Hi friends, sorry for the delay in posting my blog. In this blog I have discussed about drug toxicity, various mechanisms involved in this process, and situations of drug toxicity. Many drug candidates that undergo pre-clinical trials and clinical trials often fail to make way into the market due to their unacceptable levels of toxicity. Many of the drugs are not entirely specific in their actions. All drugs have intented and unintended effects. The unintended effects known as the side effects or adverse effects. Usually these effects are typically undesirable with few exceptions where they can be beneficial. Drug receptor interactions play an important role in understanding the adverse effects of the drugs. MECHANISMS OF DRUG TOXICITY Adverse reactions may be more likely in patients with preexisting conditions, such as liver or kidney dysfunction, depressed immune function, or pregnancy. The mechanisms of drug toxicity can be explained based on several general paradigms: * On-target adverse effects, these are due to binding of drug to its desired receptor but in the incorrect tissue or in appropriate concentration or with suboptimal kinetics. * Off-target adverse effects, these are due to drug binding to a target or receptor for which it was not intended. * Production of toxic metabolites. * Production of harmful immune responses. * Idiosyncratic responses. ON-TARGET EFFECTS Many a time's exaggeration of desired pharmacologic response due to alteration in exposure to the drug leads to drug toxicity and its adverse effects. This can be due to overdosing of drug, by alterations in the pharmacokinetics of the drug or by changes in pharmacodynamics of drug-receptor interaction that alter pharmacologic response. Most of the cells or tissues express more than one type of drug targets. An important case of on-target adverse effects is that when a drug or one of its metabolites interacts with its desired receptor but in the wrong tissue. E.g.: Antihistamine like diphenhydramine is an H1-receptor antagonist used to treat allergic conditions. But due to the ability to cross blood brain barrier it has antagonizing actions on H1 receptors in the CNS causing somnolence. At times on target side effects unmask important and previously unknown functions of the biologic target. E.g.: Statins are clinically used to reduce the cholesterol levels in hyperlipidemic patients; the main target tissue for this activity is liver where they inhibit HMG CoA reductase. Rare adverse effect of these is muscle toxicity leading to rhabdomyolysis and myositis. This effect is due to role of HMG CoA reductase in regulating the post translational modification of several proteins. OFF-TARGET EFFECTS As stated earlier these occur when drug interacts with unintended targets. Example of this is the cardiac potassium channel (hERG) inhibiting activity of Terfinadine. These unintended effects lead to fatal cardiac arrhythmias in some patients. Drug enantiomers also sometimes cause off target effects. Example of this is the thalidomide disaster which resulted in teratogenic effects in many new borns. When thalidomide was administered as a racemic mixture for treating morning sickness in pregnant women it lead to the above disaster as the (S)-enantiomer was a potent teratogen. PRODUCTION OF TOXIC METABOLITES In certain cases of drug toxicity a metabolite of the drug may show adverse effects. These kinds of effects are the results of interaction of the drug metabolites with cellular proteins and subsequent formation of complex between them. These have their toxic effects mainly on organs like Liver and other such vital organs. This can be well illustrated with the example of Acetaminophen a commonly used analgesic and antipyretic. Small percent of acetaminophen gets converted into N-acetyl-benzoquinoneimine which is conjugated to glutathione under normal circumstances. When the dose of acetaminophen exceeds therapeutic range the normal glucoronidation and sulfation pathways by which it gets metabolized are saturated and results in glutathione depletion in liver, consequently it results in damage to hepatic tissue. HARMFUL IMMUNE RESPONSES Since as such drugs are in certain cases the small molecule drugs with a mass of less than 600 Daltons act as haptens where they bind to protein molecule and are capable of triggering an immune response. The principle immune mechanisms by which drugs can produce damage are Hypersensitivity reactions and autoimmune responses. A well known example for drug induced hypersensitivity reactions is Penicillin's induced hypersensitivity reaction. Autoimmune response results when organism's immune system attacks its own cells. For example Methyldopa can cause hemolytic anemia by eliciting an autoimmune response against Rhesus antigens. IDIOSYNCRATIC RESPONSES These are rare adverse drug reactions which have no elucidated mechanisms. But these are often thought to reflect unique individual genetic differences in response to drug molecule usually by variations in drug metabolism or immune response. SITUATIONS OF DRUG TOXICITY Following are some of the various situations which might lead to drug toxicity and their consequences of adverse drug responses. 1. Drug Overdose 2. Drug-Drug Interactions * Pharmacokinetic drug interactions * Pharmacodynamic drug interactions 3. Drug-Herb Interactions References:: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition by David E. Golan. Published by Wolter Kluwer/Lippincott Williams & Wilkins.Pg:63-69