Download Drugs poisoning in animals (antibiotics, antiparasitics, NSAID etc.)

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+, Mg2+, Ca2+
• 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+ a Ca2+ in
serum (often to lethal levels, mainly in horses), increased creatine
kinase and AST
• 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
• Treatment:
- 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: anaemia, haematuria, inhibition of thyroid
gland hormones synthesis, in acid environment kidney
damage – crystallisation in tubules, formation of kidney
stones
• 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, nonintentional, 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
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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
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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. 174176
- 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