Therapeutic Drug Monitoring - NO L.O.s Flashcards
Define therapeutic drug monitoring.
The individualisation of dosage by maintaining plasma or blood drug concentrations within a target range (therapeutic range, therapeutic window).
What is the difference between pharmacokinetics and pharmacodynamics?
PHARMACODYNAMICS = “what the drug does to the body” PHARMACOKINETICS = “what the body does to the drug”
There are two major sources of variability between individual patients in drug response. What are they?
• Dose and plasma concentration (pharmacokinetic
variability)
• Drug concentration at the receptor and the response
(pharmacodynamic variability)
What does (CL) ADME stand for?
- Compliance
- Liberation
- Absorption
- Distribution
- Metabolism
- Elimination
How does time to be absorbed differ for the IV and PO routes?
IV seconds vs PO hours
Describe first pass metabolism.
Oral medication goes through intestinal tract –> portal vein to the liver –> hepatic vein through systemic circulation –> hepatic artery to liver
I.e. goes through the liver before reaching systemic circulation
What is a ‘prodrug’?
ACTIVE DRUG
What is an ‘active drug’?
inactive or active metabolite
Drugs pass into tissues after absorption. The amount varies from tissue-to-tissue. What does this depend on? (2)
Lipophilicity
Protein binding
What does the Volume of Distribution (Vd) describe?
Use low Vd and high Vd to explain.
This partitioning between blood and tissues, i.e. low Vd mainly in blood and high Vd mainly in tissues (“lipid loving”)
What factors influence Vd? (3)
- Body fat levels
- Tissue perfusion
- Plasma protein levels
What is phase I metabolism in terms of reactions? (5)
Oxidation, reduction, methylation, deamination,
hydroxylation
Includes metabolism by cytochrome P450 enzymes
What is phase II metabolism?
Conjugation
What is meant by pharmacogenomics?
Relates to the effect of genes on drug handling by the body, and drug response
Various genetic differences may account for changes in metabolism, for example genetic polymorphisms can effect drug concentration and effect, and predisposition to toxicity
Define a genetic polymorphism.
A variation in nucleotide sequence occurring at a frequency of greater than 1%
Use the example of isoniazid and genetic polymorphisms.
N-acetylation - can be fast or slow acetylators eg, slow acetylator will not metabolise isoniazid and thus risks isoniazid toxicity
What does elimination depend on? (4)
- Renal function
- Liver function
- Genetics
- Drug interactions
Define first order kinetics.
Rate of elimination proportional to amount of drug
Define zero order kinetics and give three drug examples.
Rate of elimination independent to the amount of drug (e.g. ethanol, phenytoin, salicylates) - a constant amount of drug is eliminated per unit time
Define capacity-limited kinetics.
Rate of elimination changes from first-order to zero-order as a result of saturation of elimination mechanisms
Which is better - TDM or monitoring response?
If the clinical effect can be readily measured (e.g. heart rate, blood pressure), it is obviously better to adjust the dose on the basis of response. This forms the majority of drugs.
What are the major sources of pharmacokinetic variability?
- Compliance
- Age – neonates, elderly
- Physiology – gender, pregnancy
- Disease – hepatic, renal
- Drug interactions
- Genetic polymorphisms of drug metabolism
How can variability in the pharmacokinetic phase of drug action be greatly reduced?
TDM
Name some high/wide therapeutic index drugs. (4)
- NSAIDs
- Benzodiazepines
- Antibiotics (except some)
- Beta blockers
Name some low/narrow therapeutic index drugs. (5)
- Anti-epileptics e.g. valproate, phenytoin
- Lithium
- Antibiotics eg. Gentamicin, vancomycin, amikacin
- Digoxin
- Immunosuppresives e.g. ciclosporin, tacrolimus
Which requires TDM - low or high therapeutic index drugs?
Low/narrow
TDM is useful when there is a marked pharmacokinetic variability and in drugs with a narrow therapeutic index. When else is it useful?
- Drug used prophylactically
- Drug dose and blood levels have poor relationship
- Inter-individual variation
- Avoid serious toxicity
- Subtherapeutic levels or toxic levels have serious effects
- Complex drug-drug interactions
- Desired therapeutic effect difficult to monitor
- Toxic effects similar to disease effects
- Clinical presentation may be similar to toxicity
For TDM what do you need? (4)
- To know the therapeutic and toxic range
- Be able to measure drug levels accurately
- The blood levels should reflect efficacy and toxicity
- Alteration in dosage possible
There are two major important principles in using therapeutic ranges. What are they?
- Most drugs’ responses are graded responses and are continuous through the concentration range.
- Individual patients will have individual therapeutic ranges.
Name some commonly monitored drugs.
- Digoxin
- Aminophylline
- Phenytoin
- Carbamazepine
- Lithium
- Gentamicin, Amikacin, Vancomycin
- Ciclosporin
What information is necessary for TDM?
Demographics - Age, gender
Clinical and Reason for request e.g. lack of effect, routine monitoring, suspected toxicity
Adequate sample
Right time – relation to last dose
Sample when steady state achieved (not always)
Duration of treatment with the current dose
Dosing schedule
Right lab analysis eg, HPLC,RIA
Last dose – how much and when
Other medications
When is the least variable point in the dosing interval?
the pre-dose or trough concentration
When should samples be collected for drugs with short half lives?
What about drugs with long half-lives e.g. phenobarbitone or amiodarone?
samples should be collected pre-dose
samples can be collected at any point in the dosage interval
With monitoring digoxin, when should samples be collected?
any point after the distribution phase (after 6 hours post-dose)
There are two important factors which can make
interpretation of a result difficult in some cases. What are they?
Changes in:
• Protein binding
• Active metabolites
What can change protein binding? (3)
disease states, displacement by another drug or non-linearity in protein binding
For example, the therapeutic range for phenytoin based on total drug concentration is 10-20 mg/L which corresponds to an unbound drug concentration of…?
1-2 mg/L (fraction unbound is normally 0.1).
How is fraction unbound of phenytoin affected in renal disease?
How does this affect the target range?
Increased from 0.1 to 0.2
5-10mg/L
Metabolites which may not be measured can contribute to the therapeutic response. Use imipramine and amitriptyline as examples.
The therapeutic ranges for imipramine and amitriptyline are based on the combined concentrations of parent drug and active metabolite (desipramine and nortriptyline respectively).
GENTAMICIN - what type of antibiotic is it?
Aminoglycoside
Gentamicin works via ________ dependent killing.
Concentration
What is the peak level of gentamicin?
What is the trough level?
Peak = 5-12 mg/L Trough = <1 mg/L
What is the toxic level of gentamicin (mg/L)?
12-15
Side effects of gentamicin. (3)
- Damage to the cochlear and vestibular apparatus –> loss of balance, tinnitus, loss of hearing
- May cause renal damage - risk of nephrotoxicity is increased with prolonged treatment.
- May cause allergic reactions, nausea, vomiting and rashes.
Gentamicin is highly hydrophilic - what does this mean for distribution?
How does this affect calculating the appropriate dose?
Not distributed into body fat and minimally distributed into tissue fluids.
When calculating an appropriate dose, consider using the patient’s lean mass (mass without excess fat = ideal body weight).
Where is gentamicin excreted?
What type of kinetics?
Gentamicin is excreted unmodified, by the kidneys and so follows “first order kinetics”.
How often is gentamicin given? (2)
Once daily – if normal renal function
Multiple daily dosing – in endocarditis
If giving gentamicin once daily, when do you need to check level?
How often do you check trough level if renal impairment?
After 3 doses
Daily
For multiple daily dosing of gent, what levels do you measure/when?
Peak levels after 3 rd dose and trough level before next dose
What is phenytoin?
Order of kinetics?
Anticonvulsant
Zero order
Therapeutic range of phenytoin?
Toxicity level?
8-15 mg/L
> 20 mg/L
Symptoms of phenytoin toxicity?
- Nystagmus
- Blurred vision
- Ataxia
- Drowsiness
- Coma
- Seizures
Therapeutic range of digoxin? Toxicity?
1 – 2 mcg/L
Toxicity: >2 mcg/L
Symptoms of digoxin toxicity?
- Arrhythmias
- GIT symptoms: nausea. vomiting
- CNS symptoms: visual disturbances
- Weakness
- Lethargy
How is digoxin monitored?
Trough sample at least 6 hours after dose
What are digoxin levels affected by?
- RENAL IMPAIRMENT,
- DRUGS, SUCH AS, AMIODARONE,
- LOW POTASSIUM (increases the affinity of digoxin for its receptor)
