Drug safety and drug side-effects

Question 1

All drugs are poisons. What is an Adverse Drug Reaction (ADR)?

Answer 1

An undesirable effect of drug beyond its anticipated therepeautic effects. WHO: noxious + unintentional drug effect.

Account for 6.5% of hosp admissions, 2.3% of these patients die.

Question 2

What drugs commonly account for ADR?

Answer 2

Anti-platelet, diuretics, anti-coagulants, NSAIDs account for 50% of cases.

Question 3

Describe the Type A Adverse Drug Reaction

Answer 3

• Pharmacological
• Most common type of ADR
• Consequence of drug action - predictable
• Dose-dependent
• Not usually life-threatening
• Resolved by lowering dose / withdrawing treatment
• Generally picked up + understood during drug testing

Question 4

Describe the Type B Adverse Drug Reaction

Answer 4

• Idiosyncratic or bizarre
• Unrealted to pharmaoclogy of drug - unpredictable
• Not dose related
• Often immune or genetic problem
• Can be fatal
• Need to withdraw drug - not use again
• Need longer term + widespread use in population to identify (pharmacovigilance)

Question 5

What are some examples of Type A ARDS?

Answer 5

• NSAIDs -> GI bleeds, peptic ulcer, renal impairment, bronchospasm
• Diuretics -> hypotension, dehydration, electrolyte changes
• Opioids -> vomiting, confusion, constipation, resp depression
• Insulin/oral hypoglycaemic drugs -> hypoglycaemia

These are all predictable, consequence of drug action

Question 6

What are some examples of Type B ARDs?

Answer 6

• Hypersensitivity reactions
• Anaphylaxis shock -> life-threatening
• Amoxicillin (broad-spectrum penicillin), anti-convulsants
• Steven Johnson syndrome

Question 7

What happens in Steven Johnson syndrome?

Answer 7

• Very severe, very rare, very difficult to predict
• Linked to genetics, infections, poor liver metabolism of drug metabolites
• Flu like symptoms/high fever
• Blistering of skin, mucuous membranes
• Skin falls off
• < 10% body affected - mortality of 5%
• Organ damage, blindness

Question 8

Describe the mechanisms for which drugs such as pencillin induce hypersensitivity reactions

Answer 8

• Penicillin itself is non-immunogenic with a small mol weight
• Penicillin undergoes a chemical rxn w/ plasma protein
• The penicillin-plasma protein complex is an immunogenic peniccloyl hapten
• This triggers immune response, mast cells -> histamine
• Anaphylaxis

Question 9

How can we reduce and avoid ADRs?

Answer 9

• Minor type A reactions may be tolerable
• Continue to treat + then treat the ADR w/ another drug
• Accept more severe ADRs - risk + reward balance
• Be aware of vulnerable groups + drugs - know your pharma
• Good drug history essential eg. prev drug rxns
• Keep up to date with drug info
• Patients/HCPs should report problems ASAP

Question 10

In terms of pharmacovigilance, why is it important to monitor the safety of drugs?

Answer 10

Enable clinician/patient to balance risk and reward -> benefit should always exceed risk.

Can lead to: drug withdrawal, contraindication, warnings given, dose changs.

Question 11

What was the Thalidomide 1961 scandal?

Answer 11

Thalidomide was not initially tested on pregnant animals - missed teratogenic effects -> polydactyl, syndadctyl, phocomelia.

10,000 - 20,000 people affected.

Lead to new safety procedures to prove efficency and reveal all side-effects in testing.

Question 12

Most contries have some system to monitor suspected adverse reactions, what are systems in the UK?

Answer 12

• Yellow card
• Black triangle
• Green form

Question 13

Yellow cards + black triangles allow for serious ADRs to be reported to MHRA. What is good and bad about this system?

Answer 13

Good:

• Yellow cards main method of post-marketing surveillance
• Now anyone can make a report
• Black triangle highlights possible adverse rxns to new meds

Bad:

• (Originally relied on reporting by doctors)
• Gross under-reporting suspected
• Numerator data only - nothing to compare to

Question 14

What is the green form system?

Answer 14

• Reporting limited to a small number of (usually new) drugs
• Recording any significant medical event that occurs whilst patient taking drug
• Potential to find rare + unusual side effects that may be ignored by individual doctors
• Numerator + denominator data are available - all patients monitored
• Return of forms can be poor

Question 15

How does grapefruit juice lead to increased bioavailability of a drug and hence potentially more ADRs?

Answer 15

• Grapefruit juice inhibits cytochrome P₄₅₀ enzymes in liver
• Prevents metabolism of drugs
• Inhibits P-glycoprotein transporters in intestine
• Prevent excretion of drugs into intestine
• Increased bioavailability (undesirable)
• More ADRs