TDM Therapeutic Drug Monitoring Goal of TDM is to use appropriate concentrations of difficult to manage medications to optimize clinical outcomes in patients in various clinical situations

TDM Clinical practice of measuring specific drugs at designated intervals to maintain a constant concentration in a patient’s blood stream Used for Drugs that have narrow therapeutic ranges, marked pharmacokinetic variability and have adverse effects.

Pharmacokinetics Relationship between drug dose and blood drug level Mathematical formula that takes into consideration the Absorption Distribution Metabolism Excretion

Absorption Route of Drug administration such as Enteral (by mouth), Parenteral (by Injection), or Pulmonary, Rectal or Topical. First-Pass Effect Drugs given by mouth must first go to the stomach and then intestine. They then go to the LIVER where metabolism or biliary excretion may occur before going to the general circulation. https://www.youtube.com/watch?v=xiuWdJYyIKs

Absorption Rate at which a drug leaves its site of absorption Rate is affected by area of absorbing capillary membranes and solubility in interstitial fluid pH Physical Factors such as Blood Flow or total surface area available

Distribution Blood Flow Drugs first go to the well perfused organs such as liver, kidney and brain and then to muscles, skin, fat and viscera Capillary permeability Tissue Volume Binding of drugs to Proteins Note We typically measure total drug present but what counts is the total unbound drug. Patients with low Albumin levels will have more unbound drug available Unbound = Free= Pharmacological Effect

Metabolism Biotransformation Biotransformation reactions generate more polar inactive metabolites which are readily excreted from the body and usually involve enzymes Liver is a major site of drug biotransformation Cytochrome P450 major enzyme system involved

Excretion Once drugs are in water soluble form they are excreted by KIDNEYS in URINE Also excreted in feces, bile, and Breast milk

Elimination Half Life The time it takes for an amount of drug in blood to decline to one-half its measured value The following conditions may increase half life of a drug Decreased renal blood flow (heart disease, shock) Addition of second drug which displaces it from its carrier protein Decreased metabolism (hepatic insufficiency)

Steady State In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is fairly in dynamic equilibrium with its elimination. In practice, it is generally considered that steady state is reached when a time of 4 to 7 times the half-life for a drug after regular dosing is started.

Steady State

Specimen and Collection Tubes Serum is specimen of choice for most drugs Plasma is OK for some drugs Whole Blood may be used for some example cyclosporin A Whole blood specimens may require preanalytical treatment which increases turn around time and may introduce error

Peak and Trough Peak levels need to be drawn when the drug is at its highest concentration Will vary by drug Trough levels are drawn immediately before the next dose and is the lowest concentration *Documentation of dosage and sample draw times are critical Antibiotic medication such as aminoglycosides are monitored for trough levels

Drug groups Group What they do Examples Comment Antibiotics Prevent growth of microorganisms Amikacin, gentamicin, tobramycin, vancomycin Toxic to Ear and Kidney Creatinine and BUN Antiepileptic Control seizures Phenobarbitol, Dilantin, Valproic acid, Carbamazepine(Tegretol) Antihypertensives Lower blood pressure Sodium Nitroprusside Metabolite is thiocyanate which should be regularly monitored

Drug groups continued Group Antineoplastic Reduce tumor growth Methotrexate Toxic to bone marrow and intestine Rescue drugs administered Narrow therapeutic range and many side effects Antipsychotic Mania and depression in bipolar disorders Lithium Make sure collection tube does not contain Lithium Levels above 1.5 mmol/L are considered toxic Bronchodilators Asthma Theophylline Cardioactive Drugs Heart Failure Digoxin, Procainamide, Quinidine, Lidocaine Procainamide Lidocaine also anesthetic Immunosuppressive Transplante Cyclosporine, Tacrolimus

Analytic Techniques Earliest methods were RIA and chromatography EMIT introduced in the 1970’s Immunoassay is now used on most major automated instruments