Pharmacokinetics (updated 2011) - drdhriiti


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  • The pH scale is logarithmic and as a result, each whole pH value below 7 is ten times more acidic than the next higher value. For example, pH 4 is ten times more acidic than pH 5 and 100 times (10 times 10) more acidic than pH 6. The same holds true for pH values above 7, each of which is ten times more alkaline (another way to say basic) than the next lower whole value. For example, pH 10 is ten times more alkaline than pH 9 and 100 times (10 times 10) more alkaline than pH
  • A chemical substance that takes on oxygen or gives up electrons to another substance. Read more: Oxidation-Reduction Reaction - examples, body, used, water, process, life, plants, chemical, form, energy, gas, animals, carbon, oxygen, substance, plant, Redox and electron exchanges Reduction: A process in which a chemical substance gives off oxygen or takes on electrons. Read more: Oxidation-Reduction Reaction - examples, body, used, water, process, life, plants, chemical, form, energy, gas, animals, carbon, oxygen, substance, plant, Redox and electron exchanges
  • Faeces: Liver actively transport drugs and its metabolites into bile (Glucoronides). OATP – orgnic acids and OCT – organic bases. Other lipophillic drugs – by P-gp. Most lucoronides are deconjugated by bacteria and reabsorbed in intestine – enterohepatic circulation. Drugs – erythromycin, rifmpicin and tetracycline etc. Ultimate excretion occurs in urine Milk – not importnt for mother but for fetus. Basic drugs can pass to milk as it has slightly lower pH Drugs – Saliva – Lithium, KI, heavy metals and rifampicin
  • Although Cpss cn be calculated, its real value actually varies with individuls – deviation from averge ptients
  • Pharmacokinetics (updated 2011) - drdhriiti

    1. 1. Pharmacokinetics Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. What is Pharmacokinetics <ul><ul><li>how the human body act on the drugs? </li></ul></ul><ul><li>Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. Intensity of effect is related to concentration of the drug at the site of action, which depends on its pharmacokinetic properties </li></ul><ul><li>Pharmacokinetic properties of particular drug is important to determine the route of administration, dose, onset of action, peak action time, duration of action and frequency of dosing </li></ul>
    3. 3. Relationship – Dynamics and Kinetics Dosage Regimen Concentration in Plasma Concentration at the site of action Absorption Distribution Metabolism Excretion Pharmacokinetics Pharmacodynamics Effect
    4. 4. The Pharmacokinetic Process Blood
    5. 5. The Pharmacokinetic Process
    6. 6. Biological Membrane - image
    7. 7. Drug Transportation <ul><li>Drug molecules can cross cell membrane by: </li></ul><ul><ul><li>Passive Diffusion </li></ul></ul><ul><ul><li>Protein – mediated transport (carrier mediated) </li></ul></ul><ul><ul><ul><li>Facilitated Transport </li></ul></ul></ul><ul><ul><ul><li>Active trnsport </li></ul></ul></ul><ul><ul><ul><ul><li>Primary </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Secondary </li></ul></ul></ul></ul>
    8. 8. Passive transport (down hill movement) <ul><li>Most important Mechanism for most of the Drugs </li></ul><ul><li>Majority of drugs diffuses across the membrane in the direction of concentration gradient </li></ul><ul><li>No active role of the membrane </li></ul><ul><li>Proportional to lipid : water partition coefficient </li></ul><ul><li>Lipid soluble drugs diffuse by dissolving in the lipoidal matrix of the membrane </li></ul><ul><li>Characteristics </li></ul><ul><ul><li>Not requiring energy </li></ul></ul><ul><ul><li>Having no saturation </li></ul></ul><ul><ul><li>Having no carriers </li></ul></ul><ul><ul><li>Not resisting competitive inhibition </li></ul></ul>
    9. 9. Passive transport <ul><li>Affecting factors : </li></ul><ul><ul><li>the size of molecule </li></ul></ul><ul><ul><li>lipid solubility </li></ul></ul><ul><ul><li>Polarity </li></ul></ul><ul><ul><li>degree of ionization </li></ul></ul><ul><li>PH of the environment </li></ul><ul><li>such as: fluid of body </li></ul><ul><li>fluid in cell </li></ul><ul><li>blood, urine </li></ul>
    10. 10. Remember ! <ul><li>The drugs which are ionized, high polarity and lower lipid solubility are difficult to permeate membrane </li></ul><ul><li>The drugs which are Unionized, low polarity and higher lipid solubility are easy to permeate membrane </li></ul>
    11. 11. pH Effect <ul><li>Most of drugs are weak acids or weak bases </li></ul><ul><li>The ionization of drugs may markedly reduce their ability to permeate membranes </li></ul><ul><li>The degree of ionization of drugs is determined by the surrounding pH and their pKa </li></ul>
    12. 12. Henderson–Hasselbalch Equation <ul><li>pH = pKa + log or, pH = pKa - log </li></ul>pKa = negative logarithm of acid dissociation constant [A-] = ionized Drug [HA] = unionized drug [A-] [HA] [HA-] [A-]
    13. 13. pH Vs ionization
    14. 14. Implications <ul><li>Acidic drugs are absorbed are largely unionized in stomach and absorbed faster while basic drugs are absorbed faster in intestines </li></ul><ul><li>Ion trapping </li></ul><ul><li>Basic drugs attain higher concentration intracellularly </li></ul><ul><li>Acidic drugs are excreted faster in alkaline urine – urinary alkalizers </li></ul><ul><li>Basic drugs are excreted faster in acidic urine – urinary acidifiers </li></ul>
    15. 15. Examples – common concept <ul><li>Bases are - sodium hydroxide, calcium hydroxide, and potassium hydroxide etc. </li></ul><ul><ul><li>Acidic Drugs: </li></ul></ul><ul><ul><ul><li>Phenobarbitone, sulfadiazine, penicillin, aspirin (salicylate) </li></ul></ul></ul><ul><ul><li>Hydrochloric, nitric, sulfuric, acetic, boric, benzoic etc. </li></ul></ul><ul><ul><li>Basic Drugs: </li></ul></ul><ul><ul><ul><li>Atropine, Chloroquine, Ephedrine </li></ul></ul></ul>
    16. 16. Filtration <ul><li>Passage of Drugs through aqueous pores in membrane or through Para cellular space </li></ul><ul><li>Lipid insoluble drugs can cross – if the molecular size is small </li></ul><ul><li>Majority of intestinal mucosa and RBCs have small pores and drugs cannot cross </li></ul><ul><li>But, capillaries have large paracellular space and most drugs can filter through this </li></ul>
    17. 17. Filtration
    18. 18. Carrier Mediated Transport <ul><li>Involve specific membrane transport proteins know as drug transporters or carriers – specific for the substrate </li></ul><ul><li>Drug molecules bind to the transporter, translocated across the membrane, and then released on the on other side of the membrane. </li></ul><ul><li>Specific, saturable and inhibitable </li></ul><ul><li>Depending on Energy requirement - Can be either Facilitated (passive) or Active Transport </li></ul>
    19. 19. Facilitative transporters <ul><li>Move substrate of a single class (uniporters) down a concentration gradient </li></ul><ul><li>No energy dependent </li></ul><ul><li>Similar to entry of glucose into muscle (GLUT 4) </li></ul>
    20. 20. Active Transport – energy dependent <ul><li>Active (concentrative) transporters </li></ul><ul><ul><li>can move solutes against a concentration gradient </li></ul></ul><ul><ul><li>energy dependent </li></ul></ul><ul><li>Primary active transporters - generate energy themselves (e.g. ATP hydrolysis) </li></ul><ul><li>Secondary transporters - utilize energy stored in voltage and ion gradients generated by a primary active transporter (e.g. Na+/K+-ATPase) </li></ul><ul><ul><ul><li>Symporters (Co-transporters) </li></ul></ul></ul><ul><ul><ul><li>Antiporters (Exchangers) </li></ul></ul></ul>
    21. 21. Major Drug Transporters <ul><li>ATP-Binding Cassette Transporters (ABC) Super family – Primary active transport </li></ul><ul><ul><li>P-glycoprotein (P-gp encoded by MDR1) </li></ul></ul><ul><ul><ul><li>Intestinal mucosa, renal tubules and blood brain barrier etc. </li></ul></ul></ul><ul><ul><ul><li>Mediate only efflux of solute from cytoplasm – detoxification </li></ul></ul></ul><ul><li>Solute Carrier (SLC) transporters – Secondary active transport </li></ul><ul><ul><li>Organic anion transporting polypeptides (OATPs) </li></ul></ul><ul><ul><li>Organic cation transporters (OCTs) </li></ul></ul><ul><ul><ul><li>Expressed in liver and renal tubules – metabolism and excretion of drugs </li></ul></ul></ul>
    22. 22. Pinocytosis <ul><li>It involves the invagination of a part of the cell membrane and trapping within the cell of a small vesicle containing extra cellular constituents. The vesicle contents can than be released within the cell, or extruded from the other side of the cell. Pinocytosis is important for the transport of some macromolecules (e.g. insulin through BBB). </li></ul>
    23. 23. Images from Text book
    24. 24. 1. Absorption of Drugs <ul><li>Absorption is the transfer of a drug from its site of administration to the blood stream </li></ul><ul><li>Most of drugs are absorbed by the way of passive transport </li></ul><ul><li>Intravenous administration has no absorption </li></ul><ul><li>Fraction of administered dose and rate of absorption are important </li></ul>
    25. 25. Factors affecting absorption <ul><li>Drug properties: </li></ul><ul><li>Aqueous solubility, lipid solubility, molecular weight, and polarity etc. </li></ul><ul><ul><li>Blood flow to the absorption site </li></ul></ul><ul><ul><li>Total surface area available for absorption </li></ul></ul><ul><ul><li>Contact time at the absorption surface </li></ul></ul><ul><ul><li>Affinity with special tissue </li></ul></ul><ul><li>Routes of Administration (important): </li></ul>
    26. 26. Factors affecting absorption – contd. <ul><li>Route of administration: </li></ul><ul><li>Topical: </li></ul><ul><ul><li>Depends on lipid solubility – only lipid soluble drugs are penetrate intact skin – only few drugs are used therapeutically </li></ul></ul><ul><ul><li>Examples – GTN, Hyoscine, Fentanyl, Nicotine, testosterone and estradiol </li></ul></ul><ul><ul><li>Organophosphorous compounds – systemic toxicity </li></ul></ul><ul><ul><li>Abraded skin: tannic acid – hepatic necrosis </li></ul></ul><ul><ul><li>Cornea permeable to lipid soluble drugs </li></ul></ul><ul><ul><li>Mucus membranes of mouth, rectum, vagina etc, are permeable to lipophillic drugs </li></ul></ul>
    27. 27. Factors affecting absorption – contd. <ul><li>Route of administration: </li></ul><ul><li>Subcutaneous and Intramuscular: </li></ul><ul><ul><li>Drugs directly reach the vicinity of capillaries – passes capillary endothelium and reach circulation </li></ul></ul><ul><ul><li>Passes through the large paracellular pores </li></ul></ul><ul><ul><li>Faster and more predictable than oral absorption </li></ul></ul><ul><ul><li>Exercise and heat – increase absorption </li></ul></ul><ul><ul><li>Adrenaline – decrease absorption </li></ul></ul><ul><ul><li>Hyaluronidase </li></ul></ul><ul><ul><li>Penicillin depot, insulin </li></ul></ul>
    28. 28. Factors affecting absorption – contd. <ul><li>Route of administration: Oral Route </li></ul><ul><li>Dosage forms: </li></ul><ul><ul><li>Particle size </li></ul></ul><ul><ul><li>Disintegration time and Dissolution Rate </li></ul></ul><ul><ul><li>Formulation – Biopharmaceutics </li></ul></ul><ul><li>Physiological factors: </li></ul><ul><ul><li>Lipid solubility, Ionization, pH effect </li></ul></ul><ul><ul><li>Presence of Food </li></ul></ul><ul><ul><li>Presence of Other agents </li></ul></ul><ul><ul><li>Degradation by gastric juice </li></ul></ul><ul><ul><li>Forceful extrusion – P-gp </li></ul></ul>
    29. 29. Oral Administration – 1 st pass metabolism <ul><li>Before the drug reaches the systemic circulation, the drug can be metabolized in the liver or intestine. As a Result, the concentration of drug in the systemic circulation will be reduced. </li></ul>
    30. 30. 1 st pass Elimination – Metabolism in liver Buccal cavity Stomach Intestine Rectum Portal vein Vena cava
    31. 31. Buccal and Rectal – bypasses liver Vena cava
    32. 32. Absorption – contd. <ul><li>Intravenous administration has no absorption phase </li></ul><ul><li>According to the rate of absorption: </li></ul>Inhalation->Sublingual->Rectal->intramuscular->subcutaneous->oral->transdermal Example – Nitroglycerine: IV effect – immediate, SL – 1 to 3 min and per rectal – 40 to 60 minute
    33. 33. Route for administration -Time until effect- <ul><li>Intravenous: 30-60 seconds </li></ul><ul><li>Endotracheal: 2-3 minutes </li></ul><ul><li>Inhalation: 2-3 minutes </li></ul><ul><li>Sublingual: 3-5 minutes </li></ul><ul><li>Intramuscular: 10-20 minutes </li></ul><ul><li>Subcutaneous: 15-30 minutes </li></ul><ul><li>Rectal: 5-30 minutes </li></ul><ul><li>Ingestion: 30-90 minutes </li></ul><ul><li>Transdermal: (topical) variable (minutes to hours) </li></ul>
    34. 34. Bioavailability – Practical Parameter <ul><li>Bioavailability refers to the rate and extent of absorption of a drug from dosage form as determined by its concentration-time curve in blood or by its excretion in urine. It is a measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form </li></ul><ul><li>Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion, because: </li></ul><ul><ul><li>The drug may be incompletely absorbed </li></ul></ul><ul><ul><li>The absorbed drug may undergo first pass metabolism in intestinal wall and/or liver or be excreted in bile. </li></ul></ul><ul><li>Bioequivalent </li></ul><ul><li>Practical Significance – low safety margin drugs </li></ul>
    35. 35. Biovailability - AUC Plasma concentration (mcg/ml) Time (h) 0 5 10 15 AUC p.o. F = ------------ x 100% AUC i.v. AUC – area under the curve F – bioavailability
    36. 36. Biovailability – contd. MTC MEC
    37. 37. 2. Distribution of Drugs <ul><li>It is the passage of drug from the circulation to the tissue and site of its action. </li></ul><ul><li>The extent of distribution of drug depends on its lipid solubility, ionization at physiological pH (dependent on pKa), extent of binding to plasma and tissue proteins and differences in regional blood flow, disease like CHF, uremia, cirrhosis </li></ul><ul><li>Movement of drug - until equilibration between unbound drug in plasma and tissue fluids </li></ul>
    38. 38. Volume of Distribution (V) <ul><li>Definition: Apparent Volume of distribution is defined as the volume that would accommodate all the drugs in the body, if the concentration was the same as in plasma </li></ul><ul><li>Expressed as: in Liters </li></ul><ul><li>V = </li></ul>Dose administered IV Plasma concentration
    39. 39. Volume of Distribution (V) Total Body Fluid = 42 L (approx.)
    40. 40. Volume of Distribution (V) <ul><li>Chloroquin – 13000 liters, Digoxin – 420 L, Morphine – 250 L and Propranolol – 280 L </li></ul><ul><li>Streptomycin and Gentamicin – 18 L </li></ul>(WHY ?) `Vd` is an imaginary Volume of Fluid which will accommodate the entire quantity of the drug in the body, if the concentration throughout this imaginary volume were same as that in plasma
    41. 41. Volume of Distribution (V) Vd = IV dose/C
    42. 42. Factors influencing Vd <ul><li>Lipid solubility (lipid : water partition coefficient) </li></ul><ul><li>pKa of the drug </li></ul><ul><li>Affinity for different tissues </li></ul><ul><li>Blood flow – Brain Vs Fat </li></ul><ul><li>Disease states </li></ul><ul><li>Plasma protein Binding </li></ul>
    43. 43. Clinical Significance - Summary <ul><li>Describes the amount of the Drug present in the body as a multiple of that contained in plasma – together with clearance its useful concept </li></ul><ul><li>Lipid insoluble drugs do not enter cells – Streptomycin, Gentamycin - low Vd </li></ul><ul><li>Extensively high plasma protein bound drugs have low Vd (Warfarin, Diclofenac) </li></ul><ul><li>Drugs sequestrated to other tissues – Propranolol, Digoxin </li></ul><ul><li>Pathological states – CCF, Uraemia, Cieehosis </li></ul>
    44. 44. Redistribution <ul><li>Highly lipid soluble drugs – distribute to brain, heart and kidney etc. immediately followed by muscle and Fats </li></ul>
    45. 45. Brain and CSF Penetration <ul><li>Blood brain barrier (BBB) : </li></ul><ul><ul><li>Tight junction and glial tissue BBB – only lipid soluble drugs – streptomycin </li></ul></ul><ul><ul><li>P-gp and OATP – efflux </li></ul></ul><ul><ul><li>Dopamine and levodopa </li></ul></ul><ul><ul><li>Also MAO – no active Ach entry </li></ul></ul><ul><ul><li>CTZ and Medulla </li></ul></ul>
    46. 46. Brain and CSF Penetration – contd. <ul><li>BBB is lipoidal and limits the entry of non-lipid soluble drugs (amikacin, gentamicin, neostigmine etc.). </li></ul><ul><li>(Only lipid soluble unionized drugs penetrate and have action on the CNS) </li></ul><ul><li>Efflux carriers like P-gp (glycoprotein) present in brain capillary endothelial cell (also in intestinal mucosal, renal tubular, hepatic canicular, placental and testicular cells) extrude drugs that enter brain by other processes. </li></ul><ul><li>(Inflammation of meaninges of brain increases permeability of BBB) </li></ul><ul><li>Dopamine (DA) does not enter brain, but its precursor levodopa does. This is used latter in parkinsonism. </li></ul>
    47. 47. Placental Transfer <ul><li>Only lipid soluble Drugs can penetrate – limitation of hydrophillic drugs </li></ul><ul><li>Placental P-gp serves as limiting factor </li></ul><ul><li>But, REMEMBER, its an incomplete barrier – some influx transporters operate </li></ul><ul><li>Thalidomide </li></ul>
    48. 48. Plasma Protein Binding <ul><li>Plasma protein binding (PPB): Most drugs possess physicochemical affinity for plasma proteins. Acidic drugs bind to plasma albumin and basic drugs to α 1-glycoprotein </li></ul><ul><li>Extent of binding depends on the individual compound. Increasing concentration of drug can progressively saturate the binding sites </li></ul><ul><li>The clinical significant implications of PPB are: </li></ul><ul><li>a) Highly PPB drugs are largely restricted to the vascular compartment and tend to have lower Vd </li></ul><ul><li>b) The PPB fraction is not available for action – acts as storage - equilibrium with free drug in plasma </li></ul>
    49. 49. Plasma Protein Binding – contd. <ul><li>c) High degree of protein binding makes the drug long acting, because bound fraction is not available for metabolism, unless it is actively excreted by liver or kidney tubules </li></ul><ul><li>d) The drugs with high physicochemical affinity for plasma proteins (e.g. aspirin, sulfonamides, chloramphenicol) can replace the other drugs(e.g. acenocoumarol, warfarin) or endogenous compounds (bilirubin) with lower affinity – kernicterus sulfonamide-bilirubin </li></ul><ul><li>e) Generally expressed plasma concentrations of the drug refer to bound as well as free drug , e.g. MIC of AMAs </li></ul><ul><li>f) In hypoalbuminemia, binding may be reduced and high concentration of free drug may be attained (e.g. phenytoin). </li></ul>
    50. 50. Tissue storage <ul><li>Drugs may also accumulate in specific organs or get bound to specific tissue constituents, e.g.: </li></ul><ul><li>Heart and skeletal muscles – digoxin (to muscle proteins) </li></ul><ul><li>Liver – chloroquine, tetracyclines, digoxin </li></ul><ul><li>Kidney – digoxin, chloroquine </li></ul><ul><li>Thyroid gland – iodine </li></ul><ul><li>Brain – chlorpromazine, isoniazid, acetazolamide </li></ul><ul><li>Retina – chloroquine (to nucleoproteins) </li></ul><ul><li>Iris – ephedrine, atropine (to melanin) </li></ul><ul><li>Bones and teeth – tetracyclines, heavy metals (to mucopolysaccharide of connective tissue) </li></ul><ul><li>Adipose tissues – thiopental, ether, minocycline, DDT </li></ul>
    51. 51. 3. Biotransformation Metabolism of Drugs
    52. 52. What is Biotransformation? <ul><li>Chemical alteration of the drug in the body </li></ul><ul><li>Aim: to convert non-polar lipid soluble compounds to polar lipid insoluble compounds to avoid reabsorption in renal tubules </li></ul><ul><li>Most hydrophilic drugs are less biotransformed and excreted unchanged – streptomycin, neostigmine and pancuronium etc. </li></ul><ul><li>Biotransformation is required for protection of body from toxic metabolites </li></ul>
    53. 53. Results of Biotransformation <ul><li>INACTIVATION: Active drug and its metabolite to inactive metabolites – most drugs (ibuprofen, paracetamol, chlormphenicol etc.) </li></ul><ul><li>Active drug to active product (phenacetin – acetminophen or paracetamol, morphine to Morphine-6-glucoronide, digitoxin to digoxin etc.) </li></ul><ul><li>Inactive drug to active/enhanced activity (prodrug) – levodopa - carbidopa, prednisone – prednisolone and enalpril – enalprilat) </li></ul><ul><li>No toxic or less toxic drug to toxic metabolites (Isonizide to Acetyl isoniazide) </li></ul><ul><li>(Mutagenicity, teratogenicity, carcinogenicity, hepatotoxicity) </li></ul>
    54. 54. Biotransformation - Classification <ul><li>2 (two) Phases of Biotransformation: </li></ul><ul><li>Phase I or Non-synthetic – metabolite may be active or inactive </li></ul><ul><li>Phase II or Synthetic – metabolites are inactive (Morphine – M-6 glucoronide is exception) </li></ul>
    55. 55. Phase I - Oxidation <ul><li>Most important drug metabolizing reaction – addition of oxygen or (–ve) charged radical or removal of hydrogen or (+ve) charged radical </li></ul><ul><li>Various oxidation reactions are – oxygenation or hydroxylation of C-, N- or S-atoms; N or 0-dealkylation </li></ul><ul><li>Examples – Barbiturates, phenothiazines, paracetamol and steroids </li></ul>
    56. 56. Oxidation – contd. <ul><li>In many cases insertion of Oxygen atom into the drug molecule produces short lived highly active - quinone, epoxide or superoxide intermediates </li></ul><ul><ul><li>Example: Paracetamol </li></ul></ul>
    57. 57. Phase I - Oxidation <ul><li>Involve – cytochrome P-450 monooxygenases (CYP), NADPH and Oxygen </li></ul><ul><li>More than 100 cytochrome P-450 isoenzymes are identified and grouped into more than 20 families – 1, 2 and 3 … </li></ul><ul><li>Sub-families are identified as A, B, and C etc. </li></ul><ul><li>In human - only 3 isoenzyme families important – CYP1, CYP2 and CYP3 </li></ul><ul><li>CYP 3A4/5 carry out biotransformation of largest number (30–50%) of drugs. In addition to liver, this isoforms are expressed in intestine (responsible for first pass metabolism at this site) and kidney too .. </li></ul><ul><li>Inhibition of CYP 3A4 by erythromycin, clarithromycin, ketoconzole, itraconazole, verapamil, diltiazem and a constituent of grape fruit juice is responsible for unwanted interaction with terfenadine and astemizole </li></ul><ul><li>Rifampicin, phenytoin, carbmazepine, phenobarbital are inducers of the CYP 3A4 </li></ul>
    58. 58. Oxidation - CYP CYP3A4/5
    59. 59. Nonmicrosomal Enzyme Oxidation <ul><li>Some Drugs are oxidized by non-microsomal enzymes (mitochondrial and cytoplsmic) – Alcohol, Adrenaline, Mercaptopurine </li></ul><ul><ul><ul><li>Alcohol – Dehydrogenase </li></ul></ul></ul><ul><ul><ul><li>Adrenaline – MAO and COMT </li></ul></ul></ul><ul><ul><ul><li>Mercaptopurine – Xanthine oxidase </li></ul></ul></ul><ul><li>Not induced or inhibited by other drugs </li></ul>
    60. 60. Phase I - Reduction <ul><li>This reaction is opposite of oxidation and involves CYP 450 enzymes working in the opposite direction. </li></ul><ul><li>Examples - Chloramphenicol, levodopa, halothane and warfarin </li></ul>Levodopa (DOPA) Dopamine DOPA-decarboxylase
    61. 61. Phase I - Hydrolysis <ul><li>This is cleavage of drug molecule by taking up of a molecule of water. Similarly amides and polypeptides are hydrolyzed by amidase and peptidases. Hydrolysis occurs in liver, intestines, plasma and other tissues. </li></ul><ul><li>Examples - Choline esters, procaine, lidocaine, pethidine, oxytocin </li></ul>Ester + H 2 0 Acid + Alcohol Esterase
    62. 62. Phase I – contd. <ul><li>Cyclization: is formation of ring structure from a straight chain compound, e.g. proguanil. </li></ul><ul><li>Decyclization: is opening up of ring structure of the cyclic molecule, e.g. phenytoin, barbiturates </li></ul>
    63. 63. Phase II metabolism <ul><li>Conjugation of the drug or its phase I metabolite with an endogenous substrate - polar highly ionized organic acid to be excreted in urine or bile - high energy requirements </li></ul><ul><li>Glucoronide conjugation - most important synthetic reaction </li></ul><ul><li>Compounds with hydroxyl or carboxylic acid group are easily conjugated with glucoronic acid - derived from glucose. </li></ul><ul><li>Carried out by UDP glucoronosyl transferases (UGTs) </li></ul><ul><li>Increases molecular weight of the drugs </li></ul><ul><li>Examples: Chloramphenicol, aspirin, morphine, metroniazole, bilirubin, thyroxine </li></ul><ul><li>Drug glucuronides, excreted in bile, can be hydrolyzed in the gut by bacteria, producing beta-glucoronidase - liberated drug is reabsorbed and undergoes the same fate - enterohepatic recirculation (e.g. chloramphenicol, phenolphthalein, oral contraceptives) and prolongs their action </li></ul>
    64. 64. Phase II metabolism – contd. <ul><li>Acetylation: Compounds having amino or hydrazine residues are conjugated with the help of acetyl CoA, e.g. sulfonamides, isoniazid </li></ul><ul><li>Genetic polymorphism (slow and fast acetylators) </li></ul><ul><li>Methylation: Compounds having amines and ph enols are Mrthylated, e.g. adrenaline, histamine etc </li></ul><ul><ul><li>Methionine and cysteine act as methyl donor </li></ul></ul><ul><li>Sulfate conjugation: The phenolic compounds and steroids are sulfated by sulfokinases, e.g. chloramphenicol, methyldopa and sex steroids </li></ul>
    65. 65. Phase II metabolism – contd. <ul><li>Glycine conjugation: Salicylates and drugs having carboxylic acids are conjugated with glycine but is not a major pathway </li></ul><ul><li>Glutathione conjugate: Forms mercaptopurate – minor pathway </li></ul><ul><ul><li>But, serves as major pathway for deactivation of toxic metabolites during metabolism of certain drugs, e.g. paracetamol </li></ul></ul><ul><ul><li>Saturation occurs with large production of such metabolites </li></ul></ul><ul><li>Ribonucleoside/nucleotide synthesis : activation of many purine and pyrimidine antimetabolites used in cancer chemotherapy </li></ul>
    66. 66. Phase I and Phase II Reaction Drug Metabolite Metabolite EXCRETION Metabolite Phase I Phase II Phase II Metabolism
    67. 67. Factors affecting Biotransformation <ul><li>Factors affecting biotransformation </li></ul><ul><ul><li>C oncurrent use of drugs: Induction and inhibition </li></ul></ul><ul><ul><li>G enetic polymorphism </li></ul></ul><ul><ul><li>P ollutant exposure from environment or industry </li></ul></ul><ul><ul><li>P athological status </li></ul></ul><ul><ul><li>A ge </li></ul></ul>
    68. 68. Enzyme Inhibition <ul><li>One drug can inhibit metabolism of other – if utilizes same enzyme </li></ul><ul><li>However not common because different drugs are substrate of different CYPs </li></ul><ul><li>A drug may inhibit one isoenzyme while being substrate of other isoenzyme – quinidine (A4 and D6) </li></ul><ul><li>Clinically does not usually occur - Enzyme Saturation Kinetics </li></ul><ul><li>Clinically occurs with drugs having affinity for same isoenzymes </li></ul><ul><li>Clinical outcome occurs as toxicity </li></ul><ul><li>Some enzyme inhibitors – Omeprazole, metronidazole, isoniazide, ciprofloxacin and sulfonamides </li></ul>
    69. 69. Microsomal Enzyme Induction <ul><li>Many Drugs and chemicals increases synthesis of Microsomal Enzyme Protein (CYP) </li></ul><ul><li>Rate of Metabolism increases – may be the inducing drug itself or the other drug substrate </li></ul><ul><li>Specific inducers of certain CYP </li></ul><ul><ul><li>CYP3A – antiepileptic agents - Phenobarbitone, Rifampicin and glucocorticoides </li></ul></ul><ul><ul><li>CYP2D6 – Rifampicin; CYP 2B1 - Phenobarbitone </li></ul></ul><ul><ul><li>CYP2E1 - isoniazid, acetone, chronic use of alcohol </li></ul></ul><ul><ul><li>Other inducers – cigarette smoking, charcoal broiled meat, industrial pollutants – CYP1A </li></ul></ul>
    70. 70. Microsomal Enzyme Induction – contd. <ul><li>Decreased intensity – Failure of OCPs </li></ul><ul><li>Increased intensity – Paracetamol poisoning (NABQI) </li></ul><ul><li>Tolerance – Carbmazepine </li></ul><ul><li>Faster metabolism - Some endogenous substrates are metabolized faster – steroids, bilirubin </li></ul><ul><li>Precipitation of acute intermittent porphyria – increased porphyrin synthesis by depressing delta-aminolevulenic acid </li></ul><ul><li>Possible uses – poisoning, liver disease and nonhaemolytic jaundice etc. </li></ul>
    71. 71. 4. Excretion
    72. 72. Organs of Excretion <ul><li>Excretion is a transport procedure which the prototype drug (or parent drug) or other metabolic products are excreted through excretion organ or secretion organ </li></ul><ul><li>Hydrophilic compounds can be easily excreted. </li></ul><ul><li>Routes of drug excretion </li></ul><ul><ul><li>Kidney </li></ul></ul><ul><ul><li>Biliary excretion </li></ul></ul><ul><ul><li>Sweat and saliva </li></ul></ul><ul><ul><li>Milk </li></ul></ul><ul><ul><li>Pulmonary </li></ul></ul>
    73. 73. Hepatic Excretion <ul><li>Drugs can be excreted in </li></ul><ul><li>bile, especially when the are </li></ul><ul><li>conjugated with – glucuronic </li></ul><ul><li>Acid </li></ul><ul><ul><li>Organic Bases – OCT </li></ul></ul><ul><ul><li>Others – Pgp </li></ul></ul><ul><li>Larger molecules are eliminated </li></ul><ul><li>Drug is absorbed  glucuronidated or sulfatated in the liver and secreted through the bile  glucuronic acid/sulfate is cleaved off by bacteria in GI tract  drug is reabsorbed (steroid hormones, rifampicin, amoxycillin, contraceptives) </li></ul><ul><li>Anthraquinone, heavy metals – directly excreted in colon </li></ul>Portal vein Bile duct Intestines
    74. 74. Renal Excretion <ul><li>All water soluble substances </li></ul><ul><li>Amount of Drug in urine is </li></ul><ul><li>Net Renal Excretion = (GFR + Tubular secretion) – Tubular Reabsorption </li></ul><ul><li>Glomerular Filtration </li></ul><ul><li>Tubular Reabsorption </li></ul><ul><li>Tubular Secretion </li></ul>
    75. 75. Glomerular Filtration <ul><li>Net Renal excretion: (GFR + tubular secretion) – tubular reabsorption </li></ul><ul><li>Glomerular capillaries have pores larger than usual </li></ul><ul><li>All nonprotein bound drugs (lipid soluble or insoluble) presented to the glomerulus are filtered </li></ul><ul><li>Glomerular filtration of drugs depends on their plasma protein binding and renal blood flow - Protein bound drugs are not filtered ! </li></ul><ul><li>Normal GFR – 120 ml/min </li></ul><ul><li>Renal failure and aged persons – declines progressively </li></ul>
    76. 76. Tubular Re-absorption <ul><li>Physiologically 99% of Glomerular Filtrates are reabsorbed </li></ul><ul><li>Back diffusion of Drugs (99%) – lipid soluble drugs </li></ul><ul><li>Depends on pH of urine, ionization etc. </li></ul><ul><li>Lipid insoluble ionized drugs excreted as it is – aminoglycoside (amikacin, gentamicin, tobramycin) </li></ul><ul><li>Changes in urinary pH can change the excretion pattern of drugs </li></ul><ul><ul><li>Weak bases ionize more and are less reabsorbed in acidic urine. </li></ul></ul><ul><ul><li>Weak acids ionized more and are less reabsorbed in alkaline urine </li></ul></ul><ul><li>Utilized clinically in salicylate and barbiturate poisoning – alkanized urine </li></ul><ul><li>Acidified urine – atropine and morphine etc. </li></ul><ul><li>Effects of changes in urine pH is best observed with Drugs having pKa of 5 – 8) </li></ul>
    77. 77. Tubular Secretion <ul><li>Energy dependent active transport – reduces the free concentration of drugs – further, more drug dissociation from plasma binding – again more secretion (protein binding is facilitator for excretion for some drugs) </li></ul><ul><ul><li>OATP – organic acid transport: penicillin, probenecid, uric acid salicylates, methotrexate </li></ul></ul><ul><ul><li>OCT – organic base transport: quinine, thiazides, furosemide, amiloride </li></ul></ul><ul><ul><li>P-g p </li></ul></ul><ul><li>Bidirectional transport – Blood Vs tubular fluid </li></ul><ul><li>Exogenous (drugs) Vs Endogenous (uric acid) </li></ul><ul><li>Utilized clinically – penicillin Vs probenecid and probenecid Vs uric acid </li></ul><ul><li>Salicylate Vs uricosuric action of probenecid in gout (gets block) </li></ul><ul><li>Quinidine decreases renal and biliary clearance of digoxin by inhibiting efflux carrier P-g p </li></ul>
    78. 78. Renal Excretion – must remember! <ul><li>Acidic urine </li></ul><ul><ul><ul><li>alkaline drugs eliminated </li></ul></ul></ul><ul><ul><ul><li>acid drugs reabsorbed </li></ul></ul></ul><ul><li>Alkaline urine </li></ul><ul><ul><li>- acid drugs eliminated </li></ul></ul><ul><ul><li>- alkaline drugs absorbed </li></ul></ul>
    79. 79. Kinetics of Elimination <ul><li>Pharmacokinetics - F, V and CL </li></ul>AUC p.o. F = ------------ x 100% AUC i.v. 10 mcg/ml Drug in >10 mcg/ml Plasma 500mcg/min 10 mcg/ml = 50 ml/min CL = 500 mcg/min Organ of Drug Elimination (Kidney, liver etc.)
    80. 80. Clearance <ul><li>Clearance: The clearance (CL) of a drug is the theoretical volume of plasma from which drug is completely removed in unit time </li></ul><ul><li>CL = Rate of elimination (RoE)/C </li></ul><ul><li>Example = If a drug has 20 mcg/ml and RoE is 100 mcg/min </li></ul><ul><li>CL = 100/20 = 5 ml /min </li></ul>
    81. 81. Kinetics of Elimination <ul><li>First Order Kinetics (exponential): Rate of elimination is directly proportional to drug concentration, CL remaining constant </li></ul><ul><ul><li>Constant fraction of drug is eliminated per unit time </li></ul></ul><ul><li>Zero Order kinetics (linear): The rate of elimination remains constant irrespective of drug concentration </li></ul><ul><ul><li>CL decreases with increase in concentration </li></ul></ul><ul><ul><li>Alcohol, theophyline, tolbutmide etc. </li></ul></ul>
    82. 82. Plasma half-life <ul><li>Defined as time taken for its plasma concentration to be reduced to half of its original value – 2 phases rapid declining and slow declining </li></ul><ul><li>t 1/2 = In2 / k </li></ul><ul><li>In2 = natural logarithm of 2 (0.693) </li></ul><ul><li>k = elimination rate constant = CL / V </li></ul><ul><li>t 1/2 = 0.693 x V / CL </li></ul>CL = RoE/C V = dose IV/C
    83. 83. Kinetics of Elimination Zero Order 1st Order conc. Time
    84. 84. Plasma half-life <ul><li>1 half-life …………. 50% </li></ul><ul><li>2 half-lives………… 25% </li></ul><ul><li>3 half-lives …….…..12.5% </li></ul><ul><li>4 half-lives ………… 6.25% </li></ul><ul><li>5 half-lives ………… 3.125% </li></ul><ul><li>1 st order kinetics – t1/2 does not change (V and CL remains unchanged </li></ul><ul><li>O order kinetics – t1/2 increases (CL decreases as dose is increased) </li></ul>50 + 25 + 12.5 + 6.25 = 93.75 93.75 + 3.125 + 1.56 = 98% after 5 HL
    85. 85. Repeated Dosing <ul><li>At steady state, elimination = input </li></ul><ul><li>Cpss = dose rate/CL </li></ul><ul><li>Dose Rate = target Cpss x CL </li></ul><ul><li>In oral administration </li></ul><ul><li>Dose rate = </li></ul><ul><li>In zero order kinetics: follow Michaelis Menten kinetics </li></ul><ul><li>RoE = </li></ul><ul><li>Vmax = max. rate of drug elimination, Km = Plasma conc. In which elimination rate is half maximal </li></ul>target Cpss x CL F V max x (C) K m + C Dose Rate Ave Cpss 1 st order O order
    86. 86. Excretion - The Platue Principle <ul><li>Repeated dosing: </li></ul><ul><li>When constant dose of a drug is repeated before the expiry of 4 half-life – peak concentration is achieved after certain interval </li></ul><ul><li>Balances between dose administered and dose interval </li></ul>
    87. 87. Target Level Strategy <ul><li>Low safety margin drugs (anticonvulsants, antidepressants, Lithium, Theophylline etc. – maintained at certain concentration within therapeutic range </li></ul><ul><li>Drugs with short half-life (2-3 Hrs) – drugs are administered at conventional intervals (6-12 Hrs) – fluctuations are therapeutically acceptable </li></ul><ul><li>Long acting drugs: Prolonged half-life </li></ul><ul><ul><li>Loading dose: Single dose or repeated dose in quick succession – to attain target conc. Quickly </li></ul></ul><ul><ul><ul><li>Loading dose = target Cp X V/F </li></ul></ul></ul><ul><ul><li>Maintenance dose: dose to be repeated at specific intervals </li></ul></ul><ul><ul><li>Dose Rate = </li></ul></ul>target Cpss x CL F
    88. 88. Monitoring of Plasma concentration <ul><li>Useful in </li></ul><ul><ul><li>Narrow safety margin drugs – digoxin, anticonvulsants, antiarrhythmics and aminoglycosides etc </li></ul></ul><ul><ul><li>Large individual variation – lithium and antidepressants </li></ul></ul><ul><ul><li>Renal failure cases </li></ul></ul><ul><ul><li>Poisoning cases </li></ul></ul><ul><li>Not useful in </li></ul><ul><ul><li>Response measurable drugs – antihypertensives, diuretics etc. </li></ul></ul><ul><ul><li>Drugs activated in body – levodopa </li></ul></ul><ul><ul><li>Hit and run drugs – Reserpine, MAO inhibitors </li></ul></ul><ul><ul><li>Irreversible action drugs – Orgnophosphorous compounds </li></ul></ul>
    89. 89. Prolongation of Drug action <ul><li>By prolonging absorption from the site of action – Oral and parenteral </li></ul><ul><li>By increasing plasma protein binding </li></ul><ul><li>By retarding rate of metabolism </li></ul><ul><li>By retarding renal excretion </li></ul>
    90. 90. Summary – Must Know <ul><li>Definition of Pharmacokinetics </li></ul><ul><li>Transport of Drugs across Biological Membrane – different processes with example </li></ul><ul><li>Factors affecting absorption of drugs </li></ul><ul><li>Concept of Bioavailability </li></ul><ul><li>Distribution of Drugs – Vd and its concept </li></ul><ul><li>Biotransformation Mechanisms with examples </li></ul><ul><li>Enzyme induction and inhibition concept and important examples </li></ul><ul><li>Routes of excretion of drugs </li></ul><ul><li>Orders of Kinetics </li></ul><ul><li>Definition and concept of drug clearance </li></ul><ul><li>Definition of half life and platue principle </li></ul>