Toxicity related to drug metabolism Flashcards
1
Q
Adverse reactions to drug administration
A
- Type A= reversible adverse responses
- Type A1= linked to the pharmacological effect- opiate drowsiness /RD
- Type A2= effects unrelated to drug action- anti-depressant (bruxism)
- Type B= irreversible, toxic response
- Type B1- direct necrotic injury- paracetamol
- Type B2- immune-mediated toxicity
- Type B3- cancer
2
Q
Type B1 NECROSIS
A
- Toxicity: defined as irreversible change in cellular structure leading to change in cellular function
- Usually overdosage (paracetamol)
- Necrotic injury can result from oxidation to reactive species (troglitazone)
- Necrotic injury can result from causes outside of drug metabolism (Tacrine)
3
Q
Paracetamol
A
- 70,000 0verdoses
- Only 300-500 deaths
- About 50% cleared by glucuronide and 45% sulphate
- 5% cleared to an N-acetyl, p-benzoquinoeimine(NAPQI)
- No toxicity at therapeutic doses 4g max/day
4
Q
Paracetamol overdose
A
- Regarded as >12g (150mg/kg) in adults
- NAPQI produced in same proportion but greater quantities
- Hepatic GSH ‘quenches’ the toxicity
- GSH levels gradually fall
5
Q
Paracetamol toxicity
A
- Phase I- 0-24hr, ok but feeling a bit rough, vomiting
- Phase II- 24-48 hrs, pain in abdomen, HR rises, BP falls, transaminases rise to 30-50 times normal
- Phase III- 48-72 hrs, jaundice, GIT bleeding, pain, organ failure and death
6
Q
Paracetamol: recue therapy- patient risk groups
A
- Alcoholics
- Malnourished
- HIV+
- Those taking inducers
7
Q
Paracetamol: rescue therapy timeline
A
8
Q
Type B2
Immune related drug toxicity
A
- The immune system should detect non-self anywhere in the biological system
- Inate an appropriate response
- Retain a memory of its response for next time
- Immune system should theoretically NOT react to small molecular targets (1500 D- virus not that small)
9
Q
Type B2
A
- Drugs which provoke an immune response- often confused with infection so give them antibiotics
- Anticonvulsant syndrome- difficult to rescue them
- Symptoms- rashes, fever, hepatitis/failure)
- Blood dyscrasias- immune system attacks blood cells (red or white)
- Haemolytic anaemia (NSAIDS, penicillins, cephalosporins)
- Aplastic anaemia- (Destruction of bone marrow by the immune system)- caused by chloramphenicol, chlorpromazine, anti-neoplastic agents
- Cutaneous toxicity- sulphonamides
- Hepatotoxicity (DILI drug-induced liver injury)- statins, halothane, INH, phenytoin
- Agranulocytosis- clozapine, sulphones, chlorpromazine, anti-thyroid agent
10
Q
Common features
A
- Syndromes occur at least 6 maybe 10 weeks after therapy begins (change in therapy)
- Progression is very rapid and disseminated
- Fever, rashes, hepatotoxicity
- Treatment-steroids
- Re-challenges effect occurs within days or hours
- The structurally unrelated drug must be used to maintain therapy
11
Q
How do drugs trigger an immune response
A
- Two theories on immune function
- Stranger hypothesis
- Danger hypothesis
12
Q
Stranger hypothesis
A
- Immune system reacts to non-self
- LPS, bacterial/viral proteins and DNA
- Anything that is not human
- PROBLEM: does not account for the destruction of cancer cells and the rejection of organs
- We have used this to destroy tumour- take out T cell, modify it to destroy the cancer cells - the stranger hypothesis is not quite enough
13
Q
Danger hypothesis
A
- Immune system ‘listens’-
- Detects certain trigger molecules associated with danger (infection or abnormality)
- Such as uric acid, some interlukins, cytokines, HSPs, HMGB1
- Enough trigger molecules are detected response is initiated
*
14
Q
Basic immune function
A
- The immune system looks for antigens inside and outside cells
- Processes them: two-signals needed (maybe a third)
- Initiates/does not initiate a response
- Immune reaction does/doesn’t occur
15
Q
Immune response
Intracellular detection (1)
A
- Intracellular Ag detection =>
- TAP loads protein fragments on MHC-1 =>
- MHC-I moves to cell surface and displays Ag =>
- CD-8 killer T cells detect Ag =>
- T-cells destroys the cell
16
Q
Extracellular Ag detection (2)
A
- Extracellular Ag detection =>
- APCs detect and engulf Ag =>
- MHC-II binds and displays Ag
- =>Ag presented to CD-4 + T cells with co-stimulaiton
- =>APC instructed to form Ag-directed Abs
- =>Ag presented to C-4 Tcells without Co-stimulation
- No immune response, T cells may undergo apoptosis
- =>Ag presented to CD-4 + T cells with co-stimulaiton
17
Q
How do drug toxins initiate a response
3 ideas
A
- Hapten hypothesis
- Pharmacological interaction hypothesis
- Danger signal hypothesis
18
Q
Hapten hypothesis
A
- Immune response to low molecular weight agents in certain circumstances
- Haptens: Reactive species which bind to macromolecules
- The immune system responds to the hapten/macromolecule combination
- The immune system doesn’t respond to hapten alone
- Particularly with spontaneous drugs such as penicillins
19
Q
Pharmacological interaction hypothesis
A
- Some immune responses are so fast that Ag presentation could not have occurred
- Drug/Metabolite binds directly to MHC molecules and triggers effects
- Covalent binding is not required
- Does not explain how sensitization occurred
- Same effects are Ag presenting virus epitope
20
Q
Danger signal hypothesis
A
- Immune system reveives chemical and protein signals (may or may not include metabolites and haptens)
- Drug/Metabolite may stimulate appearance of danger signal molecules
21
Q
Immune tolerance to drugs
A
- Why to some individuals develop drug allergies
- Immune sensitivities to danger signals
- Cellular repair-slow repair pre-disposes to immune reaction
22
Q
Type B3- cancer
A
- Drugs rarely implicated in cancer (except for anti-neoplastic)
- Some reactive species formed by CYPs and reductive pathways can damage to DNA unless phase II detoxified
- DNA either repaired or retained as damaged
- Malignancy can result, sometimes 20-50 years later
- Main problems: smoking, dietary agents (aflatoxins), occupational exposure, obesity- a permanent level of immune upregulation, Genetic- thiol levels
23
Q
Adverse reactions to drugs map
A
