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  1. 1. Pharmacokinetics By M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science
  2. 2. Pharmacokinetics Introduction Bioavailability Volume of Distribution Clearance  Half-Life Drug Accumulation First-pass Elimination Time Course of Drug Effect Loading Dose Maintenance Dose Therapeutic Drug Monitoring (TDM)
  3. 3. Introduction  Pharmacodynamics: concentration-effect  Pharmacokinetics: dose-concentration  Pharmacodynamics determine the magnitude of the effect at a particular concentration.  Pharmacokinetics determine how rapidly and for how long the drug will appear at the target organ.M.H.Farjoo
  4. 4. Introduction (Cont,d)  A particular patient may be different from others in responding to a drug.  This is due to the various pathologic and physiologic features.  The relationship between dose, concentration, and effect of a drug helps in treating these people.  The three major pharmacokinetic processes are:  Absorption  Distribution  EliminationM.H.Farjoo
  5. 5. Overall biologic fluid (e.g., serum) drug concentration– time curveafter extravascular drug administration. Each important process ofdrug disposition is indicated. Although these processes arecompartmentalized graphically in the figure, in reality they occursimultaneously (see text for details).
  6. 6. Introduction (Cont,d)  The "standard" dose of a drug is based on trials in healthy volunteers.  Physiologic and pathologic processes alter pharmacokinetic parameters and the standard dose.M.H.Farjoo
  7. 7. Volume of Distribution  Volume of distribution is the measure of the apparent space in the body available to contain the drug.  Volume of distribution relates the amount of drug in the body to the concentration of drug in blood or plasma.M.H.Farjoo
  8. 8. Volume of Distribution (Cont,d)  Volume of distribution can vastly exceed any physical volume in the body. (Chloroquine: 15,000 L)  It is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood.  Drugs with high volumes of distribution have higher concentrations in extravascular tissue than blood.  The Vd of drugs that are completely retained within the vasculature, equals the plasma volume.M.H.Farjoo
  9. 9. Clearance  Clearance is the most important concept to consider for long term drug administration.  The clinician usually wants to maintain steady-state concentrations of a drug and a minimum of toxicity.  Clearance is the measure of the ability of the body to eliminate the drug.  It is the single most important factor determining drug concentrations.M.H.Farjoo
  10. 10. Clearance (Cont,d)  The steady-state concentration will be achieved when the rate of drug elimination equals the rate of drug administration.  Thus:  Css = Dosing rate / CL  CL = Dosing rate / Css  Since in steady state dosing rate equals rate of elimination we have:  Clearance predicts the rate of elimination in relation to the drug concentration.M.H.Farjoo
  11. 11. Clearance (Cont,d)  Systems for elimination of drugs such as metabolizing enzymes and transporters usually are not saturated.  That is a constant fraction of drug in the body is eliminated per unit of time.  If elimination become saturated a constant amount of drug is eliminated per unit of time.  Under such a circumstance, clearance will vary with the concentration.M.H.Farjoo
  12. 12. Clearance (Cont,d)  The two major sites of drug elimination are kidneys and the liver.  In the liver, drug is eliminated by metabolization, or excretion of unchanged drug into the bile, or both.  3 factors influence clearance: the dose, the organ blood flow, and the intrinsic function of the liver or kidneys.  Abnormal clearance may be anticipated when there is major malfunction of the kidney, liver, or heart.M.H.Farjoo
  13. 13. Clearance (Cont,d)  For many drugs eliminated by the liver, no changes in clearance have been noted with hepatic disease.  This shows that hepatic disease does not always affect the hepatic intrinsic clearance.  Creatinine clearance is a useful indicator of renal function.  But there is no reliable marker of hepatic drug- metabolizing function to predict liver clearance.M.H.Farjoo
  14. 14. Clearance (Cont,d)  Elimination may also involve organs like: lung, blood, gut or muscle.  Changes in protein binding may mislead to believe clearance is changed while it is not altered.  There are two types of drug elimination:  First-order elimination  Zero order eliminationM.H.Farjoo
  15. 15. First-order Elimination  For most drugs, clearance is constant over the concentration range in clinical settings.  This means that elimination is linear and it is not saturable.  The rate of drug elimination is directly proportional to concentration.  Most drug elimination pathways will become saturated if the dose is high enough.M.H.Farjoo
  16. 16. Zero-order Elimination  For drugs with capacity-limited elimination, clearance depends on the concentration of drug in blood.  This pattern of capacity-limited elimination is important for three drugs in common use:  Ethanol  Phenytoin  AspirinM.H.Farjoo
  17. 17. Number of Fraction Percentagehalf-lives remaining remaining .5 .25 .125 n 1/(2n) 100/(2n)
  18. 18. Half-Life  Half-life is the time required to change the amount of drug in the body by one-half (50%).  The time course of drug in the body will depend on both the volume of distribution and the clearance.M.H.Farjoo
  19. 19. Half-Life (Cont,d)  Half-life indicates the time required to attain 50% of steady state after a change in the rate of drug administration.  Disease states can affect both volume of distribution and clearance.  In renal failure both the renal clearance and volume of distribution is decreased.  So the final effect on half life of some drugs (e.g. digoxine) may be minimal.  Practically it takes ~4 half-lives to reach steady state.M.H.Farjoo
  20. 20. Drug Accumulation  If the dosing interval is shorter than four half- lives, accumulation will be detectable.  An index of accumulation is the accumulation factor.M.H.Farjoo
  21. 21. Drug Accumulation (Cont,d)  For a drug given once every half-life, the accumulation factor is 2.  The accumulation factor predicts the ratio of the steady-state concentration to that after the first dose.M.H.Farjoo
  22. 22. Bioavailability  Bioavailability is the fraction of drug reaching the systemic circulation.  The area under the blood concentration-time curve is a measure of the extent of bioavailability (AUC).  For an intravenous drug, bioavailability is 100%.  For a non-IV drug, it is less than100% because of:  Absorption parameters  First-pass eliminationM.H.Farjoo
  23. 23. Route Bioavailability (%) CharacteristicsIntravenous (IV) 100 Most rapid onset Large volumes oftenIntramuscular (IM) 75 to ≤ 100 feasible; may be painful Smaller volumes than IM;Subcutaneous (SC) 75 to ≤ 100 may be painful Most convenient; first-Oral (PO) 5 to < 100 pass effect may be significant Less first-pass effect thanRectal (PR) 30 to < 100 oralInhalation 5 to < 100 Often very rapid onset Usually very slow absorption; used for lackTransdermal 80 to ≤ 100 of first-pass effect; prolonged duration of action
  24. 24. Absorption Parameters  Extent of absorption:  If too hydrophilic, the drug cannot cross the lipid cell membrane  If too lipophilic, the drug is not soluble enough to cross the water layer adjacent to the cell.  P-glycoprotein (a reverse transporter ) pumps some drugs out of gut cells back into the lumen.  Inhibition of P-glycoprotein (grapefruit juice), substantially increases drug absorption.M.H.Farjoo
  25. 25. Elimination of drugs
  26. 26. Absorption Parameters (Cont,d)  Rate of absorption:  The rate and extent of absorption are distinct entities.  The rate of absorption is determined by the site of administration and the drug formulation.  Both the rate of absorption and the extent of input can influence the clinical effectiveness of a drug  There are 2 mechanisms for absorption:  Zero-order absorption  First-orderM.H.Farjoo
  27. 27. Absorption Parameters (Cont,d)  Zero-order absorption  The rate is independent of the amount of drug remaining in the gut.  It is determined by the rate of gastric emptying or by a controlled-release drug formulation.  First-order  The rate of absorption is proportional to the gastrointestinal concentration.M.H.Farjoo
  28. 28. First-pass Elimination  After intestinal absorption drugs can be metabolized in the liver and/or excreted into the bile.  This can reduce bioavailability and the overall process is known as first-pass elimination.  If larger oral doses are given, therapeutic blood concentrations may be reached.  However, in this case, the concentrations of the drug metabolites will be increased significantly.  The metabolites may be pharmacologically active or even toxic.M.H.Farjoo
  29. 29. Hepatic metabolism Pic.
  30. 30. Hepatic metabolism Pic.
  31. 31. First-pass Elimination (Cont,d)  First-pass effect can be avoided by sublingual, transdermal and suppository preparations.  Suppositories move upward where some veins lead to the liver.  About 50% of a rectal dose can bypass the liver.  Inhalational drugs bypass the liver but the lung itself may excrete the drug.M.H.Farjoo
  32. 32. Time Course of Drug Effect  The relationship between concentration and effect is not linear.  Concentration of a drug is a function of time.  Delay in drug effect reflects the time required for the drug to distribute from plasma to the site of action.  Delayed drug effects up to days shows the slow turnover of a substance that mediates the drug effect (eg: warfarin).M.H.Farjoo
  33. 33. Time Course of Drug Effect (Cont’d)  Drugs with short half lives may have a prolonged effect.  This happens when the initial concentration is far more than the EC50 of the drug.  This is common for drugs that act on enzymes (ACE inhibitors) or compete at receptors (propranolol).  This explains why a drug with a short half-life can be given once a day.M.H.Farjoo
  34. 34. Time course of angiotensin-converting enzyme (ACE) inhibitor concentrations and effects. The blue line shows the plasma enalapril concentrations in nanograms per milliliter after a single oral dose. The red line indicates the percentage inhibition of its target, ACE. Note the different shapes of the concentration-time course (exponentially decreasing) and the effect- time course (linearly decreasing in its central portion).Enalapril (an ACEI) concentration and effect.
  35. 35. Time Course of Drug Effect (Cont’d)  Some drug effects are related to a cumulative action.  The renal toxicity of aminoglycosides is greater when administered as an infusion than intermittent dosing.  Both dosing schemes produce the same average steady-state concentration.  The intermittent dosing scheme produces much higher peak concentrations.  This saturates an uptake mechanism into the cortex; thus, total drug accumulation is less.M.H.Farjoo
  36. 36. Time Course of Drug Effect (Cont’d)  The extent of binding of an anticancer drug to DNA is proportional to drug concentration.  The effect on tumor growth is therefore a consequence of cumulative exposure to the drug.M.H.Farjoo
  37. 37. Loading Dose  When the time to reach steady state is long (long half- lives), a loading dose promptly achieves target concentration.  The volume of distribution relates the total amount of drug in the body to the concentration in the plasma.  Even if the amount of a loading dose is correct, the rate of administration is also crucial to prevent toxicity.  Slow administration of an intravenous drug (over minutes rather than seconds) is always a prudent practice.M.H.Farjoo
  38. 38. Maintenance Dose  To maintain a steady state of drug, enough drug should be given in each dose.  This dose replaces the drug eliminated since the preceding dose.  Calculation of the maintenance dose is very important.  Steady-state concentration depends only on clearance.M.H.Farjoo
  39. 39. Therapeutic Drug Monitoring (TDM)  Even by precise loading and maintenance dosing desired effect may not be seen.  This may be because of inter-individual variation due to:  Drug metabolizing pattern (fast or slow)  Pathologic factors (smoking)  Physiologic factors (pregnancy)  In these cases TDM should be done especially for drugs with narrow therapeutic index .M.H.Farjoo
  40. 40. Summary In English
  41. 41. Thank you Any question?
  42. 42. Drugs with a narrow therapeutic index (drug A, solid lines) vs a widetherapeutic index (drug B, dashed lines). Note that a drug with a narrowtherapeutic index is more likely to cause toxicity at serum concentrationsneeded to obtain an adequate therapeutic response, whereas a drug witha wide therapeutic index is unlikely to cause toxicity at concentrationsneeded for an adequate therapeutic response.