3. Drug toxicity, factors influencing drug toxicity Flashcards
Give the effects given by drugs in general
- Primary intended effects
- Secondary unintended effects (side effects/adverse effects)
“On target” adverse effects
- Intended receptor & intended tissue
- Intended receptor but unintended tissue
“Off-target” adverse effects
Unintended receptor, intended tissue
Production of toxic metabolites
Relative metabolites of drugs can be involved in several related, potentially cytotoxic, non-covalent interactions
List the types of toxic metabolite formation from drugs
- Lipid peroxidation
- Reactive oxygen species
- Depletion of glutathione
- Modification of sulfhydryl groups
- Acetaminophen = Paracetamol (overdose)
Lipid peroxidation
Peroxidation of unsaturated lipids
Initiated by:
- Reactive metabolites
- Reactive oxygen chain reaction
- Peroxidative cascade
Reactive oxygen species
Reduction of molecular oxygen
- ROS are cytotoxic
Depletion of glutathione
Glutathione redox cycle protects cells from oxidative stress
Depleted by:
- Accumulation of normal products of cell metabolism
- The action of toxic chemicals
Cell death/cellular defence against toxic compounds is impaired when glutathione falls below 20-30% of normal
Modification of sulfhydryl groups
Free sulfhydryl groups role: Catalytic activity of many enzymes
- Acute Ca2+ overload → Activation of degradative enzymes
Acetaminophen (Paracetamol) overdose
Metabolised predominantly by glucuronidation & sulfonation
- If glucuronidation & sulfonation pathways get saturated + glutathione in liver becomes depleted:
- N-acetyl-benzoquinone imine accumulation
- This reacts with nucleophilic groups on proteins
- Covalent protein derivate produced
- Highly toxic in the liver
Acetaminophen (Paracetamol) - antidote
N-acetylcysteine
- Delivered within 8-16 hours after overdose
Harmful immune responses
Drugs are xenobiotics that can be recognised by the immune system
- Caused by haptens
What are haptens?
Small molecules that when combined witha larger carrier such as a protein can elicit an immune response
Can be:
- Type I
- Type II
- Type III
- Type IV
Hapten type I
Immediate hypersensitivity
- Production of IgE in response to antigen
- E.g Penicillin
Hapten type II
Antibody-dependent cytotoxic hypersensitivity
- IgG recognise drug bound to cell as antigen
- E.g Sulphonamides
Hapten type III
Immune complex-mediated hypersensitivity
- IgG or IgM
- Antigen-antibody complexes are deposited in tissues
- Kidney, joints, lung vascular endothelium
- Complexes initiate inflammatory response (serum sickness)
- Causing damage
Hapten type IV
Delayed type hypersensitivity
- Activation of TH1 & cytotoxic T-cells
- First exposure wont produce a response
Autoimmunity
Results when organisms immune system attacks its own cells
Idiosyncratic toxicity
Toxicity for no obvious reason
Give the types of drug interaction
- Synergism
- Addition
- Potentiation
- Antagonism
Synergism
Two drugs elicit same type of response
Addition
Summation of effected responses
Potentiation
Response > Addition
Antagonism
Response < sum of responses
Which other factors can affect the toxicity of a drug?
- Preexisting conditions
- Dosage & route of administration
- Age
- Feeding
- Gender
- Tolerance
- Dependence
Preixsting conditions affecting drug toxicity
- Liver/kidney dysfunction
- Pregnancy
- Depressed immune function
Gender affecting drug toxicity
Metabolism can be faster in male because testosterone is a CPY3A inductor
Tolerance affecting drug toxicity
Body builds up a resistance by receptor regulation & altered metabolism
Dependency affecting drug toxicity
- Habitation - Force of habit, mental
- Addiction - Mental & physiological
