Drug Toxicity: Molecular Mechanisms

Question 1

What is toxicology?

Answer 1

The study and effect of poisons on the living system

Question 2

Give examples of chemical agents that can cause toxicity?

Answer 2

1. Drugs
2. Insecticides and herbicides
3. Plant toxins
4. Animal toxins
5. Chemical weapons
6. Radioactive substances

Question 3

Define what an adverse drug reaction is?

Answer 3

Noxious or unintended responses occurring at therapeutic doses

Question 4

What are type A adverse drug reactions and give an example of one?

Answer 4

1. Related to pharmacology but undesirable effects
2. Common, dose related
3. Predictable
4. Example: respiratory depression with opioids

Question 5

What are type B adverse drug reactions and give an example of one?

Answer 5

1. Unrelated to known pharmacology
2. Rare, unpredictable
3. anaphylaxis (allergic reaction) with penicillin
4. Individual allergies/genetic basis

Question 6

How are toxins absorbed by the body?

Answer 6

1. Ingestion

2. Inhalation

Question 7

What are the two phases toxins metabolised in the body?

Answer 7

1. Phase I Cytochrome P450 goes through oxidation, reduction and hydrolysis
2. Phase II Conjugation to allow excretion in urine and bile

Question 8

What is toxification and detoxification?

Answer 8

1. Detoxification: compound rendered less toxic

2. Toxification: relatively inert compound turned into a toxin

Question 9

Where are toxins stored when they are not excreted?

Answer 9

Bone and fat

Question 10

What is a type I hypersensitivity reaction?

Answer 10

IgE mast cell degranulation

Question 11

What is a type II antibody mediated cytotoxic hypersensitivity reaction?

Answer 11

Haematological reactions i.e. pertaining to the blood cells and blood forming organs

Question 12

Describe the process of how a type I hypersensitivity reaction can trigger anaphylactic shock?

Answer 12

1. Low molecular weight allergen: bee venom, peanut oil and drugs like penicillin
2. hapten attaches onto a protein to start off an immune response
3. Immunogenic conjugate is made which attaches onto Mast cells which gets degranulated
4. IgE recognition releases histamine which starts off bronchoconstriction, vasodilation and inflammation

Question 13

How do you treat a type I hypersensitivity reaction? And what does it treat?

Answer 13

1. Adrenaline (EPI PEN)

2. Treats bronchoconstriction, vasodilation and inflammation

Question 14

Describe the process of how a type II hypersensitivity reaction can deplete blood cell types?

Answer 14

1. Red blood cell has toxin antigen blinded to it
2. IgG attaches onto the antigens on the red blood cell
3. T cells binds to it which creates a cytotoxic T cell
4. Causes mediated cell lysis
5. Can deplete RBC, neutrophils and platelets

Question 15

What are the four major superfamilies of receptors that molecular drugs and toxins target?

Answer 15

1. Nuclear Receptors (regulate gene transcription factors)
2. G coupled protein receptors (metabotropic receptors)
3. Ligand gated ion channels (ionotropic glutamate)
4. Enzyme coupled receptors (tyrosine kinase)

Question 16

Give two sources of toxins that are derived from plants and their mechanisms of action?

Answer 16

1. Digoxin: Na+/K+ ATPase Inhibitor

2. Atropine: blocks muscarinic acetylcholine receptors

Question 17

Give two sources of toxins that are derived from bacteria and their mechanisms of action?

Answer 17

1. Botulinium toxin: Inhibits synaptic protein (prevents acetylcholine from leaving via exocytosis)
2. Cholera toxin: activates G alpha S proteins

Question 18

Give two sources of toxins that are derived from animals and their mechanisms of action?

Answer 18

1. Dendrotoxins (green mamba): blocks the K+ channels

2. Tetrodotoxin: blocks the Na+ channels

Question 19

What are some irreversible anti-cholinesterases used?

Answer 19

Sarin and Parathion

Question 20

What is the first line of defence against biological gases?

Answer 20

1. Atropine: mAChR blocker- central respiratory depression

2. Pralidoxime: Reactivation of acetylcholinesterase

Question 21

What are the two biochemical examples and what do they do?

Answer 21

1. Cyanide: Inhibits mitochondrial cytochrome c oxidase which prevents cellular respiration
2. Carbon monoxide: Displaces oxygen from haemoglobin causing hypoxia

Question 22

What is hepatic inflammation known as?

Answer 22

Hepatits (liver infection)

Question 23

What is chronic liver disease known as?

Answer 23

Cirrhosis

Question 24

Explain what happens to paracetamol in the body when you overdose?

Answer 24

1. Phase 1: 10% of it creates NAPQI which is hepatotoxic (binds to protein thiol group)
2. Phase 2: 90% is turned into glucuronide or sulphate conjugate
3. Phase I is excreted as a compound called glutathione conjugate which is less toxic

Question 25

Explain why an overdose can cause problems in paracetamol?

Answer 25

1. The NAPQI cannot be broken into glutathione conjugate | 2. NAPQI is toxic

Question 26

What can nephrotoxicity do, and how do the problems happen in the first place?

Answer 26

1. Changes in glomerular filteration rate - Largely due to drugs that alter blood flow - NSAIDS (aspirin) - ACE inhibitors (ramipril) 2. Allergic nephritis (inflammation of kidneys) - Allergic reaction to NSAIDS and proteins 3. Chronic nephritis - Long term NSAID and paracetamol use

Question 27

What is a mutagen?

Answer 27

1. Changes to cell DNA that are passed on when cell divides | 2. Produces a neoplastic cell the agent is termed carcinogen

Question 28

What are photo-oncogenes?

Answer 28

Promote cell cycle progression

Question 29

What are tumour suppressor genes?

Answer 29

Inhibit cell cycle progression

Question 30

What is Teratogenesis?

Answer 30

The creation of birth defects during fetal development

Question 31

What is Teratogens?

Answer 31

Substances that induce birth defects