Toxicity Caused by Commonly Used Drugs | Toxicology

After reading this article you will learn about the toxicity caused by commonly used drugs.

Tetracyclines:

Tetracyclines are generally non-toxic. The binding capacity of tetracyclines to bones and Ca²⁺ may lead to inhibition of tooth development or bone growth. The teeth may dis-colour and may cause hypoplacia of the deciduous and permanent teeth.

Tetracycline hydrochloride given i.v. to lactating animals is excreted through milk for 36 hrs. after treatment and may lead to hypersensitivity reaction in growing young ones. There is an urgent need to establish withholding times in different species because the established time in a particular species may be inadequate for other species of animals and cannot be extrapolated to another.

Chloramphenicol:

Chloramphenicol can cause a dose-dependent reversible suppression of bone marrow in all animals. This is believed due to mitochondrial injury resulting from inhibition of protein synthesis. It can also cause much rare idiosyncratic aplasia of bone marrow which is irreversible in nature and thought to be the result of inhibition of DNA synthesis.

Clinical signs of toxicity produced in cats include CNS depression, dehydration, in-appetence, vomiting, weightlessness, reversible bone marrow suppression with marrow hyperpasia and inhibition of mitotic activity. Rashes, edema, urticaria, nausea, vomiting and diarrhoea are seen as a consequence of allergic and adverse reactions of chloramphenicol in animals.

The following points must be considered while doing therapy with chloramphenicol:

(i) The therapy with chloramphenicol must be of short duration.

(ii) It should not be concurrently used with vaccines.

(iii) It may lower prothrombin level.

(iv) It can inhibit the metabolism of phenytoin, dicumarol and other drugs which are metabolized by hepatic microsomal enzymes.

(v) It may prolong duration of pentobarbitone anaesthesia in canine and feline.

(vi) Chloramphenicol inhibits microsomal enzymes and may delay biotransformation of primidone in canine and may produce sedation and primidone toxicity.

(vii) Chloramphenicol also delays biotransformation of local anaesthetics.

The use of chloramphenicol in food producing animals should be restricted due to its residual problems in food for consumption by humans

Penicillin:

Penicillin may produce allergic effects in animals undergoing treatment especially through parenteral routes. Hypersensitivity reactions to penicillins range from mild skin reactions to fatal anaphylactoid shock.

Penicillin therapy in dogs may cause salivation, shievering, vomiting and urticaria as consequence of acute allergic responses within 15 minutes after the second administration and approximately one month after the first injection. When benzyl-penicillin is given in hypertonic solutions (= 200, 000 units/kg i.v.) produces ataxia and convulsions in dogs. Procaine penicillin when given i.m. to dogs may produce neurological disorders.

Intramuscular administration of procaine penicillin G may produce acute allergic reactions in dairy cattle. The dairy cattle suffering from acute allergic reactions show symptoms of laboured breathing, salivation and cutaneous edema of the head and perineal region. Duration of reaction is 2-3 hours. In pigs it may produce shievering, depression, anorexia, vomiting, cyanosis and pyrexia. It has adverse effects in pregnant sows and abortion may occur.

It may produce hypersensitivity and anaphylactic reactions in horses. The penicillin preparations containing a carboxy-methylcellulose adjuvant produce anaphylactic reactions in cattle. Dermatitis generally results after penicillin therapy in white haired horses with thin sensitive skin. Local reactions such as muscle tenderness and edema occasionally occur at the site of injection.

Streptomycin:

The toxicity produced by streptomycin on vestibular and auditory mechanism must be borne in mind while treating the animals especially for longer period. Neurotoxic effects produced include posture and gait, ataxia, first of the hind legs and latter of the fore legs. A progressive loss of rotational nystagmus is also observed.

If streptomycin and di-hydro-streptomycin are administered for a longer period in cats, it can permanantly damage vastibular end-organ and the lesion is limited to the inner ear. When dogs are treated for cystitis, Streptomycin can damage the vestibular function.

Signs of acute streptomycin toxicity include restlessness, nausea, laboured respiration, loss of consciousness and coma. Death due to streptomycin toxicity is generally due to the respiratory failure and vasomotor depression. Cattle are sensitized due to feed contaminated by Streptomycin or intramammary infusion. Older cattle are more allergic than younger animals. It can depress cardiovascular system in animals anesthetized with pentobarbital.

Neomycin:

The repeated injections of neomycin may produce ototoxic and nephrotoxic signs after parenteral administration. Nephrotoxicity produced by Neomycin is reversible but the otoxicity is irreversible. Neomycin, when given i.v. to dogs increases excretion of calcium in urine. Therefore, animals suffering from postparturient hypocalcaemia should not be treated with neomoycin parentrally.

Gentamicin:

Gentamicin may produce renal toxicity and can damage the cochlear and vestibular portions of the 8th cranial nerve. Animals with impaired renal functions show ototoxic disturbances. Therefore, in animals suffering from renal damage, the dosage of gentamicin should be reduced and maintenance dosage be repeated at longer intervals.

The plasma gentamicin concentrations ranging between 5-7 µg/ml serve as therapeutic concentration. However, if plasma concentration exceeds 12 µg/ml are toxic. Gentamicin should not be given in dogs suffering from diarrhoea, reneal disorder, hypokalemia, hepatic disorder and sepsis to avoid nephrotoxicity.

It produces ototoxicity in fetus because of diffusion through placental barriers. Gentamicin can never be used in pregnant animals. The Gentamicin therapy should not exceed 7 days and in case, if a favourable response is not obtained within this period other antibiotics should be selected.

Polymyxin B and Colistin:

Both are nephrotoxic and should be used with great caution in animals with impaired renal functions. Neuromuscular agents are not given with polymyxin B and colistin because it can lead to muscular weakness, paresis, respiratory arrest and death.

Cephalosporins:

Local reactions which are related to the route of administration are the most frequent adverse effects. Minor gastrointestinal effects such as vomiting and diarrhoea may occur following oral administration of cephalosporins.

Hypersensitivity reactions to the cephalosporins are generally not dose-related and may include fever, skin rash, arthralgias, lymphadenopathy, eosinophilia, haemolytic anaemia and anaphylaxis. Cephalosporin by-products react with endogenous protein in vivo to form various haptens which then give rise to various types of immunologically mediated responses.

Dose dependent toxicities include neutropenia, thrombocytopenia, agranulocytosis, glomerular and interstitial nephritis, tubular necrosis, hepatitis and neurotoxicity.

All these effects are associated with very high doses and prolonged use of cephalosporins. Enterocolitis and diarrhoea may follow cephalosporin administration by any route. Cephalosporin, in light of their potential nephrotoxicity, should not be used with other nephrotoxic agents such as aminoglycosides.

Nitrofurans:

The toxic symptoms produced by nitrofurans include vomiting, diarrhoea, GI bleeding, eosinophilia, ocular disturbances, peripheral neuritis and sensitization.

Amphotericin B:

The most potential toxic effect produced by Amphotericin B is its renal toxicity. Renal damage increases BUN and non protein nitrogen decreases glomerular filtration, decrease renal plasma flow and also decrease creatinine clearance. Other toxic effects produced by Amphotericin B are fever, nausea, emesis, anorexia, hematuria and proteinuria.

Piperazine:

In high doses may produce vomition, diarrhoea, incoordination and head pressing especially in cats and dogs. In some animals especially in young ones it may cause neurologic disorders.

Benzimidazoles:

They are very safe in all domestic and wild animals. Cambendazole may produce inappetance and listlessness in cattle at a dose 3 times higher than recommended dose. Parbendazole may produce transient diarrhoea in horses treated with a dose as low as 2.5 mg/kg. Thiabendazole administered orally may produce vomition and leukopenia.

Ivermectin:

High oral doses of Ivermectin causes mydriasis in dogs. In horses, loss of vision may be seen if given on 2-consecutive days orally. Acute toxic symptoms in horses include CNS depression, listlessness, ataxia, recumbancy and death.

Thiopental Sodium:

Thiopental sodium can depress the respiratory centre. At high doses it may stop the myocardium as to paralyze respiration.

Aspirin (Acetyl Salicylic Acid):

At low doses it may induce toxic hepatitis, depression, poor appetite and vomiting and at high doses, death. A high dose causes anemia, gastritis, toxic hepatitis and suppression of erythropoiesis in bone marrow. Aspirin produces gastric haemorrhage when given in suspension form at pH 3 in dog. In dog hematomesis and gastric ulcer may be produced at oral dose of 100-300 mg/kg/day.

When Aspirin is given concurrently with gentamicin, it potentiates nephrotoxicity. Aspirin when given in combination with phenylbutazone, fenoprofen, mefenamic acid or ibuprofen causes irreversible nephrotoxicity. The over dose can produce nausea, vomiting, restlessness, CNS seizure and coma.

Treatment:

(i) Removal of Aspirin from the body.

(ii) Gastric lavage in dogs.

(iii) Oral administration of activated charcoal.

(iv) Sodium bicarbonate

(v) causes alkalization and increases renal excretion.

(v) Diuretics e.g. mannitol also increase aspirin excretion.

Phenylbutazone:

Phenylbutazone, given to horses may produce anorexia, depression, colic, hypoproteinemia, diarrhoea, weight loss, petechial hemorrhages of mucous membranes, oral and G.I. tract erosions and ulcers, renal papillary necrosis and death in horses. In Dachshund dogs, phenylbutazone produces idiosyncrasy and leads to a serious condition that includes severe hemorrhages, biliary stasis and renal tubular degeneration.

Mycotoxins:

The term mycotoxin is derived from the Greek word ‘Mykes’ meaning fungus and Latin word ‘toxicum’ meaning poison. A variety of toxic metabolites generated by parasitic or saprophytic molds have been reported to be the causes of different diseases collectively known as mycotoxicoses when ingested by animals and poultry.

Our knowledge of mycotoxicity arose out of the study of two serious disease outbreaks, one being in sheep as facial eczema caused by Sporidesmin toxin of Pithomyces chartarum (Sporidesmium bakeri) as reported by Thornton and Percival (1959) and Synge and White (1959) and the other in turkey poults occurred in Great Britain during 1960 originally termed as turkey X disease and now as aflatoxicosis caused by aflatoxins.

About 25% of world cereals are suspected to be contaminated with mycotoxins. The toxins are mainly produced by fungal genera of Aspergillus, Fusarium and Penicillium. These toxins are produced when fungi grow on crops in the field, at harvest, in storage or during processing of feed when environmental conditions are favourable. Warm and humid climate favours aflatoxins, fumonisins and ergot toxins whereas Ochratoxins, Zearalenone, Vomitoxin, T-2 toxins etc. are found in cool and moist areas of India.

Mycotoxins may act as silent killer or exert negative impact on health and productivity of livestock and poultry. Vomitoxin acts as ‘feed refusal factor’ in pigs whereas Zearalenone causes reproductive disorder in pigs and dairy animals, fumonisin is responsible for nervous ailment in equines due to its action on brain, Ochratoxin is nephrotoxic in pigs causing renal disease and suppresses immune system of poultry and aflatoxins are hepatoxic, teratogenic, carcinogenic and immuno-suppressants. Mycotoxins may be found in animal products like meat and milk e.g. aflatoxin in milk and ochratoxin in pig meat. The ingestion of such products may cause health hazard in man.

The list of mycotoxicoses reported to occur in India are summarized in table 43.1 Commonly occurring mycotoxicoses are described as follows:

i. Aflatoxicosis (Turkey X Disease):

The disease is caused by toxins produced by Aspergillus flavus and A. parasiticus. The toxigenic strains of molds grow on ground nuts, soybeans, maize and other cereals either in the field or during storage when environmental temperature is 30°C and relative humidity is 80-85%. Growing poultry specially ducklings and turkey poults, young swine, pregnant sows, calves and dogs are affected.

Toxic metabolite of Aflatoxin Bi binds to nucleic acids and nucleoproteins causing mitotic inhibition, immunosuppression, carcinogenesis and teratogensis. Liver is badly affected showing hepatocellular necrosis. In acute outbreaks, animals die after a short period of in-appetence.

Liver shows marked fatty changes, cirrhosis and Centro lobular necrosis and haemorrhage. Jaundice is characteristic symptom in pigs and dogs. In sub acute outbreaks, un-thriftiness, weakness, anorexia and sudden deaths are usual features. Prolonged feeding causes potent hepato-carcinogenic effect.

In poultry, aflatoxins cause depression, in-appetence, reduced growth, loss of condition, decreased egg production, fertility and hatchability and high mortality. Ataxia, convulsions and opisthotonos are common signs in turkey poults and ducklings.

Glomerulonephriti, liver necrosis with bile duct proliferation and catarrhal enteritis are quite characteristic. Disease is diagnosed by history, microscopic examination of liver, necropsy findings and detection of aflatoxins in feed. In poultry, biological and chemical assays are used for confirmation.

Control:

Contaminated feed should be withdrawn for feeding young, pregnant and lactating animals. Mold growth is inhibited in poultry feed by incorporation of 8-hydroxyquinoline (500 ppm i.e. 0.5g/kg), gentain violet (0.5-1.5 g/kg), propionic acid (0.5-1.5g/kg) and thiabendazole (100 mg/kg).

Feed is also modified by high level of methionine supplementation for effective detoxification of toxins by liver. Mineral clays e.g. bentonite, zeolite (HSCAS-hydrated sodium, calcium, aluminosilicate) and amino-silicates (0.5%) are most effective feed additives in poultry and pig feed for binding and interference of digestion of toxins.

Treatment:

Affected poultry should be fed a high energy good quality protein diet supplemented with both water and fat soluble vitamins.

ii. Ergotism:

The disease is recorded in cattle, sheep, pigs, horses, poultry and man. It occurs due to ingestion of sclerotia of the parasitic fungs-Claviceps purpurea which grows on cereal especially rye and grasses. Mycelia develop as hard black elongated masses known as ergots or sclerotia which develops in the ovaries of the flowers replacing grain or seed in the ears. Ergotism is due to toxic ergot alkaloids namely ergotamine and ergometrine present in sclerotia.

Ergot alkaloids have vasoconstrictor properties on arterioles causing restricted blood supply to the extremities of the body. Ergot poisoning is primarily chronic type. Cattle are affected by ingestion of infected hay or grain. Lameness is the 1st sign observed with high body temperature and increased pulse and respiratory rates.

Swelling and tenderness of the fetlock joints and pastern occur with loss of sensation followed by gangrene which may extend to hock or knee joints. Tips of tail or ears are also necrosed and sloughed. Skin becomes cyanotic. Other symptoms are diarrhoea, convulsions, agalactia and abortion. Acute symptoms in cattle are hyper excitability, muscular incoordination, tremor, blindness and fatal convulsions.

In swine reduced feed intake and weight gains are observed. In pregnant sows udder does not develop. Agalactia and birth of small litters of weak piglets are noted. In sheep, symptoms are similar to cattle. In poultry, loss of appetite, thirst, diarrhoea, paralysis and death are common symptoms. Dry gangrene affects comb, tongue and wattles of birds. Diagnosis is based on the finding of the causative fungus in grains, hay or pastures.

Control:

Change of ergot infested diets or pastures is advised.

iii. Fusarium Estrogenism Including Vulvovaginitis in Swine:

Some toxigenic strains of Fusarium spp molds may produce one or more potent trichothecane toxins and Zearalenone (F2 toxin). Zearalenone is potent non-steroidal estrogen whose effects are estrogenic. It produces reproductive disorders in animals.

It is produced in temperate climate in mold infested corn, oats, barley, wheat, sorghum, hay and pastures. Hyperemia and enlargement of the vulva are characteristic signs of the toxicity in affected weaned and pre-pubertal gilts. There is hypertrophy of mammary glands and uterus. Uterine prolapse may be seen in severe toxicity.

It causes reduction in fertility litter with smaller offsprings and malformations in sows. Heifers show wide ranging signs. They include weight loss, vaginal discharge, nymphomania, uterine hypertrophy and abortion in pregnant heifers. Animal recovers 1-4 weeks after the withdrawal of toxin contaminated feeds.

iv.Mycotoxic Lupinosis:

It is characterized by liver injury and jaundice. It results mainly by feeding sweet lupines. The casual fungus is Phomopsis leptostromiformis. It produces hepatotoxic metabolites. In sheep and cattle early signs are anorexia and listlessness followed by jaundice and ketosis. Cattle may show salivation and lacrimation.

Sheep become photosensitive. In acute outbreak, death occurs in 2-14 days. Liver lesions are characteristic. Livers are enlarged, orange yellow, fatty, contracted and fibrosed. Oral doses of Zinc (0.5 g per day) can protect sheep against lupinosis.

v. Other Mycotoxins:

Ochratoxin produced by Aspergillus ochraceus causes nephrosis in swine and poultry characterised by perirenal oedema enlarged pale kidneys with cortical cysts, tubular degeneration and fibrosis. Cattle may suffer due to mushroom poisoning.

Severe inflammation of intestinal tract, convulsion and death may be recorded due to consumption of mushroom Amanita verna and A. muscaria. Vomitoxin produced by Fusarium roseum may cause disorder in swine and dogs. Vomiting and diarrhoea are the main symptoms. Feed refusal develops when toxin is present in higher concentration. Recovery takes place when diet is changed.