Therapeutic Drug Monitoring (DONE)

Question 1

Practical approach to TDM

Answer 1

Principles in common:
Initial dosage selection- use a mix of characteristics and parameters to recommend dosage regimen
Determine when appropriate for blood sampling
Is the measured concentration consistent with the predicted PK?
If regimen needs to be changed, use blood samples

Question 2

Purpose of TDM

Answer 2

To confirm effective concentration
To investigate unexpected lack of efficacy
To check compliance
To avoid or anticipate toxic concentrations
Before increasing to unusually large doses
Limited role in toxicology

Question 3

TDM general considerations

Answer 3

Relates concentrations of drug in blood to anticipated therapeutic response
Blood concentrations surrogate for concentrations at the site of action- basis of PK
Principle for those drugs subjected to TDM is that drug concentration correlates better with drug effect than does dose to drug effect

Question 4

When to use TDM?

Answer 4

Dose cannot be titrated against response or it is dangerous to do so
Narrow therapeutic window/index
Toxic effect that is related to concentration and not easily identified or differentiated early by clinical signs
Recognised inter-individual variability in PK
The drug is being used to prevent infrequent occurrences
Blood concentrations can be accurately reliably measured

Question 5

PK considerations

Answer 5

Is the aim to provide constant concentrations e.g. digoxin, anticonvulsants
Is the aim to achieve transient high concentrations without toxicity
Are drug concentrations likely to vary greatly between individuals on the same dose e.g. phenytoin

Question 6

Lithium - TDM

Answer 6

Used for bipolar disorder
Toxic- neurological, cardiac, renal
Narrow therapeutic range- chronic concentrations of 3.0 mmol/L are potentially lethal
Renal clearance of Li can be affected by diuretics and NSAIDs

Question 7

Phenytoin - TDM

Answer 7

Variable dose dependent kinetics
Most metabolised through CYP 450s
Concentration related CNS toxicity can be partly avoided by TDM
Severe skin rashes, liver and marrow toxicity cannot be predicted or avoided
With phenytoin, small dose increases can produce disproportionate rises in blood levels and toxicity
Sometimes free unbound concentrations need to be measured e.g. hypoalbuminaemia, pregnancy

Question 8

Digoxin - TDM

Answer 8

Variable bioavailability
Variable clearance by kidney- elderly
Drug interactions are fairly common
Relationship between concentration and effect not constant
Patients may become more sensitive to a given concentration
In AF titrate against the ventricular rate
Concentrations should be measured at least 6-8 hours after the last dose

Question 9

Cyclosporin - TDM

Answer 9

Used as immunosuppressant in transplant rejection
Low therapeutic index, toxicity (kidney) is severe
Interactions are common e.g. calcium channel blockers
Plasma range 50-300 mg/L

Question 10

Theophylline - TDM

Answer 10

Declining use in asthma
Very narrow therapeutic index
At the high end toxicity is common
Toxicity is severe- GI, neuro, cardiac
Interactions are common- erythromycin, cyclosporin, cimetidine, smoking

Question 11

Gentamicin - TDM

Answer 11

Practice is changing- trend to once daily dosing

Toxicity relates to trough concentrations, particularly with prolonged therapy

Question 12

Paracetamol

Answer 12

Most common agent for intentional self harm
Ca 100-150 deaths p.a. from paracetamol
Hepatic necrosis to fulminant liver failure to death
Toxicity associated with metabolism of paracetamol

Question 13

Paracetamol overdose

Answer 13

More paracetamol is shunted to the CYP 450 system to produce NAPQI
Hepatocellular supplies of glutathione become depleted, NAPQI reacts with cellular membrane molecules, resulting in hepatocyte damage and death

Question 14

Overdose and therapeutic excess

Answer 14

Acute overdose- intentional ingestion of an overdose within a 1 hour period
Patients at risk- treatments that include P450 enzymes , carbamazepine, phenytoin, rifampicin, regular alcohol consumption, malnourished, fasting, chronic alcoholism
Staggered overdose- intentional ingestion over more than 1 hour
Obesity- care not to underestimate a mg/kg dose that is potentially toxic

Question 15

Paracetamol legislation and pack sizes

Answer 15

In 1998 UK legislation introduced to reduce paracetamol pack size sold OTC, restricted to a maximum of 32 in pharmacies and 16 in non-pharmacy outlets
43% reduction in estimated deaths in England and Wales over the immediate 11 years following new legislation