Katie Krimetz<br />Western University, <br />College of Veterinary Medicine<br />4th Year E.R. and Critical Care Rotation<...
OverviewMethylxanthine Toxicities<br />Synonyms and Sources<br />Toxicokinetics<br />Mechanism of Action<br />Toxicities/R...
Sources<br />Caffeine<br />Coffee (Coffea arabica fruit)<br />Tea (Thea sinensis leaves)<br />Chocolate<br />Cola soft dri...
Sources of Caffeine<br />Table 59-2 – 3) Carson reference, unless otherwise noted<br />
Sources<br />Image: http://www.css.cornell.edu/ecf3/Web/new/AF/pics/CacaoTree1.jpg<br />Theobromine<br />Cacao beans (seed...
Sources of Theobromine<br />Quick Tip: 1 oz milk chocolate/lb body weight  potentially lethal7<br />Table 59-2 – 3) Carso...
Sources<br />Theophylline<br />Tea<br />Human asthma medications<br />bronchodilator<br />May present risk, but <br />toxi...
Toxicokinetics<br />Caffeine<br />Absorption: Quick<br />Peak serum levels @ 30-60 min3<br />Food does not affect 1<br />D...
Toxicokinetics<br />Theobromine<br />Absorption: Slow<br />Peak serum levels @ 10 hours3<br />Increases pyloric sphincter ...
Toxicokinetics<br />Theophylline<br />Absorption: Quick<br />Peak serum levels @ 1.5 hours3<br />Depends on preparation (e...
Mechanism of Action<br />Theory 1  Antagonize cellular adenosine receptors1,7<br />CNS stimulation, diuresis, tachycardia...
Toxicity/Risk Factors<br />Caffeine – usually by ingesting chocolate<br />Mean Lethal Dose/LD50<br />DOG – 110-200 mg/kg1<...
Toxicity/Risk Factors<br />Theobromine<br />Mean Lethal Dose/LD50<br />DOG – 250-500 mg/kg1<br />CAT – 200 mg/kg1<br />The...
Clinical Signs<br />Signs within 6-12 hours7<br />Often more than one methylxanthine has been ingested<br />Renal diuresis...
Clinical Signs<br />Caffeine1<br />Vomiting, hyperactivity, tachycardia, tachypnea<br />Tremors, seizures, cyanosis, arrhy...
Clinical Signs and Differentials<br />CNS, cardiac muscle stimulation3<br />Most likely signs in acute toxicosis3<br />Smo...
Clinical Pathology<br />Rare to see lesions7<br />Diagnostic findings in GI tract at necropsy<br />Hemorrhage, hyperemia, ...
Diagnosis<br />History of exposure<br />Clinical signs<br />Measure metabolites8<br />Serum, plasma, tissues, <br />	urine...
Treatment<br />Stabilize patient first – Basic life support<br />Tremors/seizures: methocarbamol, diazepam, acepromazine<b...
Treatment<br />Within 2 hours of ingestion…1<br />Decontamination<br />Inducing emesis (OH, syrup of ipecac, apomorphine, ...
Treatment<br />Don’t forget...<br />Thermoregulation<br />Correcting acid/base abnormalities<br />Consider…<br />Urinary c...
Prognosis<br />Excellent with timely treatment and control<br />Guarded to Poor without treatment or control<br />Most pat...
References<br />Albretsen, Jay C.  Mehtylxanthines.  In: Plumlee, Konnie H.  Clinical Veterinary Toxicology.  St. Louis, M...
Questions and Discussion<br />Image: http://www.spudart.org/blog/images/2003/207-0799_IMG_400.jpg<br />Image: http://blogs...
Image: http://www.weheartfood.com/wp-content/uploads/blogger/_aR7uIk5VS2Y/R9L_gC5ER4I/AAAAAAAACTI/vtZmBBAcrMI/s1600/LolCat...
Image: http://caninecaterer.net/shopping/images/Peanut%20Butter%20Carob.JPG<br />
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Methylzanthine Toxicities Er Rotation Presentation 9 17 09

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

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  • Passes into BBB, placenta, and mammary glandsN-demethylation – releases carbon dioxide into liverphase II -conjugation reactions- creates a more hydrophyllic molecule for easier excretion/absorption (Carson, Beasley)
  • no first pass effect = little to no change when it first goes through liver  still available after liver metabolism
  • Adenosine – normally inhibitis neurotransmission, slows down cell activity, adenosine binding also causes blood vessels to dilate  antagnoized = neurotransmission allowedCa+2 – normal: Ca stored in SR of striated muscle, Ca binds to muscle fibers to allow contraction. Re-sequestration must occur for relaxationBenzodiazepine – sedative, anticonvulsant, myorelaxantPhosphodiesterase – inhibition = increased cAMP levelsK channels = normal cell depolarization
  • Propanolol reduces theopylline clearance in humans – reduces diuresis – urine is how it is excreted, NEED diuresisAvoid other meds for same reason
  • Cathartic increases GI motility
  • Methylxanthines = diuresis  no renal toxicity with raisins?Or toxic compound in raisins does not survive candy processing/heat?Mixed box of chocolates w/ nuts/fruits, etc – Assume ½ is chocolate (Grossman)
  • Methylzanthine Toxicities Er Rotation Presentation 9 17 09

    1. 1. Katie Krimetz<br />Western University, <br />College of Veterinary Medicine<br />4th Year E.R. and Critical Care Rotation<br />VCA EAH&RC, San Diego<br />9/17/09<br />Methylxanthine Toxicities<br />
    2. 2. OverviewMethylxanthine Toxicities<br />Synonyms and Sources<br />Toxicokinetics<br />Mechanism of Action<br />Toxicities/Risk Factors<br />Clinical Signs and Differentials<br />Clinical Pathology<br />Diagnosis<br />Treatment<br />Prognosis<br />
    3. 3. Sources<br />Caffeine<br />Coffee (Coffea arabica fruit)<br />Tea (Thea sinensis leaves)<br />Chocolate<br />Cola soft drinks (Cola acuninata nuts)<br />OTC stimulant tablets<br />100-200mg caffeine/tablet<br />Herbal medications (containing guarana)<br />Image: http://upload.wikimedia.org/wikipedia/commons/8/83/FruitColors.jpg<br />
    4. 4. Sources of Caffeine<br />Table 59-2 – 3) Carson reference, unless otherwise noted<br />
    5. 5. Sources<br />Image: http://www.css.cornell.edu/ecf3/Web/new/AF/pics/CacaoTree1.jpg<br />Theobromine<br />Cacao beans (seeds of Theobroma cacao)<br />Hulls/mulch often used in landscaping<br />Chocolate candy<br />Concentration is 3-10x greater than caffeine7<br />Both play a part in toxicities<br />Cola soft drinks<br />Tea<br />Image: http://www.montosogardens.com/theobroma_cacao_4_small.JPG<br />
    6. 6. Sources of Theobromine<br />Quick Tip: 1 oz milk chocolate/lb body weight  potentially lethal7<br />Table 59-2 – 3) Carson reference, unless otherwise noted<br />
    7. 7. Sources<br />Theophylline<br />Tea<br />Human asthma medications<br />bronchodilator<br />May present risk, but <br />toxicities rare3<br />Image: http://1.bp.blogspot.com/_8bMLJ1CEHMw/R9QPsXLpZzI/AAAAAAAAADg/62HWPcF5z0s/s400/tea-in-hands.jpg<br />
    8. 8. Toxicokinetics<br />Caffeine<br />Absorption: Quick<br />Peak serum levels @ 30-60 min3<br />Food does not affect 1<br />Distribution: Proportionate to body water<br />Readily absorbed from GI track7<br />Passes into all body compartments<br />Metabolism: Hepatic<br />Ɲ-demethylation2,3 CO2<br />Phase II conjugation reactions2,3 hydrophilic<br />Subsequent enterohepatic recycling7 elimination +/- absorption<br />Excretion<br />Half-life: (dogs) 4.5 hours 1,3,7<br />Bile<br />Caution: enterohepatic recirculation1,3<br />10% unchanged in urine3<br />Image: From Reference 2<br />
    9. 9. Toxicokinetics<br />Theobromine<br />Absorption: Slow<br />Peak serum levels @ 10 hours3<br />Increases pyloric sphincter tone  stays in the stomach longer8<br />Distribution:<br />Readily absorbed from GI tract<br />Passes into all body compartments1<br />Metabolism: Hepatic<br />Ɲ-demethylation2,3<br />Phase II conjugation reactions2,3<br />Enterohepatic recycling1,7<br />Excretion: slow<br />Half-life: (dogs) 17.5 hours1,3,7<br />Urine, and some through bile<br />Image: From Reference 2<br />
    10. 10. Toxicokinetics<br />Theophylline<br />Absorption: Quick<br />Peak serum levels @ 1.5 hours3<br />Depends on preparation (ex: sustained-release tabs)1<br />Food slows rate of absorption1<br />But can increase or decrease bioavailability1<br />Distribution: <br />Readily absorbed from GI track<br />Passes into all body compartments1<br />Metabolism: Hepatic<br />No significant first pass effect1<br />Ɲ-demethylation2,3<br />Phase II conjugation reactions2,3<br />Excretion<br />Half-life: 5.7 hours (dog), 7.8 hours (cat)1,3<br />10% unchanged in urine3, some through bile<br />Image: From Reference 2<br />
    11. 11. Mechanism of Action<br />Theory 1  Antagonize cellular adenosine receptors1,7<br />CNS stimulation, diuresis, tachycardia<br />Suspected to be blocked at therapeutic and toxic doses1<br />Theory 2  Increase cellular calcium entry1,7<br />Inhibits muscle uptake and sequestration of calcium1,7<br />Through sarcoplasmic reticulum of striated muscle<br />Increases strength and contractility1 since no re-sequestration<br />Theory 3  Competes for CNS benzodiazepine receptors, inhibit phosphodiesterase1,7<br />Increases cAMP levels<br />Regulates potassium channels  hypokalemia<br />Theory 4  Sympathetic stimulation1,7<br />Increases circulating levels of epinephrine and norepinephrine catecholamines<br />Hypokalemia, metabolic acidosis, cardiac disturbances1<br />
    12. 12. Toxicity/Risk Factors<br />Caffeine – usually by ingesting chocolate<br />Mean Lethal Dose/LD50<br />DOG – 110-200 mg/kg1<br />CAT – 80-150 mg/kg1<br />Mild signs  20 mg/kg7<br />Cardiotoxic  40-50 mg/kg7<br />Seizures  >60 mg/kg7<br />Image: http://www.midwayanimalhosp.com/dogchocyWEB0912_468x303.jpg<br />
    13. 13. Toxicity/Risk Factors<br />Theobromine<br />Mean Lethal Dose/LD50<br />DOG – 250-500 mg/kg1<br />CAT – 200 mg/kg1<br />Therapeutic level <br />(diuresis and cardiac stimulation)<br />20 mg/kg<br />Theophylline<br />Mean Lethal Dose/LD50<br />DOG – 290 mg/kg1<br />CAT – 800 mg/kg1<br />Image: http://itchmo.com/wp-content/uploads/2007/06/thirsty_puppy0b7cb7.jpg<br />
    14. 14. Clinical Signs<br />Signs within 6-12 hours7<br />Often more than one methylxanthine has been ingested<br />Renal diuresis3<br />Mild signs:7<br />Vomiting, diarrhea, abdominal distension, polydipsia, restlessness<br />Moderate/Progressive signs:7<br />Hyperactivity, polyuria, ataxia, tremors, seizures<br />Severe Signs:7<br />Tachycardia, PVCs, tachypnea, cyanosis, hyper-/hypotension, hyperthermia, bradycardia, coma<br />Hypokalemia  cardiac dysfunction<br />High fat content of chocolate  pancreatitis<br />Death d/t cardiac arrhythmias, hyperthermia, or respiratory failure<br />
    15. 15. Clinical Signs<br />Caffeine1<br />Vomiting, hyperactivity, tachycardia, tachypnea<br />Tremors, seizures, cyanosis, arrhythmias<br />Theobromine1<br />Vomiting, diarrhea, PU, hyperactivity, tachycardia +/- PVC, hyperthermia, tremors, seizures<br />Hematuria, muscle weakness, bradycardia, dehydration, coma, death<br />Theophylline1<br />GI most sensitive: vomiting<br />Tremors, weakness, hypotension, tachycardia +/- PVC, hyperactivity, seizures<br />
    16. 16. Clinical Signs and Differentials<br />CNS, cardiac muscle stimulation3<br />Most likely signs in acute toxicosis3<br />Smooth muscle relaxation/weakness<br />Especially bronchial muscle3<br />Differentials7<br />Amphetamine toxicity<br />Pseudoephedrine toxicity<br />Cocaine toxicity<br />Antihistamine ingestion<br />Other CNS Stimulants<br />
    17. 17. Clinical Pathology<br />Rare to see lesions7<br />Diagnostic findings in GI tract at necropsy<br />Hemorrhage, hyperemia, or congestion7<br />Agonal changes<br />Pulmonary edema or congestion7<br />Severe arrhythmias<br />
    18. 18. Diagnosis<br />History of exposure<br />Clinical signs<br />Measure metabolites8<br />Serum, plasma, tissues, <br /> urine, stomach contents, milk<br />Contact diagnostic <br />laboratory<br />Stability:<br />Serum – 14 days<br />Plasma – 4 months<br />Image: http://img524.imageshack.us/i/dairymilkdogvp3.jpg/#q=dog, chocolate<br />
    19. 19. Treatment<br />Stabilize patient first – Basic life support<br />Tremors/seizures: methocarbamol, diazepam, acepromazine<br />Ace lasts longer, some alpha-blocking effects (help to lower blood pressure)4<br />Start low (0.025-0.05 mg/kg) then in small incremental doses<br />Severe seizures: barbiturates<br />ECG  Arrhythmias1,7<br />Tachyarrhythmias: Beta-blockers  propanolol or metoprolol<br />Metoprolol preferred1,5<br />Other medications to avoid: enrofloxacin, corticosteroids, cimetidine1<br />Bradyarrhythmias: atropine<br />Ventricular tachyarrhythmias: lidocaine for dogs<br />Fluid diuresis: stabilize cardiac function and quicken urinary excretion1<br />
    20. 20. Treatment<br />Within 2 hours of ingestion…1<br />Decontamination<br />Inducing emesis (OH, syrup of ipecac, apomorphine, xylazine)<br />Gastric lavage<br />Especially for patients that needed sedation for stabilization<br />ALWAYS USE ENDOTRACHEAL TUBE<br />Adsorbent<br />Activated charcoal 1-4 g/kg1,7<br />Repeat dose every 3-8 hours in symptomatic patients<br />Reduces enterohepatic recirculation and reduces exposure to lower GI bacteria1<br />Mix with cathartic to ensure charcoal excretion<br />Sorbitol, magnesium, NaSO4<br />Image: http://gal-lori.com/wp-content/uploads/2008/06/g080123a1kittylitter.jpg<br />
    21. 21. Treatment<br />Don’t forget...<br />Thermoregulation<br />Correcting acid/base abnormalities<br />Consider…<br />Urinary catheter<br />Methylxanthines and metabolites can be reabsorbed through bladder wall1,7<br />
    22. 22. Prognosis<br />Excellent with timely treatment and control<br />Guarded to Poor without treatment or control<br />Most patients recover within 24-48 hours1<br />Clinical signs can last up to 72 hours7<br />Image: http://pixdaus.com/pics/1210617619u5cfEhB.jpg<br />
    23. 23. References<br />Albretsen, Jay C. Mehtylxanthines. In: Plumlee, Konnie H. Clinical Veterinary Toxicology. St. Louis, Missouri: Mosby; 2004: 322-326<br />Beasley, V. “Toxicants Associated with Stimulation or Seizures.” Veterinary Toxicology, IVIS. IVIS Veterinary Toxicology Editor. Last updated: 8/9/1999<br />Carson, Thomas L. Methylxanthines. In: Peterson M, Talcott P. Small Animal Toxicology. St. Louis, Missouri: Elsevier Saunders; 2006: 845-851<br />Dunayer, Eric, MS, VMD, DABT, DABVT. VIN consultant: Toxicology. ASPCA Animal Poison Control Center, 10/15/08<br />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<br />Gwaltney-Brant, Sharon, DVM, PhD, DABVT, DABT. ASPCA Animal Poison Control Center, Allied Agency of the University of Illinois. VIN Discussion: 5/23/08 <br />The Merck Veterinary Manual: Merck & Co., Inc.; 2009. http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/211104.htm<br />Wismer, Tina, DVM, DABVT, DABT. ASPCA Animal Poison Control Center, Allied Agency of the University of Illinois. VIN Dicussion: 10/1/08.<br />
    24. 24. Questions and Discussion<br />Image: http://www.spudart.org/blog/images/2003/207-0799_IMG_400.jpg<br />Image: http://blogs.nashvillescene.com/bites/trufflesbig.jpg<br />
    25. 25. Image: http://www.weheartfood.com/wp-content/uploads/blogger/_aR7uIk5VS2Y/R9L_gC5ER4I/AAAAAAAACTI/vtZmBBAcrMI/s1600/LolCatRenderer2.aspx.jpg<br />
    26. 26. Image: http://caninecaterer.net/shopping/images/Peanut%20Butter%20Carob.JPG<br />

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