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  1. 1. Presented by: Prof.Mirza Anwar Baig 1 Chapter :3 Chapter :3 Introduction to Pharmacology Introduction to Pharmacology Presented by: Prof.Mirza Anwar Baig Presented by: Prof.Mirza Anwar Baig Anjuman-I-Islam's Kalsekar Technical Campus Anjuman-I-Islam's Kalsekar Technical Campus School of Pharmacy,New Pavel,Navi School of Pharmacy,New Pavel,Navi Mumbai,Maharashtra Mumbai,Maharashtra 1 1
  2. 2. Presented by: Prof.Mirza Anwar Baig 2 Contents: 1. Important terms 2. Drug nomenclature 3. Routes of drug adminsterations 4. Pharmacokinetics (ADME)
  3. 3. Presented by: Prof.Mirza Anwar Baig 3 At the end of topic you should be able to.... Compare advantage and disadvantages of routes of drug administration. Explain the essential characteristics of drug for proper absorption & excretion. Summarize the role of distribution and metabolism in drug actions.
  4. 4. Presented by: Prof.Mirza Anwar Baig 4 1.Pharmacology: • Science of drugs (Greek:Pharmacon--drug; logos-discourse in). In a broad sense, it deals with interaction of exogenously adminstered chemical molecules (drugs) with living systems. • It encompasses all aspects of Pharmacodynamics knowledge about drugs, but most importantly- What the drug does to the body. • those that are relevant to effective and safe use for This includes physiological and biochemical medicinal purposes. The two main divisions of pharmacology are: • Pharmacodynamics: knowledge about drugs, but most importantly - What the drug does to the body. • Pharmacokinetics (Greek: Kinesis-movement):- What the body does to the drug.
  5. 5. Presented by: Prof.Mirza Anwar Baig 5 2. Drug (French: Drogue -a dry herb) "Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient." 3. Pharmacotherapeutics: • It is the application of pharmacological information together with knowledge of the disease for its prevention,mitigation or cure. • Selection of the most appropriate drug, dosage and duration of treatment taking into account the specific features of a patient are a part of pharmacotherapeutics.
  6. 6. Presented by: Prof.Mirza Anwar Baig 6 4.Clinical pharmacology: It is the scientific study of drugs in man. It includes pharmacodynamic and pharmacokinetic investigation in healthy volunteers and in patients; evaluation of efficacy and safety of drugs and comparative trials with other forms of treatment; surveillance of patterns of drug use, adverse effects etc. 5. Chemotherapy: It is the treatment of systemic infection/malignancy with specific drugs that have selective toxicity for the infecting organism malignant cell with no/minimal effects on the host cells
  7. 7. Presented by: Prof.Mirza Anwar Baig 7 6.Toxicology: It is the study of poisonous effect of drugs and other chemicals (household, environ­mental pollutant, industrial, agricultural, homi­cidal) with emphasis on detection, prevention and treatment of poisonings. It also includes the study of adverse effects of drugs, since the same substance can be a drug or a poison, depending on the dose.
  8. 8. Presented by: Prof.Mirza Anwar Baig 8 DRUG NOMENCLATURE Three categories of names: (a) Chemical name: It describes the substance chemically, e.g.1-(lsopropylamino)- 3-(1-naphthy­loxy) propan-2-ol for propranolol. This is cumbersome and not suitable for use in prescribing. A code name, e.g. RO 15-1788 (later named flumazenil) may be assigned by he manufacturer for con­venience and simplicity before an approved name is coined. b) Brand name – Original drug which is defended by patent and may be produced during patent term only by this pharmaceutical firm c) Generic name– When term of patent is discontinued the drug may be produced by different pharmaceutical companies under new product (trade) names but at the basis of original active substance (similar quantity, route of administration etc.)
  9. 9. Presented by: Prof.Mirza Anwar Baig 9 ESSENTIAL DRUGS (MEDICINES) CONCEPT The WHO has defined Essential Drugs (medicines) as "those that satisfy the priority healthcare needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost effective. Essential medicines are intended to be available within the context of functioning health systems at all times and in adequate amounts, in appropriate dosage forms, with assured quality and adequate information, and at a affordable price. For optimum utilization of resources, governments (especially in developing countries) should concentrate on well tested,cheaper,safe and efficacious drugs by identifying them as Essential medicines.
  10. 10. Presented by: Prof.Mirza Anwar Baig 10 WHO criteria for the selection of an essential medicine. a) Adequate data on its efficacy and safety should be available from clinical studies. b) It should be available in a form in which quality, including bioavailability, and stability on storage can be assured. c) Its choice should depend upon pattern of prevalent diseases; availability of facilities and trained personnel; financial resources; genetic, demographic and enviromental factors. d) In case of two or more similar medicines, choice should be made on the basis of their relative efficacy, safety, quality, price and availability, by comparative pharma­cokinetic properties and local facilities for manufacture and storage. f) Most essential medicines should be single compounds. Fixed ratio combination products should be included only when dosage of each ingradient meets the requirements of a defined population group, and when the combination has a proven advantage in therapeutic effect, safety, adherence or in decreasing the emergence of drug resistance.
  11. 11. Presented by: Prof.Mirza Anwar Baig 11 (g) Selection of essential medicines should be a continuous process which should take into account the changing priorities for public health action, epidemiological conditions as well as availability of better medicines/ formulations and progress in pharmacological knowledge. (h) Recently, it has been emphasized to select essential medicines based on rationally developed treatment guidelines. Ø First Model List of Essential Drugs along with their dosage forms and strengths in 1977 by WHO which could be adopted after suitable modifications according to local needs. Ø India produced its National Essential Drugs List in 1996 and has revised it in 2003 with the title "National List of Essential Medicines". This includes 354 medicines which are considered to be adequate to meet the priority healthcare needs of the general population of the country. Ø Adoption of the essential medicines list for procurement and supply of medicines, especially in the public sector healthcare system, has resulted in improved availability of medicines, cost saving and more rational use of drugs.
  12. 12. Presented by: Prof.Mirza Anwar Baig 12 Orphan Drugs • These are drugs or biological products for diagnosis/treatment/ prevention of a rare disease or condition, or a more common disease (endemic only in resource poor countries) for which there is no reasonable expectation that the cost of developing and marketing it will be recovered from the sales of that drug. • The list includes: Sodium nitrite, fomepizole, liposomal amphotericin 8, ancrod, rifabutin, succimer, somatropin, digoxin immune Fab (digoxin antibody), liothyronine (T3) and many more. • Though these drugs may be life saving for some patients, they are commercially difficult to obtain. • Governments in developed countries offer tax benefits and other incentives to pharmaceutical companies for developing and marketing orphan drugs (e.g. Orphan Drug Act in USA).
  13. 13. Presented by: Prof.Mirza Anwar Baig 13 Route of drug adminsteration Definition: A route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body.
  14. 14. Presented by: Prof.Mirza Anwar Baig 14 Classification Routes of administration can broadly be divided into: 1. Topical: Drugs are applied topically to the skin or mucous membranes, mainly for local action. 2. Oral: used for systemic (non-local) effect, substance is given via the digestive tract. 3. Parenteral: A drug administered parenterally is one injected via a hollow needle into the body at various sites and to varying depth. 4. Rectal: Drugs given through the rectum by suppositories or enema. 5. Inhalation: The lungs provide an excellent surface for absorption when the drug is delivered in gaseous, aerosol or ultrafine solid particle form
  15. 15. Presented by: Prof.Mirza Anwar Baig 15 ROUTES OF DRUG ADMINISTRATION Mostly common considerations are: 1. Physical and chemical properties of the drug - Solid/liquid/ gas – Solubility and stability – PH and irritancy 2. Site of desired action - localized and aprochable 3. Rate and extent of absorption of the drug from different routes. 4. Effect of digestive juices and first pass metabolism of the drug. 5. Rapidity with which the response is desired (eg.routine treatment or emergency). 6. Accuracy of dosage required (i.v. and inhalation). 7. Condition of the patient (unconscious, vomiting) etc.
  16. 16. Presented by: Prof.Mirza Anwar Baig 16 Local route • These routes can only be used for localized lesions at accessible sites and for drugs whose systemic absorption from these sites is minimal or absent. • Thus, high concentrations are attained at the desired site without exposing the rest of the body. • Systemic side effects or toxicity are consequently absent or minimal. • The same can serve as systemic route of adminis­tration, e.g. glyceryl trinitrate (GTN) applied on the skin as ointment or transdermal patch.
  17. 17. Presented by: Prof.Mirza Anwar Baig 17 A.Topical route This refers to external application of the drug to the surface for localized action. It is often more convenient as well as encouraging to the patient. Drugs can be efficiently delivered to the localized lesions on skin, oropharyngeal/nasal mucosa, eyes, ear canal, anal canal or vagina. The dosage forms are lotion, ointment, cream,powder, paints, drops, spray, lozengens, suppositories or pesseries. Nonabsorbable drugs given orally (sucralfate, vancomycin), inhalation of drugs for action on bronchi (salbutamol, cromolyn sodium) and irrigating solutions/jellys (povidone iodine,lidocaine) applied to urethra
  18. 18. Presented by: Prof.Mirza Anwar Baig 18 1- Topical route: I Skin A-Dermal – cream, ointment (local action) B- Transdermal- absorption of drug through skin (i.e systemic action) I. stable blood levels(controlled drug delivery system) II. No first pass metabolism III. Drug must be potent or patch becomes too large II Mucosal membranes • eye drops (onto the conjunctiva) • ear drops • intranasal route (into the nose)
  19. 19. Presented by: Prof.Mirza Anwar Baig 19 2- Oral route: - By swallowing. - It is intended for systemic effects resulting from drug absorption through the various epithelia and mucosa of the gastrointestinal tract.
  20. 20. Presented by: Prof.Mirza Anwar Baig 20 Advantages: 1- Convenient - portable, no pain, easy to take. 2- Cheap - no need to sterilize, compact, multi-dose bottles, automated machines produce tablets in large quantities. 3- Variety - tablets, capsules, suspensions, mixtures . Disadvantages: 1- Sometimes inefficient - low solubility drugs may suffer poor availability e.g. Griseofulvin 2- First-pass effect - drugs absorbed orally are transported to the general circulation via the liver. Thus drugs which are extensively metabolized will be metabolized in the liver during absorption. e.g. propranolol
  21. 21. Presented by: Prof.Mirza Anwar Baig 21 First pass effect: First pass effect
  22. 22. Presented by: Prof.Mirza Anwar Baig 22 1. The first pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation. 2. The greater the first pass effect, the lower the bioavailability of the drug(the rate and extent of the drug reaching systemic circulation). 3. Food and G-I motility can affect drug absorption.Often patient instructions include a direction to take with food or take on an empty stomach. 4. Absorption is slower with food(milk and milk products) for tetracyclines and penicillins, etc. However, for propranolol bioavailability is higher after food, and for griseofulvin absorption is higher after a fatty meal. First pass effect (Cont.):
  23. 23. Presented by: Prof.Mirza Anwar Baig 23 5. Sometimes may have adverse reactions – e.g. Antibiotics may kill normal gut flora and allow overgrowth of fungal varieties. Thus, antifungal agent may be included with an antibiotic. 6. Not suitable for unconscious patient - Patient must be able to swallow solid dosage forms. Liquids may be given by tube. 7.May cause irritation to gastric mucosa, nausea and vomiting. 8.Effect too slow for emergencies.
  24. 24. Presented by: Prof.Mirza Anwar Baig 24 3- Buccal/Sublingual route: • Some drugs are taken as smaller tablets which are held in the mouth (buccal tablet) or under the tongue (sublingual tablet). • Buccal tablets are often harder tablets [4 hour disintegration time], designed to dissolve slowly. • E.g Nitroglycerin, as a softer sublingual tablet [2 min disintegration time], may be used for the rapid relief of angina.
  25. 25. Presented by: Prof.Mirza Anwar Baig 25 Advantages 1- Avoid hepatic first pass - The liver is by- passed thus there is no loss of drug by first pass effect for buccal administration. Bioavailability is higher. 2- Rapid absorption - Because of the good blood supply to the area, absorption is usually quite rapid. 3- Drug stability - pH in mouth relatively neutral (gf. stomach - acidic). Thus a drug may be more stable. 3- Buccal/Sublingual route (Cont.)
  26. 26. Presented by: Prof.Mirza Anwar Baig 26 Disadvantages 1- Holding the dose in the mouth is inconvenient. 2- Small doses only can be accommodated easily. 3- Buccal/Sublingual route (Cont.)
  27. 27. Presented by: Prof.Mirza Anwar Baig 27 4- Parenteral route:
  28. 28. Presented by: Prof.Mirza Anwar Baig 28 A- Intravascular (IV, IA): - placing a drug directly into blood stream. -May be - Intravenous (into a vein) or - intraarterial (into an artery). Advantages 1- precise, accurate and immediate onset of action, 100% bioavailability. Disadvantages 1- risk of embolism. 2- high concentrations attained rapidly leading to greater risk of adverse effects. 4- Parenteral route (Cont.)
  29. 29. Presented by: Prof.Mirza Anwar Baig 29 4- Parenteral route (Cont) B-Intramuscular :(into the skeletal muscle). Advantages 1- suitable for injection of drug in aqueous solution (rapid action) and drug in suspension or emulsion (sustained release). Disadvantages 1- Pain at injection sites for certain drugs.
  30. 30. Presented by: Prof.Mirza Anwar Baig 30 C- Subcutaneous (under the skin), e.g. insulin. D- Intradermal, (into the skin itself) is used for skin testing some allergens. E- Intrathecal (into the spinal canal) is most commonly used for spinal anesthesia . F- Intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal dialysis in case of renal insuffeciency. 4- Parenteral route (Cont)
  31. 31. Presented by: Prof.Mirza Anwar Baig 31 5-Rectal route: Most commonly by suppository or enema. Advantages 1- By-pass liver - Some of the veins draining the rectum lead directly to the general circulation, thus by-passing the liver. Reduced first-pass effect. 2- Useful - This route may be most useful for patients unable to take drugs orally (unconscious patients) or with younger children. - if patient is nauseous or vomiting
  32. 32. Presented by: Prof.Mirza Anwar Baig 32 Disadvantages 1- Erratic absorption - Absorption is often incomplete and erratic. 2- Not well accepted. 5- Rectal route (Cont.)
  33. 33. Presented by: Prof.Mirza Anwar Baig 33 6- Inhalation route: - Used for gaseous and volatile agents and aerosols. - solids and liquids are excluded if larger than 20 micron. the particles impact in the mouth and throat. Smaller than 0.5 micron , they aren't retained. Advantages A- Large surface area B- thin membranes separate alveoli from circulation C- high blood flow - As result of that a rapid onset of action due to rapid access to circulation.
  34. 34. Presented by: Prof.Mirza Anwar Baig 34 Disadvantages 1- Most addictive route of administration because it hits the brain so quickly. 2- Difficulties in regulating the exact amount of dosage. 3- Sometimes patient having difficulties in giving themselves a drug by inhaler. 6- Inhalation route (Cont.)
  35. 35. Presented by: Prof.Mirza Anwar Baig 35 Comparisons:
  36. 36. Presented by: Prof.Mirza Anwar Baig 36 Comparisons:
  37. 37. Presented by: Prof.Mirza Anwar Baig 37 Pharmacokinetics Pharmacokinetics refers to what the body does to a drug & phar- macodynamics describes what the drug does to the body. • Four pharmacokinetic properties determine the onset, intensity,and the duration of drug action • Absorption: • Distribution: • Metabolism: • Elimination: Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including the route of administration, the dose,the frequency, and the duration of treatment.
  38. 38. Presented by: Prof.Mirza Anwar Baig 38 Drug absorption:
  39. 39. Presented by: Prof.Mirza Anwar Baig 39 B.Factors influencing absorption: 1.Effect of pH on drug absorption: 2. Blood flow to the absorption site: 3. Total surface area available for absorption: 4. Contact time at the absorption surface: 5. Expression of P-glycoprotein:
  40. 40. Presented by: Prof.Mirza Anwar Baig 40 1.Effect of pH on drug absorption: 5. Expression of P-glycoprotein:
  41. 41. Presented by: Prof.Mirza Anwar Baig 41 Bioavailability • Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. • For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bio- availability is 0.7 or 70%. • Determining bioavailability is important for calculating drug dosages for nonintravenous routes of administration. Determination of bioavailability:
  42. 42. Presented by: Prof.Mirza Anwar Baig 42 2.Factors that influence bioavailability: a.First-pass hepatic metabolism: b.Solubility of the drug: c.Chemical instability: d.Nature of the drug formulation:
  43. 43. Presented by: Prof.Mirza Anwar Baig 43 a. First-pass hepatic metabolism : What is FPHM: When a drug is absorbed from the GI tract, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased. This is referred to as first-pass hepatic metabolism. First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. For example: More than 90% of nitroglycerin is cleared during first-pass metabolism. Hence, it is primarily administered via the sublingual or transdermal route. Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action.
  44. 44. Presented by: Prof.Mirza Anwar Baig 44 Examples: a. Nitroglycerin pacth b. First pass effect
  45. 45. Presented by: Prof.Mirza Anwar Baig 45 b.Solubility of the drug: • Very hydrophilic drugs are poorly absorbed because of their inability to cross lipid-rich cell mem-branes. • Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. • For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. • This is one reason why many drugs are either weak acids or weak bases. c.Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes.
  46. 46. Presented by: Prof.Mirza Anwar Baig 46 d.Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, Particle size Salt form Crystal polymorphism Enteric coatings, Presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and,therefore, alter the rate of absorption.
  47. 47. Presented by: Prof.Mirza Anwar Baig 47 D.Bioequivalence Two drug formulations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Clinical effectiveness often depends on both the maximum serum drug con-centration and the time required (after administration) to reach peak concentration E.Therapeutic equivalence Two drug formulations are therapeutically equivalent if they are pharmaceutically equivalent (that is, they have the same dosage form, contain the same active ingredient, and use the same route of administration) with similar clinical and safety profiles. Therefore, two drugs that are bioequivalent may not be therapeutically equivalent.
  48. 48. Presented by: Prof.Mirza Anwar Baig 48 IV. DRUG DISTRIBUTION • Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues. • For drugs administered IV, absorption is not a factor, and the initial phase (from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which the drug rapidly leaves the circulation and enters the tissues. • The distribution of a drug from the plasma to the interstitium depends on cardiac output and local blood flow, capillary permeability, the tissue volume,the degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug.
  49. 49. Presented by: Prof.Mirza Anwar Baig 49
  50. 50. Presented by: Prof.Mirza Anwar Baig 50 Factors affecting distribution: A. Blood flow B. Capillary permeability C. Binding of drugs to plasma proteins and tissues D. Lipophilicity E. Volume of distribution
  51. 51. Presented by: Prof.Mirza Anwar Baig 51 A. Blood flow 1. The rate of blood flow to the tissue capillaries varies widely. 2. For instance, blood flow to the “ vessel-rich organs ” (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. 3. Propofol has short duration of hypnosis produced by an IV bolus. 4. High blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia. 5. A subsequent slower distribution to skel-etal muscle and adipose tissue lowers the plasma concentration so that the drug diffuses out of the CNS, down the concentration gradient, and consciousness is regained.
  52. 52. Presented by: Prof.Mirza Anwar Baig 52 B.Capillary permeability • Capillary permeability is determined by capillary structure and by the chemical nature of the drug. 1. LIVER AND SPLEEN: • A significant portion of the basement membrane is exposed due to large,discontinuous capillaries through which large plasma proteins can pass. 2. BRAIN: The capillary structure is continuous, and there are no slit junctions. • These closely jux-taposed cells form tight junctions that constitute the blood–brain barrier. • For example, a specific transporter carries levodopa into the brain. By contrast, lipid-soluble drugs readily penetrate the CNS because they dissolve in the endothelial cell membrane. • Ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endothelial cells that have no slit junctions.
  53. 53. Presented by: Prof.Mirza Anwar Baig 53 C.Lipophilicity 1. The chemical nature of a drug strongly influences its ability to cross cell membranes. 2. Lipophilic drugs readily move across most biologic membranes. 3. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. 4. The major factor influencing the distribution of lipophilic drugs is blood flow to the area. 5. In contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions.
  54. 54. Presented by: Prof.Mirza Anwar Baig 54 D.Volume of distribution The apparent volume of distribution, Vd , is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. Vd = Amount of drug in to the body (C0) Plasma concentration at time zero (C0). Although Vd has no physiologic or physical basis, it can be useful to compare the distribution of a drug with the volumes of the water compartments in the body.
  55. 55. Presented by: Prof.Mirza Anwar Baig 55 1. Distribution into the water compartments in the body: • Once a drug enters the body, it has the potential to distribute into any one of the three functionally distinct compartments of body water or to become sequestered in a cellular site. a. Plasma compartment: If a drug has a high molecular weight or is extensively protein bound, it is too large to pass through the slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. As a result, it has a low Vd that approximates the plasma volume or about 4 L in a 70-kg individual. Heparin shows this type of distribution.
  56. 56. Presented by: Prof.Mirza Anwar Baig 56 b. Extracellular fluid: • Drug with low molecular weight but is hydrophilic, it can pass through the endothelial slit junctions of the capillaries into the interstitial fluid. • Hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid. • Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the interstitial fluid, which together constitute the extracellular fluid (about 20% of body weight or 14 L in a 70-kg individual). • Example:Aminoglycoside antibiotics c. Total body water: Drug with LMW and is lipophilic, it can move into the interstitium through the slit junctions and also pass through the cell membranes into the intracellular fluid. These drugs distribute into a volume of about 60% of body weight or about 42 L in a 70-kg individual.
  57. 57. Presented by: Prof.Mirza Anwar Baig 57 2.Apparent volume of distribution: 1. A drug rarely associates exclusively with only one of the water compartments of the body. 2. Instead, the vast majority of drugs distribute into several compartments, often avidly binding cellular components, such as lipids (abundant in adipocytes and cell membranes), proteins (abundant in plasma and cells), and nucleic acids (abundant in cell nuclei). 3. Therefore, the volume into which drugs distribute is called the apparent volume of distribution (Vd ). 4. Vd is a useful pharmacokinetic parameter for calculating the loading dose of a drug.
  58. 58. Presented by: Prof.Mirza Anwar Baig 58 3.Determination of Vd : • The fact that drug clearance is usually a first-order process allows calculation of Vd . First order means that a constant fraction of the drug is eliminated per unit of time. • This process can be most easily analyzed by plotting the log of the plasma drug concentration (Cp ) versus time. • The concentration of drug in the plasma can be extrapolated back to time zero (the time of IV bolus) on the Y axis to determine C0 , which is the concentration of drug that would have been achieved if the distribution phase had occurred instantly. • This allows calculation of Vd as Vd= Dose ---------- Co
  59. 59. Presented by: Prof.Mirza Anwar Baig 59 V. DRUG CLEARANCE THROUGH METABOLISM Once a drug enters the body, the process of elimination begins. The three major routes of elimination are hepatic metabolism, biliary elimination,and urinary elimination. Together, these elimination processes decrease the plasma concentration exponentially. That is, a constant fraction of the drug present is eliminated in a given unit of time. Most drugs are eliminated according to first-order kinetics, although some,such as aspirin in high doses, are eliminated according to zero-order or nonlinear kinetics. Metabolism leads to production of products with increased polarity, which allows the drug to be eliminated.
  60. 60. Presented by: Prof.Mirza Anwar Baig 60 • Clearance(CL) estimates the amount of drug cleared from the body per unit of time. • Total CL is a composite estimate reflecting all mechanisms of drug elimination and is calculated as follows: CL = 0 . 693 × Vd / t 1/2
  61. 61. Presented by: Prof.Mirza Anwar Baig 61 Kinetics of metabolism: 1.First-order kinetics: The metabolic transformation of drugs is catalyzed by enzymes, and most of the reactions obey Michaelis-Menten kinetics. V max [ C ] v = Rate of drug metabolism = ------------------------ K m + [ C ] In most clinical situations, the concentration of the drug, [C], is much less than the Michaelis constant, K m , and the Michaelis- Menten equation reduces to v = Rate of drug metabolism = V max [ C ] K m This means that a constant fraction of drug is metabolized per unit of time (that is, with each half-life,the concentration decreases by 50%). First-order kinetics is also referred to as linear kinetics.
  62. 62. Presented by: Prof.Mirza Anwar Baig 62 2.Zero-order kinetics: • With a few drugs, such as aspirin, ethanol,and phenytoin, the doses are very large. Therefore, [C] is much greater than Km , and the velocity equation becomes V max [ C ] v = Rate of drug metabolism = [ C ] = V max • The enzyme is saturated by a high free drug concentration, and the rate of metabolism remains constant over time. This is called zero-order kinetics (also called nonlinear kinetics). • A constant amount of drug is metabolized per unit of time. The rate of elimination is constant and does not depend on the drug concentration.
  63. 63. Presented by: Prof.Mirza Anwar Baig 63 B.Reactions of drug metabolism The kidney cannot efficiently eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed in the distal convoluted tubules. Therefore, lipid-soluble agents are first metabolized into more polar (hydrophilic) substances in the liver via two general sets of reactions, called phase I and phase II.
  64. 64. Presented by: Prof.Mirza Anwar Baig 64 1.Phase I: • Phase I reactions convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group,such as –OH or –NH 2 . • Phase I reactions usually involve reduction, oxidation, or hydrolysis. • Phase I metabolism may increase,decrease, or have no effect on pharmacologic activity. • a.Phase I reactions utilizing the P450 system: • Most frequently involved reactions in drug metabolism are catalyzed by the cytochrome P450 • The P450 system is important for the metabolism of many endogenous compounds (such as ste-roids, lipids) and for the biotransformation of exogenous substances (xenobiotics). • Cytochrome P450, designated as CYP,is a superfamily of heme-containing isozymes that are located in most cells, but primarily in the liver and GI tract.
  65. 65. Presented by: Prof.Mirza Anwar Baig 65 [1] Nomenclature: The family name is indicated by the Arabic number that follows CYP, and the capital letter designates the subfamily, for example, CYP3A. A second number indicates the specific isozyme, as in CYP3A4. [2] Specificity: Different P450 isoforms present. Have the capacity to modify a large number of structurally diverse substrates. An individual drug may be a substrate for more than one isozyme. Four isozymes are CYP3A4/5,CYP2D6, CYP2C8/9, and CYP1A2. Most of the CYP3A4 are found in intestinal mucosa, accounting for first-pass metabolism of drugs such as chlorpromazine and clonazepam.
  66. 66. Presented by: Prof.Mirza Anwar Baig 66 [3] Genetic variability: P450 enzymes exhibit considerable genetic variability among individuals and racial groups. Variations in P450 activity may alter drug efficacy and the risk of adverse events. CYP2D6, in particular, has been shown to exhibit genetic polymorphism. CYP2D6 mutations result in very low capacities to metabolize substrates. No benefit from the opioid analgesic codeine due to lack the CYP2D6 enzyme that activates the drug. Clopidogrel (prodrug) in poor CYP2C19 metabolizers have a higher incidence of cardiovascular events. Although CYP3A4 exhibits a greater than 10 fold variability between individuals, no polymorphisms have been identified so far for this P450 isozyme.
  67. 67. Presented by: Prof.Mirza Anwar Baig 67 [4] Inducers: • The CYP450-dependent enzymes are an important target for pharmacokinetic drug interactions through inducing the CYP iszymes. • Certain drugs (phenobarbital, rifampin, and carbamazepine) increasing the synthesis of one or more CYP isozymes. results in loss of pharmacological effect of drugs which are metabolized by these CYP isozymes. • Rifampin significantly decreases the plasma concentrations of HIV pro- tease inhibitors, thereby diminishing their ability to suppress HIV replication. • St. John’s wort is a widely used herbal product and is a potent CYP3A4 inducer. • Many drug interactions have been reported with concomitant use of St. John’s wort.
  68. 68. Presented by: Prof.Mirza Anwar Baig 68 [5] Inhibitors: An important source of drug interactions that lead to serious adverse events. Inhibition of drugs metabolism is through competition for the same isozyme. Omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater anticoagulant effect and increased risk of bleeding. More important CYP inhibitors are erythromycin,ketoconazole, and ritonavir, because they each inhibit several CYP isozymes. Grapefruit juice inhibits CYP3A4 and leads to higher levels and/or greater potential for toxic effects with drugs, such as nifedipine, clarithromycin, and simvastatin, that are metabolized by this system.
  69. 69. Presented by: Prof.Mirza Anwar Baig 69 b.Phase I reactions not involving the P450 system: These include Amine oxidation (catecholamines or histamine) Alcohol dehydrogenation (ethanol oxidation) Esterases (metabolism of aspirin in the liver) Hydrolysis (procaine).
  70. 70. Presented by: Prof.Mirza Anwar Baig 70 2.Phase II:(conjugation reactions) • Polar metabolite of drugs can be excreted by the kidneys. • Lipophillic metabolite (after phase I metabolism) ,subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are often therapeutically inactive. • A notable exception is morphine-6-glucuronide, which is more potent than morphine. • Glucuronidation is the most common and the most important conjugation reaction. • Drugs already possessing an –OH, –NH 2 , or –COOH group may enter phase II directly and become conjugated • The highly polar drug conjugates are then excreted by the kidney or in bile.
  71. 71. Presented by: Prof.Mirza Anwar Baig 71 VI. DRUG CLEARANCE BY THE KIDNEY Polar drugs are eliminated easily from the body. Number of routes are available for elimination, the most important being elimination through the kidney into the urine. Patients with renal dysfunction may be unable to excrete drugs and are at risk for drug accumulation and adverse effects. Elimination of drugs via the kidneys into urine involves the processes – Glomerular filtration, – Active tubular secretion – Passive tubular reabsorption.
  72. 72. Presented by: Prof.Mirza Anwar Baig 72 1.Glomerular filtration: Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate. The glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish significantly in renal disease. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, variations in GFR and protein binding of drugs do affect this process.
  73. 73. Presented by: Prof.Mirza Anwar Baig 73 2. Proximal tubular secretion: Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles,(network) Two energy-requiring active transport systems take part in secretion of drugs: one for a. For anions (deprotonated forms of weak acids) b. For cations (protonated forms of weak bases). Each of these transport systems shows low specificity and can transport many compounds. Thus, competition between drugs for these carriers can occur within each transport system. Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the glomerular filtrate.
  74. 74. Presented by: Prof.Mirza Anwar Baig 74 3.Distal tubular reabsorption: As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The uncharged drug may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine,whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.” For example,a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption.
  75. 75. Presented by: Prof.Mirza Anwar Baig 75 4.Role of drug metabolism: Most drugs are lipid soluble and, without chemical modification, would diffuse from the tubular lumen to perivascular space (why) due to concentration gradient between the drug concentration in the filtrate and perivascular space. To minimize this reabsorption, drugs are modified primarily in the liver into more polar substances via phase I and phase II reactions. The polar or ionized conjugates are unable to back diffuse out of the kidney lumen.
  76. 76. Presented by: Prof.Mirza Anwar Baig 76 Summery Drug elimation:
  77. 77. Presented by: Prof.Mirza Anwar Baig 77 VII. CLEARANCE BY OTHER ROUTES Drug clearance may also occur via the intestines, bile, lungs, and breast,milk etc. Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are eliminated in the feces. The lungs are primarily involved in the elimination of anesthetic gases (for example, isoflurane). Elimination of drugs in breast milk may expose the breast- feeding infant to medications and/or metabolites being taken by the mother and is a potential source of undesirable side effects to the infant. Excretion of most drugs into sweat, saliva, tears,hair, and skin occurs only to a small extent. Total body clearance and drug half-life are important measures of drug clearance that are used to optimize drug therapy and minimize toxicity.
  78. 78. Presented by: Prof.Mirza Anwar Baig 78 A.Total body clearance: The total body (systemic) clearance, CL total , is the sum of all clearances from the drug-metabolizing and drug- eliminating organs. The kidney is often the major organ of elimination. The liver also contributes to drug clearance through metabolism and/or excretion into the bile. Total clearance is calculated using the following equation: CL total = CL hepatic + CL renal + CL pulmonary + CL other where CL hepatic + CL renal are typically the most important.
  79. 79. Presented by: Prof.Mirza Anwar Baig 79 B.Clinical situations resulting in changes in drug half-life • Adjustment in dosage is required when a patient has an abnormality. Increase in drug half-life include in case of 1) diminished renal or hepatic blood flow 2) decreased ability to eliminate drug from plasma 3) decreased metabolism, These patients may require a decrease in dosage or less frequent dosing intervals. In contrast, the half-life of a drug may be 1) decreased by increased hepatic blood flow 2)decreased protein binding, or increased metabolism. This may necessitate higher doses or more frequent dosing intervals.