toxicology TDM

• therapeutic drug monitoring ( TDM) • ID of drugs in acute intoxication • Urine testing for drugs of abuse or performance enhancers • testing for environmental or occupational exposure

analysis, assessment, and evaluation of circulating concentrations of drugs in Serum, Plasma, or Whole blood

ensure drug dosage is within the Therapeutic Range - The range that produces the maximum therapeutic benefit identify when the drug is outside of the therapeutic range • Too low - drug inefficiency • Too high - toxicity Not used for all drugs

• Drugs with low therapeutic index (ie. Narrow range between therapeutic and toxic levels) • Start or change in therapy • Neonates/ infants due to maturing renal and hepatic functions • During illness • When a drug is unexpectedly ineffective or toxic • When a new drug is added due to possible drug interactions

• Route of administration ( ex. orally, muscular injection) • Rate of absorption • Distribution of the drug within in the body • Metabolism ( liver) • Rate of elimination (kidney)

Only free drug can give a biologic response Not protien bound drug

study of the biochemical and physiological effects of drugs and the mechanisms of their actions

site at which a drug acts to initiate a specific biological effect Drug action is usually mediated through receptors such as cellular enzymes and structural or transport proteins

activity or fate of drugs in the body over a period of time. • Takes into account all of the factors that determine concentration of a serum drug level (absorption, distribution, metabolism and excretion). • Assists the health care provider in establishing or modifying a dosage regimen for each patient. • Uses mathematical modelling to determine the drug concentration in circulation Drug concentrations will swing back and forth between a maximum (peak) and minimum (trough) concentration level. Goal: • To get the peak and trough levels within the therapeutic range. • To make sure the peak is not in the toxic range

intake and elimination of a drug are in equilibrium 5 to 7 doses of a drug are usually required to achieve a steady state

Physiological Factors: • Absorption into blood (IV, IM, orally) • Distribution in body tissues • Metabolism by liver • Excretion by the kidney • Maturation or aging • Organ disease (liver & kidney esp.) • Diurnal variation (daily fluctuations) • Drug interactions Non-physiological Factors: • Drug formulation • Medication Errors • Patient compliance

A- Absorption D- Distribution M-Metabolism E- Excretion

intravenous ** -most direct & effective delivery to sites of action intramuscular (IM) injection Subcutaneous (SC) injection Transcutaneous • absorbed through skin • ex. transdermal patch rectal delivery • ex. suppository • used in infants or when oral delivery is not possible Oral administration ** • Most common method • Least invasive

efficiency of absorption from GI tract depends on: • Dissociation from its administered form • Solubility in gastrointestinal fluids • Diffusion across gastrointestinal membranes

• Tablets and capsules must dissolve before being absorbed * Liquid solutions absorbed more rapidly

• Weak acids are absorbed well in stomach (due to gastric acidity) • Weak bases best absorbed in intestine (pH is more alkaline)

Absorption occurs in predictable manner in healthy people • Absorption rates can be altered by changes in: • Intestinal mobility • pH • Inflammation • Presence of food or other drugs Absorption rates can also be affected by: • Age • Pregnancy • Pathologic conditions

The bioavailability is the fraction of a drug dose that is absorbed into the systemic circulation **In order to be useful, a drug’s bioavailability needs to be greater than 70%

Drugs administered orally are absorbed in the small intestine and are carried by the portal vein directly to the liver. • Some drugs have a high hepatic excretion rate whereby low amounts reach the systemic circulation (low bioavailability). first-pass effect - extensive metabolism of a drug with a high hepatic extraction rate by the liver before it reaches systemic circulation

• Drug distribution occurs after a drug enters the vascular department. • Many drugs bind to protein in the blood • Acidic drugs are primarily bound to albumin • Basic drugs are primarily bound to globulins

Only the free (unbound) fraction of drug can interact with the site of action & cause biologic response. • Free drug is also termed active Percentage of free drug depends on physiologic & biochemical parameters: • Inflammation, malignancies, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, acid– base disturbances • Concentration of other substances competing for binding sites (eg. other drugs, urea, bilirubin, hormones) Example: Phenytoin • In a healthy individual: 90% bound; 10% free • In uremic patients: 20-30% free • Drug dose would need to be adjusted in uremic patients

All substances absorbed from intestine enter hepatic portal system Metabolism involves the biotransformation and excretion of the drug Rate of metabolism can vary between different patients as well as with the same patient at different times and in different circumstances

• Chemical alteration of a xenobiotic within the body that generally enhances the xenobiotic’s aqueous solubility and excretion.( makes drugs water soluble & easier to excrete in urine ) **•The main biochemical pathway for drug metabolism is the hepatic mixed-function oxidase (MFO) system Converts lipophilic non-polar molecules to more polar water-soluble forms patients with liver disorders may require lower dosages

study of genetic variations in patient drug metabolism pathways and development of drug therapies to compensate for genetic differences impacting therapy regimens • Responders • Patients benefitting from therapeutic and desired effects of the drug • Nonresponders • Patients not benefitting from therapeutic and desired effects of the drug