Drug Toxicity

Drug Toxicity Overview

• No drug is entirely specific
• All drugs have intended and unintended effects
• unintended effects are considered side effects or adverse effects

Mechanisms

• Mechanisms of drug toxicity
• "on target"-adverse effects, drug is on right receptor, but may be wrong concentration, incorrect tissue or suboptimal kinetics
• "off target"-adverse effects, drug on wrong receptor
• Production of toxic metabolites
• Production of a harmful immune response
• Idiosyncratic responses

 

Let's take a look at on-target and off-target effects:

Metabolites

• Toxic metabolites
• Metabolites that are products of metabolism can be inactive, active (pharmacological effect), reactive (usually result in toxic effect)

• Harmful immune responses
• Type I
• Type II
• Type III
• Type Iv
• Drugs recognized as foreign by the immune system
• Most small molecule drug can't trigger alone
• Drug covalently bind to proteins
• Then called Haptens which can trigger immune response

Let's take a look at the 4 different types of harmful immune reactions:

 

• Idiosyncratic Toxicity
• No obvious mechanism is known
• Drug overdose
• Right dose is the difference between therapeutic efficacy and toxicity

• Drug-Drug interactions
• Can be due to
• enzyme metabolism
• Activation by both drug on same pathway
• Herbs can also effect
• Can be both bad and good
• Sometimes you may want to delay metabolism
• PCN and Probenecid (good)
• Sometimes drugs actively complement each other
• NTG and Viagra = severe hypotension (bad)

Pathology of Drug Toxicity

• Pathology of drug toxicity
• Can be parent drug (unmetabolized)
• Mostly metabolites that react with proteins, DNA, and oxidative defense molecules
• Can be acute or chronic
• May not be known before hand and only found out about after drug has been on the market for awhile

Here is a diagram showing the mechanisms of action of drug toxicity:

 

Carcinogenisis/Teratogenisis

• Carcinogenesis
• causes normal cells to transform into a neoplastic cell that expands
• Causes DNA damages or mutations
• Complex process

• Teratogenisis
• Induction of birth defects in the fetus
• Drugs that cause are called teratogens
• Please refer to Box 5-1

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