Lec 13

Question 1

What is adverse drug reaction?

Answer 1

It is a noxious / unintended response to a drug which occurs at dose normally used in humans for prophylaxis, diagnosis or treatment of diseases or for the modification of physiological function. It is common and is associated with long term disability or death.

Question 2

What are the 6 classifications of adverse drug interactions?

Answer 2

• Type A (augmented pharmacological effect): related to the main pharmacological effect of drug or cytotoxicity of drug or metabolites
• Type B (bizarre): unrelated to the main pharmacological action of the drug
• Type C (chronic effects): adverse effects associated with long term therapy
• Type D (delayed effects): effects appearing long time after treatment
• Type E (end of treatment effects): withdrawal reactions
• Type F (Failure of treatment)

Question 3

Describe two features of Type A adverse drug reaction and give 3 examples.

Answer 3

• predictable
• dose related
  e. g. bleeding with warfarin, hypoglycaemia with insulin, confusion and drowsiness with nortriptyline

Question 4

What is cytotoxicity and how does it work? What does this mean with hepatic metabolism and with polar drugs/metabolites?

Answer 4

Cytotoxicity is when drug or reactive metabolites directly damage cells either by forming covalent bond or alter target molecules via non-covalent interactions. With drugs that undergo hepatic metabolism, this can result in high levels of metabolites in the liver causing hepatotoxicity. And with polar drugs/metabolites, they can be concentrated within the nephron causing nephrotoxicity.

Question 5

Describe how paracetamol hepatotoxicity works? What is given to help?

Answer 5

Paracetamol metabolised by CYP to form NABQI (toxic intermediate metabolite). NABQI is inactivated by conjugation with glutathione forming reduced glutathione. In overdose, the glutathione is depleted and there is excessive NABQI that binds to liver macromolecules causing cell damage and acute hepatic necrosis. N-acetylcysteine facilitates glutathione synthesis.

Question 6

Give an example of drug that can cause nephrotoxicity.

Answer 6

Gentamicin - antibacterial ribosomal protein synthesis inhibitor that is excreted unchanged in urine by glomerular filtration. cytotoxic at high concentration to proximal renal tubules causing nephrotoxicity.

Question 7

What are the two major mechanisms of Type B adverse drug reaction?

Answer 7

• allergic reactions (require initial exposure and sensitisation, occurs on repeated exposure)
• pharmacogenetic variability

Question 8

Give two examples of Type B adverse drug reaction.

Answer 8

• Benzylpenicillin allergy: due to AB directed to penicilloyl-protein complex or penicillin polymers. many types of allergic reaction e.g. skin rash, analhylaxis. Can lead to death
• carbamazepine skin reaction: Its a sodium channel blocker used for epilepsy. Occasional life threatening severe skin reaction- Steven-Johnson syndrome or Toxic Epidermal Necrolysis (more severe). Effects include blistering and peeling of the skin leading to dehydration, sepsis, multiple organ failure.
  individuals with the HLA-B*1502 allele have a greater susceptibility. It is an immune-mediate adverse drug reaction.

Question 9

Describe the featuers of Type C adverse drug reaction.

Answer 9

• long-term treatment may alter the receptor expression and/or tissue sensitivity to drugs
• adverse drug reactions can occur during therapy or after withdrawal of the drug

Question 10

Provide an example of Type C.

Answer 10

haloperidol-induced dyskinesia (see slide)

Question 11

What happens with Type E? Give an example.

Answer 11

Abrupt cessation of treatment can cause symptoms because of the unopposed change in receptor expression or tissue sensitivity. Example: dexamethasone-induced adrenocorticoid insufficiency. (see slides)

Question 12

What are the two major Type D reactions and give a short explanation and an example for each

Answer 12

• carcinogenesis- drug may cause mutations by a) covalently modifying DNA in growth regulatory proto-oncogenes or tumour suppresor genes b) by promoting cell proliferation. Example: doxorubicin or cyclophosphamide which induce secondary cancers (see slides)
• teratogenecity- fetal malformations, damage resulting from drugs prescribed during pregnancy. Example: doxycycline- induced tooth discolouration and malformation (see slides)