Pharmacology and prescribing 2 Flashcards
(427 cards)
what toxicities are tested for in animals during drug development?
carcinogenicity, teratogenicity and organ-specific toxicities
what are adverse drug reactions?
- injuries following administration of a drug or combination of drugs under normal conditions of use
- unwanted or harmful effects that occur in humans after it has been marketed, due to adverse effects not being seen in animals
- suspected to be related to the drug
- has to be noxious and unintended
what are examples of adverse drug reactions that occur during prolonged use of a drug?
- osteoporosis during continued high-dose glucocorticoid therapy
- tardive dyskinesia during continuous use of antipsychotics
what are examples of adverse drug reactions occurring on ending treatment?
- within a few days: tachycardia on abrupt discontinuation of beta-adrenoceptor blockade
- months/years after discontinuation: second malignancies following successful chemotherapy
who suggested classifying ADRs according to DoTS? what is DoTS?
- Aronson and Ferner (2003)
- dose, time course and susceptibility
who suggested the ABCDE approach to classifying ADRs?
Rawlins and Thomson (1985)
what are type A ADRs?
- adverse effects related to the known pharmacological actions of the drug are predictable
- augmented
- related to dose and individual susceptibility
- common
what are examples of type A ADRs?
- postural hypotension with alpha1-adrenoceptor antagonists
- bleeding with anticoagulants
- sedation with anxiolytics
- morphine and constipation
- hypotension and antihypertensive
how serious are type A ADRs?
- often is reversible, and the problem can be dealt with by reducing the dose
- can be serious (e.g. intracerebral bleeding caused by anticoagulants, hypoglycaemic coma from insulin)
- may not be easily reversible (e.g. drug dependence from opiod analgesics)
what is an example of type A ADRs leading to discrete events rather than graded symptoms?
- makes them difficult to detect
- drugs that block COX-2 (coxibs, e.g. rofecoxib, celecoxib, valdecoxib and NSAIDs) increase risk of MI in a dose-dependent manner
when can type B ADRs be predictable?
- if taken in excessive dose (e.g. paracetamol hepatotoxicity or aspirin-induced tinnitus)
- increased susceptibility (e.g. pregnancy)
- predisposing disorder
- mutation in mitochondrial DNA
what are type B ADRs?
- adverse effects unrelated to the known pharmacological action of the drug
- unpredictable
- idiosyncratic
what are type B ADRs often initiated by? what are examples of this?
- chemically reactive metabolite rather than the parent drug
- often immunological in nature
- drug-induced hepatic/renal necrosis, bone marrow suppression, carcinogenesis and disordered fetal development
what are examples of severe type B ADRs?
- aplastic anaemia from chloramphenicol
- anaphylaxis due to penicillin
what is involved in toxicity testing in animals?
- wide range of tests in different species
- long-term administration of the drug
- regular monitoring for abnormalities
- detailed postmortem examination to detect gross or histological abnormalities
what doses are used in toxicity testing?
doses well above the expected therapeutic range
- establishes which tissues or organs are likely targets of toxic effects of the drug
why are recovery studies in toxicity testing done?
to assess whether toxic effects are reversible, and looking for irreversible changes e.g. carcinogenesis or neurodegeneration
what are the ranges of toxic effects caused by a drug?
- can range from negligible to so severe that development of the compound is stopped
- intermediate levels of toxicity are more acceptable in drugs for severe illnesses
when can safety of a drug be determined?
only during use in humans; toxicity can be detected in animals too
what are some tests of hepatic damage and renal function?
hepatic: levels of transaminase enzymes measured in blood plasma or serum
renal function: usually creatinine concentration
how does toxin-induced cell damage/death occur?
- necrosis
- apoptosis is increasingly recognised to be of equal or greater importance than necrosis, especially in chronic toxicity
- covalent or non-covalent mechanisms
- caused by reactive metabolites of the drug
what are potentially cytotoxic, non-covalent processes of drug-induced cell damage/death?
- lipid peroxidation
- generation of toxic ROS
- depletion of reduced glutathione (GSH)
- modification of sulfhydryl groups
what is the process of lipid peroxidation? what is it initiated by?
- initiated either by reactive metabolites or by ROS
- lipid peroxyradicals (ROO•) can produce lipid hydroperoxides (ROOH)
- ROOH produce further lipid peroxyradicals (ROO•)
what are defence mechanisms against lipid peroxidation?
GSH peroxidase and vitamin E