Drug poisoning in animals – antibiotics, antiparasitics, NSAID Lecture No. 12

Copyright © Mgr. Zuzana Široká, PhD.

Ionophore antibiotics

• Produced by Streptomyces spp., include salinomycin, lasalocid, monensin etc.

• Their structure similar to chelates, form complexes with ions – Na + , K + , Mg 2+ , Ca 2+ • Their toxicity potentiated by other antimicrobial agents (erytromycin, tiamulin, sulphonamides) • Toxic mainly for horses and other equidae, dogs and turkeys • Cause ion and mineral imbalance on mitochondria membranes, decrease production of ATP, influence calcium metabolism and both these mechanisms lead to cell death

• • •

Clinical signs

: - colic, diarrhoea, sweating, hyperventilation, tachycardia, incoordination, toxic polyneuropathy in cats, paralysis, hypertermia in dogs, paralysis of breathing muscles, death - biochemical examination – decreased levels of K kinase and AST + a Ca 2+ in serum (often to lethal levels, mainly in horses), increased creatine

Pathological examination

: - cyanosis of muscles and myocardium, petechias and yellowish strips of muscle signalling necrosis of myocardium, degeneration of myocytes, vacuolization of cells, lung oedema, hepatomegalia

Treatmen

t: - no specific antidote, evacuation of GIT, symptomatic - often late consequences mainly in horses due to scarification of myocardium

Aminoglycosides

• Antimikrobial and antituberculous • • drugs – streptomycin, amikacin, gentamicin etc.

• Toxic to all animals but birds are especially susceptible • Nephrotoxic and neurotoxic • Cause deafness – accumulation in liquid of internal ear – excitotoxic effect on NMDA receptors in ear

Clinical signs

: disturbances of hearing, orientation, fuzziness, damage of kidneys - oliguria, azotemia, increased creatinine – may lead to acute renal failure

Treatment

: only symptomatic and supportive, no specific antidote, damage of hearing irreversible

Sulphonamides

• • • • Common chemotherapeutics, used both in human and veterinary medicine • Quite safe, toxic in overdose • Be especially careful while administering them to dogs – idiosynkrasy non-dependent on dose, which may be seen even several days after finishing therapy

Clinical signs

gland hormones synthesis, in acid environment kidney damage – crystallisation in tubules, formation of kidney stones : anaemia, haematuria, inhibition of thyroid

Idiosynkrasy:

temperature, arthropathy, disturbances in blood count, rashes, conjunctivitis, less nephropathy, pancreatitis or paralysis of face nerves

Treatment:

only symptomatic and supportive, forced diuresis, alkalinisation of the urine

Ivermectin

• Antiparasitic agent from avermectin group (macrocyclic lactones), produced by Streptomyces avermitilis or cyamogriseus • Only for ectopic application against parasites in dogs, horses, cattle and pigs • Intoxications due to overdose or application to other species (esp. to cats) • Beware, certain races of dogs are intolerant to it - collie, Australian shepherd, some grey-hounds • Be careful also in exotic animals – described poisoning in turtles, young zebra etc. • Different susceptibility caused by mutation in so called multiple drug resistance gene, which codes P-glycoprotein responsible for excretion of xenobiotic agents through blood-brain barrier back to blood – in sensitive kinds it crosses this barrier and causes damage of brain

• • • •

Mechanism of action

: - increased release of inhibitory neurotransmitter GABA – decreased neuronal transmission

Clinical signs

: vomiting, hypersalivation, desorientation, anorexia, weakness, lethargy, ataxia, blindness, tremor. In dogs we can see also bradycardia, hypotermia, damage of vestibular apparatus, coma and death.

Pathological examination

: non-specific

Treatment

: - emetics, adsorbents, symptomatic, it is possible to administer neostigmin in severe cases – increases polarisation of nerves

Paracetamol

• • One of the most used analgesic and antipyretic medicine (Panadol, Paralen, Efferalgan etc.) • Often used in human medicine, in animals registered for treatment in pigs • Poisoning common in cats (25 % of cases lethal) and dogs, non intentional, but caused by owner without proper information

Mechanism of action

: - Metabolism a bit different in each species, but mediated by cytochrome P450 - Most toxic is a metabolite of paracetamol N-acetyl-p-chinonimine (has direct cytotoxic effect on hepatocytes and increases the production of cytokines). This compound is normally conjugated with glucuronide and excreted in urine

- In cats, there is only a weak ability to metabolise paracetamol, so for them it is toxic in low doses (60 mg/kg, according other authors 10 mg/kg), and this resembles the situation in ferrets - Cats and ferrets have a low level of glucuronyltransferase, thus all medicines metabolised via this route can cause them harm - They inactivate paracetamol with sulphation reaction, but this process is limited and has only a low capacity - In overdose a depletion of glutathione (source of sulphur) occurs, damage of erythrocytes (Heinz bodies, methaemoglobinisation, haemolytic anaemia) is present and this can lead to hypoxia and death - Moreover, in cats there is a decreased level of methaemoglobin reductase too – intensification of poisoning

•

Clinical signs

: - cyanosis, tachycardia, tachypnoe, depression, vomiting, itching and hypotermia, in cats also typical submandibular oedema and oedema of paws, in dogs oedema of periorbital part of head - haematuria and anaemia, hypoglycaemia and acidosis may be present - After 2-7 days from poisoning, late signs can develop hemoglobinuria, jaundice - If convulsions and coma occurs, it is always a bad prognostic sign – consequences of liver failure •

Pathoanatomical examination

: • - intersticial oedema and necrosis on myocardium • thrombocytopaenia and abnormal structure of thrombocytes • liver damage, jaundice

•

Treatment

: - It is important to detect it as soon as possible - Emetics, adsorbents repeatedly (enterohepatic circulation) - Antidote for paracetamol is N-acetylcysteine (NAC), which is administered orally in initial dose of 140 mg/kg and later in doses of 70 mg/kg 3-5 times - NAC improves the status by several mechanisms: 1) it is a donor of L-cysteine – precursor of glutathione 2) substrate for conjugation reactions, but this is quite a slow reaction of lower importance 3) it is a source of sulphur - Another antidote can be methionine (another source of SH groups) - Ascorbic acid (vitamin C) can be administered as an antioxidant agent – protects erythrocytes - Oxygen via inhalation, methylene blue - Forced dialysis or peritoneal dialysis without effect on excretion

NSAID – ibuprofen, diclofenac etc.

• Non-steroidal anti-inflammatory drugs • For symptomatic treatment of painful diseases, most often used in maladies and injuries of • locomotive organs • Used both in human and veterinary medicine

Mechanism of action

: - all NSAID inhibit cyclooxygenase (COX), which is an important enzyme in prostaglandin synthesis - Unfortunately, by the inhibition of this enzyme also processes of prostacyclin and prostaglandin E2 synthesis are affected - Prostacyclin and prostaglandin E2 are physiologically necessary for GIT mucosa protection – blockage causes increased secretion of digestive fluids, decreased secretion of mucus and bicarbonates, causes vasoconstriction – susceptibility to ulceration and rupture of stomach - In kidneys, NSAID decrease flow, contract renal arteriolas and can cause necrosis

• Ibuprofen is not accredited for use in animals in the Czech Republic, diclofenac only for use in horses • Both toxic mainly for dogs, cats and ferrets • Lethal dose of ibuprofen – in dogs 50 - 125 mg/kg, when nausea, vomiting, anorexia and stomach ache are seen. In this stage stomach ulcer start to develop. Doses higher than 400 mg/kg cause tremors, ataxia, kidney failure, coma and death • - in cats and ferrets- lethal doses two times lower than in dogs • Lethal doses of diclofenac – in dogs approx. 60 mg/kg • Poisonings by diclofenac are typical for dogs, who are the most susceptible species – diclofenac and a lot of other NSAID metabolised by acetylation reactions, which are limited in dogs

Clinical signs

: - vomiting, haematemesis, diarrhoea, melena, anorexia, cyanosis, weakness, ataxia - sometimes depression, dehydration and incoordination - signs can occur within 3 hours after ingestion, but also after 4 days or more. - renal insufficiency or failure after high doses - oliguria, azotaemia and increased creatinine

•

Treatment

: - Start as soon as possible - If detected soon, administer adsorbents – repeatedly – enterohepatic circulation. No emetics or lavage – risk of stomach or oesophagus rupture - Forced diuresis or haemoperfusion ineffective – NSADI usually bound to blood proteins - In kidney failure it is possible to use peritoneal dialysis - Protection of stomach – sucralfat every 8 -12 hours orally. We can use misoprostol - synthetic prostaglandin, H2 antihistaminics – ranitidin, blocker of proton pump – omeprazol - Therapy for prevention of mucosa damage should last at least 7 days - Necessary to monitor metabolic acidosis • The risk of lesions on mucosa and kidney failure is higher with time lapsed • Some dog races are more susceptible to NSAID – in Alsatian poisoning always severe, some are less susceptible - labrador retriever

• More info: www.pnas.org/cgi/doi/10.1073/pnas.0402374101

- Ivermectin and Piperazin toxicoses in dogs and cats, R. A. Lovell. Veterinary Clinics of North America - Small Animal Practice, Vol. 20, 1990, str. 453-468.

- Accidental poisoning of 17 dogs with lasalocid, G. Segev, G. Baneth, B. Levitin, A. Shlosberg, I. Aroch. Veterinary Record, Vol. 155, 2004, str. 174 176 - A chronic cardiomyopathy in feedlot cattle attributed to toxic levels of salinomycin in the feed, S. S. Bastianello, H. L. McGregor, M. L. Penrith, N. Fourie. Journal of the South African Veterinary Association, Vol. 67, 1996, str. 38-41 - Comparative vestibulotoxicity of different aminoglycosides in the guinea pig, E. Selimoglu, S. Kalkandelen, F. Erdogan. Yonsei Medical Journal, Vol. 44, 2003, str. 517-522 - Idiosyncrastic toxicity associated with potentiated sulfonamides in the dog, L. A. Trepanier. Journal of Veterinary Pharmacology and Therapeutics, Vol. 27, 2004, str. 129-138.

- Ibuprofen toxicosis in dogs, cats, and ferrets, E. Dunayer. Veterinary Medicine, Vol., 2004, str. 580-586 - Acetaminophen hepatotoxicity: NO to the rescue, J. L. Wallace. British Journal of Pharmacology, Vol.143, 2004, str. 1-2 http://www.chemsoc.org/chembytes/ezine/1997/stachuls.htm