ADVANCED PHARMACOKINETICS 6521 Midterm study guide

• Understanding the implications of changing renal function on creatinine and drug dosing. -Drug accumulation secondary to reduced renal excretion is the most important cause of ADR’s in older adults. In older adults, the proper index for renal function is creatinine clearance, not serum creatinine levels. Creatinine levels do not adequately reflect kidney function in older adults because the source of serum creatinine- lean muscle mass- declines parallel with the decline in kidney function. Creatinine levels may be normal even though renal function is greatly reduced. Most medications use adjustments for renal problems use creatinine clearance, for a few medications the estimated glomerular filtration rate (eGFR) is used. • What is the impact of the following on drug levels and dosing: o Cirrhosis- liver disease can cause drugs to accumulate because the liver is the major site for drug metabolism. If liver function declines, metabolism declines, and to prevent toxic levels from accumulating, the dosage of drugs through the hepatic metabolism must be reduced or discontinued if the liver disease develops. (pg 43) o Protein binding- The most important protein binding is plasma albumin. This is because albumin is a large molecule that cannot leave the bloodstream. Thus anything that binds to albumin is bound to stay in the bloodstream as well, resulting in bound molecules not reaching their sites of actions unless the drug is metabolized or excreted until the drug-protein bond is broken. Then the drug is free to leave the circulation. Albumin has limited binding sites so one drug and displace another causing the displaced drug to freely circulate, rise, and increase the intensity of the drug response resulting in possible toxicity (pg17) o Drug interactions-Drugs produce their effects by interacting with other chemicals. The simple occupancy theory states the more available receptors for a drug, the higher the intensity of the drug and maximum drug response occurs when all drug receptors are occupied. The modified occupancy theory describes the affinity or strength of attraction between receptor and drugs. Higher affinity produces more effective drug responses at low doses. High affinity drugs are deemed very potent. Intrinsic activity refers to the drugs ability to activate a receptor site upon binding. Drugs with high intrinsic activity cause intense receptor activity. Drugs with high intrinsic activity have high maximal efficacy. After binding, drugs can either mimic the action of endogenous regulatory molecules or block the action of endogenous regulatory molecules; drugs that mimic are agonists, drugs that block are antagonists, and drugs that only moderate intrinsic activity are partial agonist. (pg26)