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Drug Excretion and Elimination Kinetics

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Presentation made by Dr. Resu Neha Reddy, M.D. Pharmacology, Osmania Medical College. The presentation is about excretion of the drugs by kidneys, liver and other routes and kinetics of elimination, which includes zero, first and mixed (Michaelis - Menton equation) order kinetics. It also includes information regarding clearance, half-life, loading dose, maintenance dose and fixed dose drug combinations.

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Drug Excretion and Elimination Kinetics

  1. 1. DRUG EXCRETION AND ELIMINATION KINETICS By Dr. Resu Neha Reddy 1st Year PG MD PHARMACOLOGY OMC
  2. 2. Excretion  After being absorbed and biotransformed the drugs or their metabolites must be excreted out of the body  ELIMINATION = BIOTRANSFORMATION + EXCRETION  The process by which the body gets rid of the drug or its metabolites is EXCRETION Drug excretion and elimination kinetics ……
  3. 3. REMEMBER !! Drug excretion and elimination kinetics …… ELIMINATED / DO NOT CROSS THE MEMBRANE RE-ABSORBED/ CROSSES THE MEMBRANE POLAR/ WATER SOLUBLE / IONISED NON-POLAR/ LIPID SOLUBLE/ UN-IONISED
  4. 4. Drug excretion and elimination kinetics ……
  5. 5. ORGANS INVOLVED MAJOR ROUTES : Kidney Biliary / hepatic Pulmonary faecal MINOR ROUTES : Saliva Skin, Sweat Tears Breast milk Vaginal fluids Drug excretion and elimination kinetics ……
  6. 6. Renal Excretion Structure of Kidney :  The structural unit of kidney is NEPHRON  Consists of : Glomerulus Proximal convoluted tubules Henle’s loop (Descending - Ascending) Distal convoluted tubules Collecting ducts Drug excretion and elimination kinetics ……
  7. 7. Normal Kidney Functions  Regulation of electrolytes (Aldosterone)  Regulation of water balance (Anti-diuretic harmone)  Excretion of wastes & drug metabolites such as Urea Uric acid Creatinine Drug excretion and elimination kinetics ……
  8. 8. RENAL EXCRETION  Three processes are involved : Glomerular filtration Active tubular secretion Passive tubular reabsorption Drug excretion and elimination kinetics ……
  9. 9. Glomerular filtration Drug excretion and elimination kinetics ……
  10. 10. Glomerular Filtration  Blood is filtered across a semi-permeable membrane into Bowman’s Capsule  Driving force – Hydrostatic pressure of blood flowing in capillaries  Filtrate : Water, glucose, amino acids, sod.bicarbonates, organic solutes & electrolytes (sodium, potassium, chloride)  Not filtered : Blood cells, platelets, plasma proteins  Depends upon renal blood flow Drug excretion and elimination kinetics ……
  11. 11. Drug excretion and elimination kinetics …… Glomerular Filtration Rate  The amount of blood filtered by the glomeruli in a given time  GFR is used as a marker or indicator for kidney function  GFR determined by : Creatinine, Inulin (Inulin is easily filtered not reabsorbed)  Slow decline in renal function, ~1% per year
  12. 12. Factore influencing Glomerular Filtration  Molecular size : Small molecular size are filtered >20,000 not filtered (e.g. Heparin, Dextran & Insulin)  Plasma protein binding : Free drugs can be filtered Protein binding decreases renal excretion (e.g.Warfarin)  Renal blood flow : Greater the glomerular perfusion, faster is the drug removal Drug excretion and elimination kinetics ……
  13. 13. Drug excretion and elimination kinetics ……
  14. 14. Active Tubular Secretion  Glomerular filtration removes 20% of drug  The rest 80% secreted Proximal tubule  Tubular secretion Energy-requiring carrier-mediated active transport  Protein binding – Do not interfere tubular secretion  Decrease in plasma concentration of free drug dissociate protein-bound drug Drug excretion and elimination kinetics ……
  15. 15. Active Tubular Secretion  Transports drugs against concentration gradients between blood & filtrate  Secretion of ionized drugs into lumen (e.g. Penicillin)  Requires carriers ( Transporters : Organic anionic & cationic )  Saturable  Not specific ( Competition may happen )  Compound commonly used to measure – PAH, Diodrast Drug excretion and elimination kinetics ……
  16. 16. Active Tubular Secretion  Two independent carrier systems : 1) Acidic drugs - e.g. Penicillin, Salicylic acid, Thiazide diuretics, Probenecid, Indomethacin, Sulfonamides Endogenous – Uric acid 2) Basic drugs - e.g. Morphine, Quinine, Neostigmine, Procaine, Atropine Endogenous – Dopamine, Choline, Histamine, Serotonin Drug excretion and elimination kinetics ……
  17. 17. Competitive Active Tubular Secretion  Two structurally similar drugs having similar ionic charge and employing the same carrier-mediated process for excretion enter into competition  A drug with greater rate of excretion will retard the excretion of other drug with which it competes  The half – life of both drugs is increased since the total sites for active secretion are limited Drug excretion and elimination kinetics ……
  18. 18. Beneficial Competition :  Probenecid on Penicillin & Amoxycillin : Probenecid competitively inhibits tubular secretion of Penicillin and Amoxycillin increasing plasma half – life and effectiveness of these drugs in infective conditions Drug excretion and elimination kinetics ……
  19. 19. Harmful Competition : 1) Weakly acidic drugs (e.g. Lactic acid, Salicylic acid) interfere secretion of endogenous substance, Uric acid GOUT 2) Probenecid inhibits renal secretion of Nitrofurantoin thus decreases its efficacy in Urinary Tract Infections (UTIs) Drug excretion and elimination kinetics ……
  20. 20. Drug excretion and elimination kinetics ……
  21. 21. REMEMBER !!  Only nonionized and lipid soluble drug are Reabsorbed  Ionized or polar drugs are Excreted  Weak acids are excreted in basic medium  Weak bases are excreted in acidic medium  Urine is normally slightly acidic and favours excretion of basic drugs Drug excretion and elimination kinetics ……
  22. 22. Tubular Re-absorption of Drugs  After glomerular filtration, drugs may be reabsorbed from tubular lumen back into systemic blood circulation  Renal tubule Typical lipid barrier Distal region  Re-absorption increases half-life of a drug  Re-absorption may be PASSIVE or ACTIVE Drug excretion and elimination kinetics ……
  23. 23. Passive Tubular Re-absorption  Depends upon : Lipid solubility Ionisation constant ( pKa ) of the drug % of ionised & pH of the urine unionised drug Drug excretion and elimination kinetics ……
  24. 24. Active Tubular Re-absorption of Drugs  Occurs in endogenous substances or nutrients that the body needs to conserve (e.g. glucose, electrolytes, aminoacids, uric acid, vitamins)  Probenecid acts as a uricosuric agent in treatment of Gout It increases excretion of uric acid in urine by inhibiting active tubular re-absorption of endogenous metabolite uric acid Drug excretion and elimination kinetics ……
  25. 25. Urinary pH trapping ( Ion trapping )  Changing pH of urine by chemicals can inhibit or enhance the tubular drug re-absorption back into blood  Ion trapping is used to enhance renal clearance of drugs during toxicity  Urine is normally slightly acidic and favours excretion of basic drugs Drug excretion and elimination kinetics ……
  26. 26. Urinary pH trapping ( Ion trapping )  Alkalization of urine using Sodium bicarbonate (NaHCO3) or Sodium citrate increases excretion of acidic drugs as Aspirin, Barbiturates, Sulfonamides  Acidification of urine using Ammonium chloride (NH4Cl) increases excretion of basic drugs as Morphine, Amphetamine Drug excretion and elimination kinetics ……
  27. 27. Factors affecting renal excretion of drugs  Physiochemical properties of drugs 1) Molecular weight 2) Lipid solubility 3) Degree of ionization 4) Volume of distribution 5) Binding character  Biological factor e.g. Age  Disease states  Urine pH Drug excretion and elimination kinetics ……
  28. 28. RENAL EXCRETION DRUG EXCRETED = ( FILTERED + SECRETED ) – RE ABSORBED Drug excretion and elimination kinetics ……
  29. 29. Drug excretion and elimination kinetics …… Biliary Excretion  Transporters are present in the canalicular membrane of hepatocytes  P-gp & BCRP or ABCG2 transport amphipathic lipid soluble drugs  MRP2 Secretion of conjugated metabolites (e.g. Glutathione conjugates, Glucoronides and Sulfates)  Secretory transpoters also expressed on apical membrane of enterocytes  Elimination through bile : E.g. Quinine, Colchicine, D-tubocurarine, Corticosteroids & Erythromycin
  30. 30. Drug excretion and elimination kinetics …… Biliary Excretion  Enterohepatic circulation : E.g. Digitoxin, Vitamin D3, Indomethacin  Drugs excreted in bile in form of glucoronides will be hydrolized in intestine by bacterial flora liberating free drugs that can be reabsorbed back into blood if lipid soluble  E.g. Digoxin, Morphine, thyroxine, Chloramphenicol, Tetracycline  Thus prolongs duration of action
  31. 31. Drug excretion and elimination kinetics …… Biliary Excretion EXAMPLES :  Mercury poisoning – Resin administered orally binds with Dimethyl mercury excreted in the bile preventing re-absorption & toxicity  Ezetimibe – Drug that specifically reduces intestinal absorption of cholesterol. Interfere with sterol transporter system Prevent both free cholesterol and plant sterols absorption Drug – rapidly absorbed and glucoronidated to active metabolite in intestine Drug taken up by liver from portal blood and excreted in bile Half-life - >20 hours BENEFIT – Reduction in LDL cholesterol
  32. 32. Drug excretion and elimination kinetics …… Pulmonary Excretion  Gaseous and volatile substances such as general anesthetics are absorbed through lungs by simple diffusion  Factors affecting : Pulmonary blood flow Rate of respiration Solubility of substances  Alcohol which has high solubilty in blood and tissues are excreted slowly by lungs  Eucalyptus oil & garlic oil are eliminated through expectoration
  33. 33. Drug excretion and elimination kinetics …… Faecal Excretion  Orally ingested drugs which are not absorbed E.g. Magnesium sulfate, Streptomycin, Neomycin, Bacitracin, Purgatives  Drugs excreted through bile and not re-absorbed from gut E.g. Erythromycin & Corticosteroids
  34. 34. Drug excretion and elimination kinetics …… Excretion through Breast Milk  Basic drugs : Chloramphenicol, Tetracyclines, Ergotamine, Morphine, Metronidazole, Immunosuppressives, Bromocriptine, OCPs, Purgatives  Acidic drugs : Sulfonamides, Penicillin, Ampicillin, Phenobarbitone, Phenytoin  Ethanol & Urea enter breastmilk readily ,independent of pH
  35. 35. Drug excretion and elimination kinetics …… Salivary Excretion  pH of saliva varies from 5.8 to 8.4  Unionized lipid soluble drugs are excreted passively  The bitter after taste in the mouth of a patient is an indication  E.g. Caffeine, Phenytoin, Theophylline, Iodine, Potassium iodide, Lithium
  36. 36. Drug excretion and elimination kinetics …… Excretion through Skin, Hair, Sweat DRUG EXCRETORY ORGAN Griseofulvin Skin (keratin precursor cells) Arsenic, Mercury salts, Iodide Hair follicles Amines & Urea Sweat
  37. 37. Clearance  Volume of biological fluid which is completely cleared of the drug per unit time  The units of Clearance – (volume/time) mL/min or L/hr Drug excretion and elimination kinetics …… CLEARANCE = Us x V Ps
  38. 38. Drug excretion and elimination kinetics ……
  39. 39. Drug excretion and elimination kinetics ……
  40. 40. Clearance Clearance = Rate of Elimination Plasma concentration Drug excretion and elimination kinetics …… Clearance = Rate of Elimination Plasma concentration CL RENAL = RATE OF FILTRATION + RATE OF SECRETION – RATE OF RE-ABSORPTION PLASMA CONCENTRATION
  41. 41. Drug excretion and elimination kinetics …… CL R = dX / dt C CL R = Renal Clearance dX / dt = Elimination Rate Constant C = Concentration of drug in plasma CL R = Ke X C Ke = First order elimination rate constant X = Amount of drug in the body remaining to be eliminated at time T CL R = Ke Vd Where X / C = Vd then above equation becomes
  42. 42. Estimation of Creatinine Clearance Drug excretion and elimination kinetics ……  The Cockcroft – Gault Equation is used MALE Cr CL = (140 – age) x Body Weight Serum Creatinine x 72 FEMALE Cr CL = (140 – age) x Body Weight x 0.85 Serum Creatinine x 72
  43. 43. Estimation of Creatinine Clearance Drug excretion and elimination kinetics …… In ICU 80-yr-old man Serum Creatinine Levels = 1 mg/100mL Creatinine Clearance = 60 mL/min In ICU 40-yr-old man Serum Creatinine Levels = 1 mg/100mL Same weight Creatinine Clearance = 100 mL/min Thus, normal serum creatinine values in patients in ICU may sometimes be associated with significant impairment of renal function
  44. 44. Drug excretion and elimination kinetics …… Total Body Clearance ( CLTOTAL ) = CLRENAL + CLHEPATIC + CLOTHER Rate of Elimination = Q CA - Q CV = Q ( CA - CV ) Q = Blood flow CA = Arterial drug concentration CV = Venous drug concentration CL ORGAN = Q [ CA - CV ] CA Extration Ratio ( E ) = [ CA - CV ] CA CL ORGAN = Q E
  45. 45. Drug excretion and elimination kinetics …… CORRECTED DOSE Corrected Dose = Normal Dose x Patient’s creatinine clearance Normal creatinine clearance (100ml/min) Q : Normal TD = 100 mg IV BD entirely glomerular filtration Creatinine clearance = 33 ml/min Corrected Dose = ?? Q : 70% kidney 30% liver TD = 100 mg/day Creatinine clearance = 50 ml/min Corrected Dose = ?? 33 mg IV BD 65 mg / day
  46. 46. HALF - LIFE Drug excretion and elimination kinetics ……  The time duration in which the plasma concentration of the drug falls by 50%  The BIOLOGICAL EFFECT HALF-LIFE is the time duration in which the priniciple pharmacological effect of the drug declines by half  Does not reflect absorption kinetics  Reflects on elimination ( clearance ) kinetics 100 50 T ½ = 0.693 k T ½ = 0.693 x Vd CL
  47. 47. Drug excretion and elimination kinetics …… KINETICS OF DRUG ELIMINATION PART - II
  48. 48. Drug excretion and elimination kinetics ……  HALF-LIFE  STEADY STATE CONCENTRATION  ORDER OF KINETICS  FIRST ORDER KINETICS  ZERO ORDER KINETICS  MIXED ORDER KINETICS  LOADING DOSE  MAINTENANCE DOSE  FIXED-DOSE DRUG COMBINATIONS CONTENTS :
  49. 49. HALF - LIFE Drug excretion and elimination kinetics ……  The time duration in which the plasma concentration of the drug falls by 50%  The BIOLOGICAL EFFECT HALF-LIFE is the time duration in which the priniciple pharmacological effect of the drug declines by half  This is not regarded as fundamental parameter – as it is determined by  Clearance  Volume of Distribution  Reflects on elimination ( clearance ) kinetics 100 50 T ½ = 0.693 k T ½ = 0.693 x Vd CL
  50. 50. HALF - LIFE Drug excretion and elimination kinetics …… DRUG CLEARANCE (L / hr ) VOLUME OF DISTRIBUTION ( L ) HALF-LIFE ( hrs ) Ethosuximide 0.7 49 48 Flucytosine 8 49 4.2 Digoxin 7 420 40 Choloroquine 45 12,950 200 T ½ α Vd CL
  51. 51. Drug excretion and elimination kinetics …… 1) Determines the duration of action After a single dose, how longer the drug plasma concentration will stay in effective range Clinical significance of half-life 2) Determines the time required to reach steady state concentration It takes 5 half-lives to reach 97% of steady state concentration
  52. 52. THERAPEUTIC WINDOW Drug excretion and elimination kinetics ……
  53. 53. Drug excretion and elimination kinetics ……  To attain the steady-state condition, rate of infusion = rate of elimination  True steady-state concentration ( Cpss ) will be attained theoritically only at time INFINITY  After 5 half-lives steady state level is reached Time & Steady State 50% = 1 x Half-life 90% = 3.3 x Half-life 95% = 4 to 5 x Half-life ( CLINICAL ) STEADY STATE CONCENTRATION E.g. Half-life = 5 hrs Steady state = ?? Ans. 4 x 5 = 20 or 5 x 5 = 25 = 20 to 25 hrs ( CLINICAL )
  54. 54. Drug excretion and elimination kinetics ……
  55. 55. ORDER OF KINETICS Drug excretion and elimination kinetics ……  FIRST - ORDER KINETICS  ZERO - ORDER KINETICS  MIXED – ORDER KINETICS n = 1 n = 0 n = variable
  56. 56. FIRST - ORDER KINETICS Drug excretion and elimination kinetics ……  Majority of drugs obey First – Order Kinetics 1) A constant fraction of drug is eliminated at constant interval of time 2) Rate of drug elimination is directly proportional to the plasma concentration 100 50 25 50% 50% 50% 2 hr 2 hr 2 hr And so on 100 50 25 And so on200 50% 2 hr 50% 2 hr 50% 2 hr 50% 2 hr
  57. 57. HALF – LIFE IN FIRST-ORDER KINETICS Drug excretion and elimination kinetics ……  T1/2 for one compartment model = 0.693 K = Elimination Rate Constant K 0.693 = log 2  T1/2 for multi-compartment model = 0.693 x Vss (Vss=Volume of drug at steady state) CL
  58. 58. FIRST - ORDER KINETICS Drug excretion and elimination kinetics …… 3) Half-life remains constant irrespectibe of the dose Slope = - K 2.303 4) Plasma Fall-Out Curve - Curvilinear & logarithms – Linear
  59. 59. FIRST - ORDER KINETICS Drug excretion and elimination kinetics …… 5) After a single dose, 97% of drug gets eliminated in 5 half-lives 6) For multiple dose,it takes 5 half-lives to reach steady state level 100 50 25 50% 2 hr 12.5 6.25 3.125 50% 2 hr 50% 2 hr 50% 2 hr 50% 2 hr
  60. 60. FIRST - ORDER KINETICS Drug excretion and elimination kinetics …… • 7) DOUBLING the dose leads to increase in “one” more half-life 100 50 25 50% 2 hr 50% 2 hr Effect vanishes Duration of effect = 4 hr 100 50 25 50% 2 hr 50% 2 hr 200 50% 2 hr Effect vanishes Duration of effect = 6 hr
  61. 61. FIRST - ORDER KINETICS Drug excretion and elimination kinetics …… 8) The log plasma conc. Fall-out curve – 2 slopes
  62. 62. FIRST - ORDER KINETICS Drug excretion and elimination kinetics ……
  63. 63. SUMMARY FIRST - ORDER KINETICS Drug excretion and elimination kinetics ……  CHARACTERISTICS OF FIRST – ORDER KINETICS : 1) A constant fraction of drug is eliminated at constant interval of time 2) Rate of drug elimination is directly proportional to the plasma concentration 3) Half-life remains constant irrespectibe of the dose 4) Plasma Fall-Out Curve - Curvilinear & logarithms – Linear 5) After a single dose, 97% of drug gets eliminated in 5 half-lives 6) After 5 half-lives steady state level is reached 7) DOUBLING the dose leads to increase in “one” more half-life 8) The log plasma conc. Fall-out curve – 2 slopes
  64. 64. ZERO – ORDER KINETICS Drug excretion and elimination kinetics …… 1) A constant or fixed quantity / amount of the drug is eliminated per unit time 2) Rate of drug elimination is independent of the plasma concentration 50 25 NIL 25 1 hr 25 1 hr 100 75 50 25 1 hr 25 1 hr 25 25 1 hr
  65. 65. Drug excretion and elimination kinetics ……  Drugs following constant amount of drug elimination per unit time ZERO WATT Power W = Warfarin A = Alcohol, Aspirin T = Theophylline T = Tolbutamide P = Phenytoin, Phenylbutazone ZERO – ORDER KINETICS
  66. 66. ZERO – ORDER KINETICS Drug excretion and elimination kinetics …… 3) Half-life is never constant 4) Plasma Fall-Out Curve – steeply Linear & logarithms – Curvilinear T1/2 = [ A ] 2 K
  67. 67. SUMMARY ZERO – ORDER KINETICS Drug excretion and elimination kinetics ……  CHARACTERISTICS OF ZERO – ORDER KINETICS : 1) A constant or fixed quantity of the drug is eliminated per unit time 2) Rate of drug elimination is independent of the plasma concentration 3) Half-life is never constant 4) Plasma Fall-Out Curve – steeply Linear & logarithms – Curvilinear
  68. 68. Drug excretion and elimination kinetics …… Michaelis-Menton Kinetics (Mixed/Saturation) ( 1879 - 1960 ) ( 1875 - 1949 ) Maud Menton & Leonar Michaelis MICHAELIS – MENTON EQUATION : VO = Vmax [ C ] Km + [ C ]
  69. 69. Drug excretion and elimination kinetics …… Michaelis-Menton Kinetics (Mixed/Saturation) MICHAELIS – MENTON EQUATION : VO = Vmax [ C ] Km + [ C ] VO = Rate Vmax = Max. rate of drug elimination [ C ] = Initial plasma drug concentration Km = Michaelis-Menton Constant SCENARIO 1 SCENARIO 2 [ C ] <<< Km Vo α [ C ] Similar to 1st order kinetics [ C ] >>> Km Vo = Vmax Similar to zero-order kinetics
  70. 70. Michaelis-Menton Kinetics (Mixed/Saturation) Drug excretion and elimination kinetics ……  Dose – dependent kinetics  Smaller dose First – Order Kinetics  Larger dose Zero – Order Kinetics  E.g. Phenytoin, Digoxin, Warfarin, Tolbutamide & Aspirin (higher doses)  Plasma Fall – Out Curve – ZERO ORDER – LINEAR FIRST ORDER - CURVILINEAR  On log scale – ZERO ORDER – CURVILINEAR FIRST ORDER - LINEAR
  71. 71. Design and Optimization of Dosage Regimen Drug excretion and elimination kinetics ……  Very short half-life Constant IV infusion E.g. Nor-epinephrine(1-2min), Dopamine(5min), Oxytocin(3-5min)  Between 30min to 2 hrs Dose is increased so as to administer every 6-8 hourly E.g. Cephalaxin <1hr, Benzylpenicillin <1hr, Paracetamol 2hrs  Between 4 to 12hrs Every half-life interval  Between 12 to 24hrs 12 hourly interval  Longer half-life Depending upon : Vd, CL RENAL & Accumulation
  72. 72. Design and Optimization of Dosage Regimen Drug excretion and elimination kinetics …… Therapeutic dose = 50 mg Half-life = 24hrs Dosing schedule = 12hourly Dose = ?? 50 x 12 = 25 mg to be given 24 12 hourly interval Digoxin Half-life = ~40 hrs Rate of Clearance = 640 L Desipramine Half-life = 20-60 hrs Rate of Clearance = 30-60 L LOADING DOSE
  73. 73. LOADING DOSE Drug excretion and elimination kinetics ……  It is the large initial dose that is given to achieve rapid therapeutic plasma level  After administration of the drug, the plasma concentration decreases due to distribution of drug to other tissues  This dose balances the drug distribution  This is important for drugs with long half-life Loading Dose = C P x Vd F
  74. 74. Drug excretion and elimination kinetics ……
  75. 75. Drug excretion and elimination kinetics …… MAINTENANCE DOSE  It is the dose required to maintain the therapeutic level of the drug constant or in the steady state level  These doses balance the amount of drug lost during metabolism & clearance  The patient needs to take regular doses of a drug E.g. Amoxicillin (500 mg) 8 hourly to maintain the therapeutic level Maintenance Dose = C P x CL F
  76. 76. Drug excretion and elimination kinetics …… DOSING RATE ( INFUSION RATE ) The rate at which the drug should be administered to achieve a steady state level Dosing Rate ss = Cp x CL F Dosing Rate oral = Dosing Rate ss F oral If intermittent doses are given : Maintenance Dose = Dosing Rate x Dosing Interval F
  77. 77. Drug excretion and elimination kinetics …… LOADING DOSE PROBLEM 1 TD of Theophylline = 10 mg/L to relieve acute bronchial asthma Vd = 35L/70kg ; as drug is given IV - so Bioavailability F = 1 Loading Dose = ?? Loading Dose = Vd x Cp F = 35 x 10 1 = 350 mg
  78. 78. Drug excretion and elimination kinetics …… TD of Theophylline = 10 mg/L to relieve acute bronchial asthma CL = 2.8 L/hr/70kg ; as drug is given IV - so Bioavailability F = 1 Maintenance Dose = ?? MAINTENANCE DOSE PROBLEM 1 Dosing rate = CL x Cp = 2.8 x 10 = 28 mg/hr/70kg F oral = 0.96 Dosing Interval 12 hourly = ?? Maintenance Dose = Dosing rate x Dosing Interval F = 28 x 12hourly 0.96 = 350 mg 12 hourly
  79. 79. Drug excretion and elimination kinetics …… DIGOXIN Target Therapeutic Level = 1-2 μg/L aVd = 640 L LOADING DOSE = Vd x Cp = 640 x 1 = 640 μg/L or = 640 x 2 = 1280 μg/L 0.64 to 1.28 mg IN PRACTICE = 0.9 mg is administered MAINTENANCE DOSE = Usually half the LD 0.45 mg every 40 hours But inconvenient , hence scaled down to 24hours 0.45 x 24 = 0.27 mg 40 IN PRACTICE = 0.25 mg is administered every 24 hours Because of accumulation – 5 days / week
  80. 80. Drug excretion and elimination kinetics …… FIXED – DOSE DRUG COMBINATIONS  The combination of two different drugs in a single pharmaceutical formulations  Rules : 1) Should have approx. equal half-life E.g. Cotrimoxazole – Sulfamethoxozole ( 11 hrs ) + Trimethoprim ( 10 hrs ) Clavulanic acid ( 1-1.5 hr ) + Amoxy/Ampicillin ( 1-1.5 hr ) Carbidopa ( 2 hrs ) + Levodopa ( 1.7 hrs )
  81. 81. Drug excretion and elimination kinetics …… FIXED – DOSE DRUG COMBINATIONS 2) The ratio of doses in each component in a formulation depends on: a) Volume of distribution b) Peak plasma concentration ( at steady state ) E.g. DRUG HALF-LIFE VOLUME OF DISTRINUTION AMOXYCILLIN 1-2 hrs 0.21 L/kg CLAVULANIC ACID 1-1.5 hrs 0.20 L/kg AMOXYCILLIN 500 mg + CLAVULANIC ACID 125 mg 8 hourly
  82. 82. Drug excretion and elimination kinetics …… FIXED – DOSE DRUG COMBINATIONS Minimum Inhibitory Concentration : ?? For synergism optimal ratio of MIC = 1:20 Vd of Sulfamethoxazole = 0.2 L/kg Vd of Trimethoprim = 1-2 L/kg (5-6 times more) Hence given in ratio = 5:20
  83. 83. Drug excretion and elimination kinetics …… FIXED – DOSE DRUG COMBINATIONS  Dosing schedule 1) Convenience and Compliance  Cotrimoxazole - Bactericidal 2) Enhanced effect  Carbidopa & Levodopa 3) Minimization of side effects ADVANTAGES :
  84. 84. Drug excretion and elimination kinetics …… FIXED – DOSE DRUG COMBINATIONS  Cannot be adjusted independently 1) Dose adjustment  Fluctuations in plasma concentration 2) Pharmacokinetics - Do not match  Anemia – Iron + Vit B12 + Folic acid = ??? 3) Harmful / Benficial effects identity DISADVANTAGES :
  85. 85. Drug excretion and elimination kinetics …… “Only the dose makes a thing not a poison.” - Paracelsus
  86. 86. REFERENCES  Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th ed. P.17-40  Bertram G Katzung Basic & Clinical Pharmacology 13th ed. P.37-68  Rang & Dale’s Pharmacology 8th ed. P.98-130  Sunil S Jambhekar & Philip J Breen Basic Pharmacokinetics 1st ed.  Donald J Birkett Pharmacokinetics Made Easy 2nd ed.  Lippincott’s Illustrated Reviews Pharmacology 5th ed.  KD Tripati Essentials of Medical Pharmacology 7th ed. P.10-36  R S Satoskar Pharmacology and Pharmacotherapeutics 24th ed  Sharma & Sharma’s Principles of Pharmacology 3rd ed. P.48-58  Images - web Drug excretion and elimination kinetics ……
  87. 87. Drug excretion and elimination kinetics ……

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