Clinical pharmacokinetics part 1 dr jayesh vaghela
Download as PPTX, PDF27 likes2,863 views
This document discusses clinical pharmacokinetics and factors affecting drug absorption and bioavailability. It defines pharmacokinetics as what the body does to a drug, including absorption, distribution, metabolism and excretion. Absorption depends on patient factors like age, gastric emptying time, and presence of food, as well as physicochemical drug properties and pharmaceutical formulation characteristics. Understanding factors influencing absorption can help optimize drug therapy.
![Handerson-Hasselbach equation
• For weak acids,
pH = pKa + log [ionized]
[un-ionized]
• For weak bases,
pH = pKa + log [un-ionized]
[ionized]
30-Dec-13 47](https://image.slidesharecdn.com/clinicalpharmacokineticspart-1drjayeshvaghela-150925081323-lva1-app6892/85/Clinical-pharmacokinetics-part-1-dr-jayesh-vaghela-44-320.jpg)
Clinical pharmacokinetics part 1 dr jayesh vaghela
- 1. 30-Dec-13 1
- 2. CLINICAL PHARMACOKINETICS - 1 Dr. Jayesh Vaghela 30-Dec-13 2
- 3. Introduction • Application of pharmacokinetic concepts and principles in humans to design individualized dosage regimens, - To optimize the therapeutic response of a medication - To minimize the chance of an adverse drug reaction 30-Dec-13 3
- 4. PHARMACOKINETICS • Simply means, the science which deals with “ What the Body does to the drug ” • Includes 4 stages – 30-Dec-13 4 PHARMACOKINETICS ABSORPTION DISTRIBUTION METABOLISM EXCRETION
- 5. 30-Dec-13 5 Drug administration Crosses biological membrane Transport Absorption Enters Systemic Circulation Reaches body tissues Distribution
- 7. 30-Dec-13 8
- 8. BIOAVAILABILITY • DEFINITION :- “ The Rate at which & the Extent to which the Active Concentration of drug is available at the desired site of action. ” • Concept came into existence when an unusual incidence occurred in Australia in 1968. • Phenytoin toxicity in Epileptic patients. 30-Dec-13 9
- 9. BIOEQUIVALENCE Definition : • If two or more dosage forms of the same drug reach the blood circulation at the same relative rate & same relative extent, they are called Bioequivalent preparations of the generic drug. • Clinically important for the drugs having steep dose- response relationship, • e.g. Zero order kinetics ( phenytoin, warfarin ) Narrow margin of safety ( Theophylline, Tetracycline ) 30-Dec-13 10
- 10. Measurement of Bioavailability • Oral administration of 2 brand products of same drug ⇓ Plasma concentration – Time curve is obtained ⇓ 3 characteristics noted & compared : 1) Cmax 2) Tmax 3) AUC 30-Dec-13 11 Rate of Absorption Extent of Absorption
- 11. 30-Dec-13 12
- 12. Calculation of AUC Planimeter : - An instrument to mechanically measure the area of plain figures Cut & Weigh method : - Cut the area on rectilinear graph paper & weighing it by analytical method Mathematical : - Trapezoidal rule 30-Dec-13 13
- 13. Quantitative Evaluation of Bioavailability Drug Bioavailability ( % ) = AUC ( Oral ) x 100 AUC ( I.V. ) AUC (oral) = AUC obtained after oral administration of single dose AUC (IV) = AUC obtained after IV administration of same drug in the same dose. 30-Dec-13 14
- 14. 30-Dec-13 15 FACTORS AFFECTING DRUG ABSORPTION & BIOAVAILABILITY
- 18. A) Patient Factors : (1) Route of Administration : 30-Dec-13 19
- 19. Absorption via G.I.T. 30-Dec-13 20 Absorption Site pH Drugs absorbed Example Stomach Acidic Lipid soluble Non-ionized Acidic/Neutral Aspirin Mouth Lipid soluble Non-ionized Basic/Neutral Isosorbide Small intestine Morphine Colon Diazepam Rectal Ergotamine
- 20. Absorption via Parenteral Sites : 30-Dec-13 21 Intravenous injection ⇓ Direct in bloodstream ⇓ Completely absorbed, Rapidly distributed Intramuscular & Subcutaneous injection ⇓ Passive diffusion Absorption : i.m. > s.c.
- 21. Absorption via Lungs : • Rapid absorption of Lipid-soluble drugs • From pulmonary epithelium & mucous membrane of trachea & lungs • Ex. - General anaesthetics ( vapourized form ) - Salbutamol ( aqueous spray ) - Disodium cromoglycate ( suspended microfined particles) 30-Dec-13 22
- 22. Absorption via Topical sites : • Dermis – permeable for lipid-soluble drugs ◦ Transdermal patches for – GTN, Scopolamine. ◦ Applied on mucous membranes – Oxytocin, Vasopressin 30-Dec-13 23
- 23. (2) Membrane Physiology : • Nature of Cell membrane : 30-Dec-13 24
- 24. Drug transport process DRUGS ARE TRANSPORTED ACROSS THE MENBRANE PASSIVE DIFFUSION AND FILTRATION SPECIALIZED TRANSPORT CARRIER MEDIATED FACILITATED DIFFUSION ACTIVE TRANSPORT PRIMARY SECONDORY PINOCYTOSIS 30-Dec-13 25
- 26. Carrier mediated transport • Facilitated M E M B R A N E 30-Dec-13 27
- 27. • Active transport AA M E M B R A N E ATP ADP e.g.- levodopa30-Dec-13 28
- 28. Active transport PRIMARY ◦ Energy obtained directly from ATP ◦ Eg. Na+ K+ ATPase SECONDARY ◦ Energy obtained from movment of other solute (Na+) ◦ Eg- SERT, DAT 30-Dec-13 29
- 29. • Primary Active transport AA M E M B R A N E ATP ADP 30-Dec-13 30
- 30. • Secondary Active Transport AA M E M B R A N E Na+ K + ATPase ATP ADP Na+ K + ATPase H+ H+ GLUCOSE Na+ K+ 30-Dec-13 31
- 31. Pinocytosis / Cell Drinking 30-Dec-13 34 • Uptake of fluid solutes E.g. - Sabine polio vaccine (orally administered)
- 32. • Pore transport / Convective Transport : ◦ Absorption occurs through narrow, aqueous filled channels or pores in the membrane structure ◦ Ex. - Water, Sugars, Urea. - LMW drugs • Ion-pair formation : Ionized drug + opposite charged ion ⇩ Ion pair ( Neutral ) ⇩ Diffuses more easily through membrane e.g. – Quaternary Ammonium Compounds 30-Dec-13 35
- 33. (2) Age : Infants : ◦ High gastric pH ◦ Less intestinal surface & blood flow Elderly : ◦ Achlorhydria ◦ Less intestinal blood flow ◦ Altered gastric emptying 30-Dec-13 36
- 34. (3) Gastric Emptying Time • Volume of Ingested Material • Bulky material tends to empty more slowly than liquids • Type of Meal • carbohydrates > proteins > fats • Body Position • Lying on the left side decreases emptying rate, • Right side promotes it • Drugs • Anticholinergics • Narcotic analgesics • Ethanol • Reduction in rate of emptying • Emotional state • Anxiety promotes, • depression retards it • Disease states • Hypothyroidism retards it, • Hyperthyroidism promotes it. 30-Dec-13 37
- 35. (4) Intestinal Transit Time • Delayed Time is desirable for – A) Drugs that dissolve or release slowly from their dosage form (sustained release products) B) Drugs that dissolve only in intestine (enteric coated formulations) C) Drugs absorbed from specific sites in the intestine (Vit B) 30-Dec-13 38
- 36. (5) Presence of food FOOD INCREASES THE ABSORPTION OF .. Chloroquine Carbamazapine Griseofulvin FOOD DECREASES THE ABSORPTION OF .. Ampicilline Aspirin Captopril Levodopa Rifamicin Tetracycline To be taken before meals To be taken after meals 30-Dec-13 39
- 37. (6) Metabolism by Enzymes 30-Dec-13 40
- 39. Solid dosage form Solid drug particles Drug in solution at absorption site Drug in the body 1) Drug solubility & dissolution rate : 30-Dec-13 42
- 40. 2) Particle size and effective surface area: ◦ Dissolution rate of solid particles ∝ surface area ◦ Smaller particle size → greater surface area → higher dissolution rate ◦ e.g. Bishydroxycoumarin Digoxin Griseofulvin Two types of surface area ◦ 1) Absolute surface area ◦ 2) Effective surface area (More important) 30-Dec-13 43
- 41. 30-Dec-13 44 Oral Administration of Drug To fine particles Tab or Cap Drug in solution Powders & Suspensions Solutions Available for absorption in GIT
- 42. 3) Polymorphism & Amorphism : ◦ Depending upon internal structure, forms of solid may be – Crystalline or Amorphous form 30-Dec-13 45 1. Polymorphism: - Differ from each other in physical properties e.g. Solubility, Density - Ex.- Riboflavin Polymorph 3 is more water soluble than polymorph 1. 2. Amorphism: - Not having internal Crystalline structure More water soluble than crystalline form - Ex.- Novobiocin Amorphous form is more water soluble
- 43. 4) pH-Partition Theory : • Absorption is governed by – Dissociation constant pKa of the drug. Lipid solubility of the un-ionized drug. pH at the absorption site. Amount of drug that exists in un-ionized form and in ionized form is a function of – pKa of drug, & pH of the fluid at the absorption site, • It can be determined by Handerson-Hasselbach equation: 30-Dec-13 46
- 44. Handerson-Hasselbach equation • For weak acids, pH = pKa + log [ionized] [un-ionized] • For weak bases, pH = pKa + log [un-ionized] [ionized] 30-Dec-13 47
- 45. Effect of pH on drug absorption: • Acidic drugs (HA) release a proton (H+), causing a charged anion (A–) to form: HA ⇔ H+ + A- 30-Dec-13 48
- 46. • Weak bases (BH+) can also release an H+. ◦ the protonated form of basic drugs is usually charged, ◦ loss of a proton produces the uncharged base (B) BH+ ⇔ B + H+ 30-Dec-13 49
- 47. 5) Drug stability : ◦ A drug for oral use may be destabilized either during its shelf life or in the GIT. ◦ Problems resulting in poor bioavailability of an orally administered drug are – Degradation of the drug into inactive form Interactions with different components of drug itself or that present in GIT. 30-Dec-13 50
- 48. B) Pharmaceutical factors : Disintegration time : Rapid disintegration ⇓ Less disintegration time ⇓ Rapid absorption ◦ Ex.- • Coated tablets – more disintegration time slow absorption • Fine dispersible tablets – less disintegration time fast absorption 30-Dec-13 51
- 49. Manufacturing variables : ◦ Method of granulation ◦ Compression force Pharmaceutical ingredients : ◦ Vehicles ◦ Diluents ◦ Binders & granulating agents ◦ Disintegrants ◦ Lubricants ◦ Surfactants ◦ Buffers 30-Dec-13 52
- 50. Nature & type of dosage form : ◦ As a general rule, Bioavailability of different dosage forms in decreasing order is as following ◦ Solutions > Emulsions > Suspensions > Capsules > Tablets > Enteric Coated Tablets > Sustained Release Products. Product age & storage condition : ◦ Ex. – • Precipitation of the drug in solution • Hardening of tablet • Change in particle size of suspension 30-Dec-13 53
- 51. Methods to Delay Absorption 1. Using Appropriate Dosage Form : • Slow & Sustained absorption of drugs – - Retard tablets ( pot. Chloride retard tablets ) - Depot injections ( Fluphenazine depot injectons ) - Subcutaneous implants ( testosterone pellets ) 2. Changing Physical characteristics of drug : • e.g. Procaine PnG - Slightly water soluble - When given i.v. ⇨ slowly absorbed & action is prolonged 30-Dec-13 54
- 52. Contd… 3. Adding a Vasoconstrictor Drug : - Noradrenaline + Local Anaesthetic ( Xylocaine ) ⇓ - Prolongs effect of local anaesthetic effect - Reduces absorption into Systemic circulation & systemic toxicity 4. Applying a Tourniquet : - Tourniquet application ⇨ injection of L.A. below it ⇓ Delays systemic absorption Prolongs action of L.A. 30-Dec-13 55
- 53. Methods to Facilitate Absorption • Addition of enzyme Hyaluronidase (breaks down intercellular matrix) ⇓ Speeds absorption • Increasing the local blood flow to the tissue ⇓ Increased absorption 30-Dec-13 56
- 55. Drug may get Distributed into - 30-Dec-13 58 Body water Various TissuesEthanol I2 in Thyroid, Fluoride in bones, Vit A & CHQ in liver, Griseofulvin in keratin Extracellular Intracellular K+ ions, Sucrose I- ions, d-TC, Gentamicin Intravascular Interstitial Mannitol, Dextran, Heparin Digoxin, emetine
- 56. Special Compartments for Drug Distribution Plasma Protein Binding : Free Drug + Protein ⇔ Drug-Protein Complex 30-Dec-13 59 Free Drug Protein bound Drug Pharmacologically Active Inert Can diffuse through capillary wall Not accessible to capillary diffusion, metabolism or excretion
- 57. Proteins contributing to Drug Binding Plasma Albumin : • Most important contributor • Binds to Acidic drugs - Warfarin - Penicillin α1 Acid Glycoproteins : • Binds to Basic drugs - Quinidine - Imipramine Tissue Proteins & Nucleoproteins : • Digoxin Miscellaneous binding proteins : • Transcortin – corticosteroid binding protein 30-Dec-13 60
- 58. Clinical significance of PPB Highly protein bound drugs ⇓ Largely restricted to vascular compartment Lower Vd Difficult to be removed by dialysis Hypoalbuminaemia ( e.g. Liver diseases ) • higher concentration of free drug 30-Dec-13 61
- 59. Hyperalbuminaemia (e.g. M.I., Inflammation ) • higher concentration of Bound drug Displacement reactions : • drug having Higher affinity ⇓ displaces the drug having lower affinity • e.g. – Sulfonamides & Vit K ⇓ Displaces bilirubin ⇓ Kernicterus in neonates 30-Dec-13 62
- 60. Physiological Barriers to Drug Distribution Blood Brain Barrier Blood – CSF Barrier CSF – Brain Barrier Placental Barrier Significance : Prevent entry of the drug into organ & possible toxicity Contain P-glycoprotein which effluxes the drug from organ to back into blood circulation. e.g.- GIT, Brain, Kidney 30-Dec-13 63
- 62. Clinical example • Digoxin : • In 70 kg patient, • 500 μg dose → plasma concentration of 0.78 μg/L So, if 0.78 μg of digoxin is in 1 litre of plasma ⇓ 500 μg would require 641 L of plasma ⇓ Not possible 30-Dec-13 65
- 63. Apparent Volume of Distribution (aVd) • Simply means, “ the total space which should apparently be available in the body to contain the known amount of the drug ” aVd = Total amount of drug in body ( mg/kg ) plasma concentration of drug ( mg/L ) 30-Dec-13 66
- 64. Clinical significance 30-Dec-13 67 If drug does not cross capillary membrane - given by intravenous route ⇓ Vd = Plasma water i.e. 3 L e.g. – Heparin, Insulin High plasma protein bound Less Tissue protein bound e.g. – Tolbutamide Reverse is true for drugs like Metoprolol Low Vd value
- 65. If Vd is much more than the actual body volume ⇓ Widely distributed in body (adipose tissue, etc.) ⇓ Difficult to remove by dialysis if toxicity occurs e.g. – Digoxin, Imipramine. Vd < 5 L ⇨ drug within vascular compartment e.g. – Heparin, Insulin, Warfarin Vd ~ 15 L ⇨ drug restricted to Extracellular fluid e.g. – Aspirin, Tolbutamide Vd > 20 L ⇨ distributed in Total body water (Ethanol) or penetration in tissues (Digoxin) 30-Dec-13 68
- 66. Redistribution of drugs IV injection of Thiopentone ⇓ Enters brain very rapidly (1 minute after injection) (highly lipid soluble) ⇓ General anaesthesia ⇓ Being highly lipid soluble, Diffuses back to circulation from Brain ⇓ Redistributed to muscles & fat Action is terminated So, i.v. Thiopentone is ultra short acting 30-Dec-13 69
- 67. References • Principles of Pharmacology, HL Sharma KK Sharma, 2nd Edition • Applied Biopharmaceutics & Pharmacokinetics, Leon Shargel, 5th Edition • Lippincott’s Illustrated Reviews, Pharmacology 5th ed. - M. Clark, et. al., (Lippincott, 2012, ) • Goodman & Giman’s The Pharmacological Basis of Therapeutics, 12th edition • Essentials of MedicalPharmacology, KD Tripathi, 6th Edition 30-Dec-13 70
- 68. T h a n k y o u… 7130-Dec-13