What are the 5 classes of classification of drug toxicity ?
1. On-target adverse effects
2. Off-target adverse effects
3. Toxic metabolites
4. Immune responses
5. Idiosyncratic Responses
On-target effects Toxicity
1. exaggeration of the desired pharmacological action due to alterations in exposure to the drug
2.Drugs expressed in more than one cell type
Off-Target Effects Toxicity
1. occurs when the drug interacts with unintended targets usually identified in preclinical or early stage clinical trials.
3. Unintended activation of different receptor subtypes.
Production of toxic metabolites (BIOACTIVATION)
1. Prodrugs may be metabolised to produce pharmacologically active metabolites (losartan is metabolised to the active drug E3174)
2. The drug can be metabolised into a reactive species which may have an adverse effect my modifying macromolecules (can covalently bind to proteins and lipids and alter functionality )
3. Modified proteins can induce an immune response
4. oxidative stress is a key factor in toxicity induced by metabolites.
A very large proportion of problematic drugs produce reactive metabolites
toxicity of drug metabolites can only be measured empirically which means that it is very important to test them.
Example of bioactivation (Paracetamol)
smaller drugs = haptens
Bigger drugs = can directly activate immune system
the two main mechanism of immune responses are :
1. Hypersensitivity responses
2. Autoimmune responses
Types of hypersentitive immune responses
1. type 1 or immediate-type hypersensistivity
2. type 2 or antibody dependent cellular toxicity
3. type 3 or immune complex disease
4. type 4 or delayed-type hypersensitivity
1. Hapten hypothesis - Some individuals will show greater activation of a drug yielding reactive metabolite which act as haptens and lead to an immunological response. It is possible that an immune response against a self antigen could be induced (e.g. by molecular mimicry or by a change in processing of antigen leading to presentation of cryptic antigens)
2. Danger hypothesis - Reactive metabolite doesn’t result in immune response but causes cell damage/cell stress and the injured tissue (not the presence of drug or metabolite) produces danger signals (e.g. lipid oxidation products, cytokines) that induces a toxic response
3. As a result of the formation of reactive metabolites by monocytes which can lead to their activation, and as precursors to macrophages this could lead to a more generalized activation of the immune system ultimately resulting in autoimmunity
4. By inhibition of DNA methylation - Methylation of DNA inhibits transcription and therefore inhibition of methylation can lead to lymphocyte activation
What is Idiosyncratic toxicity ?
Unpredictable / life threatening
Causes not necesserily related to each other
once the drug is marketed even an incidence of 1 in 10 4 can yield hundreds of problems
Difficult to study in animal models because the genetic variation causing the adverse response is not known. Their unpredictable nature also makes prospective mechanistic studies in humans virtually impossible, and there are few valid animal models
What are the proposed mechanisms for Idiosyncratic toxicity
do it later if needed