Adverse Drug Reactions

Question 1

What factors can affect the concentration of drug reaching the tissues?

What factors can affect the response of the target tissues to the same degree of stimulation by the drug?

Answer 1

Absorption
Distribution
Metabolism
Excretion

of the drugs

Receptor sensitivity
Number
Distribution

of the target sites

Question 2

Why might the dose of drug taken by a patient differ from that intended by his or her physician?

Answer 2

Communication error
Prescription error
Dispensing medication by pharmacist error
Lack of patient compliance / non-compliance - often due to fear of side effects or result of depressed / confused mental state
Addiction
Patient may take correct dose but it may not be absorbed due to interaction with food in the stomach e.g. bisphosphonates used to treat osteoporosis = useless if taken with food or milky drinks as they are chelated by calcium, magnesuium and iron
Drug interactions
Cyt P450

Question 3

Case 1 - 72M
PMH = A. fib that cannot be converted back to sinus rhythm with usual drug treatment
Has now suffered a small ischaemic stroke

GP has prescribed warfarin to thin his blood - dose arranged according to his clotting time

But has now developed a chest infection and is given clarithromycin for 1 week

This treated the infection but he has severe nosebleeds and bruising

What has caused the adverse drug reaction and what is the drug mechanism?

Answer 3

Adverse drug interaction between clarithromycin and warfarin

Clarithromycin increased the anticoagulant affects of warfarin

Maybe the Clarithromycin made the warfarin dose stronger

Clarithromycin blocks the enzyme Cytochrome P450 responsible for breaking down warfarin - increases the half life of warfarin

So more warfarin remains in his system = increased plasma levels of warfarin = greater anticogulant effect of warfarin = excessive bleeding

Question 4

What other drugs may produce a similar affect?

Answer 4

Other antibiotics of the same class i.e. macrolides e.g. erythromycin
Some antibiotics of other classes e.g. quinolones like ciprofloxacin
Systemic antifungal drugs e.g. fluconazole
PPIs (proton pump inhibitors) - for peptic ulcers e.g. omeprazole
Some anti-HIV drugs e.g. protease inhibitors

Question 5

Several months later, 72M’s INR has fallen sharply
[INR = international normalised ratio]
He requires a much higher dose of warfarin

Tells Dr he felt depressed, so he has been taking St. John’s Wort which contains hyperforin (anti-depressant?) that he buys form a food health shop

What is INR, how is it measured and what does a fall in INR signify?

Answer 5

INR = international normalised ratio = standardised measure of blood clotting time

INR = take blood sample from patient to calculate the ratio of a patient’s prothrombin time (test) to a control (‘normal’) sample, raised to the power of ISI (international sensitivity index) value for the tissue factor used (usually 0.94-1.4)

So INR = [PT(test) / PT (normal)]^ISI

Fallen INR = increased clotting and reduced bleeding
Increased INR = decreased clotting and increased bleeding

Normal range is between 0.9-1.2

But the recommended INR for patients with A. fib = 2.0-3.0

So if his INR decreases below 2, his thrombosis risk increases, and if it increases above 4, his serious bleeding risk increases

‘natural’ products = potent effects on enzymes, pathways etc.

Question 6

Why might self-medication using St. John’s Wort be relevant to the change in warfarin requirement?

Answer 6

St. John’s Wort = widely used as a self administered antidepressant (hyperprofin), but also contains the compound hypericin, which is an inducer of cytochrome P450

This increases the metabolism of warfarin = reduced plasma warfarin levels = effect of warfarin at current dose is less effective

Question 7

What other drugs may cause a similar adverse effect?

Answer 7

There are fewer enzyme inducers than inhibitors, but other drugs that have a similar Cyt P450 inducing effect =
Rifampicin - antibiotic used in TB therapy (onset/duration of induction can depend on half-life)
Carbamazepine and phenytoin, as well as older and largely obsolete antiepileptic drugs phenobarbitone and primidone
Griseofulvin (antifungal drug)

Question 8

Follow up of 72M, his A fib has been controlled using a combination of digoxin and a beta-blocker (bisoprolol)

BUT his regular check-up shows his ventricular rate has increased

A solution may be to increase the dose of digoxin

But what is the most important blood test that should be checked first and why?

Answer 8

Must check blood tests for current K+ levels because:

Digoxin binds to the Na+/K+ ehange ATPase on cardiac myocytes and nodal tissue
Competes with K+ for its binding site
So if blood tests show low plasma K+ levels (hypokalaemia) means more digoxin binding = less competition by K+ at binding side
So increasing dose of digoxin = enhaced therapeutic and adverse effects leading to heart block
Therefore must FIRST sort out hypokaelemia before increasing digoxin dose

BUT if there is hyperkalaemia, it may indicate kidney disease = reduced clearance = more digoxin levels = increased digoxin levels

Question 9

How else could you try to ensure that the dose of digoxin is correct?

Answer 9

So you may need to also measure digoxin levels in the plasma directly (plasma digoxin levels) and see if it is within the target range

Question 10

Some months later, 72M complains for anxiety and poor sleep at night

GP prescribes benzodiazepine, Temazepam

After first dose, his wife reports confusion overnight - this has never happened with their 45F daughter who takes the same pill

Temazepam withdrawn immediately, everything else unchanged

The folowing year, 72M becomes depressed again and his appetite deteriorated - lost nearly 10kg and is reluctant to consider antidepressants

His INR has increased significantly although his warfarin treatment is unchanged

What might be the reason for his confusion?

Answer 10

Pharmokinetics = what the body does to the drug
Metabolism by liver of some drugs is reduced in older patients - so more temazepam remains in the plasma

Pharmacodynamic = what the drug does to the body i.e. intensity of the drug effect in relation to its concentration in a body fluid, usually at the site of drug action

Older patients may have increased sensitivity to drugs even if metabolism is normal - this may be due to changes in receptor number or function, or some other mechanism(s)

Question 11

Why might 72M’s INR be increasing again? (i.e. less clotting, more bleeding)

Answer 11

Metabolism of many drugs affected by malnutrition

Malnutrition is very similar to a drug which inhibits cyt pathway (e.g. clarithromycin) = more warfarin remains in the plasma

Malnutrition also decreases plasma protein levels (warfarin is heavily plasma protein bound) - so if there are fewer plasma proteins, there’s less binding of warfarin so more warfarin activity

With malnutrition, there is also:

- decreased oxidative metabolism (warfarin is metabolised by oxidation)
- decreased GFR

All of which would increase likelihood of an adverse drug reaction

Question 12

Why can the desired and unwanted responses to any given drug vary between individuals?

Answer 12

1. Absolute differences in dose administered

2. Relative overdose or underdose

Question 13

What are some causes of difference in dose administration?

Answer 13

Error in prescription or dispensing
Patient non-compliance
Drug formulation

Question 14

What are some factirs that can result in a relative over or underdose?

Answer 14

1. Environmental exposure to chemicals, including other drugs
2. Food intake
3. Fluid intake
4. Age
5. Disease

Question 15

How can environmental exposure to chemicals, including other drugs lead to a relative over or underdose?

Answer 15

Enzyme induction

Enzyme inhibition

Question 16

How can food intake lead to a relative over or underdose?

Answer 16

Drugs may interact chemically with components of food; this may alter their absorption
Foods delay gastric emptying and alter gastric pH

Question 17

How can fluid intake lead to a relative over or underdose?

Answer 17

Most drugs are better absorbed if taken with water e.g. may dissolve better
Fluids may stimulate gastric emptying

Question 18

How do newborns differ from adults that lead to a relative over or underdose?

Answer 18

Newborn infants have:
More body water than adults
Poorer renal function, with immature tubular secretion
An immature blood brain barrier
Lower capacity for drug metabolism

Question 19

How do the elderly differ from younger adults that lead to a relative over or underdone?

Answer 19

The elderly have an overall deterioration in many physiological functions that may affect:

i) Drug absorption:
- Decreased absorptive surface of small intestine
- Altered gastric and gut motility
- Increased rate of gastric emptying

ii) Drug distribution:
- Reduced lean body mass and body water, relative increase in fat
- Lipid soluble drugs have increased Vd and decreased blood levels
- Water soluble drugs have decreased Vd and increased blood levels
- Reduced plasma albumin, so fewer plasma protein binding sites

iii) Drug metabolism:
- Splanchnic and hepatic blood flow decrease by 0.3 – 1.5%/year
- Liver size and hepatocyte number decrease
- Hepatic enzyme activity and induction capacity decrease

iv) Drug excretion:
Changes in renal function are probably the most important factors affecting drug handling in the elderly. With age there is a steady decline in the following factors:
- Reduced renal mass
- Reduced renal perfusion 
- Reduced glomerular filtration rate
- Reduced tubular excretion

These changes are normal – the situation may be compounded if the patient has renal disease.

v) Organ sensitivity:
The elderly tend to be more sensitive to CNS active drugs

Question 20

How can disease lead to a relative over or underdose?

Answer 20

i) General nutritional status
- Unbalanced diets may lead to deficiency states and enzyme abnormalities
- Starvation – decreased plasma protein binding and metabolism
- Obesity – increased lipid fraction

ii) Gastrointestinal disorders e.g. achlorhydria, coeliac disease, Crohn’s disease
- Altered drug absorption

iii) Congestive heart failure (especially in the elderly) may lead to:
- Reduced splanchnic blood flow
- Intestinal mucosal oedema
- Reduced hepatic clearance

iv) Kidney failure (especially in the elderly) may lead to:
- Decreased drug excretion leading to toxicity
- Water overload leading to changes in drug concentrations in different body fluid compartments

v) Liver failure may lead to:
- Reduced metabolism
- Reduced first pass metabolism (hence increased bioavailability)
- Decreased biliary secretion and hence decreased removal
- Decreased albumin synthesis and hence reduced plasma protein binding

vi) Other acute or chronic disease states