My Clinical Notes

• Reasons for drug monitoring;
  • To check compliance – patient is taking the drug as prescribed
  • Dose is sufficient to produce the required effects and unlikely to cause toxic effects
  • To determine the type of drug(s) taken in a suspected overdose and assess the need for treatment

 

Criteria to be satisfied for tdm;

• If the desired result cannot be measured precisely e.g. the incidence of epileptic fits is a poor indicator of the optimal dosage of anticonvulsants
• If the range of plasma levels that is most effective in producing the desired result without toxic side effects has been defined and there is a narrow margin between therapeutic and toxic drug concentrations e.g. digoxin and lithium
• If the prescribed drug is the main active compound and is not metabolised significantly to an active metabolite (otherwise the active metabolite could be measured)

 

• Most drugs are taken in doses and at intervals such that a steady state plasma concentration is achieved, this occurs after a period of around 5 half lives. This is the most relevant concentration to measure
• Some drugs with short half lives have significant fluctuations in plasma concentration and it is the peak and trough concentrations taken just after or just before the drug is taken that are measured

 

The following factors may affect the blood concentration of some drugs

• Patient compliance – assay of plasma concentrations is a crude method of assessing compliance and only tests the situation at the time the blood was taken
• The entry of drugs into, and distribution through, the extracellular fluid;
  • Absorption can be affected by;
    • How lipid soluble the drug – the more so the more rapidly absorbed
    • The timing of ingestion in relation to meals
    • The rate of gastric emptying – e.g. during treatment with drugs that affect gut motility or after gastric surgery
    • Vomiting, diarrhoea and malabsorption syndromes
    • The administration of other compounds such as the bile acid sequestrants which may also bind certain drugs in the intestinal lumen
  • Volume of distribution
    • May be difficult to predict the appropriate dose of a drug in oedematous or obese patients
    • In small children with a low volume of distribution there may be a danger of overdose
    • Therefore the patients weight or surface area may need to be taken into account when dose is calculated
  • Binding to plasma albumin
    • Most drug assays estimate the total concentration of free plus protein bound drug
    • There is no valid correction factor which allows for protein abnormalities and all drugs bind proteins at different proportions
    • Binding may be affected by;
      • Abnormalities in plasma albumin concentration e.g. hepatic cirrhosis and nephrotic syndrome
      • Competition for binding sites of proteins
        • Many drugs, unconjugated bilirubin and hydrogen ions compete for binding sites
  • Metabolism and excretion of drugs
    • Blood concentration depends upon normal renal and hepatic function and acid-base and electrolyte balance
      • The rate of elimination of most drugs depends upon plasma concentration – a small increase in the dose of phenytoin may exceed the capacity of metabolic or excretory pathways causing a disproportionate rise in plasma levels – this is termed saturation kinetic
    • Metabolic conversion to active or inactive metabolites
    • Drug-drug interactions
      • One drug may alter the plasma concentration of the other, by altering its binding to plasma proteins, rate of metabolism or rate of excretion
    • Tolerance
      • Some drugs may induce the synthesis of enzymes that inactivate them
      • There may be reduced receptor sensitivity requiring high doses for the therapeutic effect
    • Patient variations
      • Rate of metabolism depends on the age of the patient
        • Premature infants have immature detoxifying mechanisms so metabolise drugs more slowly
        • Children have a high metabolic rate than adults so eliminate some drugs more rapidly
        • Elderly metabolise drugs more slowly
      • Genetic and racial factors
      • Metabolic factors
        • There is increased sensitivity to digoxin with hypercalcaemia and hypokalaemia

 

Examples of drugs monitored routinely

 

Antibiotics

• Unlike most other antiobiotics, aminoglycosides such as gentamycin have a narrow therapeutic range
• Toxic levels may cause ototoxicity or nephrotoxicity
• Measurement is indicated in infection is particularly severe or if treatment is prolonged
• Aminoglycoside concentrations are measured twice – first sample is taken before injection (trough) to ensure the concentration is not already high that it is likely to cause toxicity or so low as to be ineffective
• The second measurement is taken about 1 hour after injection (peak) to ensure an adequate concentration have been reached for antibacterial action
• Two glycopeptide antibiotics, vancomycin and teicoplanin may also cause nephrotoxitiy and ototoxicity so require their levels to be measured too
•  

 

Digoxin

• Used in CCF and AF
• Estimation of plasma concentrations are useful in the following situations;
• To assess compliance – elderly patients taking multiple medications may get confused
• In patients such as the elderly who have a low threshold for toxicity and in premature infants who have an increased elimination time
• When it is difficult to calculate the appropriate dose because of an abnormal vol of distribution e.g. obesity, oedema or in infants
• If excretion is impaired e.g. due to renal dysfunction
• If the patient is taking another drug such as amiodarone which my reduce its rate of excretion
• Plasma digitoxin levels are difficult to interpret in the presence of conditions which alter the receptor sensitivity e.g
  • Stimulatory factors
    • Hypercalcaemia
    • Hypokalaemia
    • Hypomagnesaemia
    • Hypoxia
    • Hypothyroidism
  • Inhibitory factors
    • Hypocalcaemia
    • Hyperthroidism
• Features of toxicity include nausea, vomiting and dysrhythmias
• Blood for sampling should be taken 6 hours after the last dose – absorption and distribution should be complete
• Important to check potassium levels and renal function
• Assay of digitoxin can be problematic as the antibodies used may cross react with certain endogenous substances (so called digoxin like immunoreactive substances). This may occur in pregnancy
• Digoxin overdose/toxicity can be treated by administration of inactivating digoxin antibodies (digibind)

 

Lithium

• Used for treatment of bipolar disorders
• Narrow window between therapeutic and toxic concentrations, therefore required to monitor regularly
• Take sample 12 hours after evening dose
• Not protein bound so not complicated by protein abnormalities
• Associated with hypothyroidism
• High levels may be nephrotoxic
• Oligouria and acute renal failure can reduce lithium clearance
• Therefore monitor thyroid and renal function

 

Antiepileptic drugs

• Once therapeutic concentrations have been reached, it is only necessary to monitor dose in the following cases;
  • To assess compliance
  • If the frequency of fits increases in a previously well controlled patient
  • If the clinical picture suggests toxicity
  • If another drug is prescribed that may affect plasma concentrations
• Plasma concentrations in pregnant women and children should be measured more frequently as they are more likely to develop toxicity

 

Phenytoin

• Inhibits voltage gated Na channels and is used in the treatment of partial and generalized tonic clonic seizures
• Measurement is useful as;
  • It exhibits saturation kinetics – relationship between plasma concentration and dose is non-linear
  • It is displaced from its binding sites by sodium valproate
  • It is a potent enzyme inducing drug and may enhance the metabolism of other drugs as well as causing increases in γ-GT (doesn’t necessarily mean abnormal hepatic toxicity)
• Signs of toxicity may mimic the neurological disease that can be associated with epilepsy

 

Carbamazepine

• Inhibits voltage gated Na channels – used for partial and generalised tonic clonic seizures
• It can also be used in the treatment of trigeminal neuralgia, prophylaxis for bipolar disorder and diabetic neuropathy
• It has an active metabolite formed in the liver
• It induces its own metabolism and thus plasma concentrations may fall at the end of the first month of therapy which results in the need for a dose increase

 

Valproate

• Used to treat myoclonic seizures, generalised absence seizures and partial and generalised tonic-clonic seizures
• Plasma concentrations correlate poorly  with the dose prescribed, the clinical response and toxicity, probably because of the presence of active metabolites
• Therefore the only reason for tdm is to assess compliance
• Valproate is hepatotoxic, therefore check LFTs

 

Cyclosporine

• Immunosuppressant the inhibits T cell activation by binding to calcineurin phosphatase
• Used to prevent organ rejection
• Dosage is difficult to assess as there is much variation among individuals in the rate of absorption and clearance and there is a narrow margin between therapeutic and toxic drug concentrations
• The main toxic effect is on the kidney but hepatic dysfunction can also occur
• Measuring the plasma concentration can help to distinguish between drug toxicity and rejection of a grafted kidney

 

Theophylline

• Bronchodilator used in the treatment of asthma and neonatal apnoea
• At toxic doses causes cardiac dysrthymias
• Patients requiring IV theophylline for an acute asthma attack may already be treated with the oral preparation and thus have the drug in their blood  - requiring plasma conc to be rapidly measured
• In infants the drug is used as a respiratory stimulant – significant metabolism to caffeine occurs. Both theophylline and caffeine should be assayed to order to assess therapeutic or toxic eddects
• The half life of theophylline is shortened in smokers

This entry was posted on Wednesday, March 26th, 2008 at 7:36 am and is filed under Chemical Pathology. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.