Clinical Toxicology Course

Anticoagulant rodenticides Toxicity

Mohammed El-Sakkar, MD, PhD (Pharmacology), MSc (Pediatrics), Professor

Pharmacology Department
College of Clinical Pharmacy, IAU
2022
ILOs: By the end of this lecture the students must be able to
§ List anticoagulant rodenticides
§ Discuss toxic mechanism of anticoagulant rodenticides toxicity
§ Discuss risk assessment of anticoagulant rodenticides toxicity
§ Describe clinical features of anticoagulant rodenticides toxicity
§ Identify investigations of anticoagulant rodenticides toxicity
§ Discuss management of anticoagulant rodenticides toxicity
 Anticoagulant Rodenticides
Long-acting anticoagulant rodenticides or ‘superwarfarins’
developed to counter rodent resistance to warfarin.
Examples:
Brodifacoum, Bromadiolone, Chlorophacinone, Difenacoum,
Diphacinone, Flocoumafen
§ Single ingestions can be benign, particularly in children bec
small amount will be ingested as the agent has bitter taste.
§ In contrast, massive or repeated dosing → profound and prolonged (wks to ms)
anticoagulation.
Toxic Mechanism:
§ Inhibit vitamin K-dependent formation of clotting factors II, VII, IX and X.
§ Have a higher affinity for vitamin K 2,3 epoxide reductase and higher hepatic accumulation
Ò higher potency and prolonged duration of action compare w/ warfarin.
Extrinsic pathway Intrinsic pathway Classical blood coagulation
(Damaged tissue) (Surface contact) pathway
HMW Kininogen
Warfarin
TF Prekalikrein, FXIIa (VKA) Vitamin K1

FVII FVIIa +TF FXIa FXI

Ca++
FIX FIXa FIXa FIX Inactive vit K Vit k reactivation Active vit K
K1 (Hydroquinone)
(FVIIIa, PL, Ca++) (FVIIIa, PL, Ca++) (epoxide) cycle (Liver)
FX FXa FX
FXIII
(FVa, PL, Ca++) Descarboxy
Thrombin (IIa) Prothrombin (FII)
(serine protease) prothrombin

Fibrinogen Fibrin Dabigatran (PO)

(soluble) monomer
FXIIIa Plasminogen (Fibrin-
bound or circulating)
Common pathway Endogenous
(t-PA and u-PA)
Plasmin
XL-Fibrin FDPs + D-dimer
(cross linked fibrin mesh) Plasmin inhibitors (Aminocaproic/Tranexamic)
Toxicokinetic:
§ Completely absorbed following oral administration
§ Highly lipid soluble → large Vd
§ Hepatic metabolism and enterohepatic recirculation Ò prolonged elimination (wks to ms)

Risk Assessment:
§ Single accidental ingestion does not cause significant anticoagulation
§ Anticoagulation is usually ass. w/ repeated ingestions.
§ Anticoagulation will result from >0.1 mg/kg of
brodifacoum which is equivalent in 75 kg adult to:
o 2 g/kg of 0.005% bait
o 3 x 50 g pellet packs
§ In children: They need to ingest >30 g of a 0.005% preparation as a
single dose to cause significant anticoagulation. This has never been
reported.
§ INR usually Ó 12 h post ingestion but frequently delayed to 24-48 h. Peak effect occurs at
72-96 h.
Clinical features:
§ Usually, asymptomatic
§ Severe coagulopathy Ò bruising, petechial or puerperal rashes, gingival bleeding,
epistaxis, Gl bleeding or hematuria.
§ Following acute single ingestions, coagulopathy may not be evident for 12 hrs, and is
frequently delayed 24–48 hrs. Peak effects occur at 72–96 hrs.
Investigations:
o Screening tests in deliberate self-poisoning:
• 12 lead ECG, BSL, paracetamol level
o Specific investigations as indicated
§ INR:
- will not change in first 6-12 h.
- Check INR every 12 h for first 48 h to r/o toxicity → a normal INR at 48 hours excludes
toxic ingestion.
- Do not start vitamin K until there is evidence of anticoagulation.
- Following repeated ingestion over several days, INR is abnormal at presentation. Vitamin
K therapy may commence immediately. Outpatient INR estimations are required to
monitor therapy.
§ Superwarfarin levels are useful to
- confirm dx in uncertainty or suspicion of non-accidental injury.
- determine when it is safe to withdraw vitamin K therapy.
Management:
Resuscitation, supportive care and monitoring (rarely required):
§ In Pts w/ evidence of hemorrhage: attention to ABC is very important.
§ In active uncontrolled or life-threatening hemorrhage: administer
o Fresh frozen plasma (immediate Tx),
o Prothrombinex-HT (Prothrombin complex concentrate)
o Vitamin K 10 mg IV.
§ General supportive care measures are indicated,

Decontamination
§ Following accidental ingestions → Activated charcoal is not indicated.
§ Following massive single acute deliberate self-poisoning → administer 50 g activated
charcoal to cooperative Pts who are able to drink it themselves and present w/in 12 hrs of
ingestion.
Antidotes
Vitamin K (phytomenadione) is indicated in
§ Documented anticoagulation from repeated or acute deliberate self-poisoning.
§ Prophylactic vitamin K is contraindicated (this prolongs medical supervision).
§ Vitamin K titrated to achieve safe INR levels (<4).
§ Very large daily doses of oral vitamin K are required for wks or ms.
§ Initial daily dose is variable and determined under close medical supervision w/ repeated
INR estimations.

Adverse reactions of vit K:

§ Minor facial flushing, chest tightness, dyspnea or dizziness w/ IV administration
§ Anaphylaxis following IV administration (rare)
§ Over-correction of anticoagulation → managed w/ heparinisation.