Toxicity related to drug metabolism

Question 1

Adverse reactions to drug administration

Answer 1

• 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

Question 2

Type B1 NECROSIS

Answer 2

• 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)

Question 3

Paracetamol

Answer 3

• 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

Question 4

Paracetamol overdose

Answer 4

• Regarded as >12g (150mg/kg) in adults
• NAPQI produced in same proportion but greater quantities
• Hepatic GSH ‘quenches’ the toxicity
• GSH levels gradually fall

Question 5

Paracetamol toxicity

Answer 5

• 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

Question 6

Paracetamol: recue therapy- patient risk groups

Answer 6

• Alcoholics
• Malnourished
• HIV+
• Those taking inducers

Question 7

Paracetamol: rescue therapy timeline

Answer 7

Question 8

Type B2

Immune related drug toxicity

Answer 8

• 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)

Question 9

Type B2

Answer 9

• 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

Question 10

Common features

Answer 10

• 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

Question 11

How do drugs trigger an immune response

Answer 11

• Two theories on immune function

1. Stranger hypothesis
2. Danger hypothesis

Question 12

Stranger hypothesis

Answer 12

• 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

Question 13

Danger hypothesis

Answer 13

• 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
  *

Question 14

Basic immune function

Answer 14

• 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

Question 15

Immune response

Intracellular detection (1)

Answer 15

• 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

Question 16

Extracellular Ag detection (2)

Answer 16

• 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

Question 17

How do drug toxins initiate a response

3 ideas

Answer 17

1. Hapten hypothesis
2. Pharmacological interaction hypothesis
3. Danger signal hypothesis

Question 18

Hapten hypothesis

Answer 18

• 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

Question 19

Pharmacological interaction hypothesis

Answer 19

• 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

Question 20

Danger signal hypothesis

Answer 20

• Immune system reveives chemical and protein signals (may or may not include metabolites and haptens)
• Drug/Metabolite may stimulate appearance of danger signal molecules

Question 21

Immune tolerance to drugs

Answer 21

• Why to some individuals develop drug allergies
• Immune sensitivities to danger signals
• Cellular repair-slow repair pre-disposes to immune reaction

Question 22

Type B3- cancer

Answer 22

• 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

Question 23

Adverse reactions to drugs map

Answer 23