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PED1003-Pharmacology > PED1003/L08 Toxins, Poisoning & Overdose > Flashcards

PED1003/L08 Toxins, Poisoning & Overdose Flashcards

1
Q

Define toxicology.

A

Study of noxious effects of chemicals on living systems

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2
Q

Define biochemical toxicology.

A

The interaction of xenobiotics with living organisms

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3
Q

Give 3 types of xenobiotics.

A

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

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4
Q

What is LD50?

A

Dose causing death in 50% of exposed animals

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5
Q

Describe acute toxicity. (3)

A

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

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6
Q

Describe chronic toxicity.

A

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

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7
Q

Describe the process from exposure to toxicity.

A

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

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8
Q

By which mechanism are the majority of therapeutics administered?

A

Orally

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9
Q

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

A

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

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10
Q

Why does initial phase distribution occur rapidly?

A

As a factor of blood flow to organs and tissues

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11
Q

What does subsequent distribution depend on?

A

Affinity of drugs

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12
Q

What is the aim of xenobiotic metabolism?

A

To transform lipophilic chemicals into more hydrophilic compounds for easier excretion

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13
Q

How are drugs metabolised to make them more hydrophilic?

A

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

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14
Q

Give the 2 phases of metabolism.

A

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

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15
Q

What is the major route of excretion in the body?

A

Urine via kidney

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16
Q

Describe enterohepatic recirculation.

A

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

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17
Q

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

A

Liver elimination of xenobiotics and their metabolites in bile

18
Q

Which organs are susceptible to circulating toxins in systemic circulation?

A

Highly perfused organs

19
Q

Give 3 mechanisms of toxicity.

A

Oxidative stress
DNA or protein binding
Interaction with specific targets

20
Q

Give 3 Oxygen radical species.

A

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

21
Q

How are Reactive Oxygen Species (ROS) formed?

A

Molecular oxygen can accept electrons

22
Q

What is oxidative stress?

A

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

23
Q

What is constantly produced by the mitochondrial respiratory chain?

A

H2O2 (1-3% O2 molecules in mitochondria)

24
Q

Give 3 ways in which ROS can damage cells.

A

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

25
Q

Describe oxidative damage of DNA (2).

A

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

26
Q

Describe oxidative damage to proteins (2).

A

SH groups oxidised
Abherrant folding

27
Q

Describe oxidative damage to lipids (2).

A

Lipid peroxidation
Leads to formation of malondialdehyde (DNA damaging)

28
Q

Describe depletion of reduced glutathione by ROS (1).

A

GSH plays a role in removing ROS from cells

29
Q

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

A

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

30
Q

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

A

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

31
Q

Describe protein adduct formation. (3)

A

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

32
Q

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

A

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

33
Q

Describe OP binding to active site serine. (3)

A

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

34
Q

Describe paracetamol metabolism. (3)

A

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

35
Q

Describe the action of aspirin.

A

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

36
Q

Where is aspirin rapidly and extensively absorbed?

A

Stomach and small intestine

37
Q

Describe aspirin metabolism. (2)

A

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

38
Q

Describe the effect os high plasma concentrations on salicylate metabolism.

A

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

39
Q

Describe the underlying mechanism of salicylate metabolism.

A

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

40
Q

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

A

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

41
Q

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

A

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

42
Q

How is salicylate treated?

A

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

PED1003-Pharmacology (27 decks)

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