Unit 1(g. ph) -n

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Unit 1(g. ph) -n

  1. 1. UNIT-ONE GENERAL PHARMACOLOGY
  2. 2. Specific Objectives: At the end of this lesson students will be able to :  Define: Pharmacology ,drugs  Identify branches of pharmacology  Lists out sources of drugs  Describe dosage forms of drugs and drug naming systems  Identify routes of drug administration  Describe pharmacokinetic and pharmacodynamic processes of drugs  Discuss steps in new drug development process
  3. 3. I. INTRODUCTION  The term ‘pharmacology’ is derived from two Greek words: ’Pharmacon‟ -which means ‘a drug‟ and „Logos’ - meaning ‘a reasonable’ or ‘rational discussion’  Pharmacology can be defined as the study of drugs and their interaction with living system [study of Action and Effect of drugs on physiological system] or  The science of substances used to prevent, diagnose, and treat disease.
  4. 4.  Mainly includes pharmacokinetics and Pharmacodynamics  It also includes history, source, physicochemical, properties of drugs dosage forms and method of administration.  It is a discipline devoted to patient therapy through the use of drugs  Utilizes concepts from human biology, pathophysiology, and chemistry
  5. 5. History of Pharmacology  One of the oldest form of healthcare, practiced in virtually every culture dating to antiquity  Applying products to relieve suffering has been recorded throughout history , but  Modern pharmacology began in the early 19th century through the isolation of specific active agents from their complex mixtures
  6. 6. Subdivision / branches of pharmacology 1. Pharmacodynamics:  The study of the biological and therapeutic effects of drugs and molecular mechanism of action (what the drug does to the body”) 2. Pharmacokinetics: Study of drug movement in and alteration of drug by the body It deals with drug disposition (absorption, distribution, metabolism and excretion (ADME) of drugs (“what the body does to the drug”)
  7. 7. 3. Pharmaco-therapeutics:  It deals with the proper selection and use of drugs for the prevention and treatment of disease, drug adverse and toxic effects contraindications , precautions as well as drug interactions 4.Toxico dynamics:  It is the study of poisonous effect of drugs and other chemicals with emphasis on detection ,prevention ,and treatment of poisonings  Many drugs in larger doses may act as poisons
  8. 8. 5. Clinical Pharmacology:  It is scientific study of drugs in man.  Includes :  Pharmacokinetics,  Pharmacodynamics ,  Evaluation of efficacy and safety of drugs as well as  Comparative trials with other forms of treatment
  9. 9. 6. Pharmacogenetics:  Is the study of the genetic variations that cause individual differences in drug response (concerned with unusual i.e. idiosyncratic drug responses that have hereditary basis)  Genetic variation in any of subcellural steps involved in pharmacokinetics could lead to idiosyncratic drug responses.
  10. 10. 1. Transport [ Absorption, Plasma protein binding] 2. Transducer mechanisms[receptors, enzyme induction or inhibition] 3. Biotransformation 4. Excretory mechanism (renal and biliary transport) Examples of Pharmacogenetic disorders; Less enzyme or defective proteins, increased resistance to drugs ,disorders due to unknown etiology.
  11. 11. Drug  The term drug is derived from the French word ‘drogue‟ which means ‘a dry herb‟.  Are chemical substances which change the function of biological system by interacting at molecular level;  May be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or
  12. 12.  For their toxic effects on regulatory processes in parasites infecting the patient.  Can also be defined as any substance that is used for the prevention, diagnosis or treatment of disease.
  13. 13. Sources of drugs Drugs are obtained from……… .Naturally 1. Minerals: Liquid paraffin, magnesium sulfate, magnesium trisilicate, kaolin, etc. 2. Animals: Insulin, thyroid extract, heparin and antitoxin sera, etc. 3. Plants: Morphine, digoxin, atropine, castor oil, etc. 4. Micro organisms: Penicillin, streptomycin and many other antibiotics
  14. 14. 5. Synthetic source: Aspirin, sulfonamides, Paracetamol, zidovudine, etc. 6. Semi –synthetic forms:Ampicillin, Cloxacillin,...
  15. 15. Drug components and dosage forms  Dosage form - is the form by which drugs prepared so that it’s convent for administration to the patient  Most pharmaceutical dosage forms constitute two components.  These are: Active ingredients Additives (pharmaceutical exciepients)
  16. 16.  Active ingredients: Are the main components of the dosage form, which is responsible for the both desired and undesired pharmacological effects Additives (pharmaceutical exciepients): Are substances other than active ingredients (medicaments) in the formulation which don't have any pharmacological action
  17. 17. Used to give a particular shape to the formulation to increase the stability and/or to increase palatability and elegance of the preparation. Classification of Dosage Forms:  Basically dosage forms/types of preparations are classified in three major classes  These are: Solid, Semi-solid ,liquid preparations miscellaneous forms and
  18. 18. Solid Dosage forms:  This class include:  Internal: Which are intended to be administered orally or parenterally or to be used in mouth cavity E.g.: Powders, Tablet, Capsules, Pills, and Lozenges  External: used topically (applied on the skin),dusting powders
  19. 19. 1.Tablet:  Is a hard, compressed medication in round, oval or square shape A coating may be applied to: 1- Hide the taste of the tablet's components. 2- Make the tablet smoother and easier to swallow . 3- Make it more resistant to the environment. 4- Extending its release so that duration of action
  20. 20.  Different types of tablets 1-Buccal and sublingual tablet:  Medications are administered by placing them in the mouth, either under the tongue (sublingual) or between the gum and the cheek (buccal).  Dissolve rapidly and absorbed through the mucous membranes of the mouth,  Avoid the acid and enzymatic environment of the stomach and the drug metabolizing enzymes of the liver. Examples: Nitroglycerine tablet (Sublingual)
  21. 21. 2- Chewable tablet:  They are tablets that chewed prior to swallowing.  Are designed for administration to children, geriatrics ,and to increase rate of dissolution E.g. Vitamin products, antacids(MTS)
  22. 22. Hard gelatin capsule 2.Capsule: Soft gelatin capsule  It is a medication in a gelatin container.  Advantage: Mask the unpleasant taste of its contents. The two main types of capsules are: 1- Hard-shelled capsules- Which are normally used for dry, powdered ingredients, 2- Soft-shelled capsules- Primarily used for oils and for active ingredients that are dissolved or suspended in oil.
  23. 23. 3.Lozenge:  It is a solid preparation consisting of sugar and gum,  Used to medicate the mouth and throat for the slow administration of cough remedies. 4.Pills:  Are oral dosage forms which consist of spherical masses prepared from one or more medicaments incorporated with inert excipients
  24. 24. 5.Powder (Oral): Two kinds of powder intended for internal use. 1-Bulk Powders -Are multidose preparations  They contain one or more active ingredients,  Contain non-potent medicaments such as antacids  The powder is usually dispersed in water 2-Divided Powders- are single-dose presentations of powder ( a small sachet)  Intended to be issued to the patient as such, to be taken with water.
  25. 25. Dusting powders:  Are free flowing very fine powders for external use.  Not for use on open wounds unless the powders are sterilized
  26. 26. Semi-solid dosage forms:  Semi-solid for internal use. E.g. Gels, Jellies  External Semi-solids Jellies E.g. Ointments, Creams, Gels,
  27. 27. 1- Ointments:  Are semi-solid, greasy preparations for application to the skin, rectum or nasal mucosa.  May be used as emollients(having the quality to soften the skin) or to apply suspended or dissolved medicaments to the skin.
  28. 28. 2- Gels (Jellies):  Gels are semisolid systems  Having a high degree of physical or chemical cross- linking.  Used for medication, lubrication and some miscellaneous applications like carrier for spermicidal agents to be used intra vaginally
  29. 29. Liquid dosage forms:  Three different classes of liquids based on type of preparations are: Solution, Suspension, Emulsion a-Solution:  Solutions are clear Liquid preparations containing one or more active ingredients dissolved in a suitable vehicle. b- Emulsion:  Are stabilized oil-in-water/water- in – oil dispersions,  Either or both phases of which may contain dissolved solids. c-Suspension:  Liquid preparations containing one or more active ingredients suspended in a suitable vehicle.  May show a sediment which is readily dispersed on shaking
  30. 30. Syrup:  It is a concentrated aqueous solution of a sugar, usually sucrose.  Flavored syrups are a convenient form of masking disagreeable tastes. Elixir:  It is pleasantly flavored clear preparation of potent or nauseous drugs.  Contain a high proportion of ethanol or sucrose together with antimicrobial preservatives
  31. 31. Linctuses:  Are viscous, liquid oral preparations  Usually prescribed for the relief of cough.  Contain a high proportion of syrup and glycerol which have a demulcent effect on the membranes of the throat.  The dose volume is small (5ml) Gargles:  Are aqueous solutions used in the prevention or treatment of throat infections.  Prepared in a concentrated solution with directions for the patient to dilute with warm water before use Mouthwashes: Similar to gargles but are used for oral hygiene and to treat infections of the mouth.
  32. 32. Rectal dosage forms: Suppository:  It is a small solid medicated mass,  Usually cone-shaped ,  It is inserted either into the rectum (rectal suppository), vagina (vaginal suppository or pessaries) where it melts at body temperature or dissolve in body fluid(pessaries)
  33. 33. Enema:  Is the procedure of introducing liquids into the rectum and colon via the anus. Types of enema: 1-Evacuant enema: used as a bowel stimulant to treat constipation E.g. Soft soap enema & MgSo4 enema 2- Retention enema:  Their volume does not exceed 100 ml. E.g. Barium enema is used as a contrast substance in the radiological imaging of the bowel( Local effect)
  34. 34. Transdermal patch or skin patch:  Is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream.  It provides a controlled release of the medicament into the patient.  The first commercially available patch was scopolamine for motion sickness.
  35. 35. Inhaled dosage forms: 1- Inhaler :  Inhalers are solutions, suspensions or emulsion of drugs in a mixture of inert propellants held under pressure in an aerosol dispenser.  It is commonly used to treat asthma and other respiratory problems
  36. 36. 2- Nebulizer or (atomizer):  Is a device used to administer medication to people in forms of a liquid mist to the airways.  Commonly used in treating asthma, and other respiratory diseases.  Usually reserved only for serious cases of respiratory disease, or severe attacks.
  37. 37. Ophthalmic dosage forms: 1- Eye drops:  Are saline-containing drops used as a vehicle to administer medication in the eye. 2- Ophthalmic ointment & gel:  These are sterile semi-solid preparations intended for application to the conjunctiva or eyelid margin.
  38. 38. Sterile products:  Are products which intended for Parentral, administration or ophthalmic use  Could be administered through injection ,infusion  In the form of drops used in eye
  39. 39. Drug nomenclature (naming system)  Three basic drug names 1. Chemical Name – Helpful in predicting a substances physical and chemical properties – Often complicated and difficult to remember or pronounce E.g. Chemical name for diazepam: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4benzodiazepin-2-one
  40. 40.  Generic Name  Name is assigned by the U.S. Adopted Names Council  Less complicated and easier to remember  Only one generic name for each drug  Less expensive Used internationally in pharmacopeias Non- proprietary name
  41. 41.  Trade Names  Assigned by company marketing the drug  Sometimes called proprietary, product or brand name  A single drug may have multiple names  Selected to be short and easy to remember  Shorter and easier than generic name
  42. 42. Example: Generic substance Brand Name  Aspirin - Anacin, Bayer, Excedrin  Diphenhydramine- Benadryl, Caladryl, Allerdryl  Ibuprofen- Advil, Motrin, Midol  Digoxin Lanoxin  Levothyroxine Sodium Synthroid  Warfarin Coumadin
  43. 43. 2.PHARMACOKINETIC PRINCIPLES (DRUG DISPOSITION)
  44. 44.  Pharmacokinetics -is currently defined as the study of the time course of drug Absorption, Distribution,Metabolism, and Excretion  Examines the movement of a drug over time through the body and metabolic alteration by enzymes  These fundamental pathways of drug movement and modification in the body control  Speed of onset of drug action,  The intensity of the drug's effect, and  The duration of drug action
  45. 45.  First, drug absorption from the site of administration permits entry of the therapeutic agent (either directly or indirectly) into circulatory system (Absorption)  Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids (Distribution)  Third, the drug may be metabolized by the liver, kidney, or other tissues (Metabolism)  Finally, the drug and its metabolites are removed from the body in urine, bile, or feces (Elimination)
  46. 46. Passage of drugs across membrane Structure of biological membrane  The absorption, distribution, and excretion involve passage of a drug across cell membranes  The plasma membrane consists of a bilayer of amphipathic lipids  Membrane proteins embedded in the bilayer serve as receptors, ion channels, and transporters to transduce electrical or chemical signaling pathways
  47. 47. Ways of drug passage across CM 1. Filtration [aqueous diffusion]   Size should be less than size of pore Has to be water soluble E.g. Na+, Cl-, K+, Urea ... 2. Passive(Simple) Diffusion [Direct penetration]  Transport from high to low concentration  Deriving force is concentration gradient across CM  Does not involve carriers,  Not saturable and show low structural specificity. Majority of drugs are absorbed by this mechanism But, the drug has to be lipid soluble  
  48. 48. 3. Carrier mediated absorption a. Facilitated diffusion  Passive diffusion but facilitated  Does not require energy,  Can be saturated, and may be inhibited  E.g. Tetracycline, Pyrimidine, levodopa & amino acids into brain b. Active transport  Use ATP & carrier proteins  Saturable and structurally specific  Against the concentration gradient, competitive inhibition E.g. Penicillin secretion, alpha methyldopa, 5-fluoro uracil
  49. 49. 4. Endocytosis & pinocytosis  Process by which large molecules are engulfed by the cell membrane & releases them intracellularlly. E.g. Proteins, toxins(botulinum, diphtheria), norepinephrine
  50. 50. Fig.2a Mechanisms involved in the passage of drugs across CM
  51. 51. Fig.2b Mechanisms involved in the passage of drugs across CM
  52. 52. Fig.2c. Passage of drugs across membrane
  53. 53. Routes of Drug Administration Two major classes of routes of drug administration, A. Enteral routes- Administering a drug through alimentary tract [Oral, sublingual, and rectal routes] Is the simplest and most common means of administering drugs B. Parentral routes- Administering a drug through other sites or non alimentary [ i.e. Injection, or local application on skin and mucus membrane
  54. 54. Fig.1 Route of drug administrations
  55. 55. Fig. 2. Enteral routes of drug administration
  56. 56. Fig.3 Parentral and other routes of drug administration
  57. 57.  The route of administration is determined primarily by:  Properties of the drug (water or lipid solubility, ionization, etc.) ,  Therapeutic objectives (the desirability of a rapid onset of action or the need for long-term administration or restriction to a local site)  Patient characteristics (whether the patient is conscious or not)
  58. 58. Enteral routes I. Oral: Provides many advantages to the patient such as  Oral drugs are easily self-administered and  Safe, more convenient and economical  Need no assistance for administration  Limit the number of systemic infections that could complicate treatment  Toxicities or overdose by the oral route may be overcome with antidotes such as activated charcoal
  59. 59.  However ;the pathways involved in drug absorption are the most complicated, and the drug is exposed to harsh gastrointestinal (GI) environments that may limit its absorption  Some drugs undergo first-pass metabolism in the liver,where they may be extensively metabolized before entering the systemic circulation E.g. Nitroglycerin
  60. 60.  Ingestion of drugs with food, or in combination with other drugs, can influence absorption  Action slower and thus not suitable for emergencies  Unpalatable drugs difficult to administer  Not suitable for uncooperative /unconscious, vomiting patients  Certain drugs are not absorbed sufficiently (polar drugs) from GIT
  61. 61. II. Sublingual  Placement under the tongue allows a drug to diffuse into the capillary network and, therefore, to enter the systemic circulation directly.  Has several advantages including:  Rapid absorption,  Convenience of administration,  Low incidence of infection,  Avoidance of the harsh GI environment, and  Avoidance of first-pass metabolism`
  62. 62. III Rectal: .  Has advantage of preventing the destruction of the drug by intestinal enzymes or by low pH in the stomach  Also it is useful if the drug induces vomiting when given orally,  If the patient is already vomiting, or if the patient is unconscious  Is commonly used to administer antiemetic agents however
  63. 63.  Only fifty percent of the drainage of the rectal region bypasses the portal circulation  Absorption is slower, irregular, incomplete and often unpredictable  It is rather inconvenient and embarrassing
  64. 64. II. Parenteral Parenteral:  Par = beyond and enteral = intestine  Drug directly introduced into tissue fluids or blood without having to cross the intestinal mucosa  Used for drugs that are poorly absorbed from the tract ( heparin) and for agents that GI are unstable in the GI tract ( insulin)  Also used for treatment of unconscious patients under circumstances that require a rapid onset of action
  65. 65.  Have the highest bioavailability and  Are not subject to first-pass metabolism or harsh GI environments  Provides the most control over the actual dose of drug delivered to the body  However, these routes are irreversible and may cause pain, fever, and infections  The three major Parentral routes are:  Intravascular (intravenous[ IV] or intra-arterial [ IA] ),  Intramuscular[IM], and  Subcutaneous [ SC]  Other Parentral routes include: Intradermal ,Intrathecal, Intrarticular, Interaperitonial
  66. 66. 1. Intravenous (IV):  Is the most common Parentral route  Permits a rapid effect and a maximal degree of control over the circulating levels of the drug; however  It is the most risky route  Injected drugs cannot be recalled by strategies such as emesis or by binding to activated charcoal  May also induce hemolysis or possibilities of embolism  Expertise is needed to give injection
  67. 67.  Useful for compounds that are:  Poorly or erratically absorbed,  Extremely irritating to tissues, or  Rapidly metabolized before or during their absorption from other sites.  The rate of injection should be slow enough to:  Prevent excessively high local drug concentrations  Allow for termination of the injection if undesired effects appear
  68. 68. 2. Intramuscular (IM) :  Drug is injected in one of the large skeletal muscles: deltoid, triceps, gluteus maximus, rectus femoris  Mild irritation can be applied and absorption is faster than SC (high tissue blood flow)  It can be given in diarrhea or vomiting  By passes 1st pass effect  Many vaccines are administered intramuscularly N.B. The volume of injection should not exceed 10 ml
  69. 69. 3. Subcutaneous (SC):  The drug is deposited in the loose subcutaneous tissue( the layer of skin directly below the dermis and epidermis)  Unsuitable for irritant drug administration and with slow absorption rate  Self injection is simple  Oily solution or aqueous suspensions can be injected for prolonged action  Highly effective in administering vaccines and such medications as insulin.
  70. 70. C. Others 1. Inhalation(Pulmonary administration)  Provides rapid delivery of a drug ,producing an effect almost as rapidly as IV injection  Used for drugs that are gaseous (for example, some anesthetics) or those that can be dispersed in an aerosol  This route is particularly effective and convenient for patients with respiratory complaints (such as asthma, or COPD )  Poor ability to regulate the dose  Irritation of the pulmonary mucosa
  71. 71. 2. Intranasal:  Involves administration of drugs directly into the nose  Nasal decongestants such as the anti-inflammatory corticosteroid furoate  Desmopressin is administered intranasally in the treatment of diabetes insipidus;  The abused drug, cocaine, is generally taken by intranasal sniffing
  72. 72. 3. Topical:  Topical application is used when a local effect of the drug is desired  Application could be on mucous membranes, skin or the eye  For example, clotrimazole is applied as a cream directly to the skin in the treatment of dermatophytosis
  73. 73. 4. Transdermal:  This route of administration achieves systemic effects by application of drugs to the skin,.  Most often used for the sustained (continuous) delivery of drugs, such as the antianginal drug nitroglycerin, the antiemetic scopolamine, and the once-a-week contraceptive patch  (Ortho Evra) that has an efficacy similar to oral birth control pills  The rate of absorption can vary markedly
  74. 74. I. Drug Absorption  It is a process by which the drug leaves the site of administration to circulatory system  In case of IV or IA administration, drug by passes absorption and enters the circulation directly
  75. 75. Fig.4 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action.
  76. 76. Factors affecting drug absorption and bioavailability 1. PH of absorption area-  Most drugs are either weak acids or weak bases.  Basic drugs are absorbed better at higher PH and  Acidic drugs are absorbed better at lower PH. 2. Area of absorbing surface Small intestine has microvillus;  It has absorption surface 1000 times that of stomach 3. Particle size of the drug and formulation
  77. 77. 4. Gut motility (contact time at absorption area) Faster is the motility, lower is the absorption E.g. Diarrhea, food in the stomach both decrease drug absorption 5. Blood flow to GIT  Blood flow to the intestine is higher and so absorption is high from intestine
  78. 78. 6. Presence of other agents:  Vitamin C enhances the absorption of iron from the GIT  Calcium present in milk and in antacids forms insoluble complex with some antibiotics( decrease its absorption) 7. Enterohepatic recycling: 8. First-pass hepatic metabolism 9. Pharmacogenetic factors: 10. Disease states:
  79. 79. Bioavailability(F):  Fraction of administered drug that reaches the systemic circulation/site of action in chemically unchanged form following non-vascular administration or  Amount of drug available in the circulation/site of action  It is expressed in percentage N.B. When the drug is given IV/IA, the bioavailability is 100%
  80. 80. Plasma level (mg/Li) A MTC B MEC C Time (hr) Fig.3 Plasma –drug level curves following administration of three formulations (A, B, C) of the same drug. Formulation A; has quick onset, short duration of action and has toxic effects. Formulation B; has longer duration of action and is non-toxic Formulation C; in adequate plasma level and therapeutically ineffective. Note: MTC-Minimum toxic concentration. MEC-Minimum effective concentration
  81. 81. II. Drug distribution  Is the process by which a drug reversibly leaves the blood stream & enters the interstitium and/or cells of the tissues  Cardiac output, regional blood flow, capillary permeability, extent of plasma protein and specific organ binding, regional differences in pH, transport mechanisms available and tissue volume determine the rate of delivery
  82. 82.  Liver, kidney, brain, and other well-perffused organs receive most of the drug [First phase] or central compartment whereas  Delivery to muscle, most viscera, skin, and fat is slower [Second phase] or peripheral compartments
  83. 83. Fig. 4 Factors that affect drug concentration at its site of action
  84. 84. Factors affecting rate of drug distribution A. Blood flow  The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs  Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles; adipose tissue, bone lower rate of blood flow B. Plasma protein binding Drug molecules may bound reversibly to plasma proteins such as Albumin, Globulin, Lipoproteins, α1 Acid Glycoprotein's...  Binding is relatively nonselective to chemical structure  Bound drugs are pharmacologically inactive, while free drugs leave plasma to the site of action ( are pharmacologically active)
  85. 85.  Acidic drugs bind principally to albumin, basic  Drugs frequently bind to other plasma proteins, such as lipoproteins and 1-acid glycoprotein (1-AGP), N.B. Protein binding acts as temporary store of drugs(reservoir)
  86. 86. Albumin:  Is the most important contributor to drug binding - Has a net negative charge at serum pH  Basic, positively charged drugs are more weakly bound  Disease states (E.g., hyperalbuminemia, hypoalbuminemia, uremia, hyperbilirubinemia) change in plasma protein binding of drugs
  87. 87. α1 Acid Glycoprotein:  α1-AGP is a determinant of the plasma protein binding of basic drugs, chlorpromazine, imipramine, and nortriptyline  There is evidence of increased plasma α1-AGP levels in certain physiological and pathological conditions, such as injury, stress, surgery resulting in ______????
  88. 88. A drug with a higher affinity may displace a drug with weaker affinity Increases in the non–protein-bound drug fraction (i.e., free drug) An increase in the drug‟s intensity of pharmacological response, side effects, and potential toxicity (Only a limited number of drugs) , but  Depends on the volume of distribution (Vd) and the therapeutic index of the drug (TI)
  89. 89. C . Capillary permeability  Determined by capillary structure and by the chemical nature of the drug  In the brain, the capillary structure is continuous no slit junctions  Liver and spleen a large part of the basement membrane is exposed due to large, discontinuous capillaries Large plasma proteins can pass  Also ,can be influenced by agents that affect capillary permeability (E.g., histamine) or capillary blood flow rate (E.g., norepinephrine)
  90. 90. Blood-brain barrier[BBB]  Ionized or polar drugs generally fail to enter the CNS  While lipid-soluble drugs readily penetrate into the CNS Placental Barrier  Does not prevent transport of all drugs but is selective Blood-Testis Barrier  Found at the specialized Sertoli–Sertoli cell junction  This barrier may prevent Cretan chemotherapeutic agents from reaching specific areas of the testis
  91. 91. D. Drug structure:  The chemical nature of a drug strongly influences its ability to cross cell membranes E. Affinity of drugs to certain organs:  Drugs will not always be uniformly distributed to and retained by body tissues Eye: Chlorpromazine and other phenothiazines bind to melanin and accumulate Retinotoxicity Chloroquine concentration in the eye can be approximately 100 times that found in the liver.
  92. 92.  Adipose tissue (Fat): DDT, chlordane  Bone: TTC, lead, and the antitumor agent cisplatin  Liver : Chloroquine,  Thyroid gland :Iodine  Lung: Basic amines (E.g., antihistamines, imipramine, amphetamine,methadone, and chlorpromazine
  93. 93. F. Presence of back transporter proteins  Like P- glycoprotein (Pgp), multidrug resistance–associated protein (MDRP), and breast cancer resistance protein (BCRP);  Are located in many tissues E.g. in the placenta Function as efflux transporters, moving endogenous and exogenous chemicals from the cells back to the systemic circulation Protect the fetus from exposure to unintended chemicals
  94. 94. III. Biotransformation/metabolism of drug  Alteration of drug structure and/activity by action of enzymes  Main site of biotransformation: Liver  Other tissues include the:  Gastrointestinal tract,  The lungs, the skin, and  The kidneys
  95. 95. Enzymes Responsible for Metabolism of Drugs  Microsomal enzymes:  Present in the smooth endoplasmic reticulum of the liver, kidney and GIT E.g. Glucuronyl transferase, dehydrogenases , hydroxylases and cytochrome P450 enzymes (primarily found in the liver and GI tract) CYP3A4, CYP2D6, CYP2C9/10, CYP2C19, CYP2E1, and CYP1A2  Non-microsomal enzymes:  Present in the cytoplasm, mitochondria of different organs E.g. esterases, amidase, hydrolase
  96. 96. Therapeutic consequences of metabolism:  Increase in solubility of drugs  Activation of pro drugs (converted to active drug) E.g. L-dopa (inactive) dopamine(active)  Inactivation of active drugs E.g.Phenobarbital(active) hydroxypentobarbital(inactive)]  Alteration of activity E.g. [Codeine(Less active) Morphine( more active)
  97. 97.  Decreseasing/increasing toxicity of the drug E.g.- Metabolism of acetaminophen Fig. Metabolism of acetaminophen (AC) to hepatotoxic metabolites. (GSH, glutathione; GS, glutathione moiety; Ac*, reactive intermediate.)
  98. 98. Reactions of drug metabolism 1. Phase I biotransformation Drug is changed to more polar metabolite by introducing or unmasking polar functional groups like OH, NH2 etc..  Increase, decrease, or leave unaltered the drug's pharmacologic activity  Consists of reactions:  Oxidation - Introduction of an oxygen and/or the removal of a hydrogen atom or hydroxylation, dealkylation or demethylation of drug molecule   Reduction - By the enzyme reductase Hydrolysis -Splitting of drug molecule after adding water
  99. 99. N.B Phase I metabolites are too lipophilic and can be retained in the kidney tubules 2. Phase II reaction/biosynthesis or [conjugation]  Conjugation reaction with endogenous compounds glucuronic acid, sulfuric acid, acetic acid, or an amino acid  Makes drugs most often therapeutically inactive, more polar and water soluble and easily excreted
  100. 100. Examples of phase II reactions I. Glucuronide conjugation It is the most common E.g. Phenobarbitone, chloramphenicol, Morphine, sulphonamide, ASA etc Note: Neonates are deficient in this conjugating system II. Sulfate conjugation:  Transfers sulfate group to the drug molecules E.g. phenols, catechols, steroids etc
  101. 101. III. Acetyl conjugation: INH, hydralazine, dapsone, IV. Glycine conjugation: E.g. salicylic acid, isonicotinic acid, p-amino salicylic acid V. Methylation: E.g. Adrenaline is methylated to metanephrine by catechol-o-methyl transferase
  102. 102. Fig. Examples of phase II conjugation reactions in drug metabolism
  103. 103. Factors affecting drug biotransformation  Genetic polymorphism  Disease conditions especially of the major drug metabolizing sites  Age  Predisposing factors to enzyme induction or inhibition
  104. 104. Regulation of the CYP Enzymes:  CYP450 enzymes can be regulated by the presence of other drugs or by disease states Enzyme Inhibition:  It is the primary mechanism for drug-drug pharmacokinetic interactions  The most common type of inhibition is simple competitive inhibition  A second type of CYP enzyme inhibition is mechanism based inactivation (or suicide inactivation)
  105. 105. Enzyme Induction:  It can be due to:  Synthesis of new enzyme protein or  Decrease in the proteolysis degradation of the enzyme  The net result is the increased turnover (metabolism) of substrate  Most commonly associated with therapeutic failure due to inability to achieve effective drug level in bld
  106. 106. Table 1 Liver enzyme inhibitors and CYP isoforms inhibited
  107. 107. Table 2. Liver enzyme inducers and CYP isoforms induced
  108. 108. IV. Drug Excretion  Excretion is transport of unaltered or altered drug out of the body  Rate of excretion influences duration of drug action Routes of Drug Excretion  Minor route of excretion: Eye, breast, skin  Intermediate route: Lung [volatile drugs like inhalational anesthetics] Bile [digoxin, rifampin]
  109. 109.  Renal excretion- major route for most drugs & involves  Glomerular filtration  Active tubular secretion  Passive tubular reabsorption Glomerular filtration:  Depends on the:  Concentration of drug in the plasma,  Molecular size, shape and charge of drug, and  Glomerular filtration rate Note: In congestive cardiac failure, the glomerular filtration rate is reduced due to decrease in renal blood flow.
  110. 110. Fig. Renal excretion of drugs. Filtration of small non–protein-bound drugs occurs through glomerular capillary pores. Lipid-soluble and un-ionized drugs are passively reabsorbed throughout the nephron. Active secretion of organic acids and bases occurs only in the proximal tubular
  111. 111. Active tubular secretion:  Primarily occurs in the proximal tubules I. For anions II. For cations  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 E.g. Probenecid, and penicillins, Acetazolamide, benzyl penicillin, dopamine, pethidine, thiazide diuretics,
  112. 112. Tubular re -absorption:  Occurs either by simple diffusion or by active transport  Manipulating the pH of the urine  Increase the ionized form of the drug in the lumen  Minimize the amount of back diffusion, and hence, increase the clearance of an undesirable drug. E.g. 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
  113. 113.  If overdose is with a weak base, such as cocaine, acidification of the urine with NH4Cl leads to protonation of the drug and an increase in its clearance Hepatobilary Excretion Conjugated drugs are excreted by hepatocytes in to the bile  Certain drugs may be reabsorbed back from intestine after hepatic excretion and this is known as enterohepatic cycling E.g. CAF, oral estrogen
  114. 114. Pulmonary excretion:  Drugs that are readily vaporized, such as many inhalation anaesthetics and alcohols are excreted through lungs  The rate of drug excretion through lung depends on  The volume of air exchange,  Depth of respiration,  Rate of pulmonary blood flow and  The drug concentration gradient
  115. 115. Mammary excretion:  Many drugs mostly weak basic drugs are accumulated into the breast milk ???  Therefore lactating mothers should be cautious of furosemide, morphine, streptomycin etc
  116. 116. Summery Points:  Route of drug administrations  Pharmacokinetics –Def, Components ( in order)  Factors affecting drug absorption  Factors affecting drug distribution in the body  Bioavailability  Biotransformation, sites, enzymes , reaction phases , factors affecting  Excretion , routes, steps
  117. 117. Review question  A drug M is injected IV into a laboratory subject. It is noted to have high serum protein binding. Which of the following is most likely to be increased as a result? A. Drug interaction B. Distribution of the drug to tissue sites C. Renal excretion D. Liver metabolism
  118. 118. Pharmacokinetic variables and Dose calculation  Two models exist to study and describe the movement of xenobiotics (Drugs) in the body with mathematical equations 1. Classical compartmental models (one or two compartments) 2. Physiologic models
  119. 119. Classical compartmental model:  The body represented as consisting of one or two compartments  A central compartment- representing plasma and tissues that rapidly equilibrate with chemical(Liver, Kidney),  Peripheral compartments-represent tissues that more slowly equilibrate with chemical???  Assumes that the concentration of a compound in blood or plasma is in equilibrium with concentrations in tissues, and
  120. 120.  Changes in plasma concentrations repesent change in tissue concentrations  Valuable in predicting the plasma chemical concentrations at different doses ,but  Have no apparent physiologic or anatomic reality, and  Under ideal conditions, classic models cannot predict tissue concentrations,
  121. 121. Fig. 1. Compartmental pharmacokinetic models Where ka is the first- order extravascular absorption rate constant into the central compartment (1), kel is the first-order elimination rate constant from the central compartment (1), and k12 and k21 are the first-order rate constants for distribution of chemical into and out of the peripheral compartment (2) in a twocompartment model.
  122. 122. One-Compartment Model:  The simplest pharmaco-kinetic analysis  Describe the body as a homogeneous unit  Compounds rapidly equilibrate, or mix uniformly, between blood and the various tissues  Plasma changes assumed to reflect proportional changes in tissues chemical concentration  Is applied to xenobiotics (drugs) that rapidly enter and distribute throughout the body
  123. 123.  The data obtained yield a straight line when they are plotted as the logarithms of plasma concentrations versus time C0 Slope= Kel/ -2.303 C LogC 1/2C0 Time t 1/2 Time Fig.2. Concentration versus time curves of chemicals exhibiting behavior of a one-compartment pharmacokinetic model on a linear scale (left) and a semilogarithmic scale (right).
  124. 124.  A curve of one compartment type can be described by the expression : C = C0 x e-Kel x t on Linear scale Log C= -Kel/2.303 X t + logC0 on logarithmic scale C = Blood or plasma chemical concentration over time t, C0 = Initial blood concentration at time t = 0, and kel = First-order elimination rate constant( dimension t-1)
  125. 125. Two-Compartment Model:  Implies more than one dispositional phases  The chemical requires a longer time for its concentration in tissues to reach equilibrium with the concentration in plasma, and  The semilogarithmic plot of plasma concentration versus time yield a curve  A multicompartmental analysis of the results is necessary
  126. 126. Distribution phase,(decrease more rapidly) C Slope= β/ -2.303 LogC 1/2C Elimination phase(decrease slowly) t 1/2 Time Time Fig.3 Concentration versus time curves of chemicals exhibiting behavior of a two-compartment pharmacokinetic model on a linear scale (left) and a semilogarithmic scale (right  The curve described by multiexponential mathematical equation : C= A x e-α x t + B x e-β x t where A and B are proportionality constants and α and β are the first-order distribution and elimination rate constants, respectively
  127. 127. Physiologic models:  Consider the movement of xenobiotics based on known or theorized biologic processes and  Are unique for each xenobiotics  Allows the prediction of tissue concentrations Advantages:  Provides [Tx] time course in any organ  Estimation of effect of changing physiological parameters on tissue [Tx] Disadvantages: More information needed , Mathematics difficult,
  128. 128. First order Kinetics  Elimination rate proportional to total amt in the body  Semi log plot of [Tx] vs time is straight line  Vd, Cl, T1/2, Ke or β are independent of doses  Tissue [Tx] decrease by Kel or β like plasma [Tx]
  129. 129. Zero-order kinetics  Saturation of metabolism  An arithmetic plot of plasma concentration versus time yields a straight line  Non linear kinetics (Constant amount of drugs eliminated per unit time)  Clearance slows as drug concentration rises  A true T1/2 or kel does not exist, but differs depending upon drug dose
  130. 130. Saturation Pharmacokinetics:  As the dose of a compound increases, its Vd or its rate of elimination(Kel )may change ,because Biotransformation, Active transport processes, and Protein binding have finite capacities and can be saturated  The rate of elimination is no longer proportional to the dose and the transition from first-order to saturation kinetics (Zero-order)
  131. 131. First-order Toxic kinetics Saturation- Toxic kinetics First-order First-order First-order No change Fig. Vd, Cl and T1/2 following first-order pharmaco kinetics (left ) and changes following saturable pharmacokinetics (right)
  132. 132. Characteristics of saturation phrmaco kinetics:  Vd, Cl, T1/2, Kel change with dose  Non proportional changes in response to increasing dose  The composition of excretory products changes quantitatively or qualitatively with the dose,  Competitive inhibition by other chemicals that are biotransformed or actively transported by the same enzyme system occurs,
  133. 133. Volume of distribution [Vd]:  Hypothetical volume of fluid in to which the drug is disseminated  Correctly called the apparent volume of distribution, because  It has no direct physiologic meaning and does not refer to a real biological volume  Represents the extent of distribution of chemical out of plasma and into other body tissues
  134. 134. E.g. Apparent Vd of amiodarone is 400 lit  Drugs that are extensively bound to plasma proteins, but are not bound to tissue compartments, - Vd approximately equals to plasma volume  If the drug is highly lipid soluble, its volume of distribution will be very high because it will concentrate in the adipose and other lipid tissues and its concentration in the plasma will be very low
  135. 135. Effect of large Vd on half-life of a drug:  If the Vd for a drug is large, most of the drug is in the extraplasmic space and unavailable to the excretory organs.  Therefore, any factor that increases the volume of distribution can lead to an increase in the half-life and extend the duration of action of the drug.
  136. 136.  Vd relates the amount of the drug in the body to the concentration of the drug (C) in the plasma Vd = D /Co ; D-total amount of drug in the body Co- plasma concentration of the drug at zero time  Described in units of liters or liters per kilogram of body weight N.B. Maximum actual Vd= Total body water( 42 lit)  Apparent Vd= The theoretical volume of body fluid in to which a drug is distributed  May not correspond to anatomical space
  137. 137. Example : A 23-year-old, 90-kg female is seen in the emergency department 2 hours after the ingestion of 50 of her brother's Theo-Dur (300 mg) tablets. Her initial theophylline serum concentration is 40 mg/L. Q. Estimate a peak serum concentration knowing that theophylline has a Vd of 0.5 L/kg, F = 1 (100% bioavailable).
  138. 138. Calculation: Vd = Dose IV/C0 = Dose(other route)xF Co Where: F= fraction of drug available to systemic cir C0= Initial peak plasma concentration Thus C0= Dose X F / Vd Co = 50 x 300 mg x 1 = 0.333 mg/ml o.5 L/ Kg x 90 Kg
  139. 139. Review Question  An agent is noted to have a very low calculated volume of distribution (Vd). Which of the following is the best explanation? A. The agent is eliminated by the kidneys, and the patient has renal insufficiency B. The agent is extensively bound to plasma proteins C. The agent is extensively sequestered in tissue D. The agent is eliminated by zero-order kinetics
  140. 140. Clearance:  Is the volume of fluid containing chemical that is cleared off a drug per unit of time.  Describes the rate of chemical elimination from the body  Has the units of flow (ml/min) Example: A clearance of 100 mL/min means that 100 mL of blood or plasma containing xenobiotic is completely cleared in each minute.
  141. 141.  Clearance characterizes the overall efficiency of the removal of a chemical from the body i.e High values of clearance indicate efficient and rapid removal, Low clearance values indicate slow and less efficient removal
  142. 142.  Total body clearance is defined as the sum of clearances by individual eliminating organs: Cl = Clr + Clh + Cli . . . Where- Clr-renal, Clh -hepatic, and Cli- intestinal clearances respectively  After IV , bolus administration, total body clearance is defined as Cl = Dose IV/AUC0-∞ Where –Dose IV is the IV dose at time zero AUC0-∞ is the area under the chemical concentration versus time curve from time zero to infinity
  143. 143.  Can be estimated by creratinien clearance Cr cl= UxV/C U -is the concentration of creatinine in urine (mg/mL); V - is the volume flow of urine (mL/min); C - is the plasma concentration of creatinine (mg/mL  If the volume of distribution and elimination rate constants are known Cl can also be calculated Cl = Vd × kel - for a one-compartment model ,first order process
  144. 144. For flow dependent elimination CL = Q.(Ca- Cv) = Q.E Ca Where Q- is blood flow, Ca- is the concentration entering the organ, and Cv -is the concentration leaving the organ, E- is drug extraction by the organ Note: Clearance is an exceedingly important pharmaco kinetic concept
  145. 145. Half-Life( t1/2):  Is the time required for the blood or plasma concentration of a drug to decrease by one-half,(50%) t1-t2= Lnc1 –LnC2 = t1/2= Ln2 = 0.693 Ke Ke Ke  t1/2 is influenced by both Vd for a chemical and the rate by which the chemical is cleared from the blood (Cl)  If Vd and Cl are known: t1/2 = (0.693 × Vd)/Cl
  146. 146.  For a fixed Vd, T1/2 decreases as Cl increases, Half life in minute  For a fixed Cl, as the Vd increases, T1/2 increases Fig.2 The dependence of T1/2 on Vd and Cl NB. Values for Vd of 3,18, 40 L represent approximate volumes of plasma water, extracellular fluid and total body water, respectively
  147. 147. Fig. Elimination of a hypothetical drug with a half-life of 5 hours. The drug concentration decreases by 50% every 5 hours (i.e., t1/2 5 hrs). The slope of the line is the elimination rate (ke).
  148. 148.  In general it takes five half lives‘ to either reach steady state for repeated dosing or for drug elimination once dosing is stopped. Example:  A 45year- old man a known chronic alcoholic was admitted to the hospital for ingestion of about 2.5 lit of solvent containg 30% Volume by volume of methanol. Q. What is t1/2 of methanol during dialysis if the patient had serum methanol of 265 mg/ dl at the start of dialysis and 65 mg/dl after 5.5 hrs?
  149. 149. Calculation:  Using the following formulas Kel= (1/t) LnC1/C2)=0.26 /hr t1/2=Ln2 /Kel= 2.7 hr
  150. 150.  limination: E  Includes biotransformation, exhalation, and excretion  For one-compartment model occurs through a first-order process; i.e  Constant fraction of xenobiotics is eliminated per unit time ( the amount of drug eliminated at any time is proportional to the amount of the chemical in the body at that time) ; Only at chemical concentrations that are not sufficiently high to saturate elimination processes
  151. 151.   The equation for a monoexponential model C = C0 x e-Kel x t Transformed to a logarithmic equation that has the general form of a straight line, Log C= -Kel/2.303 X t + logC0 Where: -Log C0 represents the y-intercept or initial concentration -( kel/2.303) represents the slope of the line =Log(C1-C2)/(t2-t1) - The first-order elimination rate constants( Proportion of a drug removed per unit time (kel = –2.303 × slope)
  152. 152.  The fraction of dose remaining in the body over time (  C/C0) is calculated using the elimination rate constant by rearranging the equation for the C/C0 = Anti log [(–kel/2.303) × t] Tab.1 Elimination of four different doses of a chemical at 1 hour after administration Dose mg Chemical remaining ( mg) Chem. Eliminated (mg) Che. Eliminated (% of dose) 10 7.4 2.6 26 30 22 8 26 90 67 23 26
  153. 153. Drug Accumulation:  Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval.  The fraction lost is 1 minus the fraction remaining just before the next dose.  The fraction remaining can be predicted from the dosing interval and the half-life.  A convenient index of accumulation is the accumulation factor(AF) AF = 1______________ = Fraction lost in one dosing interval __ 1__________ 1 – Fraction remaining Q. For a drug given once every half-life, what is the accumulation factor?
  154. 154. Bioavailability:  Bioavailability is the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form.  Bioavailability of drugs given orally and some other routes may not be 100% because of one of the following reasons:   Incomplete extent of absorption and First-pass elimination
  155. 155.  The systemic bioavailability of the drug (F) can be predicted from the extent of absorption (f) and the extraction ratio (ER): F= f (1-ER) Where ER = Cl Liver/Q Q- is hepatic blood flow, normally about 90 L/h in a person weighing 70 kg
  156. 156. Example: Morphine is almost completely absorbed (f = 1), so that loss in the gut is negligible.  However, the hepatic extraction ratio for morphine is 0.67, Q. What is bioavailability of morphine?
  157. 157. Determination of bioavailability:  Is determined by comparing plasma levels of a drug after a particular route of administration with plasma drug levels achieved by IV injection  By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC).  Thecurve reflects the extent of absorption of the drug.
  158. 158. For other routes F= Dose(IV) x (AUC0-∞)other Dose( other) x (AUC0-∞)other Fig. Representative plasma concentration–time relationship after a single oral dose of a hypothetical drug.
  159. 159. Plasma concentration Time ____________ Fig. Representative plasma concentration–time curve (AUC) after single dose of oral(Blue) and IV( Red) of a hypothetical drug.
  160. 160. Clinical Implications of Altered Bioavailability  Some drugs undergo near-complete presystemic metabolism and thus cannot be administered orally. E.g. Lidocaine, nitroglycerin  Other drugs underging very extensive presystemic metabolism but; can still be administered PO using much higher doses than those required IV. E.g. IV dose of verapamil would be 1 to 5 mg, compared to the usual single oral dose of 40 to 120 mg.
  161. 161. Steady State Concentration(Css): Plasma level of the drug  Is plasma level of a drug where drug elimination is in equilibrium with that absorbed (rate in=rate out)  It takes at least four to five half live’s to reach Css C max C min Time (multiple of t ½) Fig. Steady state plasma concentration after repeated administration
  162. 162. Dosage regimen:  Is a systematic way of drug administration or  It is the one in which the drug is administered:  In suitable doses,  By suitable route,  With sufficient frequency that ensures maintenance of plasma concentration within the therapeutic window without excessive fluctuation and drug accumulation for the entire duration of therapy.)
  163. 163. Two major parameters that can be adjusted in developing a dosage regimen are: 1. The dose size:  It is the quantity of the drug administered each time.  The magnitude of therapeutic & toxic responses depend upon dose size.  Amount of drug absorbed after administration of each dose is considered while calculating the dose size.  Greater the dose size greater the fluctuation between Css,max & Css,min (max. and min. steady state concentration) during each dosing interval & greater chances of toxicity.
  164. 164. Points to be considered while selecting dose of a drug to a patient A. Defined target drug effect when drug treatment is started B. Identify nature of anticipated (expected) toxicity C. Other mechanisms that can lead to failure of drug effect should also be considered; E.g. Drug interactions and noncompliance
  165. 165. D. Monitoring response to therapy, by physiologic measures or by plasma concentration measurement 2. Dose frequency:  It is the time interval between doses.  Dose interval is inverse of dosing frequency.  Dose interval is calculated on the basis of half life of the drug.
  166. 166.  When dose interval is increased with no change in the dose size ,Cmin, Cmax & Cav decrease, but  When dose interval is reduced, it results in greater drug accumulation in the body and toxicity. N.B.  By considering the pharmacokinetic factors that determine the dose-concentration relationship, it is possible to individualize the dose regimen to achieve the target concentration
  167. 167. Fig. Temporal characteristics of drug effect and relationship to the therapeutic window (e.g., single dose, oral administration)
  168. 168. There are two types of dosing:  Constant ; and  Variant dosing Variant dosing includes; 1. A loading dose:  Is one or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly.
  169. 169. 2. Maintenance dose:  Dose given at an adjusted rate to maintain a chosen steady state concentration .  The amount is equivalent to daily excreted dose
  170. 170. Maintenance Dose:  It is the amount of drug prescribed or administered on a continuing basis.  Thus, calculation of the appropriate maintenance dose is a primary goal.  At steady state, the dosing rate ("rate in") must equal the rate of elimination ("rate out"). Dosing Rate ss = Rate elimination ss Dosing Rate ss = CL x TC ; Where CL= Clearance TC= Target concentration
  171. 171. If intermittent doses are given, the maintenance dose is calculated from: Maintenance dose = Dosing rate x Dosing interval Example; A target plasma theophylline concentration of 10 mg/L is desired to relieve acute bronchial asthma in a patient. If the patient is a nonsmoker and otherwise normal except for asthma the mean clearance is 2.8 L/h/70 kg. If the drug is given by intravenous infusion, F = 1. Dosing rate = CL x TC = 2.8L/h/70 Kg x 10 mg/L = 28 mg/h/70 Kg
  172. 172.  To maintain this plasma level using oral theophylline, which might be given every 12 hours using an extendedrelease formulation (Foral for theophylline is 0.96) Q. When the dosing interval is 12 hours, what is the size of each maintenance dose?
  173. 173. Calculation: Maintenance dose= Dosing rate x Dosing interval F = 28 mg/h x 12 hrs 0.96 = 350 mg
  174. 174. Loading Dose:  Is one or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly.  The appropriate magnitude for the loading dose is Loading dose = Target Cp x Vdss F Vd ss= Volume of distribution at steady state  It desirable if the time required to attain steady state by the administration of drug at a constant rate is long relative to the temporal demands of the condition being treated.
  175. 175. Example.  In administration of digitalis ("digitalization") to a patient with Cp = 1.5 ng/ml and Vdss= 580 liter , F= 0.7 Loading dose = 1.5 ng/ml X 580 liter =1243 μg ~ 1mg 0.7  To avoid toxicity, this oral loading dose, which also could be administered IV , would be given as an initial 0.5-mg dose followed by a 0.25-mg doses 6 to 8 hours later, with careful monitoring of the patient ...
  176. 176. Disadvantages of Loading dose administration:  Sensitive individuals may be exposed abruptly to a toxic concentration of a drug.  If the drug has long half-life It takes long time for the concentration to fall if the level achieved was excessive  Loading doses tend to be large, and they are often given parentrally and rapidly; this can be particularly dangerous if toxic effects occur as a result of action of the drug at sites that are in rapid equilibrium with plasma
  177. 177. Factors Affecting dose and drug responses  Individuals may vary considerably in their responsiveness to a drug;  Quantitative variations in drug response are in general more common and more clinically important  An individual patient is hypo reactive or hyper reactive to a drug  Intensity of effect of a given dose of drug is diminished or increased in comparison to the effect seen in most individuals.
  178. 178.  Decrease in response as a consequence of continued drug administration, is called tolerance  If diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis.  Four general mechanisms may contribute to variation in drug responsiveness among patients or within an individual patient at different times
  179. 179. 1. Alteration in concentration of drug that reaches the receptor:  Patients may differ  In the rate of absorption of a drug,  In distributing it through body compartments, or  In clearing the drug from the blood.  Some differences can be predicted on the basis of age, weight, sex, disease state, liver and kidney function  Other -active transport of drug from the cytoplasm
  180. 180. 2. Variation in concentration of an endogenous receptor ligand:  Contributes greatly to variability in responses to pharmacologic antagonists E.g. Propranolol which is a -adrenoceptor antagonist will markedly slow the heart rate of a patient whose endogenous catecholamines are elevated (as in pheochromocytoma) but will not affect the resting heart rate
  181. 181. 3. Alterations in number or function of receptors  Change in receptor number may be caused by other hormones; E.g. Thyroid hormones increase both the number of receptors in rat heart muscle and cardiac sensitivity to catecholamines.
  182. 182. 4. Changes in components of response distal to the receptor  Compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. E.g. - Compensatory increases in sympathetic nervous tone and fluid retention by the kidney can contribute to tolerance to antihypertensive effects of a vasodilator drug
  183. 183. The impact of age  Age is associated with changes in body composition, such as:  A relative increase in body fat,  A decrease in drug clearance,  A higher sensitivity to pharmacodynamic processes.
  184. 184.  Renal clearance is decreased due to a reduction in renal functioning.  The functioning of CYP enzymes tends to be lower with increasing age,
  185. 185.  Dose adjustment based on age (Young‟s formula) Child dose = Age (yr) X Adult dose Age + 12  Based on the body weight (clerk‟s formula); Child dose =Weight (pound) X Adult dose 150 Note: 1kg = 2.2 pound  Based on body surface area: Child dose = BSA of chiled x Adult dose 1.72 N.B. 1.72 is average BSA of an adult
  186. 186. The impact of gender:  Males and females are not identical E.g. Females respond rapidly even to lower concentration of alcohol Gender affects drug response in two ways 1. Differences exist in pharmacokinetic properties between men and women. E.g. The clearance of drugs metabolized by CYP3A4 is higher in women than in men
  187. 187.  It has been suggested that this is caused by lower P-gp efflux transporter activity in women. 2. Difference in pharmacodynamic actions of a drug between genders. E.g. Aspirin has a major role in the prevention of myocardial infarction in men, in contrast many women do not respond to aspirin therapy  Special care should be exercised when drugs are administrated during menstruation, pregnancy & lactation.
  188. 188. The impact of co-morbidity:  Co-morbidities in liver and kidney organs may influence drug response. E.g. The risk of adverse drug reactions is increased in patients with reduced kidney function who use drugs with a narrow therapeutic window and which are excreted unchanged by the kidney.  Inflammation of meninges (meningitis)  Under conditions of decreased tissue perfusion like heart failure and shock,(hemorrhagic and cardiogenic )
  189. 189. The impact of environmental factors  Environmental factors, such as diet, smoking, hygiene, stress and exercise, contribute to the variation in drug response. E.g. Grapefruit juice, which contains ingredients that inhibit CYP3A4 enzymes, The impact of body weight  In obese people, the distribution of drugs throughout body tissues differs from lean people
  190. 190. The impact of repeated administration and drug accumulation  If a drug is excreted slowly, its administration may build up a sufficiently high concentration in the body to produce toxicity. E.g. Digitalis, emetine The impact of drug tolerance  When an unusually large dose of a drug is required to elicit an effect ordinarily produced by the normal therapeutic dose of the drug, the phenomenon is termed as drug tolerance
  191. 191. The impact of co-prescribed drugs  Polypharmacy, the use of multiple drugs by one patient, is common.  These drugs may influence each other resulting in drug-drug interactions (DDIs).
  192. 192. The impact of genetic factors  Genetic variation in the DNA encoding proteins can result in a change in amino acid sequence in the protein or differences in transcription rates.  These deviations may result in the increased or reduced effectiveness of drugs. E.g. Acetylation of INH in slow and fast acetylators

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