The study of the effect of drugs on the function of living systems
The study of the effect of poisons on the function of living systems
Name 3 chemical agents that cause toxicity
- Plant toxins
Define: Adverse drug reaction
Noxious or unintended responses occurring at therapeutic doses
Explain Type A (augmented) ADRs
- Related to known pharmacology but undesirable
Give an example of a Type A (augmented) ADR
Haemorrhage with anticoagulants (e.g. warfarin)
Explain Type B (bizarre) ADRs
- Unrelated to known pharmacology
- Often idiosyncratic (= peculiar, individual)
Give an example of a Type B (bizarre) ADR
Anaphylaxis with penicillin
The effects of the body on the poison
Relates to ADME
What information does toxicokinetics provide?
Makes it possible to predict concentration of toxin that has reached the site of injury and the resulting injury
Compound rendered less toxic
Occurs during metabolism
Relatively inert compound converted into toxin
Occurs during metabolism
Name 2 ways that toxins are 'absorbed'
Ingestion (salmonella) or inhalation (asbestos)
How many phases of metabolism of toxins are there?
2: Phase I and Phase II
What occurs during Phase I of metabolism of toxins?
Hydrolysis by cytochrome P450
What occurs during Phase II of metabolism of toxins?
Conjugation to allow excretion in urine and bile
Where may toxins be stored if they aren't excreted?
Bone (e.g. lead)
Fat (e.g. DDE, a metabolite of the pesticide DDT)
- The toxin may be slowly released into the body
Name a common form of ADR
How many clinical syndromes of allergic reaction are there?
4: Type I, II, III & IV
What is a Type I allergic reaction?
- A hypersensitivity reaction
- Mediated by IgE = an antibody
- IgE causes degranulation of mast cells = release of histamine
What is a Type II allergic reaction
- Antibody-mediated cytotoxic hypersensitivity
- Involve haematological reactions = those pertaining to the blood cells and blood-forming organs
What is a Type III allergic reaction?
Immune complex-mediated hypersensitivity
What is a Type IV allergic reaction?
What can Type I hypersensitivity reactions trigger?
What is a hapten?
A small molecule that binds to a bigger molecule which triggers an immune response
What is the molecular process of a Type I hypersensitivity reaction?
- Low MW allergen enters the body
- A hapten binds to the allergen to form an immunogenic conjugate
IgE recognition of immunogenic complex causes degranulation of mast cells
- Massive histamine release
What does the release of histamine from the mast cells cause?
What substance is used to treat allergic reactions?
What is the molecular process of a Type II hypersensitivity reaction? (Antibody-mediated cytotoxic hypersensitivity)
- The toxin antigens bind to RBCs
- Antibody IgE molecules trigger T cells
- T cells begin lysis = cytotoxic T cell-mediated cell lysis
How can sulphonamides be toxic?
Can deplete red blood cells = haemolytic anaemia
Due to Type II hypersensitivity reaction
How can some NSAIDs be toxic?
They can deplete neutrophils = agranulocytosis
Due to Type II to hypersensitivity reaction
How can quinine an heparin be toxic?
They can deplete platelets = thrombocytopenia
Due to Type II hypersensitivity reaction
Define: Haemolytic anaemia
When the levels of RBCs are depleted (e.g. by sulphonamides)
When the levels of neutrophils are depleted (e.g. by some NSAIDs)
When the levels of platelets are depleted (e.g. by quinine and heparin)
Name the 4 major superfamilies of receptor
Ligand-gated ion channels (voltage-gated ion channels)
GPCRs (metabotropic receptors)
Enzyme-coupled receptors (tyrosine kinase activity)
Nuclear receptors (regulate gene transcription)
Name 4 targets of toxins
Enzymes (metabolic and catabolic pathways)
Carriers (uptake/transport systems)
Others e.g. proteins involved in vesicle release
What do animal toxins block?
What substance blocks voltage-gated K+ channels?
What substance acts on Na+ channels?
What effect does blocking the Na+ channels have?
Block action potentials
What kind of toxin blocks ion conduction?
What do dendrotoxins block?
Voltage-gated K+ channels
What does Tetrodotoxin act on?
List 4 symptoms of high quantities of acetylcholine
Bradycardia (= abnormally slow heart action)
Increased secretion (eyes watering, nose running)
Name the enzyme that oximes reactivate
Name the strong nucleophile that reactivates ACh-esterase
What does cyanide inhibit?
Cytochrome C oxidase
What effect does inhibiting cytochrome C oxidase have?
Prevents cellular respiration
Where is Cytochrome C oxidase found?
What effect does carbon monoxide have on haemoglobin and what does this cause?
It displaces the oxygen causing hypoxia = COHb
Deficiency in the amount of oxygen reaching the tissues
Name the 2 organs that are particularly susceptible to toxin damage
Liver and kidney
Why are the liver and kidney more susceptible to toxin damage?
Their major role is excretion
What is toxin damage of the liver called?
What is hepatic necrosis caused by?
Define: hepatic necrosis
Death of liver tissue
What is hepatitis?
What can cause hepatitis?
Halothane (anaesthetic) can covalently bind to liver proteins to trigger an autoimmune response
What is cirrhosis?
Chronic liver damage
What can cause cirrhosis?
Long term alcohol (ethanol) abuse causes:
- Malnutrition (ethanol becomes a food source)
What effect can paracetamol poisoning have on the liver?
Hepatic necrosis = death of liver tissue
What effect can halothane (anaesthetic) have on the liver?
What effect can long term alcohol abuse have on the liver?
Can cause cirrhosis = chronic liver damage
What occurs in Phase II conjugation (metabolism) with regards to paracetamol?
90% of the paracetamol is safely conjugated with conjugating agents (e.g. sulphate)
What occurs in Phase I metabolism of paracetamol?
10% of the paracetamol undergoes Phase I reactions
- This produces an intermediate species (NAPQI)
NAPQI = very toxic to the liver (binds to protein thiol groups)
- = Hepatotoxicity
Why is NAPQI very toxic to the liver?
It binds to the protein thiol groups = hepatotoxicity
Name the process that NAPQI undergoes
Phase II conjugation with glutathione = makes NAPQI non-toxic and it is therefore safely excreted
Why is it more difficult to get rid of NAPQI after a paracetamol overdose?
Large quantities of NAPQI produced
Enzymes are saturated
- Levels of glutathione are quickly depleted
Name 2 treatments for paracetamol overdose
Acetylcysteine and Methionine
Why are acetylcysteine and methionine used to treat paracetamol overdose?
Both are glutathione precursors = more glutathione and excess NAPQI is excreted
Poisonous effects of some substances on the kidney
What effect does altering the blood flow have on the kidney?
Causes changes in glomerular filtration rate (GFR)
Name 2 types of drug that can cause changes in the GFR due to altering blood flow
NSAIDs (e.g. aspirin) - reduce prostaglandins (prevent arachidonic acid binding to cyclooxygenases) which in turn reduces blood flow/GFR
ACE inhibitors (e.g. ramipril) - increase blood flow/GFR
How do NSAIDs affect the GFR?
NSAIDs reduce the GFR as they lower the number of prostaglandins which reduces blood flow
How do ACE inhibitors affect the GFR?
ACE inhibitors increase blood flow and so increase the GFR
Why can lowering the GFR have dangerous consequences?
Makes it more difficult to excrete toxic compounds
Define: Allergic nephritis
Inflammation of kidney due to allergic reaction
Give 2 examples of substances that can cause allergic nephritis
Antibiotics (e.g. metacillin)
Name 2 drugs that can cause chronic nephritis
Long term NSAID and paracetamol use
- A physical or chemical agent
- That causes changes to the DNA
- Increasing the frequency of mutation above the natural background level
- The mutations are passed on when the cell divides
A mutagen that capable of causing cancer
Name the 2 major classes of gene that are involved in carcinogenesis
- Tumour-suppressor genes
What is the role of proto-oncogenes?
Promote cell progression
Define: neoplasm/neoplastic cell
- An abnormal mass of tissue
- Results when cells divide more than they should or do not die when they should (due to a mutation)
- May be benign or malignant (cancerous)
What is the role of tumour-suppressor genes?
Inhibit cell cycle progression
The property or capability of producing congenital malformations
The creation of birth defects during foetal development
Substances that induce birth defects
Name a teratogen
How was thalidomide able to cause birth defects?
The (R)-enantiomer was a sedative but the (S)-enantiomer was a teratogen
What was thalidomide marketed to treat?
Marketed as an anti-emetic to treat morning sickness in pregnant women
And as a sleeping pill (sedative)
Name the cellular process that occurs during blastocyst formation
What substances affect blastocyst formation?
Cytotoxic drugs (toxic to cells)
What are the 3 stages of foetal development?
- Blastocyst formation
Name the cellular processes that occur during organogenesis
What substances affect organogenesis?
Teratogens = thalidomide, retinoids, antiepileptics, warfarin
Name the cellular processes that occur during maturation
What substances affect maturation?