Sept 2009 - An assigned toxicity presentation given during my ER & CC rotation; reviews methylxanthine (chocolate/caffeine) toxicity in dogs

1. Katie Krimetz Western University, College of Veterinary Medicine 4th Year E.R. and Critical Care Rotation VCA EAH&RC, San Diego 9/17/09 Methylxanthine Toxicities

2. OverviewMethylxanthine Toxicities Synonyms and Sources Toxicokinetics Mechanism of Action Toxicities/Risk Factors Clinical Signs and Differentials Clinical Pathology Diagnosis Treatment Prognosis

3. Sources Caffeine Coffee (Coffea arabica fruit) Tea (Thea sinensis leaves) Chocolate Cola soft drinks (Cola acuninata nuts) OTC stimulant tablets 100-200mg caffeine/tablet Herbal medications (containing guarana) Image: http://upload.wikimedia.org/wikipedia/commons/8/83/FruitColors.jpg

4. Sources of Caffeine Table 59-2 – 3) Carson reference, unless otherwise noted

5. Sources Image: http://www.css.cornell.edu/ecf3/Web/new/AF/pics/CacaoTree1.jpg Theobromine Cacao beans (seeds of Theobroma cacao) Hulls/mulch often used in landscaping Chocolate candy Concentration is 3-10x greater than caffeine7 Both play a part in toxicities Cola soft drinks Tea Image: http://www.montosogardens.com/theobroma_cacao_4_small.JPG

6. Sources of Theobromine Quick Tip: 1 oz milk chocolate/lb body weight  potentially lethal7 Table 59-2 – 3) Carson reference, unless otherwise noted

7. Sources Theophylline Tea Human asthma medications bronchodilator May present risk, but toxicities rare3 Image: http://1.bp.blogspot.com/_8bMLJ1CEHMw/R9QPsXLpZzI/AAAAAAAAADg/62HWPcF5z0s/s400/tea-in-hands.jpg

8. Toxicokinetics Caffeine Absorption: Quick Peak serum levels @ 30-60 min3 Food does not affect 1 Distribution: Proportionate to body water Readily absorbed from GI track7 Passes into all body compartments Metabolism: Hepatic Ɲ-demethylation2,3 CO2 Phase II conjugation reactions2,3 hydrophilic Subsequent enterohepatic recycling7 elimination +/- absorption Excretion Half-life: (dogs) 4.5 hours 1,3,7 Bile Caution: enterohepatic recirculation1,3 10% unchanged in urine3 Image: From Reference 2

9. Toxicokinetics Theobromine Absorption: Slow Peak serum levels @ 10 hours3 Increases pyloric sphincter tone  stays in the stomach longer8 Distribution: Readily absorbed from GI tract Passes into all body compartments1 Metabolism: Hepatic Ɲ-demethylation2,3 Phase II conjugation reactions2,3 Enterohepatic recycling1,7 Excretion: slow Half-life: (dogs) 17.5 hours1,3,7 Urine, and some through bile Image: From Reference 2

10. Toxicokinetics Theophylline Absorption: Quick Peak serum levels @ 1.5 hours3 Depends on preparation (ex: sustained-release tabs)1 Food slows rate of absorption1 But can increase or decrease bioavailability1 Distribution: Readily absorbed from GI track Passes into all body compartments1 Metabolism: Hepatic No significant first pass effect1 Ɲ-demethylation2,3 Phase II conjugation reactions2,3 Excretion Half-life: 5.7 hours (dog), 7.8 hours (cat)1,3 10% unchanged in urine3, some through bile Image: From Reference 2

11. Mechanism of Action Theory 1  Antagonize cellular adenosine receptors1,7 CNS stimulation, diuresis, tachycardia Suspected to be blocked at therapeutic and toxic doses1 Theory 2  Increase cellular calcium entry1,7 Inhibits muscle uptake and sequestration of calcium1,7 Through sarcoplasmic reticulum of striated muscle Increases strength and contractility1 since no re-sequestration Theory 3  Competes for CNS benzodiazepine receptors, inhibit phosphodiesterase1,7 Increases cAMP levels Regulates potassium channels  hypokalemia Theory 4  Sympathetic stimulation1,7 Increases circulating levels of epinephrine and norepinephrine catecholamines Hypokalemia, metabolic acidosis, cardiac disturbances1

12. Toxicity/Risk Factors Caffeine – usually by ingesting chocolate Mean Lethal Dose/LD50 DOG – 110-200 mg/kg1 CAT – 80-150 mg/kg1 Mild signs  20 mg/kg7 Cardiotoxic  40-50 mg/kg7 Seizures  >60 mg/kg7 Image: http://www.midwayanimalhosp.com/dogchocyWEB0912_468x303.jpg

13. Toxicity/Risk Factors Theobromine Mean Lethal Dose/LD50 DOG – 250-500 mg/kg1 CAT – 200 mg/kg1 Therapeutic level (diuresis and cardiac stimulation) 20 mg/kg Theophylline Mean Lethal Dose/LD50 DOG – 290 mg/kg1 CAT – 800 mg/kg1 Image: http://itchmo.com/wp-content/uploads/2007/06/thirsty_puppy0b7cb7.jpg

14. Clinical Signs Signs within 6-12 hours7 Often more than one methylxanthine has been ingested Renal diuresis3 Mild signs:7 Vomiting, diarrhea, abdominal distension, polydipsia, restlessness Moderate/Progressive signs:7 Hyperactivity, polyuria, ataxia, tremors, seizures Severe Signs:7 Tachycardia, PVCs, tachypnea, cyanosis, hyper-/hypotension, hyperthermia, bradycardia, coma Hypokalemia  cardiac dysfunction High fat content of chocolate  pancreatitis Death d/t cardiac arrhythmias, hyperthermia, or respiratory failure

15. Clinical Signs Caffeine1 Vomiting, hyperactivity, tachycardia, tachypnea Tremors, seizures, cyanosis, arrhythmias Theobromine1 Vomiting, diarrhea, PU, hyperactivity, tachycardia +/- PVC, hyperthermia, tremors, seizures Hematuria, muscle weakness, bradycardia, dehydration, coma, death Theophylline1 GI most sensitive: vomiting Tremors, weakness, hypotension, tachycardia +/- PVC, hyperactivity, seizures

16. Clinical Signs and Differentials CNS, cardiac muscle stimulation3 Most likely signs in acute toxicosis3 Smooth muscle relaxation/weakness Especially bronchial muscle3 Differentials7 Amphetamine toxicity Pseudoephedrine toxicity Cocaine toxicity Antihistamine ingestion Other CNS Stimulants

17. Clinical Pathology Rare to see lesions7 Diagnostic findings in GI tract at necropsy Hemorrhage, hyperemia, or congestion7 Agonal changes Pulmonary edema or congestion7 Severe arrhythmias

18. Diagnosis History of exposure Clinical signs Measure metabolites8 Serum, plasma, tissues, urine, stomach contents, milk Contact diagnostic laboratory Stability: Serum – 14 days Plasma – 4 months Image: http://img524.imageshack.us/i/dairymilkdogvp3.jpg/#q=dog, chocolate

19. Treatment Stabilize patient first – Basic life support Tremors/seizures: methocarbamol, diazepam, acepromazine Ace lasts longer, some alpha-blocking effects (help to lower blood pressure)4 Start low (0.025-0.05 mg/kg) then in small incremental doses Severe seizures: barbiturates ECG  Arrhythmias1,7 Tachyarrhythmias: Beta-blockers  propanolol or metoprolol Metoprolol preferred1,5 Other medications to avoid: enrofloxacin, corticosteroids, cimetidine1 Bradyarrhythmias: atropine Ventricular tachyarrhythmias: lidocaine for dogs Fluid diuresis: stabilize cardiac function and quicken urinary excretion1

20. Treatment Within 2 hours of ingestion…1 Decontamination Inducing emesis (OH, syrup of ipecac, apomorphine, xylazine) Gastric lavage Especially for patients that needed sedation for stabilization ALWAYS USE ENDOTRACHEAL TUBE Adsorbent Activated charcoal 1-4 g/kg1,7 Repeat dose every 3-8 hours in symptomatic patients Reduces enterohepatic recirculation and reduces exposure to lower GI bacteria1 Mix with cathartic to ensure charcoal excretion Sorbitol, magnesium, NaSO4 Image: http://gal-lori.com/wp-content/uploads/2008/06/g080123a1kittylitter.jpg

21. Treatment Don’t forget... Thermoregulation Correcting acid/base abnormalities Consider… Urinary catheter Methylxanthines and metabolites can be reabsorbed through bladder wall1,7

22. Prognosis Excellent with timely treatment and control Guarded to Poor without treatment or control Most patients recover within 24-48 hours1 Clinical signs can last up to 72 hours7 Image: http://pixdaus.com/pics/1210617619u5cfEhB.jpg

23. References Albretsen, Jay C. Mehtylxanthines. In: Plumlee, Konnie H. Clinical Veterinary Toxicology. St. Louis, Missouri: Mosby; 2004: 322-326 Beasley, V. “Toxicants Associated with Stimulation or Seizures.” Veterinary Toxicology, IVIS. IVIS Veterinary Toxicology Editor. Last updated: 8/9/1999 Carson, Thomas L. Methylxanthines. In: Peterson M, Talcott P. Small Animal Toxicology. St. Louis, Missouri: Elsevier Saunders; 2006: 845-851 Dunayer, Eric, MS, VMD, DABT, DABVT. VIN consultant: Toxicology. ASPCA Animal Poison Control Center, 10/15/08 Grossman, Mark, DVM MS. VIN consultant: Toxicology, Associate Editor: Dermatology. Coordinator: Georgia Animal Poison Information Center. Co-Owner: Roanoke Island Animal Clinic, Manteo, NC 27954, 1/20/09 Gwaltney-Brant, Sharon, DVM, PhD, DABVT, DABT. ASPCA Animal Poison Control Center, Allied Agency of the University of Illinois. VIN Discussion: 5/23/08 The Merck Veterinary Manual: Merck & Co., Inc.; 2009. http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/211104.htm Wismer, Tina, DVM, DABVT, DABT. ASPCA Animal Poison Control Center, Allied Agency of the University of Illinois. VIN Dicussion: 10/1/08.

24. Questions and Discussion Image: http://www.spudart.org/blog/images/2003/207-0799_IMG_400.jpg Image: http://blogs.nashvillescene.com/bites/trufflesbig.jpg

25. Image: http://www.weheartfood.com/wp-content/uploads/blogger/_aR7uIk5VS2Y/R9L_gC5ER4I/AAAAAAAACTI/vtZmBBAcrMI/s1600/LolCatRenderer2.aspx.jpg

26. Image: http://caninecaterer.net/shopping/images/Peanut%20Butter%20Carob.JPG