BMS2043 - Therapeutic Drug Monitoring & Substance Abuse Investigation (PDF)

BMS2043- ANALYTICAL AND CLINICAL BIOCHEMISTRY THERAPEUTIC DRUG MONITORING DR PENNY LYMPANY [email protected] 28AY04 OBJECTIVES Definition of TDM Principles Applications Examples WHAT IS TDM? Drug measurements in body fluids – aid to patient management Optimise treatment Routine in labs since 19...

BMS2043- ANALYTICAL AND CLINICAL BIOCHEMISTRY THERAPEUTIC DRUG MONITORING DR PENNY LYMPANY [email protected] 28AY04 OBJECTIVES Definition of TDM Principles Applications Examples WHAT IS TDM? Drug measurements in body fluids – aid to patient management Optimise treatment Routine in labs since 1970s If dose does not have desired effect – twice is better? Not necessarily! Clinical response  concentration at site of action FACTORS AFFECTING DRUG AVAILABILITY Source: Ayala N., Keil D Therapeutic Drug Monitoring. Clinical Chemistry: Principles, Techniques and Correlations, Eds. Bishop, Fody, and Schoeff. Philadelphia: Lippincott Williams & Wilkins, 7th ed Refer to the lecture on drug metabolism! THERAPEUTIC WINDOW Lag period ?loading dose Duration of action When to take a sample? PEAKS AND TROUGHS THINGS TO CONSIDER Drug at site of action or compartment Dosing regimen Compliance Dosing - ?errors Physiological differences – body mass Drug interactions Pharmacokinetics Clinical effects Drug receptor status Genetics Drug Interactions Tolerance Pharmacodynamics 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 metabolism close to max capacity of enzymes involved (zero order kinetics) QUALITY CONTROL What is quality control? Procedures to confirm validity of biochemical results Monitoring analytical performance Internal QC – controls, reproducibility (drift) External QC – EQA e.g. UKNEQAS QC – MORE INFORMATION 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 This Photo by Unknown Author is licensed under CC BY-NC-ND This Photo by Unknown Author is licensed under CC BY-SA-NC 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 PATIENT GROUPS Renal &hepatic impairment (drug/metabolite accumulation) Dialysis and hemofiltration patients (increased elimination) Patients with uncompensated cardiac dysfunction Patients with air way disease Diabetic patients Obstetric patients Geriatric patients Paediatric patients (especially neonates) obese/undernourished patients Burns patients. CF 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 Digoxin – cardiac glycoside - CHF – affected by serum electrolytes, hyperthyroidism – immunoassay Quinidine – trough level monitoring – immunoassay Procainamide – cardiac arrhythmia – altered renal/hepatic function affects conc. Antibiotics- aminoglycosides Anti-epileptic drugs Phenobarbital – hepatic metabolism – administered as pro-drug primidone Phenytoin – seizures Psychoactive drugs Lithium TCAS Immunosuppressive drugs e.g. cyclosporin Anti-neoplastics e.g. methotrexate DRUGS REQUIRING TDM – EXAMPLE - AMINOGLYCOSIDE Aminoglycoside antibiotics are used to treat bacterial infections e.g. streptomycin specifically target aerobic gram-negative bacteria - inhibit protein synthesis Very poor oral absorption - wide distribution occurs Little or no binding to plasma proteins – low Vd (0.25 L/kg) Not metabolised - excreted almost entirely into urine by GF Elimination half-life 2-3 hours approx. 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 Ototoxicity – generate free radicals in inner ear – damage to sensory cells and neurones – mild reversible hearing loss This Photo by Unknown Author is licensed under CC BY-SA DRUGS OF ABUSE Misuse of therapeutic drugs Performance enhancement – athletic Professional, industrial settings Medicolegal DRUGS OF ABUSE - EXAMPLES Amphetamines used clinically for narcolepsy, ADHD Initial well-being, followed by restlessness and possible psychosis Measurement – liquid chromatography, GC Anabolic Steroids clinical application male hypogonadism Increase muscle mass, improved athletic performance Cannabinoids – marijuana THC most abundant Metabolite in urine 3-5 days after single use GC/MS This Photo by Unknown Author is licensed under CC BY-NC-ND Cocaine high conc. CNS stimulation – excitement and euphoria GC/MS Opiates analgesia, sedation, anaesthesia GC/MS This Photo by Unknown Author is licensed under CC BY-NC-ND CLINICAL BIOCHEMISTRY – CONT MYOCARDIAL INFARCTION & CLINICAL DIAGNOSIS MYOCARDIAL INFARCTION TIMELINE Atherosclerotic plaque build-up in coronary artery Rupture of the plaque Thrombus formation – prevents blood flow Damage to heart tissue (myocardium) This Photo by Unknown Author is licensed under CC BY CLINICAL ENZYMOLOGY OF MYOCARDIAL INFARCTION Creatine kinase (CK) – sensitive but non-specific Aspartate aminotransferase (AST) (also in liver) Lactate dehydrogenase (LDH) – not specific to heart This Photo by Unknown Author is licensed under CC BY-NC CREATINE KINASE VS. TROPONIN Because blood specimens may be taken at different times after the onset of infarct, the enzyme test most appropriate may vary. Creatine kinase is the test of choice. LDH & CK – isoenzyme pattern FABP & troponin more sensitive LDH ISOENZYME PATTERNS BIOCHEMICAL MARKERS FOLLOWING AN MI LIVER FUNCTION TESTS AND ATHEROSCLEROSIS LIVER FUNCTION TESTS (LFT) Total protein (serum) Albumin Globulins A/G ratio (albumin-globulin) Protein electrophoresis Urine protein Bilirubin: direct + indirect = total Aspartate transaminase (AST) Also marker of liver injury? Alanine transaminase (ALT) Gamma-glutamyl transpeptidase (GGT) Alkaline phosphatase (ALP) LIVER FUNCTION TESTS: BILIRUBIN glucuronyltransferase UDP-glucuronosyltransferases Tsai and Tarng 2018 Int. J Mol Sci, 20, 117 ATHEROSCLEROSIS & CHOLESTEROL http://en.wikipedia.org/wiki/Ath erosclerotic_plaque CHOLESTEROL AND OTHER LIPIDS ARE CARRIED ON LIPOPROTEIN PARTICLES Lipids carried through the plasma via lipoproteins surface is made of protein (called apolipoprotein) and a phospholipid monolayer interior contains cholesterol, TAGs, and cholesteryl esters, which are more nonpolar than cholesterol Apolipoprotein B-100 (apoB-100) is one of the largest single polypeptide chains known FOUR MAJOR CLASSES OF LIPOPROTEIN MOLECULES TABLE 21-1 Major Classes of Human Plasma Lipoproteins: Some Properties Composition (wt %) Lipoprotein Density (g/ml) Protein Phospholipids Free cholesterol Cholesteryl esters Triacylglycerols Chylomicrons 11 mM (hyperglycaemia) Low blood [glucose]: < 4 mM (hypoglycaemia) GLUCOSE TOLERANCE TEST KETOACIDOSIS Image adapted from University of California, San Francisco, USA, 2016. TYPE 2 DIABETES A heterogeneous group of syndromes characterised by an elevation of fasting blood glucose caused by a relative deficiency in insulin. INSULIN RESISTANCE AND TYPE 2 DIABETES INSULIN RESISTANCE Peripheral tissues, such as muscle and adipose tissue, lose the ability to uptake plasma glucose efficiently at physiological concentrations of insulin. pancreas secretes more insulin to compensate. OVERLOADING ADIPOCYTES ? ANY QUESTIONS? We made it! This Photo by Unknown Author is licensed under CC BY-SA Please use the discussion board for general questions and queries