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Special Considerations for Special Patients

Karla Smith DVM Consulting Veterinarian in Clinical Toxicology

ASPCA Animal Poison Control Center

Special Patients

♦ Scent Detection Canines § Working dogs – e.g., military, TSA § Competition dogs – scenting sports

♦ Breeding bitches §  Pregnancy § Cesarean Section §  Lactation

Scenting background

♦ Olfactory receptors (ORs) are the first dedicated molecule with which odorants physically interact.

♦ Dogs are macrosomatic with more than 300 million ORs.

♦ By comparison humans are microsomatic, having approximately 400 ORs

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Scenting background, con’t.

♦  OR genes were first discovered in Rattus norvegicus in 1991.

♦  They form the largest known gene superfamily, known as the olfactory subgenome.

♦  Humans have 900 OR genes (60% nonfunctional pseudogenes)

♦  Dogs have 1,094 OR genes (18% nonfunctional pseudogenes)

♦  Rats have 1,493 OR genes

Scenting background, con’t.

♦  The average dog inhales 30 ml of air per nostril per sniff.

♦  Each nostril samples air separately assisting with odor localization.

♦  Active sniffing is “nose down, tail up”

Scent Detection Dogs: Working ♦  There are currently

thousands of dog used by DEA, HS, US Military and others trained as scent detection dogs.

♦  They can be trained to detect drugs, explosives, fire accelerants, human remains and other animal species including bed bugs.

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Scent Detection Dogs: Sport

♦  Owners compete for titles in four different organizations.

♦  19,500 dogs registered with NACSW in 2018

Scent Detection Dogs: Sport

♦  Dogs are trained to find and alert on specific scents (Birch, Anise, Clove, Cypress, Myrrh and Vetiver) and are rewarded with food by their handler for a successful search.

Drugs and Olfaction

♦ Over 1300 new drugs approved by the FDA between 1950 and 2013

♦ Evaluations of clinical trials, medication inserts and clinical reports identified over 350 drugs that elicit taste complaints and over 70 with olfactory effects.

♦  50% of the top 100 drugs of 2017 have the potential to induce chemosensory complaints and side effects.

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Chemosensory Disorders

♦ Ansomia – total loss of smell ♦ Hyposmia* – decreased smell sensation ♦ Dysosmia* – distorted smell sensation ♦ Hyperosmia* – heightened sensitivity to

smell ♦ Phantosmia – odor that occurs in absence

of stimulation

Drug targets and olfaction

♦ Human OR are G protein coupled which is linked to adenylyl cyclase.

♦ Receptor activation leads to intracellular increase in cAMP, which targets olfactory specific ion channels.

♦ Drugs interfering with this cascade could modulate olfactory signaling.

♦ Opioids, Caffeine, Theophylline

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Drugs and Olfaction

♦ Known Problem Drugs ♦ Suspected Problem Drugs

§  Bonus Info: Zinc §  Bonus Info: Fats

♦ Known Safe Drugs ♦ Suspected Safe Drugs

Known problem drugs - Steroids

♦ Ezeh administered dexamethasone (2 mg/kg/day) and found decreased olfactory acuity in laboratory dogs after 7 days.

♦ However, in humans with nasal inflammation administration of steroids improved olfaction, likely due to resolution of inflammation.

♦ Weigh risk vs benefit

Known problem drug - Metronidazole

♦  Jenkins administered metronidazole (25 mg/kg PO BID x 10 days) to 18 adult Labrador Retrievers enrolled in detection dog training.

♦  9 of 18 dogs had degradation of the detection threshold for ammonium nitrate and trinitrotoluene (days 5 and 10).

♦ All dogs returned to normal after a 10 day washout period.

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Suspected problem drugs - THC

♦  7 men and 8 women were given 20 mg of THC. ♦  Olfactory function was assessed before drug

administration and 2 hours afterwards. ♦  THC increased the odor threshold ♦  THC decreased odor discrimination ♦  Perhaps due to regulation of neuronal activity

and signaling in olfactory bulb

Suspected problem drug - Sildenafil

♦  20 men were given 50 mg (day 0) followed by 100 mg (day 4 and 8).

♦  On day 0 olfactory tests were performed 1 hour before and 1 hour after drug administration.

♦  On days 4 and 8 olfactory tests were performed at 1 hour after administration.

♦  There was no change in olfactory function at 50 mg.

♦  Scores of both odor threshold and odor discrimination were altered after 100 mg.

Bonus - Zinc and drug interactions

♦  Zinc metabolism is directly related to olfaction function in both humans and laboratory animals.

♦  Zinc nanoparticles added to explosives enhanced the odorant response in trained detection dogs.

♦  Zinc chelation causes hyposmia at the OR level. ♦  Some CV drugs such as ACE Inhibitors

(enalapril) chelate zinc and cause hyposmia in humans

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Bonus Info: Dietary Fat Sources

♦  17 certified detection dogs were fed 3 different diets (HF, LF, HPUF) for 12 weeks.

♦  The dogs then completed 8-12 scent trials. ♦ Dogs on the HPUF diet utilizing corn oil

showed mild improvement in olfaction.

Bonus Info: effects of fat on olfaction

♦  18 male English Pointers were fed either §  A) 12% fat as beef tallow §  B) 16% fat as equal amounts beef tallow and

corn oil, or § C) 16% fat as equal amounts beef tallow and

coconut oil. ♦ Dogs fed coconut oil had decreased

odorant-detecting capabilities when week 4 values were compared with week 12 values.

Known safe drug - Doxycycline

♦  Jenkins administered doxycycline (5 mg/kg PO BID x 10 days) to the same 18 dogs.

♦ No significant degradation was noted at days 5 and 10 during doxycycline administration.

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Known safe drugs – Fentanyl and Naloxone

♦  10 dogs who were enrolled in, or graduates of the PVWDC, were sedated with 0.3 mg of fentanyl and then reversed with either IN or IM naloxone.

♦  The dogs searched a scent wheel at 2h, 24h and 48h post sedation and reversal.

♦ No difference in olfactory abilities was noted in general, or comparing IN to IM naloxone.

Bonus Info: Scent Wheel

♦  Scent wheels have numbered ports that contain different odors.

♦  Dogs are trained to detect Universal Detector Calibrant.

Suspected safe drug - Apomorphine

♦  12 Parkinson’s disease patients were given apomorphine

♦  Olfactory dysfunction occurs early in PD. ♦  The goal was to determine if olfactory ♦  dysfunction was due to dopamine deficiency. ♦  There were no significant differences in any

olfactory parameters before and after apomorphine.

♦  We can extrapolate that apomorphine is a reasonable drug for inducing emesis.

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Some other drugs that may affect olfaction

♦  Phenylbutazone ♦  Vincristine ♦  Doxorubicin ♦  Morphine ♦  Azathioprine ♦  Chlorpheniramine

Drugs and Breeding Bitches ♦  Background on Canine Pregnancy

§  Bonus Info: USDA Pregnancy Categories

♦  Pregnancy §  Known Problem Drugs §  Suspected Problem Drug

•  Bonus Info: Raspberry Leaf

§  Presumed Safe Drugs ♦  Caesarean Section

§  Known Problem Drugs §  Suspected Safe Drugs

♦  Lactation §  Suspected Safe Drugs

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Pregnancy

Background on Canine Pregnancy

♦  Average length of gestation in the bitch is 63 days.

♦  Implantation of the embryos in the uterus occurs at ~day 19

♦  Potentially harmful drugs administered before this time are likely to result in acute embryotoxicity and loss of pregnancy.

♦  Pregnancy may also be lost if the embryo is exposed to drugs that inhibit implantation.

Background on Canine Pregnancy, con’t.

♦  Organogenesis begins at approximately day 22. The embryos are at their most susceptible to drugs that may affect the CV or CNS.

♦  By day 45 organogenesis is complete and the embryos are growing larger. They are now resistant to teratogenic effects of drugs but will still be impacted by drugs that alter the onset of parturition or cause vasoconstriction of placental vessels leading to hypoxia.

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Background on Canine Pregnancy - Physiological Changes

♦  Increased blood volume

♦  Increased HR and CO ♦  Decreased gastric

motility ♦  Increased gastric

emptying time ♦  Increased GFR

US FDA Pregnancy Categories ♦  A - No risk in controlled human studies: Adequate

and well-controlled human studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

♦  B - No risk in other studies: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

US FDA Pregnancy Categories, con’t.

♦  C - Risk not ruled out: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

♦  D - Positive evidence of risk: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

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US FDA Pregnancy Categories, con’t.

♦ X - Contraindicated in pregnancy: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Major factors influencing fetal toxicity ♦  Drug itself: maternal

and fetal concentrations and potential toxicity.

♦  Stage of pregnancy during exposure.

♦  The fetus is at greatest risk in the first 20 days when uterine fluid attains drug concentrations similar to maternal circulation.

Known Problem drugs - NSAIDs

♦ Use of NSAIDs is associated with increased risk of miscarriage, especially when used for more than one week around the time of conception.

♦ Prostaglandins are modulators of renal blood flow and renin secretion in the fetus.

♦ Aspirin, ibuprofen and indomethacin cause rapid vasoconstriction reducing GFR leading to oliguric renal failure.

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Known Problem drugs - Corticosteroids

♦ Steroid use is a known cause of cleft palate in mice and is a suspected cause in humans.

♦ Walker and Fraser induced cleft palates in 100% of mice administered 2.5 mg of cortisone 2x during gestation.

♦ Steroids are involved in cellular processes that lead to fusion of the palatal shelves.

Known Problem drugs – Corticosteroids, con’t.

♦ Steroid use is also associated with early miscarriage in women.

♦ Although used late in gestation steroid use may speed the development of surfactant in the lungs, improving outcome for pre-term infants.

♦  There are NO studies to support use of steroids to stimulate surfactant in dogs.

Suspected Problem Drug - Metronidazole

♦  Conflicting data ♦  Crosses the placenta and rapidly enters fetal

circulation (in humans) ♦  Quebec – increased risk for spontaneous

abortion. ♦  Israel – no increase in the risk for major fetal

malformations, although exposed infants had a lower mean birth weight.

♦  Hungary – increased risk for cleft lip when administered in the second or third month of pregnancy.

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Metronidazole

♦  In animal studies, the administration of oral metronidazole during organogenesis to rats and rabbits at doses up to 60 times the recommended human dose, based on body surface area, did not result in fetotoxicity or teratogenicity

Bonus Info - Raspberry Leaf

♦  Raspberry leaf contains fragarine, a plant compound that helps tone and tighten muscles in the pelvic area.

Bonus Info - Raspberry Leaf, con’t.

♦  The concern is that raspberry can trigger involuntary uterine contractions and potentially interfere with implantation.

♦  Toward the end of the pregnancy the risk is for premature labor.

♦  In humans it is not considered safe in the first trimester (12 weeks)

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Presumed safe: Betalactam antibiotics

♦ Betalactams are the first choice for treating infections during pregnancy because of their low risk of harming the fetus, and low transplacental passage, due mostly to simple diffusion

What about a C-Section?

Known Problem Drug - Fentanyl

♦ Pure mu opioid receptor agonist. ♦ Highly lipid soluble and is reported to

cross the human placenta at a rate of 86% ♦  The application of a fentanyl patch to

pregnant sheep (placed in the inguinal region) showed a 77% placental transfer rate at 12 hours post application.

♦ Neonates are more sensitive to CNS and respiratory depression of opioids.

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Presumed safe drug - Alphaxalone

♦ Acts as a GABA agonist, similar to benzodiazepines.

♦ No significant difference in puppy mortality at 24 hours and 3 months compared to propofol.

♦ Apgar scores were greater for puppies for up to 60 minutes post delivery where dams received alphaxalone compared to propofol.

Lactation

Background on Canine Lactation

♦  Characteristics of drugs which facilitate secretion include: §  High lipid solubility §  Low molecular weight §  Non-ionized state

♦  In general a neonate receives 1-2% of the maternal dose

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Presumed safe: Moxidectin

♦  2.1 +/- 0.3% of a single dose of 0.2 mg/kg administered to lactating sheep was excreted for more than 35 days.

♦ Although the total amount was small, moxidectin preferentially entered milk compared to plasma.

♦  In humans the relative infant dose compared to the maternal dose was 8.7 +/- 3.1%.

Review: Special Patient Considerations ♦  Scent Detection

Canines §  Background on

Canine Olfaction §  Working dogs §  Competition dogs

♦  Breeding bitches §  Background on

Canine Pregnancy §  Pregnancy §  Cesarean Section §  Lactation

References ♦  Jenkins, Eileen K, et al. “Effects of oral administration of

metronidazole and doxycycline on olfactory capabilities of explosive detection dogs.” American Journal of Veterinary Research 77.8 (2016):pages 906 -912.

♦  Kraus, Bonnie H. “Anesthesia for cesarean section in the dog.” Iowa State University Digital Repository. 2016.

♦  Lotsch, Jorn, et al. “Olfactory drug effects approached from human-derived data.” Drug Discovery Today 20.11 (2015): pages 1398-1406.

♦  Musk, Gabrielle C, et al. “The uptake of transdermal fentanyl in a pregnant sheep model.” Veterinary Anaesthesia and Analgesia 44.6 (2017) : pages 1382-1390.

♦  Rebuelto, Marcela, et al. “The antibiotic treatment of dogs and cats during pregnancy.” Veterinary Medicine International 2010, Online.

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References

♦  Schiffman, Susan S. “Influence of medications on taste and smell.” World Journal of Otorhinolaryngology 4 (2018): pages 84-91.

♦  Wang, Jing-Jie, et al. “Impact of antibiotics on smell dysfunction.” World Journal of Otorhinolaryngology 4 (2018): pages 33-38.

♦  Essler, J.L., et al. “A Randomized Cross-Over Trial Comparing the Effect of Intramuscular Versus Intranasal Naloxone Reversal of Intravenous Fentanyl on Odor Detection in Working Dogs.” Animals 2019, 9, 385.

♦  Korth-Bradley, J.M., et al. “Excretion of Moxidectin into Breast Milk and Pharmacokinetics in Healthy Lactating Women.” Antimicrobial Agents and Chemotherapy 55:11 (2011): pages 5200-5204.

♦  Ceckova-Novotna, M., et al. “P-glycoprotein in the placenta: Expression, localization, regulation and function.” Reproductive Toxicology 22(2006): pages 400-410.

References ♦  Gudziol, V., et al. “Sildenafil Affects Olfactory Function.” The Journal

of Urology 177 (2007): pages 258-261. ♦  Quignon, P., et al. “Comparison of the canine and human olfactory

receptor gene repertoires.” Genome Biology 4 (2003) online. ♦  Ezeh, P., et al. “Effects of steroids on the olfactory function of the

dog.” Physiology and Behavior 51,6 (1992): pages 1183-1187. ♦  Walter, C., et al. “Effects of 20 mg oral delta-9 THC on the olfactory

function of healthy volunteers.” British Journal of Clinical Pharmacology 78, 5 (2014): pages 961-969.

♦  Jenkins, E.K, et al. “When the Nose Doesn’t Know: Canine Olfactory Function Associated with Health, Management, and Potential Links to Microbiota.” Frontiers in Veterinary Science 2018 online.

♦  Roth, J., et al. “Apomorphine does not influence olfactory thresholds in Parkinson’s disease.” Functional Neurology 13, 2 (1998): pages 99-103.