S3: Drug Safety and Drug Side Effects

Question 1

What is the difference between a poison and a remedy with drugs?

Answer 1

All drugs are poisons and have the ability to be toxic.

Question 2

What is an adverse drug reaction (ADR)?

Answer 2

An ADR is an undesirable effect of a drug beyond its anticipated therapeutic effects. The WHO define it as a noxious and unintentional drug effect.

Question 3

Describe type A ADR

Answer 3

Type A is also called pharmacological.

• These are ADRs that are predictable from knowledge of the drugs pharmacodyamics and pharamacokinetics i.e. the ADR is a consequence of the drug action.
• These are the most common type of ADR.
• They are often dose dependent but are usually not life threatening.
• This type of ADR can usually be stopped by lowering the dose or withholding treatment.
• The drug reactions are generally picked up and understood during the drug testing and are not thought to be severe enough to withdraw the drug from the market.

Question 4

Describe type B ADR

Answer 4

Type B ADRs are idiosyncratic or bizarre side effects.

• These effects are not related to the dose of the drug and are unrelated to the known pharmacology of the drug (not related to their mechanism of action to our knowledge). This makes them difficult to predict.
• They often involve the immune system or genetic abnormality making reactions more likely to be fatal.
• If type B ADR occurs, the drug must be withdrawn and not used again.
• Due to the nature of the effects they are unlikely to be picked up during the drug testing, there needs to be widespread use of the drug in the population to identify these Type B ADRs. This is why you need monitoring throughout giving the drug to the general population (pharmacovigilance) to see if these reactions occur.

Question 5

Describe type A NDRs for NSAIDs

Answer 5

NSAIDs adverse effects include: GI bleeds, peptic ulcers, renal impairment and bronchospasm.

• This is due to COX inhibition in order to reduce prostaglandins which signal pain so NSAIDs reduce pain but also reduce the protective effects of PGs in the gut so bleeds are more likely.
• PGs are also bronchodilators so you don’t want them to be reduced in those with ashthma.
• PGs also involved in renal dilatation so reduced PG can lead to poor kidney blood flow causing renal issues.

Question 6

Describe type A NDRs for diuretics

Answer 6

Diuretic adverse side effects include: Hypotension, dehydration, electrolyte changes.
- Again all of these are predictable because they produce vasodilatation and a lot of fluid excretion.

Question 7

Describe type A NDRs for opioids

Answer 7

Opioids adverse effects include: vomiting, confusion, constipation, urinary retention, respiratory depression (overdose).
- This is due to stimulation of opiate receptors, so too much stimulation can cause these effects.

Question 8

Describe type A NDRs for insulin/oral hypoglycaemia drugs

Answer 8

Insulin/Oral hypoglycaemic drugs can lead to hypoglycaemia.

- If you give insulin wrongly it can lead to excess glucose uptake and storage making the person hypoglycaemic.

Question 9

Why are type B ADRs really dangerous?

Answer 9

• These are the unpredictable, hypersensitivity type reactions.
• Importantly they can lead to anaphylactic shock which is life-threatening. This is because in anaphylactic shock a huge amount of histamine is released resulting in bronchospasm and constriction. It can also cause a huge drop in BP. Together this means you can’t perfuse your vital organs (e.g. brain) properly leading to death.
• e.g. Amoxicillin (a broad-spectrum penicillin) is an example of a drug that is linked to hypersensitivity reactions, as well as anti-convulsants.

Question 10

What is Steven Johnson syndrome?

Answer 10

It is a very dangerous type B ADR which is rare, sever and hard to predict.
- We think it is linked to genetics and the infection a person may have at the time and or poor liver metabolism of drug metabolites.
- It starts with flu-like symptoms and high fever, the immune system gets initiated which starts attacking cells causing blistering of the skin and mucous membranes.
The skin gets attacked and the epidermis gets separated from the dermis, so the skin essentially falls off.

Question 11

How do drugs induce hypertsensitivity reactions? Use penicillin as an example

Answer 11

• The mechanism is not fully known.
• Drugs tend to be small molecular weight substances (<200 mw), this is good as they are small enough to get pass our immune system undetected.
• If the drug is big, then our immune system may identify it and start breaking down the drug triggering an immune response.
• So we try to keep drugs small when developing them.
• However, with some drugs e.g. penicillin (low mw) can bind to plasma proteins which increases its molecular weight. This is called a hapten which is immunogenic and means the immune system sees it as a foreign body and therefore triggers an immune response.
• If this has happened before, you have primed mast cells which then dump a load of histamine causing anaphylactic shock.
• It could be genetic factors that leads to plasma proteins that bind/don’t bind penicillin, this may be the reason why some people are allergic and some aren’t. It’s dependent on the type of plasma proteins they produce.

Question 12

Describe ADR due to chronic drug administration

Answer 12

• Some drugs must be taken in the long term, like corticosteroids for arthritis, lupus, IBS. This can overtime lead to thinning of the skin, buffalo hump, osteoporosis.
• These are predictable drug effects but are quite severe, however here it’s not as simple as just withdrawing the drug or lowering the dose because we are dealing with a chronic condition.
• There is a balance between benefit and risk of these type A reactions.

Question 13

Explain options for reducing and avoiding ADR

Answer 13

• Minor type A reactions may be tolerable, such as indigestion with NSAIDs. So you explain to the patient taking the NSAIDs for the arthritis does seem to outweigh a bit of indigestion.
• Another option is we continue to treat using the drug at hand (e.g. opiates for pain relief) but then treat the ADR with another drug (the constipation caused by the opiates we treat with another drug).
• Sometimes the patient may have to simply “accept” more severe ADRs based on the risk-reward balance. An example would be alopecia caused by chemotherapy (by the cytotoxic drugs), the risk is cancer being untreated or losing your hair. It is an important balance.

Question 14

What do healthcare professionals need to do to reduce/avoid ADR in patients?

Answer 14

• Be wary of vulnerable groups of people and drugs that are likely to cause interactions e.g. those with comorbidities, the elderly, the young.
• Getting a good history is essential to find out if there has been any previous drug reactions e.g. allergies.
• Must keep up to date with drug information via BNF, as this is being updated all the time, especially if certain drug is still being monitored.
• Report problems ASAP.

Question 15

What is pharmacovigilance?

Answer 15

Pharmacovigilance is about monitoring the safety of drugs and it enables the clinician/patient to balance risk and reward. Benefit should always exceed risk.

Question 16

What can pharmacovigilance lead to?

Answer 16

• A drug being withdrawn from the maket.
• Contraindications identified, so drug is no longer given to people with x, y, z.
• Warnings may be given.
• There can be dose changes, seen in the BNF.

Question 17

Describe the thaliomide incident in 1961

Answer 17

• Thalidomide was used to treat morning sickness in pregnant women, however it was identified there was a link between women taking thalidomide having children with physical abnormalities like polydactyl (more than 5 digits), syndactyl (fusion of 2 or more digits) and phocomelia (short arm/leg bones). 10,000-20,000 people were affected.
• Thalidomide wasn’t initially tested on pregnant animals, therefore the teratogenic effects of the drug were missed.
• This led to new safety procedures to prove efficiency and reveal all side-effects in testing.

Question 18

What is the three tier system for monitoring ADR in the UK?

Answer 18

• Yellow card
• Black triangle
• Green form

Question 19

Describe yellow cards

Answer 19

• Yellow cards are a way of monitoring ADRs after the drug has gone to market. They are the main method of post-marketing surveillance.
  s anyone can fill in the yellow form, doctors or patients, forms are available online, from the BNF etc.
• However a problem with this system is it only gives us the number of ADRs for that drug, it doesn’t tell us about the number of people taking the drug.
  Because of this it’s difficult to ascertain how much of a problem these ADRs are in the general population.

Question 20

What are black triangles?

Answer 20

Drugs that a very new to the market will often have a black triangle on them. Therefore special caution should be taken when prescribing the drug, there should be close monitoring of the drug. This is because the trials may not have picked up the rarer side effects.

Question 21

Describe the green form system

Answer 21

• The green form system is that anyone who is taking a new drug you may set up a green form for them. This means that anything that happens to that person medically during the time they are taking it, then you record it. This gives the potential to find rare and unusual side effects that may be ignored by individual doctors.
• We get a numerator and denominator, as we have picked up the patients taking the drug and the ADRs that are being suffered from. Hence all patients taking the drug are monitored. This is a big positive.
• However return of forms can be poor, which is a weakness of the green card system.

Question 22

Explain the Northwick Park Hospital Disaster 2006

Answer 22

• There was a phase I trial going on, this is where you give a dose of the drug that seems to be relatively safe, just to see what happens when you give it to a human being. You’re not seeing its efficacy, just whether it is safe!
• 6 men were given a monoclonal antibody to stimulate T-lymphocytes. They were given a subclinical dose (500x less than what was shown to be toxic in animals).
• All participants reported severe ADRs and went into organ failure. One lost fingers and toes, all are now at high risk of cancer and autoimmune diseases.
  This is because the drug caused a “cytokine storm”, there was a huge increase in immune cells that released loads of cytokines and this crashed the immune system.
• The actual dosage was safe, but the problem is thought to be that the drug was given too fast.

Question 23

Describe pharmakinetic drug interaction and ADR with grapefruit juice as an example

Answer 23

A drugs’ ADME has a profound effect on the way that drug behaves, but it also has a profound effect on how other drugs behave that are given at the same time. Because of this if more than one drug at a time is being taken, there can be interactions between the drugs reactions.

• An example is grapefruit juice.
• Grapefruit juice inhibits cytochrome P450 enzymes in the liver, P450 are extremely important in metabolism of drugs. Grapefruit juice also inhibits P-glycoprotein transporters in the intestine, these transporters usually excrete drugs into the intestine so they leave the body in the faeces.
• This means grapefruit juice prevents/reduces the ability to breakdown drugs and also prevents excretion of drugs into the intestine.
• This means if you are taking grapefruit juice at the same time as this drug, then the drug concentration will increase. This can potentially .lead to more ADRs, as same dosage is no longer appropriate because it isn’t being excreted.

Question 24

Describe pharmakinetic drug interaction and ADR with diuretics and lithium as an example

Answer 24

• Diuretics are used for heart failure, hypertension etc. and work by blocking exchangers in the kidney. They also interfere with excretion of lithium which is used to treat bipolar disorder.
• This can lead to lithium toxicity.