II. PHARMACOKINETICS06-Nov-12          By: Takele B., CVMA, AAU   1
Learning Objectives• Define PK• Importance of PK• The factors that modify the PK of drugs06-Nov-12         By: Takele B., ...
PHARMACOKINETIC IMPORTANCE•    To know the dose•   To know the suitable route of adm•   To know the dosage interval•   To ...
General Concepts                                 Drug Dose                                Administration                  ...
Pharmacokinetics• The changes that occur to the drug when it is  inside the body.• The ways in which the body processes dr...
Pharmacokinetics            Fate of drugs in the animal body06-Nov-12            By: Takele B., CVMA, AAU   6
I. Absorption    The transfer of a drug from its site of administration to its site     of action (or measurement)       ...
Barriers to Drug Delivery                                                                                    Effect       ...
Major Sites of Administration                               Lungs                               Mouth                     ...
Absorption from the Small Intestine  The small intestine is the major drug absorbing site due to the greatly  enhanced ava...
Requirements for Oral Absorption            Dissolution            Transfer across the Gut Wall                Paracell...
Dissolution       The process by which a drug moves from the solid state into solution                    Dosage          ...
Microvilli                                    Microvilli        Brush Border        Membrane        Epithelial        Cell...
Routes of Passage across theSmall Intestinal Epithelial Cell                         Gut Lumen                         Par...
Transcellular Absorption -   Membrane Structure      The major route of drug absorption      The compound passes through...
Membrane Partition- Ionizable             compoundsAdministration Site      Membrane                   Systemic Circulatio...
Movement of Drugs Across the Cell                     Membrane• Pharmacokinetics includes the movement of  substances acro...
Movement of Drugs…cont’d• Passive diffusion:       movement of particles from an area of high concentration        to an ...
Movement of Drugs…cont’d• Active transport:   – molecules move against the concentration     gradient from areas of low co...
Movement of Drugs…cont’d• Pinocytosis/phagocytosis:      – Molecules are physically taken in or engulfed.      – Pinocytos...
Barriers to Drug Absorption  P-glycoprotein  First Pass Extraction:       – gut wall       – liver06-Nov-12             ...
First-Pass Extraction                       Gut wall                                                  Portal     Liver    ...
Gut Wall Metabolism• The major isoform present in gut is CYP3A4• In the small intestine this approaches 50% of  hepatic le...
Absorption Parameters   Bioavailability:   • The extent to which a drug can overcome     the barriers to absorption (inclu...
Oral Bioavailability Oral Bioavailability (%)= AUCoral x                ivDose   x   100                           AUCiv  ...
Factors that affect Absorption      The factors that modify the absorption of drugs is either       related             ...
Absorption….2-Degree of ionization   The greater the degree of ionization the lesser the   absorption because the lesser L...
Absorption 3-Valency  Ferrous salt are better absorbed from the alimentary canal   than ferric salt 4-Pharmaceutical form...
AbsorptionB. Factors related to the patientsa)Routes of administration:      Excellent from pulmonary alveoli,      very...
b) Sites of absorptionGIT      Characters:      1) Very large surface area      2) Good blood supply      3) Internal envi...
Sites of absorption….. SKIN    Characters:    1) Large surface area    2) Out layer of dead cells    3) Poor blood supply ...
Absorption…c)Area and vascularity of the absorbing surface:      Absorption is directly proportion to both area and      ...
Drug Absorption Terms• Bioavailability: percent of drug administered that actually  enters the systemic circulation• Ioniz...
06-Nov-12   By: Takele B., CVMA, AAU   34
06-Nov-12   By: Takele B., CVMA, AAU   35
06-Nov-12            XX   By: Takele B., CVMA, AAU   36
Factors affecting BA   1. Hepatic 1st pass metabolism   2. Solubility of a drug:             e.g. lipophilic better orally...
II.Distribution Is the process by which the drug reversibly leaves the  bloodstream and enters to interstitial (ECF) and/...
06-Nov-12   By: Takele B., CVMA, AAU   39
06-Nov-12   By: Takele B., CVMA, AAU   40
Binding of drugs to proteins Drugs are distributed and bind to α-acid glycoprotein and  proteins (albumin &globulin) bou...
Volume of distributions, VdIs a hypothetical volume of fluid into which the drug is disseminated.Vd= D/C : is drug speci...
06-Nov-12   By: Takele B., CVMA, AAU   43
III. Biotransformation• Refers to the chemical alterations that drug  undergoes within living organism. The main purpose ...
Biotransformation---Biotransformation reaction are classified intoA.Phase I or non-synthetic reactions:These involve:1.Oxi...
Biotransformation---All the above reaction may result in:1. Activation of pharmacologically inactive cpds to active ones  ...
Biotransformation--- B-Phase II or synthetic reaction • It involves the conjugation of the parent compound   or its metabo...
Biotransformation---1. Conjugation of CAF with glucuronic acid2. Conjugation of phenol with sulphate3. Conjugation of sulp...
06-Nov-12                 By: Takele B., CVMA, AAU   49            The biotransformation of drugs
Kinetics of Metabolism1. First order kinetics:• The metabolic transformation of drugs is catalyzed by  enzymes, and most o...
• Effect of drug dose on the rate of drug metabolism  06-Nov-12           By: Takele B., CVMA, AAU    51
2-zero order kinetics• The enzyme is saturated by a high free-drug conc, and  the rate of metabolism constant over time.• ...
Effect of drugs on hepatic microsomal                      enzymeA-Activators or inducerse.g.phenobarbitone, phenylbutazon...
Effect of drugs on hepatic microsomal enzymeB-Inhibitors e.g. Cimetidine,chloramphenicol,allopurinol,estrogen  and proges...
The biotransformation can lead to:• 1) Transformation of molecules into more polar    metabolite• 2) Change molecular weig...
IV. Drug Elimination• Removal of drugs from the body occurs via a  number of routes:              major: through a kidney...
Biliary excretion Large and polar substances can be excreted via this route. Bile is excreted by hepatocytes into the ca...
06-Nov-12   By: Takele B., CVMA, AAU   58
06-Nov-12   By: Takele B., CVMA, AAU   59
06-Nov-12   By: Takele B., CVMA, AAU   60
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2. pharmacokinetics ( By Dr. Takele Beyene, DVM, MSc,PhD,@AAU)

  1. 1. II. PHARMACOKINETICS06-Nov-12 By: Takele B., CVMA, AAU 1
  2. 2. Learning Objectives• Define PK• Importance of PK• The factors that modify the PK of drugs06-Nov-12 By: Takele B., CVMA, AAU 2
  3. 3. PHARMACOKINETIC IMPORTANCE• To know the dose• To know the suitable route of adm• To know the dosage interval• To know the period of medication06-Nov-12 By: Takele B., CVMA, AAU 3
  4. 4. General Concepts Drug Dose Administration Absorption/distributionPharmacokinetics metabolism/excretion Drug/ReceptorPharmacodynamics InteractionPharmacotherapeutics Drug Effect or Response 06-Nov-12 By: Takele B., CVMA, AAU 4
  5. 5. Pharmacokinetics• The changes that occur to the drug when it is inside the body.• The ways in which the body processes drugs:  Absorption  Distribution  Metabolism  Excretion06-Nov-12 By: Takele B., CVMA, AAU 5
  6. 6. Pharmacokinetics Fate of drugs in the animal body06-Nov-12 By: Takele B., CVMA, AAU 6
  7. 7. I. Absorption The transfer of a drug from its site of administration to its site of action (or measurement) Dose Administration Site of Site Action Absorption Barriers 06-Nov-12 By: Takele B., CVMA, AAU 7
  8. 8. Barriers to Drug Delivery Effect Cellular delivery Target Tissue distribution Liver metabolism Gut metabolism Intestinal absorption Ingestion Systemic Circulation06-Nov-12 By: Takele B., CVMA, AAU 8
  9. 9. Major Sites of Administration Lungs Mouth Nose GI Skin Muscle06-Nov-12 By: Takele B., CVMA, AAU 9
  10. 10. Absorption from the Small Intestine The small intestine is the major drug absorbing site due to the greatly enhanced available surface area. Luminal Folds (3 fold increase) Villi (10-fold increase) Microvilli (20-fold increase) Overall, a 600-fold increase in surface area vs. a cylinder 06-Nov-12 By: Takele B., CVMA, AAU 10
  11. 11. Requirements for Oral Absorption Dissolution Transfer across the Gut Wall Paracellular Transcellular06-Nov-12 By: Takele B., CVMA, AAU 11
  12. 12. Dissolution The process by which a drug moves from the solid state into solution Dosage form Dissolution Granules Dissolution Solution Absorption Deaggregation Dissolution The drug must be in solution to be absorbed 06-Nov-12 By: Takele B., CVMA, AAU 12
  13. 13. Microvilli Microvilli Brush Border Membrane Epithelial Cell Intestinal wall epithelial cells have many finger-like projections on their luminal surface called microvilli which form the brush border membrane06-Nov-12 By: Takele B., CVMA, AAU 13
  14. 14. Routes of Passage across theSmall Intestinal Epithelial Cell Gut Lumen ParacellularActive Efflux Transcellular Transport Serosal Side06-Nov-12 By: Takele B., CVMA, AAU 14
  15. 15. Transcellular Absorption - Membrane Structure  The major route of drug absorption  The compound passes through the cell membrane  Requirement for adequate lipophilicity Phospholipid Head Lipophilic Tail Protein06-Nov-12 StructureB., CVMA, AAUCell Membrane By: Takele of the 15
  16. 16. Membrane Partition- Ionizable compoundsAdministration Site Membrane Systemic Circulation BH+ B B BH+  Only unionized drug typically cross membranes  Ionized drug must first lose charge  Dependent upon pKa and permeation rate of unionized form 06-Nov-12 By: Takele B., CVMA, AAU 16
  17. 17. Movement of Drugs Across the Cell Membrane• Pharmacokinetics includes the movement of substances across cell membranes• Basic mechanisms: – Passive diffusion – Facilitated diffusion – Active transport – Pinocytosis/phagocytosis06-Nov-12 By: Takele B., CVMA, AAU 17
  18. 18. Movement of Drugs…cont’d• Passive diffusion:  movement of particles from an area of high concentration to an area of low concentration – good for small, lipophilic, nonionic particles• Facilitated diffusion:  passive diffusion that uses a special carrier molecule – good for bigger molecules that are not lipid soluble06-Nov-12 By: Takele B., CVMA, AAU 18
  19. 19. Movement of Drugs…cont’d• Active transport: – molecules move against the concentration gradient from areas of low concentration of molecules to areas of high concentration of molecules; – involves both a carrier molecule (transporter) and energy – SAR very specific=Not many drugs absorbed by this route – Many types for nutrient molecules – Can be saturated by high concentration good for accumulation of drugs within a part of the body06-Nov-12 By: Takele B., CVMA, AAU 19
  20. 20. Movement of Drugs…cont’d• Pinocytosis/phagocytosis: – Molecules are physically taken in or engulfed. – Pinocytosis is engulfing liquid; – Phagocytosis is engulfing solid particles –Good for bigger molecules or liquids06-Nov-12 By: Takele B., CVMA, AAU 20
  21. 21. Barriers to Drug Absorption  P-glycoprotein  First Pass Extraction: – gut wall – liver06-Nov-12 By: Takele B., CVMA, AAU 21
  22. 22. First-Pass Extraction Gut wall Portal Liver vein To site of measurement Metabolism Metabolism To Feces • Gut wall and liver are major drug metabolizing organs Oral Bioavailability = % absorbed - % extracted06-Nov-12 By: Takele B., CVMA, AAU 22
  23. 23. Gut Wall Metabolism• The major isoform present in gut is CYP3A4• In the small intestine this approaches 50% of hepatic level• Gut wall metabolism contributes extensively to the first pass extraction of: Midazolam, Verapamil, Cyclosporin, Felodipine e.t.c!! 06-Nov-12 By: Takele B., CVMA, AAU 23
  24. 24. Absorption Parameters Bioavailability: • The extent to which a drug can overcome the barriers to absorption (including first pass metabolism)06-Nov-12 By: Takele B., CVMA, AAU 24
  25. 25. Oral Bioavailability Oral Bioavailability (%)= AUCoral x ivDose x 100 AUCiv poDose Where AUC is the area under the plasma concentration versus time course06-Nov-12 By: Takele B., CVMA, AAU 25
  26. 26. Factors that affect Absorption The factors that modify the absorption of drugs is either related  to the drug or  to the patientsA. Factors related to the drugs1-Drug solubility Insoluble drugs are not absorbed e.g. barium sulphate06-Nov-12 By: Takele B., CVMA, AAU 26
  27. 27. Absorption….2-Degree of ionization The greater the degree of ionization the lesser the absorption because the lesser Lipophilic properties of the drug ions.• Ionized drug ------ polar ---- less lipid solubility ---Less absorption.• Unionized drug --- non-polar --- more lipid soluble ---More absorption06-Nov-12 By: Takele B., CVMA, AAU 27
  28. 28. Absorption 3-Valency  Ferrous salt are better absorbed from the alimentary canal than ferric salt 4-Pharmaceutical form  Drugs in aqueous solution are more rapidly absorbed than those given in oily solutions or suspension and  the smaller the particle size of the powder the more efficient is their absorption.06-Nov-12 By: Takele B., CVMA, AAU 28
  29. 29. AbsorptionB. Factors related to the patientsa)Routes of administration:  Excellent from pulmonary alveoli,  very good from sublingual mucosa.  best from parenteral sites  For oral drug, it is absorbed first from GIT either through passive diffusion or active transport06-Nov-12 By: Takele B., CVMA, AAU 29
  30. 30. b) Sites of absorptionGIT Characters: 1) Very large surface area 2) Good blood supply 3) Internal environment (pH) is vary throughout the GIT 4) Presence of gut contents 5) Gut flora06-Nov-12 By: Takele B., CVMA, AAU 30
  31. 31. Sites of absorption….. SKIN Characters: 1) Large surface area 2) Out layer of dead cells 3) Poor blood supply 4) Epidermis is packed with keratin N.B: Absorption through skin is limited to lipid soluble compoundsLUNGS Characters: 1) Large surface area 2) Blood flow 3) Both lipid soluble and water soluble compounds can be absorbed 06-Nov-12 By: Takele B., CVMA, AAU 31
  32. 32. Absorption…c)Area and vascularity of the absorbing surface: Absorption is directly proportion to both area and vascularityd)State of health absorbing surface06-Nov-12 By: Takele B., CVMA, AAU 32
  33. 33. Drug Absorption Terms• Bioavailability: percent of drug administered that actually enters the systemic circulation• Ionization: the property of being charged – Hydrophilic = ionized – Lipophilic = nonionized• Nature of the drug: pH of drug – Weakly acid drugs = hydrophilic form in alkaline environment – Weakly alkaline drugs = hydrophilic form in acid environment• Ion trapping: when drugs change body compartments, they may become ionized and trapped in the new environment• Drug form is important; oral drugs must have different properties than parenteral drugs AAU06-Nov-12 By: Takele B., CVMA, 33
  34. 34. 06-Nov-12 By: Takele B., CVMA, AAU 34
  35. 35. 06-Nov-12 By: Takele B., CVMA, AAU 35
  36. 36. 06-Nov-12 XX By: Takele B., CVMA, AAU 36
  37. 37. Factors affecting BA 1. Hepatic 1st pass metabolism 2. Solubility of a drug: e.g. lipophilic better orally than 3. Chemical instability: e.g. insulin and penicillin G in GIT 4. Nature of drug formulation e.g. particle size, salt form06-Nov-12 By: Takele B., CVMA, AAU 37
  38. 38. II.Distribution Is the process by which the drug reversibly leaves the bloodstream and enters to interstitial (ECF) and/or cells or tissues/its site of action After absorption of a drug, it is usually distributed through the different tissues and the body fluid compartment including: A-The plasma. B-the ECF and C- the ICF.06-Nov-12 By: Takele B., CVMA, AAU 38
  39. 39. 06-Nov-12 By: Takele B., CVMA, AAU 39
  40. 40. 06-Nov-12 By: Takele B., CVMA, AAU 40
  41. 41. Binding of drugs to proteins Drugs are distributed and bind to α-acid glycoprotein and proteins (albumin &globulin) bound drugs are pharmacologically inactive. only the free, unbound can act its target sites in the tissue , elicit biologic response, and be available to process of elimination. Acidic drugs- albumin Basic drugs- globulin & α-acid glycoprotiens• NB. Hypoalbuminemia can affect the level of free drug 06-Nov-12 By: Takele B., CVMA, AAU 41
  42. 42. Volume of distributions, VdIs a hypothetical volume of fluid into which the drug is disseminated.Vd= D/C : is drug specific C- plasma drug conc. D- total amount of drug in the body06-Nov-12 By: Takele B., CVMA, AAU 42
  43. 43. 06-Nov-12 By: Takele B., CVMA, AAU 43
  44. 44. III. Biotransformation• Refers to the chemical alterations that drug undergoes within living organism. The main purpose is  to convert lipid soluble drug into more polar (water soluble) or greater hydrophilic properties  thus facilitating their renal excretion.• The liver is the major site for drug metabolism.06-Nov-12 By: Takele B., CVMA, AAU 44
  45. 45. Biotransformation---Biotransformation reaction are classified intoA.Phase I or non-synthetic reactions:These involve:1.Oxidation e.g. ethyl alcohol ----- acetaldehyde -----acetic acid ------- CO2 +H2O+energy2.Reduction e.g.chlorahydrate ------- trichloroethanol3.Hydrolysis e.g. Acetylcholine ----- Choline+Acetate06-Nov-12 By: Takele B., CVMA, AAU 45
  46. 46. Biotransformation---All the above reaction may result in:1. Activation of pharmacologically inactive cpds to active ones Imipramine (inactive) ------Despiramine (active)2.Conversion of an active drug to metabolite that is also active Phencetin (active ---- Acetaminophen (paracetamol) (more active).3.Inactivation  Acetylcholine (active) ------- choline +acetic acid (inactive)4.Conversion to a toxic compound  Methanol ----------- Formaldhyde (retinotoxic)06-Nov-12 By: Takele B., CVMA, AAU 46
  47. 47. Biotransformation--- B-Phase II or synthetic reaction • It involves the conjugation of the parent compound or its metabolites with certain acid radicals or amino acids. • Synthetic reaction often result in inactivation of drug and convert the drug to water soluble state. • Example of synthetic(conjugation) reactions include:06-Nov-12 By: Takele B., CVMA, AAU 47
  48. 48. Biotransformation---1. Conjugation of CAF with glucuronic acid2. Conjugation of phenol with sulphate3. Conjugation of sulphonamide with acetic acid4. Conjugation of salcylate with glycine.06-Nov-12 By: Takele B., CVMA, AAU 48
  49. 49. 06-Nov-12 By: Takele B., CVMA, AAU 49 The biotransformation of drugs
  50. 50. Kinetics of Metabolism1. First order kinetics:• The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis- Menten kinetics. – The rate of drug metabolism is directly proportional to the conc of free drug, and 1st order kinetics are observed. – This means that a constant fraction of drug is metabolized per unit time. 06-Nov-12 By: Takele B., CVMA, AAU 50
  51. 51. • Effect of drug dose on the rate of drug metabolism 06-Nov-12 By: Takele B., CVMA, AAU 51
  52. 52. 2-zero order kinetics• The enzyme is saturated by a high free-drug conc, and the rate of metabolism constant over time.• Sometimes referred to clinically as nonlinear kinetics.• A constant amount of drug is metabolized per unit of time. 06-Nov-12 By: Takele B., CVMA, AAU 52
  53. 53. Effect of drugs on hepatic microsomal enzymeA-Activators or inducerse.g.phenobarbitone, phenylbutazone, phenytoin, Rifampin, tobacco smoking, androgen These drugs induce or stimulate the microsomal enzyme so increase degradation of other drugs or their own degradation06-Nov-12 By: Takele B., CVMA, AAU 53
  54. 54. Effect of drugs on hepatic microsomal enzymeB-Inhibitors e.g. Cimetidine,chloramphenicol,allopurinol,estrogen and progesterone. These drugs inhibit the microsomal enzymes, so delay the rate of degradation of the drugs and prolong their effects. 06-Nov-12 By: Takele B., CVMA, AAU 54
  55. 55. The biotransformation can lead to:• 1) Transformation of molecules into more polar metabolite• 2) Change molecular weight and size of drug• 3) Facilitate excretion and elimination drug from the organismConsequences• - Decrease the half-life of drugs• - Exposure to drug is shorten• - Accumulation of drug is reduced• - Probable reduce biological activity (toxicological 06-Nov-12 By: Takele B., CVMA, AAU 55 effects)
  56. 56. IV. Drug Elimination• Removal of drugs from the body occurs via a number of routes:  major: through a kidney into the urine. Others: bile, intestine, lung, milk in nursing dams,Renal excretion• Factors affecting excretion via kidney: – • size (< 300) – • Ionization (ionized) – • Solubility (water soluble) 06-Nov-12 By: Takele B., CVMA, AAU 56
  57. 57. Biliary excretion Large and polar substances can be excreted via this route. Bile is excreted by hepatocytes into the canaliculi and flows into the bile duct to the intestine. Gut microflora can convert some drugs to more lipid soluble products, which can be reabsorbed into the portal venous blood supply. This is called intrahepatic recirculation.• Billiary excretion can leads to: – 1- increasing half-life of drug – 2- increasing hepatic exposure to drug – 3- may cause hepatic damage06-Nov-12 By: Takele B., CVMA, AAU 57
  58. 58. 06-Nov-12 By: Takele B., CVMA, AAU 58
  59. 59. 06-Nov-12 By: Takele B., CVMA, AAU 59
  60. 60. 06-Nov-12 By: Takele B., CVMA, AAU 60

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