents

Sclerosing agents are a diverse group of pharmacological or chemical substances used to induce localized inflammation, fibrosis, and ultimately obliteration of unwanted vascular, lymphatic, cystic, or tissue spaces. These agents act by damaging the endothelial lining of vessels or cavities, triggering an inflammatory cascade that culminates in the deposition of fibrous tissue. This process is referred to as sclerosis—a term derived from the Greek word skleros, meaning hard.

Sclerosing therapy is clinically utilized across multiple disciplines, including vascular surgery (e.g., treatment of varicose veins), interventional radiology (e.g., ablation of cysts or lymphatic malformations), gastroenterology (e.g., esophageal varices), pulmonology (e.g., pleurodesis for recurrent pleural effusions), and oncology (e.g., treatment of certain tumors or lymphatic malformations). The pharmacodynamic properties, selection criteria, delivery method, and potential adverse effects vary depending on the specific agent and target condition.

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1. Definition and Classification

Sclerosing agents are chemical compounds administered to obliterate unwanted vascular structures, serous cavities, or cystic spaces through controlled induction of endothelial or epithelial injury and fibrosis. Based on their mechanism of action, sclerosing agents are categorized into the following types:

A. Detergent-Type Sclerosants

These disrupt lipid molecules within the cell membrane, leading to cell lysis.

• Examples: Sodium tetradecyl sulfate (STS), Polidocanol, Sotradecol

• Used for: Varicose veins, spider veins, venous malformations

B. Osmotic Sclerosants

Cause endothelial damage via osmotic dehydration leading to desquamation.

• Examples: Hypertonic saline (20–23.4%), Hypertonic dextrose

• Used for: Reticular veins, small varices

C. Chemical Irritants (Corrosive Agents)

Directly damage tissue via chemical burning or inflammation.

• Examples: Ethanol, Iodine, Phenol, Doxycycline

• Used for: Pleurodesis, cyst ablation, vascular malformations

D. Biologic Agents

Induce fibrosis via inflammatory or immunogenic pathways.

• Examples: Talc (sterile), OK-432 (Picibanil), Bleomycin

• Used for: Pleurodesis, lymphangioma, peritoneal sclerosis

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2. Mechanism of Action

Sclerosing agents act by one or more of the following:

• Endothelial Injury: Detergents and hypertonic solutions damage the endothelial lining, exposing subendothelial collagen and initiating platelet adhesion and thrombosis.

• Thrombosis Formation: Induced by contact with collagen and release of pro-coagulant factors, leading to vascular occlusion.

• Inflammation and Fibrosis: Local inflammatory reaction recruits fibroblasts and promotes deposition of collagen.

• Tissue Shrinkage and Collapse: Especially in cystic or serous cavities, leading to adhesion of surfaces (e.g., pleural layers in pleurodesis).

The end result is permanent obliteration of the space or vessel through fibrosis and scarring.

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3. Commonly Used Sclerosing Agents and Formulations

Agent	Class	Formulation	Route	Clinical Use
Sodium tetradecyl sulfate (STS)	Detergent	1–3% solution	Intravenous, intralesional	Varicose veins, hemangiomas
Polidocanol	Detergent	0.5–3% solution	Intravenous, foam	Spider veins, reticular veins
Hypertonic saline	Osmotic	20–23.4% solution	Intravenous	Reticular/spider veins
Ethanol (Absolute)	Irritant	95–100% ethanol	Intralesional, intra-arterial	AV malformations, cystic tumors
Doxycycline	Irritant	10–20 mg/mL	Intrapleural, intralesional	Pleurodesis, renal cyst ablation
Talc (Sterile)	Biologic/Irritant	Powder/suspension	Intrapleural	Pleurodesis for malignant effusions
Bleomycin	Cytotoxic/Irritant	1–3 IU/mL	Intrapleural, intralesional	Lymphangioma, pleurodesis
OK-432 (Picibanil)	Biologic	Lyophilized suspension	Intralesional	Lymphatic malformations

4. Indications and Clinical Applications

A. Varicose Veins and Chronic Venous Insufficiency

• Agents: STS, polidocanol (foam or liquid)

• Procedure: Sclerotherapy, ultrasound-guided foam sclerotherapy

• Effect: Endothelial destruction → thrombosis → fibrosis → vein collapse

• Note: Foam sclerosants (e.g., STS mixed with CO₂ or air) improve contact with vein wall

B. Pleurodesis (Recurrent Pleural Effusions or Pneumothorax)

• Agents: Talc, doxycycline, bleomycin

• Mechanism: Induce inflammation between pleura to prevent fluid re-accumulation

• Delivery: Chest tube or thoracoscopy

C. Lymphatic Malformations and Cystic Lesions

• Agents: Ethanol, OK-432, doxycycline, bleomycin

• Indications: Lymphangioma (cystic hygroma), thyroid cysts, renal cysts

• Preferred in pediatrics: OK-432 and bleomycin due to lower toxicity

D. Gastrointestinal Bleeding from Varices

• Agents: STS, ethanolamine oleate, polidocanol

• Delivery: Endoscopic injection into bleeding varices (esophageal or gastric)

E. Hydrocele and Seromas

• Agents: Phenol, tetracycline, alcohol

• Mechanism: Obliteration of tunica vaginalis or serous cavity

• Used when: Surgery is contraindicated or for recurrence prevention

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5. Pharmacodynamics and Pharmacokinetics

The action of sclerosing agents is local and not systemic in most therapeutic uses. Systemic absorption is usually minimal but can be significant with high-volume or vascular intralesional injections (e.g., ethanol in AV malformations).

Agent	Onset of Action	Duration	Metabolism	Elimination
STS	Immediate	Days–weeks	Minimal systemic effect	Renal, hepatic
Polidocanol	Immediate	Days–weeks	Hepatic	Renal
Ethanol	Immediate	Persistent fibrosis	Hepatic alcohol dehydrogenase	Urinary, respiratory
Doxycycline	Delayed (hours)	Weeks	Hepatic	Renal, fecal
Talc	Slow	Weeks–months	Not metabolized	Local fibrotic
Bleomycin	Delayed	Days	Hepatic	Renal

6. Adverse Effects and Toxicity

System	Adverse Effects
Local	Pain, inflammation, ulceration, necrosis (if extravasated), skin staining
Vascular	Thrombophlebitis, deep vein thrombosis, embolism (esp. foam)
Systemic	Hypotension, allergic reactions, hemolysis (rare)
Respiratory	Acute respiratory distress (talc), pulmonary fibrosis (bleomycin)
Neurological	Stroke or visual disturbances (rare, from paradoxical embolism with foam)
Gastrointestinal	Ulceration or perforation if sclerosants enter GI tract during variceal injection

Special note: Ethanol injections in high volume can cause cardiac arrhythmias, CNS depression, metabolic acidosis, and hemolysis.

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7. Contraindications

Contraindication	Details
Active infection at injection site	Risk of exacerbation and systemic spread
Known allergy to sclerosant	Cross-sensitivity possible among detergents
Pregnancy and lactation	Avoid ethanol, bleomycin, and other cytotoxic agents
Coagulopathy or anticoagulation therapy	Increased risk of bleeding or hematoma
Severe cardiovascular disease	Caution with agents causing bradycardia or hypotension
Pulmonary dysfunction	Avoid bleomycin and talc in patients with ILD or COPD

8. Drug Interactions

Agent	Interacting Substance	Effect	Notes
Ethanol	Disulfiram, metronidazole	Disulfiram-like reaction	Avoid concurrent use
Bleomycin	Oxygen therapy (high FiO₂)	Increased risk of pulmonary fibrosis	Monitor oxygen exposure
Doxycycline	Antacids, iron supplements	↓ Efficacy (chelation)	Separate administration by 2 hours
STS	Heparin	Additive thrombosis risk	Monitor coagulation closely

9. Precautions and Monitoring

• Pre-procedural imaging: To define vascular or cystic anatomy and avoid misplacement

• Volume control: Especially with ethanol or foam sclerosants

• Ultrasound or fluoroscopy guidance: For targeted delivery

• Vital signs monitoring: Especially during intravascular injections

• Post-procedural follow-up: Imaging to confirm obliteration or monitor for recurrence

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10. Formulation and Storage Guidelines

Agent	Stability	Storage Conditions
STS	Stable in sealed vials	Store at room temperature (15–30°C)
Polidocanol	Stable in solution or foam	Use within minutes of foam preparation
Talc (sterile)	Stable dry powder	Store in a dry container at room temperature
Doxycycline	Reconstitute before use	Store reconstituted solution in refrigerator for up to 24 hours

11. Examples of Commercial Products (Selected Agents)

Generic Name	Brand Names	Formulations Available
Sodium tetradecyl sulfate	Sotradecol (U.S.), Fibrovein (UK)	0.1%, 0.5%, 1%, 3% injectable solution
Polidocanol	Asclera (U.S.), Aethoxysklerol (EU)	0.5%, 1%, 2%, 3% injectable or foam
Talc (sterile)	Sclerosol Intrapleural Aerosol	2 g in canister
Doxycycline	Vibramycin (off-label use)	10 mg/mL solution
Bleomycin	Blenoxane	15 IU vials
OK-432 (Picibanil)	Japan-only approved	Lyophilized vial for reconstitution

12. Emerging and Investigational Sclerosing Agents

• Ethanolamine oleate: Investigated for varices; can cause hemolysis and renal failure in large doses

• N-butyl cyanoacrylate (NBCA): Used in endoscopic sclerotherapy (vein embolization)

• Foam sclerosants with microbubble stabilization: Under development for enhanced precision

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13. Summary Table of Key Agents

Agent	Class	Indications	Key Risks
STS	Detergent	Varicose veins, spider veins	Local necrosis, DVT
Polidocanol	Detergent	Reticular veins, venous malformations	Stroke (foam embolism)
Ethanol	Irritant	AVMs, cysts, lymphatic lesions	Arrhythmias, necrosis
Talc	Biologic	Pleurodesis	ARDS, fever, chest pain
Doxycycline	Irritant	Pleurodesis, renal cysts	Pain, fever, sterile abscess
Bleomycin	Cytotoxic	Lymphangiomas, pleurodesis	Pulmonary fibrosis