Therapeutic Drug Monitoring Flashcards
What is therapeutic drug monitoring?
- The use of drug measurements in body fluids to aid the management of drug therapy for the cure, alleviation, or prevention of disease
- Aims to aid clinicians in choice of drug dosing to provide optimum treatment for the patient and avoiding iatrogenic toxicity
When is the use of Therapeutic Drug Monitoring valid?
- Poor correlation between dose and effect
- Good correlation between plasma drug concentration and effect
- Narrow concentration interval between therapeutic and toxic effects
- Absence of good clinical/laboratory markers of effect
Why is Poor correlation between dose and effect important for TDM?
- For many drugs, dose is the primary determinant of effect. Standard doses can be used to titrate and TDM not required
- TDM of benefit where there is poor correlation between dose and effect i.e. where there is wide inter-individual pharmacokinetic (movement of drugs within the body) variation
Why is good correlation between plasma drug concentration and effect important in TDM?
Essential requirement for valid TDM! Concentration must give accurate information about the biological effect/toxicity of the drug
A close concentration-effect relationship requires:
- Little between-individual pharmacodynamic variation such as relationship between the concentration of the drug at its site of action and its effect
- No active metabolites that contribute to effect that are not measured by the assay (e.g. carbamazepine)
- Reversible mode of action at the receptor site (e.g. valproate)
Kinetic homogeneity”: Assumption that pharmacological response of drug is correlated to its concentration at the site of action, and that this is in turn related to its plasma concentration
Why is Narrow concentration interval between therapeutic and toxic effects important in TDM?
Therapeutic index = the margin between the therapeutic dose and the toxic dose – the higher (or wider) the better
- Many drugs where TDM is used have a low (narrow) therapeutic index – margin between desirable and toxic dose is small
- Symptoms of disease and of toxicity are hard to distinguish
- Efficacy of the drug is hard to assess clinically
TDM unnecessary for drugs with a high therapeutic index as its is safe to use at much higher doses than required
Essential that a well-defined therapeutic range exists!
Why is Absence of good clinical/laboratory markers of effect important for TDM?
- No point undertaking TDM if desired/toxic effects of drugs can be assessed via clinical assessment/laboratory tests
- Examples: Antihypertensives (blood pressure), Statins (Lipids), Oral hypoglycaemic drugs (Glucose/HbA1c), Warfarin (INR)
- Rare circumstances where TDM may be useful if drug not providing expected clinical effect e.g compliance issues or poor absorption/receptor dysfunction
What are indications for Therapeutic Drug Monitoring?
- Avoidance of toxicity: Toxicity is a clinical syndrome, not diagnosed by TDM but knowledge of drug concentration in plasma often valuable especially where the drug and the condition give similar features
- Dosage adjustment: Especially where pharmacokinetics changing
- Compliance checking: With care (the pharmacokinetic variability that makes TDM useful may provide a range of results )
- Establishing a baseline: To ensure sufficient drug is reaching receptor to produce desired effect and relating this dose to a plasma concentration
What are some patient information requirment for Therapeutic Drug Monitoring?
- Patient: Age, Gender, Renal/hepatic function, Symptoms
- Clinical indication: I.e. compliance/control/toxicity
- Drug: Dose, Length of treatment, Time of dose, Other drugs
- Sample: Time collected
What are the appropriate samples used for TDM?
Serum/plasma samples most commonly used in TDM
Timing of sample of critical importance
- Steady state concentrations of drugs most informative
- Often trough (pre-dose) samples used
- Exception = suspected overdose/toxicity
What are some factors that infleunce Acucurate analysis fo drugs?
- Requirement for specificity is crucial: Should ideally detect all pharmacologically active substances
- ‘Older’ drugs tend to be measured by immunoassay. Homogenous immunoassays have rapidly increased use of TDM such as FPIA, EMIT, CEDIA, KIMS etc
- ‘Newer’ drugs often measured by chromatography such as GC-MS, HPLC, LC-MS
How can results for TDM be interperated?
Requires knowledge of pharmacokinetics/dynamics of individual drugs from both the biochemist and the clinician.
Needs to be in response to a well formulated question
The aim of TDM is NOT to get drug concentrations into a nominal ‘target’ range
- Ranges are adjunctive to clinical judgement and do not replace it
- Optimum drug levels vary from patient to patient
Treat the patient and not the concentration
What are the indications, dose, mode of action, measurement and sampling time for Lithium?
- Indication: Prophylaxis/treatment of bipolar disorder and mania and Refractory depression
- Dose: Orally as lithium salts (carbonate) (1/2 day)
- Mode of action: Unclear – modulates neurotransmission
- Measurement: Direct ISE or colorimetric assays
- Sampling time: 12 hours post dose in steady state
What is the pharmacokinetics of Lithium?
- Renally excreted
- Not bound to plasma proteins
- Evenly distributed throughout body water
- Accumulates in brain, kidney, thyroid
- Thiazide diuretics and NSAIDs reduce clearance
What is the target range for Lithium?
- Levels up to 1.2 mmol/L in acute therapy
- 0.6 – 0.8 suggested NICE target in long-term treatment
- 0.4-1.0 mmol/L as standard target
Lower levels in elderly and higher in younger or acute cases
How can Lithium lead to diabetes insipidus, hypothyroidism and hyperparathyroidism/hypercalcaemia?
Diabetes Mellitus
- Due to lithium accumulation in renal tubules – leads to ADH resistance
- Common renal SE of lithium tx
Hypothyroidism
- Inhibits release for thyroid hormones – mechanism poorly understood
- Often associated goitre (~40%) and hypothyroidsim (~20%)
- Hypothyroidism is often mild/subclinical
- Less commonly associated with hyperthyroidism
Also (rarely) hyperparathyroidism/hypercalcaemia
- Likely due to an increase at which calcium supresses PTH release
What are side effects of Lithium?
- Toxicity
- Chronic lithium therapy associated with hypothyroidism and diabetes insipidus (DI)
- Also (rarely) hyperparathyroidism/hypercalcaemia
How can lithium be toxic?
Highly toxic and has narrow therapeutic range
- Acute toxicity: Ataxia, confusion, tremor, muscle weakness, seizures, slurred speech, renal damage.
- Levels >1.5 mmol/L require urgent review
- Levels >3.0 mmol/L can be fatal even in patients maintained on Lithium
- Treated with dialysis if severe
Chronic accumulation worse than acute toxicity (TDM essential)
- Declining renal function leads to greatest danger of toxicity.
- Lithium deposits in brain, thyroid, kidneys.
What are the indications, dose, mode of action, measurement and sampling time for digoxin?
- Indication: Chronic cardiac failure and atrial flutter/fibrillation
- Dose: Orally (typical maintenance dose 125ug) or IV for emergency loading
- Mode of action: Cardiac glycosid. It binds Na-K ATPase pump of cardiac myocytes – to inhibit it. Increased intracellular Na concentration causes increased intracellular Ca2+, which increases cardiac contractility
- Measurement: Immunoassay
- Sampling time: 6 hours post-dose
What is the target range for Digoxin?
- 0.9 – 2.0 ug/L typical reference range
- 0.5 – 1.0 ug/L recommended by UK Pathology Harmony
What are Pharmacokinetics of Digoxin?
- Mostly renal excretion
- Around ¼ protein bound
- High Vd and renal excretion means long half-life
- Several drug interactions that affect absorption, binding, clearance
What are factors that that are related to toxicity of digoxin?
Toxic effects digoxin related to
- Concentration – more likely >2ug/L
- Age
- Degree of heart failure
- Electrolyte imbalances (hypokalaemia potentiates digoxin toxicity, also hypercalcaemia, hypomagnesaemia)
- Care in elderly and impaired renal function
