This document summarizes key concepts in pharmacokinetics and pharmacodynamics from Katzung Chapter 3. It discusses clearance and the two major sites of drug elimination, the kidneys and liver. It also covers volume of distribution, half-life, drug accumulation, and bioavailability. Bioavailability is affected by the extent of drug absorption, first-pass metabolism in the liver, and the rate of absorption via different administration routes.
This document summarizes key concepts in pharmacokinetics and pharmacodynamics from Katzung Chapter 3. It discusses clearance and the two major sites of drug elimination, the kidneys and liver. It also covers volume of distribution, half-life, drug accumulation, and bioavailability. Bioavailability is affected by the extent of drug absorption, first-pass metabolism in the liver, and the rate of absorption via different administration routes.
This document summarizes key concepts in pharmacokinetics and pharmacodynamics from Katzung Chapter 3. It discusses clearance and the two major sites of drug elimination, the kidneys and liver. It also covers volume of distribution, half-life, drug accumulation, and bioavailability. Bioavailability is affected by the extent of drug absorption, first-pass metabolism in the liver, and the rate of absorption via different administration routes.
CLEARANCE o Measure of the ability of the body to eliminate the drug o Has an additive character o 2 major sites of elimination: KIDNEYS and LIVER o CL = rate of elimination / concentration
A) Capacity limited elimination/ Mixed order/ Saturable/ Dose or Concentration dependent/ Non linear/ Michaelis Menten Elimination o Phenytoin, Ethanol, Aspirin o Clearance is dependent on concentration of drug that is achieved o Rate of elimination = Vmax x C/ Km + C o Vmax = maximum elimination capacity o Km = Drug concentration where rate of elimination is 50% of Vmax o If dosing rate exceed elimination capacity, steady state cant be achieved B) Flow dependent elimination o Rate of drug delivery to organ of elimination determines elimination of drug o Called HIGH EXTRACTION DRUGS almost completely extracted from blood by organs VOLUME OF DISTRIBUTION o Measure of apparent space in the body available to contain the drug o V = amount of drug in the body / concentration of drug in blood or plasma o V = conc. In extravascular tissues than in vascular component not homogeneously distributed o Drugs retained in vascular component = V HALF LIFE o The time required to change the amount of drug in the body by during elimination or in a constant infusion o T1/2 = 0.7 x Volume of distribution/ clearance o Indicated the time required to attain 50% of steady state or to decay 50% from steady state after a change in the rate of drug administration DRUG ACCUMULATION o Inversely proportional to fraction of dose lost in each dosing interval o Fraction lost = 1 minus fraction remaining just before next dose o Peak concentrations after intermittent doses at steady state = peak concentration after the first dose multiplied by the accumulation factor
BIOAVAILABILITY o Fraction of unchanged drug reaching systemic circulation following administration by any route o AUC is proportional to extent of bioavailability if elimination is first order SITE BIOAV % REMARKS Intravenous 100 Most rapid onset Intramuscular 75 to 100 Large volumes Subcutaneous 75 to 100 Smaller volumes Oral 5 to 100 Most convenient; significant first pass Rectal 30 to 100 Less first pass than PO Inhalation 5 to 100 Very rapid onset Transdermal 80 to 100 Very slow absorption; prolonged duration of action A) Extent of Absorption If too hydrophilic, drug cant cross lipid cell membrane If too lipophilic, drug isnt soluble enough to cross water adjacent to cell Inhibition of P-glycoprotein and gut wall metabolism = absorption of drug B) First Pass Elimination Reduction in bioavailability when drug enters gut wall portal blood liver systemic circulation Extraction ratio (ER) = CL liver / Q Q = hepatic blood flow 90L/h in a 70kg person Systemic bioavailability of drug (F) = f x (1-ER) f = extent of absorption C) Rate of Absorption Determined by site of administration and drug formulation D) Zero Order Drug Absorption Rate is independent of the amount of drug remaining in the gut which is determined by rate of gastric emptying or controlled release drug formulation E) First Order Drug Absorption When dose is dissolved in the gastrointestinal fluids, the rate of absorption is proportional to gastrointestinal concentration EXTRACTION RATIOS AND FIRST PASS EFFECT o Systemic clearance is not affected by bioavailability but can affect extent of availability cause it determines extraction ratio o Drugs with extraction ratios show marked variations in bioavailability between subjects due to differences in hepatic function and blood flow ALTERNATIVE ROUTES OF ADMINISTRATION AND FIRST PASS EFFECT o Hepatic first pass avoided by sublingual tablets/ transdermal preparations/ rectal suppositories