BIOPHARMACEUTICS

1. BIOPHARMACEUTICS

2. WHAT IS BIOPHARMACEUTICS? • Biopharmaceutics can be defined as the study of how • the physicochemical properties of drugs, • dosage forms and • routes of administration • affect the rate and extent of drug absorption. • Bioavailability is therefore defined as: • the rate and extent of drug absorption

3. If a drug is given intravenously it is administered directly into the blood, and therefore we can be sure that all the drug reaches the systemic circulation. The drug is therefore said to be 100% bioavailable All other routes of administration where a systemic action is required, involve the absorption of the drug into the blood.

4. Absorption phase Elimination phase MSC Plasma Concentration Cmax Therapeutic range (window) MEC AUC tmax Time A typical blood plasma concentration-time curve obtained following the peroral administration of a single dose of a drug in a tablet

5. Cmax: the highest plasma drug concentration observed. Tmax: the time at which Cmax occurs following administration of an extravascular dose. AUC: Area under the curve MSC: Maximum safe concentration MEC: Minimum effective concentration Therapeutic range: The range of plasma concentrations between the minimally effective concentration and the maximum safe concentration Absorption phase: Absorption rate > Elimination rate Elimination phase: Elimination rate > Absorption rate

6. Routes of drug administration The route of administration determines the site of application of the drug product. Often the goal is to attain a therapeutic drug concentration in plasma from which drug enters the tissue (therapeutic window between toxic concentration and minimal effective concentration).

7. Routes of administration are classified into: ENTERAL and PARENTERAL Enteral means through the GI tract and includes oral, buccal, and rectal. Parenteral means not through the alimentary canal and commonly refers to injections such as IV, IM, and SC; but could also include topical and inhalation

8. A. Enteral Routes 1. Sublingual (buccal) Certain drugs are best given beneath the tongue (sublingual) or retained in the cheek pouch (buccal) and are absorbed from these regions into the local circulation.

9. These vascular areas are ideal for lipid-soluble drugs that would be metabolized in the gut or liver, since the blood vessels in the mouth bypass the liver (do not undergo first pass liver metabolism), and drain directly into the systemic circulation. This route is usually reserved for nitrates and certain hormones.

10. Diagram of first pass effect biliary tract metabolised drug liver portal vein gut unmetabolised drug to circulation

11. 2. Oral By far the most common route. The passage of drug from the gut into the blood is influenced by biologic and physicochemical factors and by the dosage form. For most drugs, 2- to 5-fold differences in the rate or extent of gastrointestinal absorption can occur, depending on the dosage form. Generally, the bioavailability of oral drugs follows the order: solution > suspension > capsule > tablet > coated tablet.

12. 3. Rectal The administration of suppositories is usually reserved for situations in which oral administration is difficult. This route is more frequently used in small children. It by-passes the liver

13. B. Parenteral Routes 1. Intravenous injection Used when a rapid clinical response is necessary, e.g., an acute asthmatic episode. This route allows one to achieve relatively precise drug concentrations in the plasma, since bioavailability is 100%.

14. Most drugs should be injected over 1-2 minutes in order to prevent the occurrence of very high drug concentrations in the injected vein, possibly causing adverse effects. Some drugs, particularly those with narrow therapeutic indices or short half-lives, are best administered as a slow IV infusion or drip.

15. 2. Intramuscular injection Drugs may be injected into the arm (deltoid), thigh (vastus lateralis) or buttocks (gluteus maximus). Because of differences in vascularity, the rates of absorption differ, with arm > thigh > buttocks. Drug absorption may be slow and erratic. Lipid solubility and degree of ionization influence absorption. It should not be assumed that the IM route is as reliable as the IV route.

16. 3. Subcutaneous injection Some drugs, notably insulin, are routinely administered SC. Drug absorption is generally slower SC than IM, WHY? due to poorer vascularity. Absorption can be facilitated by heat, massage or vasodilators. It can be slowed by coadministration of vasoconstrictors, a practice commonly used to prolong the local action of local anesthetics. As above, arm > thigh.

18. 4. Topical application a. Eye For desired local effects. b. Intravaginal For infections or contraceptives. c. Intranasal For alleviation of local symptoms. Directly from nasal capillaries into circulation.

19. d. Skin Systemic absorption does occur and varies with the area, site, drug, and state of the skin. Dimethyl sulfoxide (DMSO) enhances the percutaneous absorption of many drugs. e. Drug patches (drug enters systemic circulation by zero order kinetics – a constant amount of drug enters the circulation per unit time).

20. 5. Inhalation Volatile anesthetics, as well as many drugs which affect pulmonary function, are administered as aerosols. The large alveolar area and blood supply lead to rapid absorption into the blood. Drugs administered via this route are not subject to first-pass liver metabolism.

21. 6. Other ROA's • Other routes of administration include: • intra-arterialfor cancer chemotherapy to maximize drug concentrations at the tumor site • intrathecal directly into the cerebrospinal fluid.

22. Why are there different routes? • Solubility or stability of the drug • The absorption from the different sites. Many drugs are absorbed from stomach and small intestine and not absorbed rectally. • Toxic when given by certain routes. • Ineffective, destroyed or inactivated in certain organs e.g. penicillin in stomach. • Convenience of the patient

24. The concentration of the drug in blood plasma depends onLADME 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. D = Distribution the process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues).

25. The concentration of the drug in blood plasma depends onLADME 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.

26. ADME

28. 1. ABSORPTION

29. Absorption • The absorption of a drug from the GIT is the passage of the substance from the lumen through several membranes into the blood stream. • Main factors affecting oral absorption: • Physiological factors • Physical-chemical factors • Formulation factors BLOOD GIT

30. 1. Physiological Factors Affecting Oral Absorption • A- Membrane physiology • B- Passage of drugs across membranes • Active transport • Facilitated diffusion • Passive diffusion • Pinocytosis • Pore transport • Ion pair formation

31. C- Gastrointestinal physiology • GIT physiology and drug absorption • Gastric emptying time and motility • Effect of food on drug absorption • Enterohepatic circulation • First pass effect

32. A. Membrane physiology Membrane structure (Fluid Mosaic Model) The biologic membrane consists mainly of a lipid bilayer containing primarily phospholipids and cholesterol, with imbedded proteins. The membrane contains also small aqueous channels or pores.

33. Phospholipid Bilayers Phospholipids are amphiphilic in nature. Polar heads are oriented toward the water and the fatty acid tails are oriented toward the inside of the bilayer. Thefatty acid tails are flexible, causing the lipid bilayer to be flexible. At body temperature, membranes are a liquid with a consistency that is similar to cooking oil.

34. Cholesterol Cholesterolis a major membrane lipid. It may be equal in amount to phospholipids.It is similar to phospholipids in that one end ishydrophilic the other end ishydrophobic. Cholesterol makes the membrane less permeable to most biological molecules. Proteins Proteinsare scattered throughout the membrane. They may be attached to inner surface, embedded in the bilayer, or attached to the outer surface.

36. Functions of Membrane Proteins Channel

37. A. Channel proteins A protein that allows a particular molecule or ion to freely cross the membrane as it enters or leaves the cell. B. Carrier proteins A protein that selectively interacts with a specific molecule or ion so that it can cross the cell membrane to enter or exit the cell.

38. C. Receptor proteins A protein that has a specific shape so that specific molecules can bind to them. The binding of a molecule, such as a hormone, can influence the metabolism of the cell. D. Enzyme proteins An enzyme that catalyzes a specific reaction.

39. E. Cell-recognition proteins Glycoproteins that identify the cell. They make up the cellular fingerprint by which cells can recognize each other. F. Cell Adhesion Proteins Adjacent cells stick together via interlocking proteins on their membranes

40. B. Passage of Drugs Across Membranes • The membrane can be viewed as a semipermeable lipoidal sieve that allows the passage of: • lipid-soluble molecules across it by passive lipid • diffusion • water and small hydrophilic molecules through • its numerous aqueous pores. • other molecules by a number of transporter • proteins or carrier molecules that exist in the • membrane.

41. There are two main mechanisms of drug transport across the gastrointestinal epithelium: Paracellular: i.e. between the cells. Transcellular: i.e. across the cells The transcellular pathway is further divided into simple passive diffusion, carrier-mediated transport (active transport and facilitated diffusion) and endocytosis.

42. 1. Passive Transport • Most (many) drugs cross biological membranes by passive diffusion. • Diffusion occurs when the drug concentration on one side of the membrane is higher than that on the other side (according to concentration gradient). • Drug diffuses across the membrane in an attempt to equalize the drug concentration on both sides of the membrane.

43. The rate of transport of drug across the membrane can be described by Fick's first law of diffusion:- • D: diffusion coefficient • This parameter is related to: • the size of the drug • lipid solubility of the drug • viscosity of the diffusion medium, the membrane. • As lipid solubility increases or molecular size decreases then D increases and thus diffusion rate also increases.

44. A: surface area As the surface area increases the rate of diffusion also increase. The surface of the intestinal lining (with villae and microvillae) is much larger than the stomach. Therefore absorption is generally faster from intestine compared to stomach. x: membrane thickness The smaller the membrane thickness the quicker the diffusion process. e.g. the membrane in the lung is quite thin thus inhalation absorption can be quite rapid.

45. (Ch -Cl): concentration difference. Since V, the apparent volume of distribution, is at least four liters and often much higher the drug concentration in blood or plasma will be quite low compared with the concentration in the GI tract. It is this concentration gradient which allows the rapid complete absorption of many drug substances. Normally Cl << Ch then:- Thus the absorption of many drugs from the G-I tract can often appear to be first-order.

46. 2. Facilitated Transport • Is also the movement of molecules from a high concentration to a low concentration. • Lipid insoluble substances such as glucose and amino acids are taken across by "carrier proteins". • No chemical energy is required in this process, WHY? • eg. amino acids, glucose and other breakdown products of food are absorbed by the small intestinefacilitated diffusion

47. Active Transport • It is the movement of molecules across a living membrane • from an area of low concentration to an area of high concentration • with the aid of a carrier protein and • using energy or ATP. • The rate of drug absorption increases with drug concentration until the carrier molecules are completely saturated, the rate then remains constant 3. Active Transport

49. Mechanism of Drug Transport ?

50. 4. Endocytosis Surrounding a substance with the cell membrane and the subsequent formation of a vesicle to bring these substances into the cell. This process is energy dependent.