1. Veterinary Specialists of South Florida Presents:

3. Outline  Clinical Case Summary  Definition  Etiology and Pathophysiology  Epidemiology  Clinical Presentation  Diagnosis  Treatment/Prognosis

4. Chook  4 yo FS Australian Shepherd  8 AM Owner dewormed horses with 2% Ivermectin Paste  10 AM Chook was normal when owner left the house  12 PM Daughter found Chook wobbly and stumbling around

5. Chook - Presentation Alert and hyper-responsive MM – pink & moist, CRT < 2 seconds Temp = 102.4 F HR = 200, RR = pant Absent menace and PLR’s bilaterally Mydriasis

6. Chook - Diagnosis Ivermectin Toxicity ○ History of exposure ○ Breed susceptibility ○ Physical exam findings

7. Chook - Treatment IV catheter placed IV fluids started Owner decline further treatment

8. Ivermectin Toxicity - Definition  Ivermectin toxicity A clinical syndrome that is used to describe an exposure to the macrocyclic lactone antiparasitic drug ivermectin  Other drugs Milbemycin, moxidectin, selamectin, doramectin, eprinomectin, abamectin

9. Etiology & Pathophysiology  Enhance the release of GABA (inhibitory neurotransmitter)  Parasites GABA mediated neurons present throughout PNS -> enhanced GABA release -> paralysis  Mammals GABA mediated neurons restricted to CNS & BBB excludes the drug at therapeutic dosages  Overdose With overdosages, or animals with a defect in the BBB, drug enters the CNS and causes an inhibitory effect -> CNS depression

10. Epidemiology  Young animals  More likely in dogs, but cats can show clinical signs as well  Genetics and Breed predispositions  Risk Factors LA formulations for SA CNS disease or BBB disruption

11. Genetics & Breed Predispositions  MDR-1 gene mutation Autosomal recessive trait Defect in the P- glycoprotein multidrug transporter in the BBB Defect allows Ivermectin to pass into the CNS at even low doses, causing toxicosis

13. Breeds Affected  www.vetmed.wsu.edu/depts-vcpl/breeds.aspx

14. Ivermectin Dosages  Heartworm prevention 0.006 mg/kg PO q 30 days  Off-label use Dosage range from 0.05-0.3 mg/kg PO/SQ  Most dogs tolerate up to 2.5 mg/kg PO  LD 50 in Beagles = 80 mg/kg  In MDR-1 gene mutation dogs Up to 0.1 mg/kg (16X label dose)

15. Clinical Presentation  History Exposure to ivermectin containing compounds  Presenting Complaint Depression, disorientation, vocalization, stupor, ataxia, tremors, vomiting, anorexia, recumbency, blindness, coma, seizure, death

16. Clinical Presentation  Physical Exam Findings Mydriasis +/- blindness CNS depression Ataxia Disorientation Hypersalivation Tremors +/- bradycardia, vomiting, seizures Hypothermia or hyperthermia

17. Differential Diagnosis  Other intoxications  Brain neoplasia  Encephalitis  Hepatic encephalopathy  Blue-green algae  Hypoglycemia  Hypocalcemia  Phenobarbital toxicity

18. Initial Database  Neurological examination  No specific clinical pathologic alterations expected  Baseline CBC/Chem/UA Bile acids +/- thoracic/abdominal imaging

19. Advanced Testing  Physostigmine 1 mg/40 lbs or 0.06 mg/kg IV Supports diagnosis -> not confirmatory Not generally recommended  Ivermectin sensitivity testing Tests for the presence of the MDR-1 gene mutation WSU  Other Liver, adipose tissue, brain or serum levels

20. Treatment - Goals  Manage life-threatening situations  Supportive care  Decrease absorption/enhance elimination  Nursing care – comatose patients

21. Treatment - Immediate  Induce emesis Recent ingestion No signs of respiratory distress, comatose state  Gastric lavage Control airway and respiration  Activated charcoal Orogastric/nasogastric intubation

22. Treatment – Supportive Care  Manage seizures  Continue activated charcoal administration  Fluid therapy/Electrolyte balance  Manage comatose patients Supportive care is the mainstay of treatment

23. Prognosis  Largely dependent on Dose Relative individual sensitivity Provision of supportive care  May require supportive care for one day, several days, or even several weeks  Even those in a coma, or a seemingly hopeless case, can have a full recovery

24. References  Cote, Etienne. Interceptor toxicity. Cote Clinical Veterinary Advisor pp 610-611, Copyright © 2009 Elsevier Inc.  Dowling P. Pharmacogenetics: It’s not just about ivermectin in collies. Clinical Pharmacology Update; 47: 1165-1169, 2006.  Edwards G. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria Journal, 2:58, 2003.  Hopper K, Aldrich J, Haskins SC. Ivermectin Toxicity in 17 Collies. J Vet Intern Med; 16:89-94, 2002.  Mealey KL, Northrup NC, Bentjen SA. Increased toxicity of P-glycoprotein- substrate chemotherapeutic agents in a dog with MDR1 deletion mutation associated with ivermectin sensitivity. J Am Vet Med; 223(10):1453-5, 1434, 2003..  Merola V, Khan S, Gwaltney-Brant S. Ivermectin Toxicosis in Dogs: A Retrospective Study. J Am Anim Hosp Assoc. 45:106-111, 2009.  Paul AJ, Tranquilli WJ. Ivermectin. Kirk RW, editor: Current veterinary therapy X, Philadelphia, 1989, WB Saunders.  Peterson, Michael E.; Talcott, Patricia A. Small Animal Toxicology, 2 nd Edition. Elsevier, Missouri, 2006, pp 785-93.  Plumb, Donald C. Plumb’s Veterinary Drug Handbook, 5 th Edition. Blackwell Publishing, 2005, pp 763-4.  Shell, L. Ivermectin. VIN database, 2006.  Veterinary Clinical Pharmacology Laboratory. Affected Breeds. Washington State University. 2010.

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