The Central Nervous System (CNS) is particularly vulnerable to direct and indirect drug-induced toxicities due to the high
metabolic rate of neurons, their marked need for external nutritional support, and their unique lack of a regenerative capacity
leading to accumulated lesions and additive effects of toxic injuries. There is also the possibility of delayed manifestation
of an adverse drug reaction when neuronal reserve can no longer compensate, which often makes it difficult to find a drug
cause to effect relationship. A compromised blood-brain barrier (BBB) such as in pediatric patients, certain diseases and
breed particularities may render the CNS particularly vulnerable to toxic effects of drugs which normally would not cause
significant adverse effects when administered at therapeutic doses. Typical clinical signs of neurological drug-induced adverse
reactions include emesis, diarrhea, salivation, fever, disorientation, ataxia, trembling, seizures, depression, coma and blindness.
Documented examples of drugs associated with neurotoxicities in dogs and cats include ivermectin (Collies and Australian shepherds),
phenothiazines, butyrophenones, metoclopramide, tricyclic antidepressants, metronidazole, fluoroquinolones, aminoglycosides
(neuromuscular blockade) and amitraz.
Drug-induced adverse reactions may affect either the auditory system or the vestibular system or both. Vestibular damage is
easier to detect in dogs and cats than auditory damage especially in older cognitively challenged patients. Ototoxic effects
may be reversible or irreversible. Anticancer drugs such as vincristine, vinblastine and cisplatin are toxic to the hair cells
of the organ of Corti thereby affecting the auditory system of the ear. Furosemide on its own, can cause cochlear damage,
or enhance the ototoxicity of aminoglycosides when administerd concomitantly. Other examples of ototoxic drugs include fluoroquinolones,
chlorhexidine and propylene glycol.
Both Type A and B adverse drug reactions are manifested in the skin either as an allergic reaction or an immune-mediated reaction
such as lupus erythematosus, pemphigus or pemphigoid skin lesions. Similar to the liver and the kidneys, the skin has metabolizing
enzymes which makes it susceptible to drug-induced reactions from the parent drug and/or metabolites. Alopecia or generalized
exfoliation has been reported with the administration of anticancer drugs, hormonal therapy, glucocorticoids (cushinoid presentation),
hetacillin (cats), and flea collar and lime-sulfur dips, respectively. Eczema or eczematous dermatitis has been associated
with coal tar shampoo, diethylcarbamazine, 5-fluorocytosine, griseofulvin, topical neomycin, phenothiazine derivatives and
sulphonamides. Pruritus has been associated with human recombinant erythropoietin (with skin or mucocutaneous lesions), KBr,
methimazole and diethylcarbamazine; purpura or pemphigus has been reported with chloramphenicol and thiabendazole, whereas
urticaria and angioedema were associated with tetracyclines and Vitamin K.
Endocrine system reactions
The endocrine system offers several targets where drugs may interfere with important hormonal axes such as the thyroid and
cortisol systems. Drug-induced decrease in hormonal concentration may include the suppression of hormone release, decreased
hormone synthesis or altered peripheral metabolism of the hormone. Hypothyroidism may be caused by hepatic metabolizing inducers
such as phenobarbital, rifampin and glucocorticoids, or by sulphonamides and antithyroid drugs. A decrease in the hypothalamus-pituitary-adrenal
(HPA) axis has been documented in dogs with the use of glucocorticoids. The inhibitory effect of ketoconazole on testosterone
and adrenal steroid production has been used to treat prostatic cancer, benign prostatic hypertrophy and hyperadrenocorticism.
Drug-induced adverse reactions may affect the bone marrow and/or mature circulating cells. Both the parent drug and/or metabolite(s)
may cause toxicity to the stem or mature hematological cells. Anemia, leucopenia or thrombocytopenia, or a combination of
all of them (pancytopenia) can reflect drug damage to the bone marrow. Hematological disorders are assessed by cell count,
time to onset after drug exposure, course of the reaction and time to resolution after discontinuation of the drug. Reactions
may be immunological or non-immunological. Examples of non-immunological reactions include anticancer drugs, estrogen derivatives,
phenobarbital (reversible) and chloramphenicol. Manifestation of anemia may be caused by NSAIDs and anticoagulants, due to
their predictable pharmacological effect on platelets and coagulation cascade, and in cats by methimazole, propylthiouracil,
acetaminophen or benzocaine due to the formation of methemoglobin.
Drug toxicity to the lung may be caused by gaseous or particulate toxicants, or systemic exposure. As for the liver, kidneys,
skin and hematological cells, lungs are susceptible to the parent drug and metabolite(s) as they possess Clara cells or type
II alveolar cells which contain cytochrome P450 enzymes for local metabolism of drugs. Since the "shock" organ for the cat
is lungs, Type I allergic drug reactions (Type B adverse drug reactions) are expected in this species, primarily manifested
as acute respiratory difficulties.