PED1003/L08 Toxins, Poisoning & Overdose

Question 1

Define toxicology.

Answer 1

Study of noxious effects of chemicals on living systems

Question 2

Define biochemical toxicology.

Answer 2

The interaction of xenobiotics with living organisms

Question 3

Give 3 types of xenobiotics.

Answer 3

Therapeutic drugs
Recreational drugs
Environmental drugs
Occupational chemicals
Natural toxins
Engineered materials

Question 4

What is LD50?

Answer 4

Dose causing death in 50% of exposed animals

Question 5

Describe acute toxicity. (3)

Answer 5

Rapid development whilst chemical or metabolite are still in body
Short lived, but may be lethal
Results from single or short term exposure
Easily identified
May be an antidote

Question 6

Describe chronic toxicity.

Answer 6

Delayed symptoms, develop after chemical excreted
Retrospective detection
May be cumulative effect from long-term low level exposure
BUT can occur from single, acute exposure

Question 7

Describe the process from exposure to toxicity.

Answer 7

Exposure site to site of action (target organ)
Reaction of toxicant with target
Cellular effect
Repair (or disrepair)

Question 8

By which mechanism are the majority of therapeutics administered?

Answer 8

Orally

Question 9

Describe the pathway from oral administration to absorption of a drug (3).

Answer 9

Absorbed through buccal/oral mucosa, stomach and/or intestine
pH differs in compartments; differences in ionisation state of drugs
Non-ionised forms are more readily absorbed

Question 10

Why does initial phase distribution occur rapidly?

Answer 10

As a factor of blood flow to organs and tissues

Question 11

What does subsequent distribution depend on?

Answer 11

Affinity of drugs

Question 12

What is the aim of xenobiotic metabolism?

Answer 12

To transform lipophilic chemicals into more hydrophilic compounds for easier excretion

Question 13

How are drugs metabolised to make them more hydrophilic?

Answer 13

Inserting functional groups which aid conjugation to high MW, water soluble compounds

Question 14

Give the 2 phases of metabolism.

Answer 14

Phase I - functionalisation
Chemical -> activated chemical
Phase II - conjugation (detoxification)
Activated chemical -> elimination

Question 15

What is the major route of excretion in the body?

Answer 15

Urine via kidney

Question 16

Describe enterohepatic recirculation.

Answer 16

Certain metabolites de-conjugate in bile (enzymatic activity of gut microflora) and be available for re-absorption

Question 17

What mechanism of elimination avoids exposure of other organs via systemic circulation?

Answer 17

Liver elimination of xenobiotics and their metabolites in bile

Question 18

Which organs are susceptible to circulating toxins in systemic circulation?

Answer 18

Highly perfused organs

Question 19

Give 3 mechanisms of toxicity.

Answer 19

Oxidative stress
DNA or protein binding
Interaction with specific targets

Question 20

Give 3 Oxygen radical species.

Answer 20

O2-* - superoxide
O* - oxygen free radical
OH* - hydroxyl radical

Question 21

How are Reactive Oxygen Species (ROS) formed?

Answer 21

Molecular oxygen can accept electrons

Question 22

What is oxidative stress?

Answer 22

Imbalance between cellular production of ROS and ability to detox them/ability to repair damage

Question 23

What is constantly produced by the mitochondrial respiratory chain?

Answer 23

H2O2 (1-3% O2 molecules in mitochondria)

Question 24

Give 3 ways in which ROS can damage cells.

Answer 24

Oxidative damage to DNA
Oxidative damage to proteins
Oxidative damage to lipids
Depletion os reduced glutathione
Loss of cellular homeostasis

Question 25

Describe oxidative damage of DNA (2).

Answer 25

DNA bases become oxidised Misincorporations/mutations Implicated in a range of disease states

Question 26

Describe oxidative damage to proteins (2).

Answer 26

SH groups oxidised Abherrant folding

Question 27

Describe oxidative damage to lipids (2).

Answer 27

Lipid peroxidation Leads to formation of malondialdehyde (DNA damaging)

Question 28

Describe depletion of reduced glutathione by ROS (1).

Answer 28

GSH plays a role in removing ROS from cells

Question 29

Describe ROS-induced loss of cellular homeostasis (3).

Answer 29

Increase in [Ca2+] inside cell Damage to Ca2+/ATPase pump Trigger for apoptosis

Question 30

Describe activation of a procarcinogen (benzo[a]pyrene). (4)

Answer 30

Benzo[a]pyrene oxidised by CYP1A1 Oxidation by epoxide hydrolase Oxidation by CYP1A1 Benzo[a]pyrene diol epoxide forms adduct with guanine

Question 31

Describe protein adduct formation. (3)

Answer 31

Chemicals or their metabolites react with amino acid residues on proteins Leads to abherrant protein folding Alters function or hypersensitivity response

Question 32

Describe the action of organophosphorus insecticides and nerve agents. (3)

Answer 32

Target ACh Bind to serine in active site Some Ops require prior metabolic activation to bind serine residue

Question 33

Describe OP binding to active site serine. (3)

Answer 33

d+ and d- attract Binding -O- Releases H+ ion

Question 34

Describe paracetamol metabolism. (3)

Answer 34

Therapeutic dose - majority metabolised by conjugation (60%) Some detoxification (35%) Some oxidation by Cytochrome P450s

Question 35

Describe the action of aspirin.

Answer 35

Aceylates COX-1 (Prostaglandin G/H synthase 1) Inhibits COX-2 Suppresses synthesis of Prostaglandins and thromboxanes

Question 36

Where is aspirin rapidly and extensively absorbed?

Answer 36

Stomach and small intestine

Question 37

Describe aspirin metabolism. (2)

Answer 37

Converted to salicylic acid by plasma and tissue hydrolases after absorption Metabolised in liver by conjugation to glycine (50%), glucuronide (32%), oxidation and remainder (13%) excreted by kidney unchanged

Question 38

Describe the effect os high plasma concentrations on salicylate metabolism.

Answer 38

Excretion becomes zero order Half life increases from 3-5h to 12-15h Small increases in salicylate absorption result in disproportionate increase in plasma concentration

Question 39

Describe the underlying mechanism of salicylate metabolism.

Answer 39

Salicylate acts as uncoupler of mitochondrial oxidative phosphorylation Inhibits TCA cycle Perturbs proton gradient for ATP synthesis in mitochondria by moving protons from intermembrane space into matrix

Question 40

Give a short-term effect of ox-phos coupling. (3)

Answer 40

Stimulation of respiratory centre in hypothalamus Detects low ATP, high ADP and stimulates hyperventilation Respiratory alkalosis

Question 41

Give 3 long-term effects of ox-phos coupling.

Answer 41

Plasma pH reduced Absorption into CNS increases Glucose can no longer be metabolised efficiently to energy in neurones Eventual loss of fluids and electrolytes

Question 42

How is salicylate treated?

Answer 42

Gastric lavage and activated charcoal Fluid and electrolyte balance Alkalinisation of urine Renal and haemodialysis