Management of Snake Bite

1. Introduction / Overview

Snake envenomation remains a significant cause of morbidity and mortality worldwide, with an estimated 5–15 million bites annually and 125,000–190,000 deaths. The clinical spectrum ranges from local tissue damage and coagulopathy to systemic neurotoxicity and cardiovascular collapse. Prompt recognition and evidence‑based management are essential to reduce complications and improve survival. This chapter integrates pharmacologic principles with clinical practice, focusing on antivenom therapy, adjunctive measures, and special considerations across diverse patient populations.

Learning Objectives

• Describe the pathophysiologic mechanisms of venom components and their interaction with host tissues.
• Identify the pharmacologic basis for antivenom selection and administration.
• Explain the pharmacokinetic properties of antivenom preparations and their clinical implications.
• Recognize common adverse effects, contraindications, and drug interactions associated with antivenom therapy.
• Apply special management strategies for vulnerable groups, including pregnant women, infants, and patients with organ dysfunction.

2. Classification

2.1 Antivenom Preparations

Antivenoms are biologic products derived primarily from hyperimmune sera of mammals (commonly horses, sheep, or rabbits). They are classified by the source of the venom used for immunization and the species of the host animal. Major categories include:

• Monovalent antivenoms – Target a single venom species (e.g., Bothrops asper antivenom).
• Polyvalent antivenoms – Contain antibodies against multiple venom species, often used in regions with diverse snake fauna (e.g., Indian polyvalent antivenom).
• Recombinant or monoclonal antivenoms – Emerging technologies aim for greater specificity and reduced immunogenicity.

2.2 Chemical Composition

While antivenoms are biologic, their active components are immunoglobulin (IgG) or antibody fragments (Fab, F(ab’)₂). The selection of fractionation affects potency, half‑life, and immunogenicity. For example, F(ab’)₂ preparations lack the Fc region, reducing the risk of serum sickness but shortening the duration of action compared with whole IgG antivenoms.

3. Mechanism of Action

3.1 Venom Pathophysiology

Venoms are complex mixtures of proteins and peptides that exert their effects through enzymatic activity, receptor modulation, and membrane disruption. Key toxic components include:

• Phospholipases A₂ – Cause myotoxicity and hemolysis.
• Snake venom metalloproteinases (SVMPs) – Induce hemorrhage and coagulopathy.
• Three‑finger toxins – Act on nicotinic acetylcholine receptors, leading to neuroparalysis.
• Kallikrein‑like enzymes – Promote hypotension via bradykinin release.

3.2 Antivenom Pharmacodynamics

Antivenoms neutralize venom by binding to circulating toxins with high affinity, thereby preventing interaction with cellular targets. The binding kinetics depend on antibody avidity and epitope specificity. Neutralization leads to:

• Inhibition of enzymatic activity (e.g., SVMP inhibition restores clotting factor function).
• Blockade of receptor binding (e.g., neutralizing neurotoxins restores neuromuscular transmission).
• Facilitation of toxin clearance via opsonization and immune complex formation.

The therapeutic effect is dose‑dependent and may vary with venom load, time elapsed since bite, and individual patient factors such as body weight and comorbidities.

4. Pharmacokinetics

4.1 Absorption

Antivenoms are administered intravenously, ensuring immediate availability in systemic circulation. In cases where intravenous access is delayed, intramuscular or subcutaneous routes have been explored, but absorption is slower and less predictable, potentially compromising efficacy.

4.2 Distribution

IgG and its fragments exhibit distinct distribution profiles. Whole IgG antivenoms distribute into the vascular and interstitial spaces with a typical volume of distribution (Vd) of 0.4–0.6 L/kg. F(ab’)₂ preparations have a smaller Vd (≈0.3 L/kg) owing to their reduced molecular size. Penetration into tissues affected by venom damage remains limited; therefore, early administration is critical to intercept circulating toxins before extensive tissue uptake occurs.

4.3 Metabolism

Antivenoms are primarily catabolized by proteolytic pathways within the reticuloendothelial system. The rate of metabolism is influenced by antibody subclass and presence of Fc receptors. Recombinant antivenoms may possess engineered modifications to alter degradation rates.

4.4 Excretion

Renal excretion of intact IgG is negligible due to its large molecular weight. However, catabolized peptides and small fragments are eliminated via the kidneys. Renal function may affect the clearance of antibody fragments, particularly in the case of F(ab’)₂ preparations.

4.5 Half‑Life and Dosing Considerations

The terminal half‑life of whole IgG antivenoms ranges from 7 to 14 days, whereas F(ab’)₂ preparations have a shorter half‑life (~5–7 days). Clinical dosing regimens are primarily weight‑based, with typical initial doses ranging from 5–20 mL/kg, adjusted according to venom potency and clinical presentation. Repeated dosing may be necessary in severe envenomation or if clinical deterioration occurs after initial therapy.

5. Therapeutic Uses / Clinical Applications

5.1 Approved Indications

Antivenoms are indicated for the neutralization of venomous snake bites that produce systemic or significant local effects. Indications include:

• Coagulopathy or hemorrhage secondary to SVMP activity.
• Neuroparalysis due to three‑finger toxins.
• Myotoxicity or rhabdomyolysis from phospholipase A₂‑rich venoms.
• Severe local tissue necrosis or compartment syndrome.

5.2 Off‑Label Uses

While antivenoms are not approved for non‑snake envenomations, anecdotal evidence suggests potential benefits in certain cases of scorpion or spider bites where cross‑reactive antibodies may exist. However, such uses lack robust evidence and are generally discouraged outside controlled research settings.

6. Adverse Effects

6.1 Common Side Effects

Adverse reactions are primarily immunologic. The most frequently reported events include:

• Infusion reactions – Flushing, pruritus, or mild hypotension during administration.
• Fever or chills, often transient and self‑limited.
• Transient elevation of serum creatinine due to complement activation.

6.2 Serious or Rare Adverse Reactions

Serious events, though uncommon, warrant vigilance:

• Allergic reactions – Anaphylaxis may occur within minutes of infusion; pre‑medication with antihistamines and corticosteroids is sometimes employed, although evidence of efficacy is variable.
• Serum sickness – Presents 7–14 days post‑administration with fever, arthralgia, and rash; managed with NSAIDs and corticosteroids.
• Arthritis or vasculitis – Rare immune‑mediated complications.

6.3 Black Box Warnings

Given the potential for severe hypersensitivity, antivenoms are accompanied by warnings regarding anaphylaxis and serum sickness. Clinicians must ensure that resuscitative equipment and medications (epinephrine, antihistamines, corticosteroids) are readily available during administration.

7. Drug Interactions

7.1 Major Drug‑Drug Interactions

Because antivenoms are biologic agents with minimal metabolic pathways, direct pharmacologic interactions are rare. Nevertheless, concurrent use of medications that modulate immune responses may influence antivenom efficacy or adverse event profile:

• Immunosuppressants (e.g., corticosteroids, cyclosporine) – May reduce antibody clearance but could also blunt immune complex formation, potentially altering the risk of serum sickness.
• Non‑steroidal anti‑inflammatory drugs (NSAIDs) – May mask fever associated with serum sickness, delaying recognition.
• Concurrent use of drugs that cause hypotension (e.g., vasodilators) may exacerbate venom‑induced cardiovascular collapse.

7.2 Contraindications

Absolute contraindications to antivenom therapy are rare but include:

• History of severe hypersensitivity to antivenom components.
• Uncontrolled asthma or severe atopic disease where anaphylaxis risk is unacceptably high.

8. Special Considerations

8.1 Pregnancy and Lactation

Animal‑derived antivenoms cross the placenta and are excreted into breast milk. While data are limited, the potential for fetal or neonatal sensitization exists. Antivenom therapy is generally considered acceptable in pregnancy when benefits outweigh risks, with close monitoring for maternal and fetal complications. Breastfeeding is typically discouraged during the first few weeks post‑administration.

8.2 Pediatric Considerations

Pediatric dosing is typically weight‑based, with careful titration to avoid over‑ or under‑dosing. Children may exhibit higher rates of hypersensitivity due to immature immune systems. Monitoring for serum sickness is particularly important, as clinical manifestations may be subtle and delayed.

8.3 Geriatric Considerations

Elderly patients often have comorbidities such as hypertension, diabetes, or renal impairment that may influence antivenom pharmacokinetics. Reduced renal function can prolong the half‑life of antibody fragments, potentially increasing the risk of delayed adverse events. Dose adjustments are usually not required, but vigilant monitoring for hypotension and renal function changes is advised.

8.4 Renal and Hepatic Impairment

Impaired renal function may affect the clearance of catabolized antibody fragments, though whole IgG antivenoms are largely unaffected. Hepatic impairment can influence the synthesis of complement proteins and may alter immune complex clearance. In both scenarios, antivenom efficacy is not markedly compromised, but the risk profile for serum sickness may be altered.

9. Summary / Key Points

• Prompt recognition of venomous snakebite and early antivenom administration are critical to mitigate systemic and local complications.
• Antivenoms neutralize venom through high‑affinity antibody binding, preventing interaction with host targets.
• Whole IgG antivenoms have longer half‑lives than F(ab’)₂ preparations, influencing dosing intervals and monitoring strategies.
• Hypersensitivity reactions, including anaphylaxis and serum sickness, represent the most significant adverse events; preparedness for emergency management is essential.
• Special populations—pregnant women, infants, the elderly, and patients with organ dysfunction—require individualized dosing and monitoring, yet antivenom remains the cornerstone of therapy when clinically indicated.

Clinicians should maintain a high index of suspicion for envenomation in patients presenting with unexplained coagulopathy, neuroparalysis, or local tissue damage, and should initiate antivenom therapy in accordance with local guidelines and venom prevalence. Continued research into recombinant and monoclonal antivenoms promises to refine efficacy and safety profiles in the future.

References

1. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
2. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
3. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
6. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
7. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
8. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.