Week 7 - Clinical Biochemistry Flashcards
What is TDM?
- Drug measurements in body fluids – aid to patient management
- Optimise treatment
- Routine in labs since 1970s
MTD
max. tolerated dose
MED
min. effective dose
MED
min. effective dose
bioavalability
how much of drug that is available when body gets intravenous and where
Therapeutic window
in-between MTD and MED
What are the 3 things to consider when choosing drug dosage?
- dosing regimen
- drug at site of action or compartment
- clinical effects
Things to consider - Pharmokinetics
compliance
dosing
physiological differences- body mass
drug interactions
Things to consider - Pharmacodynamics
drug receptor status
genetics
drug interactions
tolerance
PHARMACOKINETICS
Bioavailability
First pass metabolism
Distribution – solubility – lipid or water
Volume of distribution – theoretical value
Metabolism/excretion
Clearance – body weight, renal/hepatic function
Elimination rate
Plasma protein binding – bound - inert
PHARMACODYNAMICS
Relationship between drug concentration and effect
Receptors – pathological condition, other drugs
Most drugs have a linear relationship between dose and plasma conc.
Some exceptions – phenytoin – rate of mettabolism close to max capacity of enzymes involved (zero order kinetics)
What is quality control?
Procedures to confirm validity of biochemical results
Monitoring analytical performance
Internal QC – controls, reproducibility (drift)
External QC – EQA e.g. UKNEQA
QC - Levey-Jennings chart
Results expected to be =/- 2SD from mean
Trend – 6 or more showing consecutive move in same direction (up or down)
Shift – 6 or more results on one side of the mean
QC PARAMETERS
- All laboratory trimmed means (ALTM) – remove top & bottom 5% of results – target value
- Bias - % deviation from target value
- Rolling bias – mean of current and previous 5 results
- Rolling variability – mean of current and previous 5 results (ignoring direction)
- Bias index score (BIS) – comparison of deviation from target
- Overall lab performance – mean of BIS for all analytes
- Method bias – mean from ALTM for each method
INDICATIONS FOR TDM
Suspected toxicity due to drug or metabolite – overdose
A sub therapeutic response of a drug – dosage, dialysis, nonadherence,
disease state
Assessment of potential drug interactions
Assessment of therapy when the patient is clinically unstable or has organ
damage
Assessment of therapy following initiation or change of regimen
Evaluation of patient compliance
Narrow therapeutic index
A high incidence of adverse effects
SUSPECTED TOXICITY DUE TO DRUG OR METABOLITE
Too much of a drug – intentional or not
Dose too high
Liver/kidney damage – metabolism/excretion
Drugs with lower therapeutic index
Examples
Levothyroxine
Carbamazepine
Digoxin
Lithium carbonate
Warfarin
POTENTIAL DRUG INTERACTIONS
Example – digoxin
Unexpectedly high [digoxin] – interaction with amiodarone, quinidine, verapamil
Serum concentrations of hepatically cleared drugs affected by drugs which include or inhibit cyt P450
THE ASSESSMENT OF THERAPY WHERE THE PATIENT IS CLINICALLY UNSTABLE
Cancer treatment – cancer drugs represent a challenge – toxicity/lack of
specificity – optimal dose narrow range
TDM NOT REQUIRED
- Drugs with broad therapeutic index
- Toxicity is not a realistic concern (Penicillin)
- Effects can be measured using functional laboratory tests (Anticoagulants)
- Plasma concentration not predictably related to effects(anticoagulants)
- “Hit and run drugs”: Omeprazole, MAO inhibitors.
DRUGS THAT REQUIRE TDM - GENERAL
Cardioactive drugs
Antibiotics- aminoglycosides
Anti-epileptic drugs
Psychoactive drugs
Immunosuppressive drugs e.g. cyclosporin
Anti-neoplastics e.g. methotrexate
Cardioactive drugs
- Digoxin
–> cardiac glycoside - CHF – affected by serum electrolytes, hyperthyroidism – immunoassay - Quinidine
–> trough level monitoring – immunoassay - Procainamide
–> cardiac arrhythmia – altered renal/hepatic function affects conc.
Anti-epileptic drugs
Phenobarbital
– hepatic metabolism – administered as pro-drug primidone
Phenytoin
– seizures
Psychoactive drugs
- Lithium
- TCAS
DRUGS REQUIRING TDM – EXAMPLE - AMINOGLYCOSIDE - WHAT DOES IT TREAT?
Aminoglycoside antibiotics are
used to treat bacterial infections e.g. streptomycin
DRUGS OF ABUSE
Misuse of therapeutic drugs
Performance enhancement – athletic
Professional, industrial settings
Medicolegal
How do aminoglycoside antibiotic kill bacteria?
specifically target aerobic gram-negative bacteria - inhibit protein synthesis
Aminoglycoside absorbtion
very poor oral absorption
- wide distribution occurs
How much does aminoglycoside bind to plasma?
little or no binding to plasma protein
Is aminoglycoside metabolised?
no
- its excreted almost entirely into urine by GF
Aminoglycoside Half-Life
elimination half-life of 2-3 hours approx
Aminoglycoside Distribution
Distributed by active transport to renal transport cells
- accumulates in the
kidney causing nephrotoxicity
- Main toxic effect within the tubular cell by altering phospholipid
metabolism - Also cause renal vasoconstriction
AMINOGLYCOSIDE- Ototoxicity
– generate free radicals in inner ear – damage to sensory cells and
neurones
– mild reversible hearing loss
Amphetamines - Drug Abuse
- used clinically for narcolepsy, ADHD
- Initial well-being, followed by restlessness and possible psychosis
- Measurement – liquid chromatography, GC
Anabolic Steroids - Drug Abuse
- clinical application male hypogonadism
- Increase muscle mass, improved athletic performance
Cannabinoids – marijuana - Drugs of Abuse
- THC most abundant
- Metabolite in urine 3-5 days after single use
- GC/MS
Cocaine - Drugs of Abuse
- high conc. CNS stimulation – excitement and euphoria
- GC/MS
Opiates - Drugs of Abuse
- analgesia, sedation, anaesthesia
- GC/MS
How do liver enzymes play a role in terms of liver damage?
When your liver gets damaged or a part of the liver gets damaged, it’ll release enzymes into the bloodstream.
What enzyme is used as a biomarker of prostate cancer?
acid phophotase
