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Pharmacokinetics revision 2021 PROF SATYA

This interesting and useful ppt highlights different pharmacokinetic concepts with illustrations for easy understanding - an overview for revision for medical and paramedical students

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Pharmacokinetics revision 2021 PROF SATYA

  1. 1. PHARMACOLOGY
  2. 2. The young physician starts life with 20 drugs for each disease, and the old physician ends life with one drug for 20 diseases… Sir. William Osler 1849 - 1919
  3. 3. FOUR PROCESSES OF DRUG THERAPY
  4. 4. FOUR PROCESSES OF DRUG THERAPY 1. The pharmaceutical process 2. The pharmacokinetic process 3. The pharmacodynamic process 4. The therapeutic process
  5. 5. PHARMACEUTICAL PROCESS
  6. 6. PHARMACOKINETIC PROCESS
  7. 7. PHARMACODYNAMIC PROCESS
  8. 8. THERAPEUTIC PROCESS
  9. 9. FOUR SIMPLE QUESTIONS 1. Is the drug getting into the patient ? 2. Is the drug getting to its site of action? 3. Is the drug producing the required pharmacological effect ? 4. Is the pharmacological effect being translated into an appropriate therapeutic effect?
  10. 10. Site of Action Dosage Effects Plasma Concen. Pharmacokinetics Pharmacodynamics
  11. 11. DR.V.SATHYANARAYANAN M.B.B.S., M.D., ACME PROFESSOR OF PHARMACOLOGY SRM MCH & RC, KATTANKULATHUR CHENNAI, INDIA GENERAL PHRMACOLOGY - PHARMACOKINETICS
  12. 12. PHARMACOKINETICS
  13. 13. PHARMACOKINETICS WHAT THE BODY DOES TO THE DRUG
  14. 14. WHAT THE BODY DOES TO THE DRUG ?
  15. 15. Pharmacokinetic Process Extravascular Administration Intravascular Administration Gut Wall Body tissues Blood Liver Kidney ABSORPTION DISTRIBUTION METABOLISM EXCRETION
  16. 16. PHARMACOKINETICS CONCERNED ABOUT IS THE DRUG GETTING TO ITS SITE OF ACTION ?
  17. 17. DRUG ABSORPTION
  18. 18. OVERVIEW 1. Definition of absorption 2. Processes involved in absorption 3. Factors affecting drug absorption 4. Bioavailability 5. Bioequivalence
  19. 19. DRUG ABSORPTION What is absorption ? Movement of drug from its site of administration into the circulation
  20. 20. PROCESSES OF DRUG ABSORPTION PASSIVE DIFFUSION CARRIER MEDIATED TRANSPORT  FACILITATED DIFFUSION  ACTIVE TRANSPORT FILTRATION PINOCYTOSIS
  21. 21. The most important Bio transport process for majority of drugs is a. Pinocytosis b. Filtration c. Active transport d. Passives diffusion
  22. 22. Passive diffusion depends on A. Lipid solubility of a drug B. Intact mucosal surface C. Availability of carrier substance D. Availability of energy
  23. 23. FACTORS AFFECTING DRUG ABSORPTION Lipid solubility pH Aqueous solubility Concentration Area of absorbing surface Vascularity of absorbing surface Route of administration Pharmaceutical factors Biological factors Disease states
  24. 24. Pharmacokinetics (how the body handles drugs) (a,d,m,e) most drugs are weak acids or bases: HA H+ + A- BH+ B + H+ only the non-ionized form can cross cell membranes when H increases get more HA and BH+ even if the drug is not ionized, it still needs to be lipid soluble to cross cell membranes pH=pKa + log (base) (acid)
  25. 25. Acidic drugs are absorbed better at a. Acidic pH b. Alkaline pH c. Neutral pH d. Un ionized state
  26. 26. BIOAVAILABILITY (F) It is a measure of the (F) fraction / percentage of administered dose of a drug that reaches the systemic circulation in the unchanged form.
  27. 27. Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver to systemic circulation BIOAVAILABILITY
  28. 28. BIOAVAILABILITY=AUC(ORAL)×100 ---------------------------------- AUC(IV) DETERMINING BIOAVAILABILITY
  29. 29. Bioavailability of a drug given by I.V. route a. 100% b. 75 % c. 92 % d. 25 %
  30. 30. FACTORS AFFECTING BIOAVAILABILITY Pharmaceutical factors: Particle size Diluting substances Tablet size Pressure used in tabletting machine All factors above affect disintegration and dissolution  affect absorption and bioavailability
  31. 31. BIOLOGICAL INEQUIVALENCE Oral formulation of a drug from different manufacturers or different batches from same manufacturers may have the same amount of drug but may not yield same blood levels.
  32. 32. SIGNIFICANCE OF BIOAVAILABILITY VARIATION For drugs with narrow safety margin eg digoxin For drugs need precise control eg oral hypoglycemics Success & failure of antimicrobial drugs
  33. 33. SUMMARY What is absorption ? Processes of absorption Factors affecting drug absorption Bioavailability Factors affecting bioavailability Bioequivalence and bioinequivalence
  34. 34. DISTRIBUTION
  35. 35. DISTRIBUTION If a drug  to act throughout the body  it has to be distributed to other body compartments through blood Concentration gradient
  36. 36. DISTRIBUTION Most drugs distribute widely in part dissolved in body water in part bound to plasma protein in part bound to tissues Often distribution is uneven – bind to PP or tissue proteins or localized in particular organs.
  37. 37. IMPORTANCE OF DISTRIBUTION Site of localization of a drug Influences its action eg. Cross BBB  Brain The amount of protein or tissue binding  affect time it spends in the body  determines its duration of action.
  38. 38. FACTORSAFFECTINGEXTENTOF DISTRIBUTION Lipid solubility Ionisation at physiological pH Extent if binding to PP, tissue protein Difference in regional blood flow Movement of drug proceeds until equilibrium is achieved
  39. 39. REDISTRIBUTION Highly lipid soluble drugs  distributed to organs of high blood flow , later to less vascular tissues When the blood level decreases  the drug is withdrawn into the bloodstream from the distributed organs If the action is in the high vascular organs  redistribution results in termination of drug action --- eg. Thiopentone Greater the lipid solubility, faster the redistribution
  40. 40. Volume of Distribution (Vd) The ‘apparent’ volume of distribution: A theoretical volume only The volume of the compartment necessary to account for the total amount of drug Assuming the drug is present throughout the body in the same concentration as it is in the plasma
  41. 41. Volume of Distribution Vd will vary between different drugs according to: Lipid and water solubility High lipid solubility lets the drug cross membranes Plasma or tissue protein binding properties High protein binding leaves less drug circulating in the plasma
  42. 42. Volume of Distribution Vd = X Cp Where X = total amount of drug in body Cp = plasma concentration of drug
  43. 43. Imagine the body was a bucket Dose In Overflow into tissues Excretion Blood stream Tissues
  44. 44. A low volume of distribution tells us that the drug is mainly confined to blood and body water Very little has ‘overflowed’ into the tissues
  45. 45. A high volume of distribution tells us that the drug is widely distributed to the tissues A lot has ‘overflowed’ into the tissues
  46. 46. ENTEROHEPATIC CIRCULATION A number of drugs undergo glucuronide conjugation  excreted in bile reach intestines  drugs undergo hydrolysis by intestinal bacteria  reabsorption of parent drug  HELPS TO SUSTAIN THE PLASMA CONCENTRATION
  47. 47. Following drugs undergo enterohepatic cycling EXCEPT A. Erythromycin B. Doxycycline C. Oral contraceptives D. Gentamicin
  48. 48. PLASMA PROTEIN AND TISSUE BINDING Like many natural substances drugs too circulate around the body (Iron, Copper, Cortisol)
  49. 49. PLASMA PROTEIN BINDING Most drugs possess physiochemical affinity for plasma proteins Significant for few drugs like phenytoin, warfarin, tolbutamide
  50. 50. FACTORS MODIFY PROTEIN BINDING Disease: May modify protein binding of drugs Eg. chronic renal failure  products of metabolism compete for binding sites  decreased protein binding of drugs Hypoalbuminemia  dec binding  inc free drug  inc.toxicity eg phenytoin Chronic liver disease inc bilirubin compete for pp binding  inc.free drug  toxicity eg. Diazepam, theophylline
  51. 51. Clinically significant implications High Protein binding  restricted to vascular compartment  dec Vd Bound form is not available for action Forms the temporary storage site in equilibrium with the free drug High degree of PP binding not available for metabolism or elimination makes the drug long acting
  52. 52. Clinically significant implications Plasma concentration refers to bound and free drug One drug can bind to many sites More than one drug can bind to same site Displacement reactions  drugs bind with higher affinity will displace that bound with lower affinity eg. salicylates displace tolbutamide Indomethacin displace warfarin
  53. 53. PENETRATION INTO BRAIN AND CSF Lipoidal  limit the entry of non-lipid soluble drugs Efflux carriers like P-glycoprotein extrude many drugs Inflammation of meninges  increases permeability Enzymatic BBB  MAO, cholinesterase present in capillary walls  do not allow catecholamines, Acetyl choline
  54. 54. PASSAGE ACROSS PLACENTA placental membranes are lipoidal Allow free passage of lipophilic drugs Restrict hydrophilic drugs P-glycoprotein limit fetal exposure to maternally administered drugs Incomplete barrier  almost any drug taken by mother can affect the fetus & new born
  55. 55. Spot the drug which doesnot cross the placental barrier a. Ethyl alcohol b. Heparin c. Phenytoin d. Tetracyclines
  56. 56. TISSUE STORAGE Examples of some drugs and their storage sites Digoxin  Heart Chloroquine  Retina Atropine  Iris Tetracyclines  Bone and teeth Iodine  Thyroid Chlorpromazine  Brain Thiopentone  Adipose tissue
  57. 57. METABOLISM
  58. 58. BIOTRANSFORMATION What is it ? Types Changes CP450 Enzyme Induction Enzyme Inhibition Factors Affecting it First pass metabolism
  59. 59. CLASSIFICATION Non synthetic / phase I reaction - metabolite may be active or inactive Synthetic / conjugation / Phase II reaction - metabolite is mostly inactive
  60. 60. PHASE I (NONSYNTHETIC REACTIONS) OXIDATION REDUCTION HYDROLYSIS CYCLIZATION DECYCLIZATION
  61. 61. PHASE II (SYNTHETIC REACTIONS) GLUCURONIDE CONJUGATION ACETYLATION METHYLATION SULFATE CONJUGATION GLYCINE CONJUGATION GLUTATHIONE CONJUGATION
  62. 62. Non synthetic reactions are all of the following except a. Glucuronide conjugation b. Oxidation c. Reduction d. Hydrolysis.
  63. 63. Synthetic reactions are the following except a. Glucuronide conjugation b. Acetylation c. Methylation d. Hydrolysis
  64. 64. MICROSOMAL ENZYME INDUCTION Many drugs, insecticides increase the synthesis of microsomal enzyme protein specially Cytochrome P450 and glucuronyl transferase increased rate of metabolism of inducing drugs and other drugs.
  65. 65. INDUCING SUBSTANCES Barbecued meat, Barbiturates * D.D.T * Phenytoin * Chronic Alcohol * INH * Rifampicin * Griseofulvin * Tobacco smoke Occurs within few days Lasts for 2 – 3 weeks
  66. 66. CLINICAL RELEVANCE Drug interactions: Failure of contraception with OCP, Warfarin Disease may result: Phenytoin  Vit D Tolerance: Alcohol, Rifampin Increase variability in response to drugs: Alcohol, heavy smoking Drug Toxicity: Rifampicin with Paracetamol Production of hepatotoxic metabolite Precipitation of acute intermittent porphyria May interfere with adjustment of dose (eg.) Oral anticoagulants
  67. 67. MICROSOMAL ENZYME INHIBITION Inhibition of metabolizing enzymes Increase concentration of metabolized drugs Fast time course Effects are more selective and profound Toxicity (eg.) Cimetidine CP450 enzyme inhibitors Erythromycin Quinolones Omeprazole, ketoconazole
  68. 68. INTERACTING DRUGS Theophylline Warfarin Terfenadine
  69. 69. Identify the microsomal enzyme inducer a. Ofloxacin b. Rifampin c. Clarithromycin d. Allopurinol
  70. 70. FIRST PASS METABOLISM (presystemic metabolism) DEFINITION: Metabolism of a drug during its passage from the site of absorption into the systemic circulation SITES – Intestinal wall, liver, skin, lungs Clinical relevance: important Determinant of “ORAL BIO AVAILABILITY” EXAMPLES: Low – Theophylline Intermediate – Aspirin High – Morphine (not given orally) - Propranolol (high oral dose)
  71. 71. If first pass metabolism is HIGH 1. Oral dose higher than sublingual or parenteral dose 2. Oral bio availability in liver disease 3. Bio availability of competing drug 4.marked individual variation in the oral dose
  72. 72. Drug which has extensive first pass metabolism is a. Lorazepam b. Sulfonamides c. Propranolol d. Amoxicillin
  73. 73. EXCRETION
  74. 74. OUTLINE Types of drug elimination Vital facts of drug elimination Pharmacokinetic parameters Drug dosage Dosing schedule Therapeutic drug monitoring Prolongation of drug action
  75. 75. KIDNEY filtration secretion (reabsorption) LIVER metabolism secretion LUNGS exhalation OTHERS mother'smilk sweat, salivaetc. Elimination of drugsfromthebody M A J O R M I N O R
  76. 76. Probenecid increases the duration of action of A. Erythromycin B. Atropine C. Penicillin D. Ciprofloxacin
  77. 77. RENAL TUBULAR EXCRETION DRUGS COMPETE for active transport utilizing the same carrier Eg. PENICILLIN + PROBENACID PROBENACID competes with PENICILLIN for secreting into tubules  penicillin stays back not secreted  penicillin stays in blood for a long time  increased duration of action of penicillin Quinidine decreases the clearance of digoxin
  78. 78. Acidic drugs are excreted better at a. Acidic pH b. Alkaline pH c. Neutral pH d. Un ionized state
  79. 79. RENAL TUBULAR REABSORPTION If fluid becomes more alkaline  acidic drug ionizes  becomes less lipid soluble  decreased reabsorption  increased elimination Eg. Aspirin overdose : sodium bicarbonate is given to alkalinize urine  increased elimination of aspirin
  80. 80. Other routes: Common route of excretion: Definition: Vital facts: Process by which metabolites and drugs are eliminated from the body Urine Feces, saliva,sweat,breast milk Effect of old age: Decreased renal function PHARMACOKINETICS: EXCRETION
  81. 81. BREAST MILK Examples for drugs taken by the mother pose HAZARD in suckling child: Theophylline  asthma – irritability, disturbed sleep (eliminated slowly) Anticancer, Antidepressants Antiepilepsy drugs Antipsychotics Beta blockers Aspirin, hormones, some anti microbials
  82. 82. ENTEROHEPATIC CIRCULATION A number of drugs undergo glucuronide conjugation  excreted in bile reach intestines  drugs undergo hydrolysis by intestinal bacteria  reabsorption of parent drug  HELPS TO SUSTAIN THE PLASMA CONCENTRATION
  83. 83. Hofmann elimination of drug occurs with a. Pancuronium b. Corticosteroids c. Morphine d. Atracurium
  84. 84. KINETICS OF ELIMINATION
  85. 85. Elimination • Zero order: constant rate of elimination irrespective of plasma concentration. • First order: rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time. Rate of elimination ∝ Amount Rate of elimination = K x Amount
  86. 86. Zero order kinetics is exhibited by A. Phenobarbitone B. Ampicillin C. Doxycycline D. Ethyl alcohol
  87. 87. PHARMACOKINETICS HELPS TO OPTIMIZE DRUG THERAPY  DOSE  DOSAGE REGIMEN  DOSAGE FORM
  88. 88. • Dose: The quantity of drug administered at one time • 500mg of Paracetamol • Dosage: The amount of the drug that should be given over time • 500 mg Paracetamol TID for 3 days DOSE Vs DOSAGE
  89. 89.  Can be studied by measuring  The concentrations of the Drug and metabolites  In blood and/or urine  Over periods of time  after dosing The pharmacokinetic process
  90. 90. PHARMACOKINETIC PARAMETERS BIOAVAILABILITY VOLUME OF DISTRIBUTION CLEARANCE HALF-LIFE PROTEIN BINDING
  91. 91. PK PARAMETERS  Bioavailability  quantifies absorption  Volume of distribution  quantifies distribution  Clearance  quantifies elimination  Half-life  secondary PK parameter
  92. 92. PRINCIPLE Elimination of drugs from the body usually follows first order kinetics with a characteristic half-life (t1/2) and fractional rate constant (Kel).
  93. 93. • Half life is the time required to reduce the plasma concentration to 50% of its original value • Will determine dosing requirements / how long a drug will remain in the body • Used in determining dosing interval DRUG HALF-LIFE (t1/2 )
  94. 94. • 1 t1/2 - 50 % drug is eliminated • 2 t1/2 - 50+25 (75 %) drug is eliminated • 3 t1/2 - 50+25 +12.5 (87.5 %) drug is eliminated • 4 t1/2 - 50+25 +12.5+6.25 (93.7 %) drug is eliminated Thus, nearly complete drug elimination occurs in 4-5 half lives. DRUG HALF-LIFE (t1/2 )
  95. 95. Onrepeateddosing ofadrugwithplasmahalf-lifeof6hours undergoing firstorder kinetics ofeliminationwill reachsteadystateconcentration after a. 12 hours b. 15 hours c. 30 hours d. 60 hours
  96. 96. 50 25 12.5 6.25 3.12 1.56 DRUG HALF-LIFE (t1/2 )
  97. 97. PRINCIPLE The half-life of elimination of a drug (and its residence in the body) depends on its clearance and its volume of distribution t1/2 is proportional to Vd t1/2 is inversely proportional to CL t1/2 = 0.693 x Vd/CL
  98. 98. Pharmacokinetic parameters • Volume of distribution Vd = DOSE / C0 • Plasma clearance Cl = Kel .Vd • plasma half-life t1/2 = 0.693 / Kel • Bioavailability (AUC)x / (AUC)iv Get equation of regression line; from it get Kel, C0 , and AUC
  99. 99. Knowledge of pharmacokinetic data about a drug tells us:  What dose to give  How often to give it  How to change the dose in certain clinical conditions  How some drug interactions occur
  100. 100. Dosing • Dosing Interval - How often the drug should be given • Loading dose – Which puts the plasma concentration in the therapeutic range • Maintenance dose - Routine smaller doses to maintain the steady state (Plateau)
  101. 101. Loading dose to fill up the tissues Dose In Overflow into tissues Excretion Blood stream Tissues
  102. 102. Uses of Volume of Distribution Imagine a bucket with a leak You give a loading dose to fill up the bucket in the first place After that you only need to give enough to replace the amount leaking out. This is the maintenance dose.
  103. 103. Concentration due to a single dose Concentration due to repeated doses The time to reach steady state is ~4 t1/2’s
  104. 104. DOSING SCHEDULE  To specify an initial dose  To specify a maintenance dose  Dose calculation by body weight and surface area
  105. 105. DRUG DOSAGE  Fixed dose – desired effect well below toxic dose eg analgesics  Variable dose – with crude adjustments eg antidepressants  Variable dose – with fine adjustments eg antidiabetics, antihypertensives  Maximum tolerated dose – anticancer drugs, some antimicrobials  Minimum tolerated dose – long term corticosteroid therapy
  106. 106. THERAPEUTIC DRUG MONITORING  As a guide to the effectiveness of drug therapy – plasma gentamicin & other antimicrobials, theophylline  To reduce the risk of ADR – Lithium, aminoglycosides  To check the patient compliance – anti epilepsy drugs  To diagnose and to treat overdose
  107. 107. PROLONGATION OF DRUG ACTION  Large dose  Vasoconstriction – adrenaline along with local anesthetic  Slowing of metabolism  Delayed excretion – probenecid with penicillin  Alteration of chemical structure – BZDines  Modified release systems – sustained release, depot preparations, hyaluranidase
  108. 108. SUMMARY
  109. 109. Pharmacokinetic Process Extravascular Administration Intravascular Administration Gut Wall Body tissues Blood Liver Kidney ABSORPTION DISTRIBUTION METABOLISM EXCRETION
  110. 110. PHARMACOKINETICS DETERMINE ROUTE OF ADMINISTRATION OF THE DRUG DOSE LATENCY OF ONSET TIME OF PEAK ACTION DURATION OF ACTION FREQUENCY OF ADMINISTRATION
  111. 111. PHARMACOKINETIC PARAMETERS BIOAVAILABILITY VOLUME OF DISTRIBUTION CLEARANCE HALF-LIFE PROTEIN BINDING
  112. 112. Pharmacokinetic data about a drug tells us: What dose to give How often to give it How to change the dose in certain medical conditions How some drug interactions occur
  113. 113. PRINCIPLE The absorption, distribution and elimination of a drug are qualitatively similar in all individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually and doses adjusted accordingly.
  114. 114. The good physician treats the disease; The great physician treats the patient who has the disease ! WILLIAM OSLER 1849 - 1919
  115. 115. QUESTIONS IN PHARMACOKINETICS
  116. 116. ESSAYS Explain the term bioavailability. Explain factors modifying bioavailability. 1 Discuss drug absorption and factors affecting it. 2 Discuss biotransformation reactions with appropriate examples 3
  117. 117. 1. Explain factors affecting bioavailability with suitable examples. 2. Explain protein binding of drugs with suitable examples. Give its clinical importance 3. Describe redistribution of drugs with examples 4. Definition of biotransformation of drugs. Two examples for synthetic biotransformation reactions. 5. Explain the clinical importance of plasma half life with examples. 6. Write briefly on bio-in equivalence. 7. Explain with an example how urinary pH influences drug excretion 8. Write two drugs inducing microsomal enzymes. give one example and its clinical relevance SHORT NOTES (5 marks)
  118. 118. Explain briefly the following terms with examples , giving the clinical significance of each of them 1. Enzyme induction 2. enzyme inhibition 3. Plasma half- life 4. Zero order kinetics. 5. First pass metabolism SHORT NOTES
  119. 119. ANYWAY……

This interesting and useful ppt highlights different pharmacokinetic concepts with illustrations for easy understanding - an overview for revision for medical and paramedical students

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