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1. HONEYLENE B. PALOMA, RPH. INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS 2. BASIC TERMINOLOGIES Drug  any substance that interacts with a molecule or protein…
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  • 1. HONEYLENE B. PALOMA, RPH. INTRODUCTION TO BIOPHARMACEUTICS AND PHARMACOKINETICS
  • 2. BASIC TERMINOLOGIES Drug  any substance that interacts with a molecule or protein that plays a regulatory role in living systems.
  • 3. Introduction to biopharmaceutics:  Biopharmaceutics: the study of how the physicochemical properties of drugs, dosage forms and routes of administration affect the rate and extent of the drug absorption.  Thus, biopharmaceutics involves factors that influence the: 1) protection and stability of the drug within the product; 2) the rate of drug release from the product; 3) the rate of dissolution of the drug at the absorption site; and 4) the availability of the drug at its site of action .
  • 4. Generally, the GOAL of biopharmaceutical studies is to develop a dosage form that will provide consistent bioavailability at a desirable rate.
  • 5. Pharmacokinetics – “what the body DOES to the drug”. This phase of drug delivery system involves ADME Pharmacodynamics – “what the drug DOES to the body”; the biochemical & physical effects of drugs on the body & the mechanism of drug action. Pharmacotherapeutics – the use of drugs to prevent and treat diseases. BASIC TERMINOLOGIES
  • 6. Pharmacokinetics vs Pharmacodynamics…concept Fluoxetine increases plasma concentrations of amitriptyline. This is a pharmacokinetic drug interaction. Fluoxetine inhibits the metabolism of amitriptyline and increases the plasma concentration of amitriptytline.
  • 7. Pharmacokinetics vs Pharmacodynamics…concept If Fluoxetine is given with Tramadol, serotonin syndrome can result. This is a pharmacodynamic drug interaction. Fluoxetine and Tramadol both increase availability of serotonin leading to the possibility of “serotonin overload” This happens without a change in the concentration of either drug.
  • 8. 9 Dynamic Relationship Drug release and dissolution Drug in Systemic circulation Pharmacologic or clinical response Excretion and metabolism Drug in tissuesAbsorption Elimination Relationship between the drug, the drug product and the pharmacologic effect BIOPHARMACEUTICS PK PD
  • 9. Applications of Pharmacokinetic studies: 1. Pharmacological testing – assess the relationship bet the drug C and pharmacological activities. This is important to determine how much and how often the drug should be given. 2. Toxicological testing – assess tissue accumulation of drugs and how it is related to drug toxicity.
  • 10. Applications of Pharmacokinetic studies: 3. Evaluation of Organ Function – evaluate the function of eliminating organs. 4. Dosage Regimen Design – design the dosing regimen (dose and dosing interval of a specific drug) that can achieve the maximum therapeutic effect w/ minimal toxicity.
  • 11. WHAT ARE THESE ELIMINATING ORGANS? 1 2 3 4 5 6
  • 12. Bioavailability: The rate and extent of drug absorption. Bioavailable dose: The fraction of an administered dose of a particular drug that reaches the systemic circulation intact. Plasma level-time curve:
  • 13. The plasma level-time curve is generated by measuring the drug concentration in plasma samples taken at various time intervals after a drug product is administered. The concentration of drug in each plasma sample is plotted against the corresponding time at which the plasma sample was removed.
  • 14. Drug Product Performance Parameters: 1- Minimum effective concentration (MEC): The minimum concentration of drug needed at the receptors to produce the desired pharmacologic effect. 2- Minimum toxic concentration (MTC): The drug concentration needed to just produce a toxic effect. 3- Onset time: The time required for the drug to reach the MEC. 4- Duration of action: The difference between the onset time and the time for the drug to decline back to the MEC.
  • 15. 5- The time of peak plasma level: The time of maximum drug concentration in the plasma and is proportional to the rate of drug absorption. 6- The peak plasma level: The maximum drug concentration, usually related to the dose and the rate constants for absorption and elimination of the drug. 7- Area under the curve: It is related to the amount of drug absorbed systemically.
  • 16. • chemical nature of a drug • Inert excipients • method of manufacture • physicochemical properties of drug such as pKa, particle size, partition coefficient, polymorphism etc. Factors influencing the BIOAVAILABILITY of a Drug
  • 17. Route of Administration Determines Bioavailability (AUC)
  • 18. WHY ARE DRUG CONCENTRATION SAMPLES TAKEN FROM THE BLOOD / PLASMA?
  • 19. Drug Concentration In Tissues Tissue biopsies used for verification of malignancy. Small sample is removed, hence measurement of drug concentration difficult. Used to ascertain if the drug reached the tissue & reached the proper concentration within the tissues.
  • 20. Drug Concentrations in Urine & Feces It is an indirect method to ascertain the bioavailability of a drug. The rate & extent of drug excreted in urine reflects the rate & extent of systemic drug absorption. Measurement of drug in feces may reflect drug that has not been absorbed after an oral dose or may reflect drug that has been expelled by biliary secretion after systemic absorption.
  • 21. Used for TDM because only free drug diffuse into the saliva, saliva drug levels tend to approximate free drug rather than total plasma drug conc. The ratio of saliva/plasma drug concentration ratio less than 1 for many drugs. It is influenced by pKa of a drug & pH of the saliva. Drug Concentration in Saliva
  • 22. 2 General Classifications of Drugs BASIC TERMINOLOGIES 1. Endogenous 2. Exogenous 1. Hormones 2. Neurotransmitters 3. Mediators 3 groups of endogenous chemical messengers/drugs that target receptors
  • 23. 1. Hormones - produced by endocrine tissue and carried in the blood to their receptor targets. e.g. adrenaline, insulin, ADH-vasopressin and aldosterone 2. Neurotransmitters - released by neuron terminals; chemical messengers bind to receptors on neurons and other cells, either stimulating or inhibiting activity in those cells. e.g. noradrenaline, acetylcholine and serotonin (5-HT)
  • 24. Neurotransmitters
  • 25. 3. Mediators - locally acting chemical messengers released by cells and having an effect on adjacent cells. e.g. histamine leukotrienes
  • 26. PHARMACOKINETIC PRINCIPLES Routes of administration are determined by: 1. Properties of the drug 2.Therapeutic objectives 2 major routes of administration: 1. Enteral (extravascular) - administering the drug by mouth; the simplest and most common 2.Parenteral (intravascular)- introduces drugs directly across the body’s barrier defenses into the systemic circulation or other vascular tissue. 3.Others
  • 27. Routes of Administration
  • 28. Injection is the most common parenteral route. Enteral has advantages: ~ Can be self administered ~ Limits systemic infections that could complicate treatment ~ Toxicities or overdose may be overcome with antidotes. The Universal Antidote is a mixture that contains activated charcoal, magnesium oxide, and tannic acid.
  • 29. Enteral can be further classified into: A. Oral B. Sublingual C. Buccal D. Sublabial E. Perlingual
  • 30. Parenteral has Advantages Fast: 15–30sec for IV, 3–5 mins for IM and SC 100% bioavailability suitable for drugs not absorbed by the digestive system or those that are too irritant One injection can be formulated to last days or even months, e.g. Depo-Provera IV can deliver continuous medication, e.g., morphine for patients in continuous pain, or saline drip for people needing fluids
  • 31. Other Routes Inhalation Intranasal Intrathecal/ intraventricular Rectal Transdermal
  • 32. Topical  local effect, substance is applied directly where its action is desired; applied to a localized area of the body or to the surface of a body part or through mucous membranes in the body. epicutaneous enemas eye drops ear drops
  • 33. ORGANIZATION OF THE HUMAN BODY
  • 34. ORGANIZATION OF THE HUMAN BODY
  • 35. ORGANIZATION OF THE HUMAN BODY
  • 36. TISSUES AND THEIR MAIN LOCATION
  • 37. TISSUES AND THEIR MAIN LOCATION
  • 38. TISSUES AND THEIR MAIN LOCATION
  • 39. TISSUES AND THEIR MAIN LOCATION
  • 40. TISSUES AND THEIR MAIN LOCATION
  • 41. TISSUES AND THEIR MAIN LOCATION
  • 42. TISSUES AND THEIR MAIN LOCATION
  • 43. Membranes Types of Membranes: Cell Membranes: This barrier is permeable to many drug molecules but not to others, depending on their lipid solubility. Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through. Walls of Capillaries: Pores between the cells are larger than most drug molecules, allowing them to pass freely, without lipid solubility being a factor. Blood/Brain Barrier: This barrier provides a protective environment for the brain. Speed of transport across this barrier is limited by the lipid solubility of the psychoactive molecule. Placental Barrier: This barrier separates two distinct human beings but is very permeable to lipid soluble drugs.
  • 44. THEORIES ON CELL STRUCTURE  Unit membrane theory  Fluid Mosaic Model  Modified Fluid Mosaic Model
  • 45. LADMER Processes can be divided into two classes: a. drug input b. drug output INPUT PROCESSES are: L = Liberation, the release of the drug from it's dosage form. A = Absorption, the movement of drug from the site of administration to the blood circulation.
  • 46. FACTORS AFFECTING LIBERATION 1. Surface area “the larger the surface area exposed to the solvent, the faster the dissolution rate.” 2. Solubility For weakly acidic drugs, solubility increases w/ an increasing pH of the solvent. For basic drugs, solubility increases with decreasing pH.
  • 47. Despite the effect of pH on the intrinsic solubility of the drug compound, there are cases of compounds with poor aqueous solubility. In such cases, the solubility of the drug in water is sometimes enhanced by the formation of salts. “salts of the weak acids and salts of weak bases generally have much better aqueous solubility than the corresponding free acid or free base.”
  • 48. FACTORS AFFECTING LIBERATION 3. Crystal or Amorphous Form “the amorphous form is more soluble than the crystalline form.” 4. Agitation 5. State of hydration “Anhydrous form of the drug is more readily soluble than the hydrated one.” 6. Drug Design
  • 49. INPUT PROCESSES Bioavailability  describes the rate and extent of drug input. The fraction of administered drug that reaches systemic circulation. IV route drugs  100% bioavailability.
  • 50. ABSOLUTE BIOAVAILABILITY Is the measurement of a test formulation dose against an IV reference dose the bioavailability of which is 100% by definition. Absolute Bioavailability % = AUC test / Dose test X 100AUC IV / Dose IV
  • 51. RELATIVE BIOAVAILABILITY Is the measurement of a test formulation dose against a reference formulation. The two formulations are may be considered bioequivalent if the range of the ratio of their AUCS is 0.8 to 1.25. Relative Bioavailability % = AUC test / Dose test X 100 AUC reference / Dose reference
  • 52. FACTORS THAT INFLUENCES BIOAVAILABILITY (additional): a.First-pass hepatic metabolism b.Solubility of the drugs “for a drug to be readily absorbed, it should be largely hydrophobic, yet have some solubility in aqueous solutions.” c. Chemical instability d. Nature of drug formulation BIOEQUIVALENCE  If 2 related drugs show comparable bioavailability and similar times to achieve peak blood concentrations. THERAPEUTIC EQUIVALENCE  2 similar drugs are therapeutically equivalent if they have comparable efficacy and safety.
  • 53. OUTPUT PROCESSES D = Distribution, process by w/c a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues.
  • 54. Drug Distribution  Dependent upon its route of administration and target area, every drug has to be absorbed, by diffusion, through a variety of bodily tissue.  Tissue is composed of cells which are encompassed within membranes, consisting of 3 layers, 2 layers of water-soluble complex lipid molecules (phospholipid) and a layer of liquid lipid, sandwiched within these layers. Suspended within the layers are large proteins, with some, such as receptors, transversing all 3 layers.  The permeability of a cell membrane, for a specific drug, depends on a ratio of its water to lipid solubility. Within the body, drugs may exist as a mixture of two interchangeable forms, either water (ionized- charged) or lipid (non-ionized) soluble. The concentration of two forms depends on characteristics of the drug molecule (pKa, pH at which 50% of the drug is ionized) and the pH of fluid in which it is dissolved.  In water soluble form, drugs cannot pass through lipid membranes, but to reach their target area, they must permeate a variety of types of membranes.
  • 55. M = Metabolism, the chemical conversion or transformation of drugs into compounds which are easier to eliminate. E = Excretion, the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes. R = Response, the action of the body to the drug administered OUTPUT PROCESSES
  • 56. Presystemic metabolism: Definition:The metabolism of orally administered drugs by gastrointestinal and hepatic enzymes, resulting in a significant reduction of the amount of unmetabolized drug reaching the systemic circulation. Gut wall metabolism - This effect is known as first-pass metabolism by the intestine. - Cytochrome P450 enzyme, CYP3A, that is present in the liver and responsible for the hepatic metabolism of many drugs, is present in the intestinal mucosa and that intestinal metabolism may be important for substrates of this enzyme e.g. cyclosporin. -
  • 57. Presystemic metabolism: Hepatic metabolism - After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. - The liver metabolizes many drugs (e.g. propranolol), sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. - This first pass through the liver thus greatly reduces the bioavailability of the drug.
  • 58. Presystemic metabolism (Cont.)
  • 59. Hepatic metabolism (Cont.)
  • 60. PORTAL CIRCULATION When the drug is taken orally, absorption will most probably happen in the small intestine. The drug is considered absorbed when it is transported from the lumen of the small intestine into the blood stream. Blood drained from the small intestine is first passed on to the liver through the portal vein before being released into the systemic circulation. Drugs that are absorbed through the portal vein may be subjected to liver activity before being released into the systemic circulation. portal circulation refers to the circulation of the blood from the small intestine to the liver, via the portal vein. Blood flow to the liver is unique in that it receives oxygenated and de- oxygenated blood.
  • 61. FIRST PASS EFFECT First pass effect is the inactivation of drugs by the liver immediately after absorption through the portal circulation. The liver metabolizes many drugs altering the concentration of the active drug that will eventually be released into the systemic circulation. First pass effect may greatly reduce bioavailability of a drug.
  • 62. The dose of propranolol administered intravenously is less than that administered orally. Why is this so?
  • 63. Examine the schematic diagram of the different routes of drug administration showing potential for first pass effect and how it can affect bioavailability.
  • 64. In your lesson plan, discuss the schematic diagram and answer the following questions: 1.Give 2 enteral and 2 topical routes of administration that bypass first pass effect. 2.If you want to insert a box for percutaneous administration in the above illustration. Where will you put it?
  • 65. Absorption Main factors affecting oral absorption: I Physiological factors. II Physical-chemical factors. III Formulation factors. I Physiological factors affecting oral absorption: 1- Membrane physiology. 2- Passage of drugs across membranes. 3- Gastrointestinal physiology. I. Characteristics of GIT physiology and drug absorption II. Gastric emptying time and motility III. Effect of food on drug absorption
  • 66. Physiological factors influencing bioavailability: 1- Membrane physiology:
  • 67. 1- Membrane physiology (Cont.): - The cell membrane is the barrier that separates the inside of the cell from the outside. - The cell membrane is made up of phospholipids, proteins, and other macromolecules. - The phosopholipids make up a bilayer. It contains hydrophilic and hydrophobic molecules. - The proteins in the cell membrane are located within the phospholipid bilayer. - So, the biologic membrane is mainly lipid in nature but contains small aqueous channels or pores.
  • 68. 2-Passage of drugs across membranes: DRUG TRANSPORT: 1. PASSIVE DIFFUSION 2. CARRIER-MEDIATED 2.1 FACILITATED DIFFUSION 2.2 ACTIVE TRANSPORT 3. PORE, CONVECTIVE, PARACELLULAR 4. VESICULAR TRANSPORT 4.1 ENDOCYTOSIS 4.1.1 PHAGOCYTOSIS 4.1.2 PINOCYTOSIS 4.2 EXOCYTOSIS 5. ION PAIR FORMATION 6. TRANSPORTER PROTEIN EFFLUX
  • 69. 1. Passive diffusion: - Most drugs cross biologic membranes by passive diffusion. - Diffusion occurs when the drug concentration on one side of the membrane is higher than that on the other side. - The process is passive because no external energy is expended. - The driving force for passive diffusion is the difference in drug concentrations on either side of the cell membrane.
  • 70. ABSORPTION OF DRUGS
  • 71. 2. CARRIER- MEDIATED 2.1 Facilitated diffusion: - Play a very minor role in absorption. - A drug carrier is required but no energy is necessary. e.g. vitamin B12 transport. - Saturable if not enough carrier and structurally selective for the drug and shows competition kinetics for drugs of similar structure. - No transport against a concentration gradient only downhill but faster.
  • 72. involves specific carrier proteins that span a membrane energy dependent driven by the hydrolysis of ATP capable of moving drugs against a concentration gradient – that is, from a region of low concentration to one of higher drug concentration. 2.2 ACTIVE TRANSPORT
  • 73. BOTH DOESN’T REQUIRE ENERGY The rate of passive transport depends on the permeability of the cell membrane SIMILARITIES DIFFERENCES > involves a carrier, transmembrane proteins > can be saturated > doesn’t involve a carrier > not saturable > shows a low structural specificity
  • 74. Fick’s First Law of Diffusion The amount, M, of material flowing through a unit cross section, X, of a barrier in unit time, t, is known as the flux, J. The flux, in turn, is proportional to the concentration gradient, dC/dt. “Diffusion will stop when the concentration gradient no longer exists.”
  • 75. Diagram of Passive Transport with a Concentration Gradient -The rate of transport of drug across the membrane can be described by Fick's first law of diffusion:- Fick's First Law, Rate of Diffusion
  • 76. The negative sign of equation signifies that diffusion occurs in a direction opposite to that of increasing concentration. Diffusion occurs in the direction of decreasing concen
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