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Clinicians are frequently asked to monitor the effects of drug treatment with the objective of ensuring safe and effective
therapy. In this issue we present the first in a series of articles which focus on optimal monitoring of drug treatment.
Monitoring takes many forms and there is evidence that in many situations it is done inappropriately (too much or too
little or at the wrong time) or not targeted at specific parameters that are clinically useful. A New Zealand study showed
that over 50% of serum digoxin concentrations were not taken at the correct time to allow meaningful interpretation of
the result, and 5% of the measurements led to inappropriate dose adjustments.1 Other studies have shown excessive
and unnecessary monitoring of antiepileptic drug concentrations and we now know that routine monitoring of CK and liver
function tests in people taking statins is unnecessary. On the other hand, failure to check the CBC in a person taking
clozapine or not attaining therapeutic drug concentrations in a person taking lithium can have severe consequences. Monitoring
is also much more than objective laboratory testing as it often includes the participation of the patient by their informed
reporting of signals of clinical response or adverse drug reactions.
Despite comprising at least 30 - 40% of all blood tests in general practice,2 monitoring is relatively poorly
studied and is often associated with non-specific and even vague guidelines. Improvements in monitoring by clinicians
and patients are likely to improve benefits, reduce adverse events and reduce costs.
Some examples of monitoring include:
- Monitoring laboratory tests (e.g. LFTs, CBC) to check for early signs of an adverse drug reaction.
Objective monitoring for adverse effects
- Monitoring drug concentrations (e.g. digoxin, lithium) to attain therapeutic response without dose related toxicity,
or to confirm compliance.
- Monitoring for signs or symptoms which may be indicative of a side effect or adverse drug reaction, e.g. delirium
or constipation with a tricyclic antidepressant, or muscle pain with a statin.
Subjective monitoring for adverse effects
- Monitoring biochemical markers as a response to treatment and/or toxicity, e.g. lipid profile with statins, INR with
warfarin, TSH with thyroxine.
- Monitoring clinical response to treatment, e.g. preventers and relievers in asthma therapy.
This article provides a general introduction to some of the principles of monitoring the response to drug therapy in
order to ensure optimum response without significant adverse effects. In future issues suggested monitoring strategies
will be described for specific drug and therapeutic categories.
An overriding principle of monitoring is that there should be justification and some degree of assurance that the practice
will actually meet the objectives the test. Furthermore, the test must be correctly performed, e.g. in the right time
frame, and be interpreted correctly to be meaningful.
Monitoring Strategy (adapted from Glasziou et al2)
- Is the test a good predictor of relevant clinical outcomes or adverse effects?
Will routine monitoring of CBC detect drug-induced agranulocytosis? Are clinical symptoms more reliable?
- Can the test detect changes in risk early?
Is the CBC likely to pick-up on a downward trend in the blood count as an early sign of the problems?
- Is there an optimum interval for monitoring?
Is the blood dyscrasia more likely to occur within a certain timeframe that may dictate the duration of monitoring?
- Is random testing useful or can it be made acceptable by repeated measurements?
What is the value of a one-off CBC? Is there any value in monitoring more frequently?
- Is the test accessible and acceptable to patients and cost effective for health care providers?
If checking the CBC is very unlikely to detect an outcome is it worthwhile?
- Are there any additional risk factors which provide further justification for testing?
Will a history of blood dyscrasias or concurrent use of a medicine with a similar adverse effect profile provide
justification to change the monitoring parameters?
Objective monitoring for adverse effects.
Many drugs have laboratory monitoring recommendations mentioned in their data sheets. However, if the above criteria
are applied the supporting evidence for many monitoring schedules is relatively weak. In addition, vague statements such
as periodic checking of liver function or occasional checking of electrolytes are generally unhelpful as they lack precise
“Know the abnormality that you are going to follow
during treatment. Pick something you can measure.”
Meador C. A Little Book of Doctors’ Rules.
Lyons: IARC Press, 1999
The antithyroid drug carbimazole can cause agranulocytosis but this is relatively rare and it usually occurs rapidly
without an indicative downward trend in the blood count. Therefore a routine CBC every few months or random testing are
very unlikely to identify the event. Early signs of infection such as a sore throat or fever are much more reliable predictors
of agranulocytosis so the emphasis should be placed on educating the patient on early warning signs rather than blood
In contrast clozapine induced agranulocytosis is much more common, usually occurs early in treatment and can often be
detected early by regular blood tests which can show a downward trend in the neutrophil count. More is known about the “natural
history” of clozapine induced agranulocytosis which justifies the rigorous and specific monitoring regimen.
If the effect is relatively common, such as hypothyroidism induced by lithium, regular measurement of TSH is justified
as the condition can be detected before significant symptoms appear allowing the introduction of thyroid replacement therapy
or an alternative drug.
Monitoring drug concentrations
Therapeutic drug monitoring (TDM) by measuring serum concentrations is useful for a relatively small range of drugs
that meet specific criteria. For most drugs, the serum concentration does not correlate well with therapeutic effect and
treatment is guided solely by clinical response. For drugs that do have a good correlation between concentration and effect,
TDM can assist monitoring and guide dose adjustment in addition to assessing clinical response.
Generally, criteria for TDM are as follows:
- There is a narrow range between a sub-therapeutic serum drug concentration (SDC) and a toxic SDC. This is referred
to as the drug’s therapeutic range.
- There is a predictable relationship between the SDC and therapeutic or toxic effects.
- The measurement of SDC must be better or enhance other methods of monitoring.
- There is an unpredictable relationship between the dose administered and the SDC.
- There is a suitable assay for the drug.
Lithium is a good example where TDM is useful if not essential for optimal treatment. Serum lithium concentrations are
clearly related to clinical effect; if the concentration is too low a clinical response is unlikely but if the concentration
is too high the risk of toxicity is increased. The range that includes clinical response without toxicity is the therapeutic
concentration range. Unfortunately, due to interindividual variability in drug handling, it is not possible to accurately
predict what lithium concentration will be attained from any given dose. Therefore TDM can be used to titrate the initial
dose to give a target drug concentration and the dose can be further adjusted according to clinical response or adverse
effects. If response is sub-optimal, the SDC may guide the magnitude of a dose increase without significant risk of adverse
effects. Subsequently, measurement of SDC can be used to check compliance or assess the impact of drug interactions that
may change lithium concentrations. Other drugs which are candidates for TDM include digoxin, some antiepileptic drugs,
theophylline and some antibiotics. In future issues specific monitoring strategies will be discussed.
Subjective monitoring of adverse effects
Patients and carers should be informed about what to look for and report early signs of possible adverse effects. This
has to be done in the context of explaining the benefits of treatment.
A person taking a statin should be informed to report myalgia especially if this is of sudden onset, is severe or worsens
or appears with an increase in dose. A subsequent check of the CK may indicate the need to reduce the dose or consider
alternative treatment. In this case subjective reporting of symptoms may indicate the potential value of an objective
The situation with statins is well known but it should be realised that all drugs have adverse effects that are potentially
preventable if the early warning signs are recognised. Many adverse effects are very predictable as they are dose related
and an extension of the drug’s pharmacological effect.
Advice directly to the patient about what to look for, or a simple note in the patient’s records, can be valuable
in detecting adverse effects at an early stage and possibly preventing more serious consequences. For example, if a patient
in residential care is prescribed haloperidol for psychoses and agitation, a flag can be made in the patient’s notes
to “monitor” for common adverse effects such as constipation and hypotension. Early identification of these
effects can reduce drug related morbidity.
Some examples of subjective monitoring parameters with possible causes and action points are given in Table 1. This
will be expanded in future issues.
: Some examples of subjective monitoring parameters with possible causes and action points
|Drug or drug class
||Monitoring parameter, possible cause and action.
|Drugs causing leucopenia
||Infection, sore throat, fever
|Drugs with anticholinergic effects
||Constipation, urinary retention, drowsiness
Reduce doses or modify drug treatment
||Postural hypotension, dizziness; especially on diuretics.
Modify doses or drugs, check electrolytes
|Serotonin Re-uptake Inhibitors
||Agitation and restlessness in early treatment. Dose may be too high or drug unsuitable.
Reduce dose or change drug. Review diagnosis.
||Darkened stools may indicate GI bleeding.
Check for blood in stools. CBC.
||Changes in vision, especially colour vision may indicate digoxin toxicity or hypokalaemia
Check serum digoxin concentration, renal function and electrolytes
||Ataxia may indicate toxicity due to high blood concentrations.
Check serum concentration of phenytoin and compliance
||Intractable cough – may indicate pneumonitis
- Sidwell A, Barclay M, Begg E, Moore G. Digoxin therapeutic monitoring; An audit and review. NZMJ;2003:116:U704
- Glasziou P, Irwig L, Mant D. Monitoring in chronic disease: a rational approach. BMJ 2005;330:644-648