Revised drug therapy

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Revised drug therapy

  1. 1. DRUGTHERAP Y
  2. 2. The Life of a DrugABSORPTION Site of drug administration DISTRIBUTION From blood to the site of action METABOLISM Biotransformation of the drug Removal of drug EXCRETION from the body
  3. 3. Pharmacokinetics
  4. 4. Is the druggetting into thepatient?
  5. 5. AIM: Adequate drug doses must be delivered to the target tissues so that therapeutic yet non- toxic levels are obtained
  6. 6. DISINTEGRATIO N  BREAKDOWN OF SOLID FORM OFDRUG INTO SMALLER PARTS
  7. 7. DISSOLUTIONDisintegration ofsmaller particles in the GIT fluid for absorption
  8. 8. RATE LIMITING  Time it takes for the drug to disintegrate & become available for absorption
  9. 9. BIOAVAILABILITY FRACTION OF ADMINISTERED DRUG THAT REACHES THE CIRCULATION IN A CHEMICALLY UNCHANGED FORM
  10. 10. BIOAVAILABILITY  If 100 mg of a drug is administered orally and 70 mg of the drug is absorbedunchanged, the bioavailability is 70%
  11. 11. ABSORPTION  Process by which drug molecules are transferredfrom the site of administration in the body to the circulating fluids
  12. 12. PRINCIPAL MECHANISMS INVOLVED IN THEPASSAGE OF DRUGS ACROSS CELL MEMBRANES
  13. 13. MECHANISMS : SIMPLE DIFFUSION AQUEOUS DIFFUSION SPECIFIC CARRIER MEDIATED TRANSPORT SYSTEM -Active Transport -Passive Transport
  14. 14. Cell Membranes: This barrier is permeable to many drug molecules but not to others, depending on their lipid solubility Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through.
  15. 15. A STEADY STATE is achieved when the concentration of thenon-ionized species is the same on both sides of the membranes
  16. 16. SIMPLE DIFFUSION Lipid Diffusion - LIKE dissolves LIKE - Drug molecules dissolves in the membrane to penetrate to the other side
  17. 17. AQUEOUS DIFFUSION FILTRATION THROUGH PORES The size of the drug molecule is relative to the size of the pores H2O soluble drugs penetrate cell membrane through this process
  18. 18. ACTIVE TRANSPORT Process by which a substance is transported against a concentration gradient Drug moves from LOWER- HIGHER concentration Energy dependent Involves SPECIFIC CARRIERS Driven by Hydrolysis of ATP
  19. 19. PASSIVE TRANSPORT FACILITATED DIFFUSION a passive process whereby drugs can move across cell membranes more rapidly than simple diffusion Vast majority of drugs gain access to the body by this process
  20. 20. PASSIVE TRANSPORT Involves the action of a specific but saturable carrier system Can only work in the presence of an appropriate concentration gradient
  21. 21. FACTORS AFFECTING ABSORPTION Physico-chemical Factors Site of Absorption/ Blood Flow at the Site Drug Solubility Effects of Food - Blood Flow - Gastric Emptying
  22. 22. PHYSICO-CHEMICAL FACTORS Lipid solubility Degree of Ionization Effect of pH Molecular Weight, Size & Shape Chemical Stability
  23. 23. LIPID SOLUBILITYSIMPLE DIFFUSION - degree of lipid solubility of the drug determines the total amount of drug being transferred
  24. 24. DEGREE OF IONIZATION Most drugs are WEAK ELECTROLYTES either weak acids or weak bases Drugs that are weak electrolytes dissociate in solution as both NON-IONIZED & IONIZED FORM
  25. 25. Most drugs are partially ionized at physiologic pH , and only the non- ionized species is soluble in lipid
  26. 26. DEGREE OF IONIZATION Non-Ionized - Non-Polar -Lipid Soluble Form Molecules Ionized - Polar -Lipid Insoluble Form Molecules
  27. 27. EFFECT OF pH
  28. 28. DISSOCIATION CONSTANT Measure of the strength of the interaction of a compound with a proton Indication of drug molecules to be ionized
  29. 29. IONIZATION V.S pH Amount of ionization of a drug depends on the pH at the drug site in the tissues & its dissociation characteristics
  30. 30. DISSOCIATION CONSTANT The pKa of a compound is the same as the pH at which it would be half dissociated & half ionized
  31. 31. CLINICALSIGNIFICANCE: Knowing the pKa of a drug, gives the patient the idea as to the extent to which it ionizes at any pH
  32. 32. ASA – pKa 3.5Stomach – pH 1.0-1.5 At the pH of 3.5, ASA is 50% ionized DECREASE pH below 3.5 DECREASE ionization to less than 50% thus INCREASE the amount of un-ionized form- GREATER drug absorption
  33. 33. MOLECULAR WEIGHT, SIZE AND SHAPE  Substances with high molecular weight are not usually absorbed intact except in minute quantities  They are absorbed by enzymatic actions
  34. 34. MOLECULAR WEIGHT, SIZE AND SHAPE H2O soluble molecules small enough can pass through the membrane channels 30 Angstrom -capillary membrane 4 Angstrom -other cell membranes
  35. 35. MOLECULAR WEIGHT, SIZE AND SHAPE Process of FILTRATION thru single cell membranes may occur with drugs of molecular weight of 200 daltons or less Drugs up to 60,000 daltons molecular weights can filter thru capillary membranes
  36. 36. CHEMICAL STABILITY Unstable drugs may be inactivated in the GIT
  37. 37. SITE OF ABSORPTION Total Surface Area available for absorption Intestine has a surface area about 1,000 times larger than the stomach Intestine surface is very rich in microvilli Absorption in the intestine is much efficient than the stomach
  38. 38. BLOOD FLOW TO THE SITE OF ABSORPTION Blood flow from the intestine is much greater than the stomach
  39. 39. EFFECTS OF FOOD Food influences the amount of drug absorbed & the rate at which drug is absorbed from the GIT by affecting the: BLOOD FLOW GASTRIC EMPTYING
  40. 40. BLOOD FLOW LIQUID GLUCOSE MEAL DECREASES BLOOD FLOW
  41. 41. BLOOD FLOW MEAL RICH IN PROTEIN INCREASES BLOOD FLOW
  42. 42. Increase absorption in the presence of food:  Griseofulvin  Lithium Citrate  Propoxyphene  Propanolol
  43. 43. Decrease absorption in the presence of food:  Aspirin  Penicillin  Acetaminophen
  44. 44. GASTRIC EMPTYING  Food that delays Gastric Emptying also delays the absorption of orally administered drugs
  45. 45. DELAY GASTRIC EMPTYING  Low pH or High Fat Solutes  Hot Meals Solution Rich in Fats & Carbohydrates
  46. 46. Slow gastric emptying may also reduce the amount of drug absorbed because ofthe degradation in theacidic contents of the stomach !
  47. 47. Rule of Thumb: If food reduces absorption of drugs, giving the drug at least 1 hour before meals will minimize this effect If food enhances drug absorption the drug is given with meals
  48. 48. DISTRIBUTION
  49. 49. DISTRIBUTION Process by which the drug becomes available to body fluids such as plasma, interstitial fluids & intracellular fluids and body tissues
  50. 50. PRIMARY PURPOSE OF DRUG TRANSPORT Allow drug to reach its site of action at specific tissue sites
  51. 51. Transport In Plasma DISTRIBUTION SITE SITE OF PLASMA OFADMINISTRATION ACTION
  52. 52. Receptors involved in theAction of Commonly UsedDrugsRECEPTOR Main Action of Natural AgonistADRENOCEPTOR Alpha 1  Vasoconstriction Alpha 2  Hypotension/sedation Beta 1  Heart Rate Beta 2  Bronchodilation Vasodilation Uterine relaxation
  53. 53. Receptors involved in theAction of Commonly UsedDrugs RECEPTOR Main Action of Natural Agonist CHOLINERGIC  Muscarinic  Heart Rate Secretion Gut Motility Bronchoconstriction  Nicotinic  Contraction of Striated Muscle
  54. 54. Receptors involved in theAction of Commonly UsedDrugs RECEPTOR Main Action of Natural Agonist HISTAMINE  H1  Bronchoconstriction Capillary Dilation  H2  Increase Gastric Acid
  55. 55. Receptors involved in theAction of Commonly UsedDrugs RECEPTOR  Main Action of Natural Agonist DOPAMINE  CNS Neurotransmitter OPIOID  CNS Neurotransmitter
  56. 56. FORMS OF DRUG INSIDE THE BODY FREE / UNBOUND  BOUND STATE STATEACTIVE FORM INACTIVE FORMPlasma H2O Albumins & Globulins
  57. 57. Only free drugs arebiologically active and can cause a pharmacologic response
  58. 58. The patterns of distribution in the body determine how rapidly adrug will elicit a desiredresponse, the duration of the response, & in some cases whether aresponse will be elicited at all
  59. 59. Drug activity is related to itsconcentration in plasma H2O
  60. 60. BIOLOGIC HALF-LIFE (t ½) Time necessary for the body to eliminate half the quantity of the drug present in the circulation
  61. 61. Biologic Half-Life  It takes several half lives before more than 90% of the drug is eliminated in the system  SHORT HALF-LIFE (4-8 Hours)  LONG HALF-LIFE (24 Hours or longer)
  62. 62. Biologic Half-lifeASA - 650 mg t1/2 - 3 hrs. T 1/2 Time of Dosage % LEFT Elimination Remaining 1 3 325 50 2 6 162 25 3 9 81 12.5 4 12 40.5 6.25 5 15 20 3.1 6 18 10 1.55
  63. 63. Without tissuestorage sites , many drugs would rapidly be metabolized&eliminated from the body ,having little time to exert any effect
  64. 64. STORAGE DEPOT( Non-Specific Site ) Areas for transient storage It may prevent or prolong the action of drugs Site of drug loss or storage
  65. 65. AFFINITY TISSUES May be sites of ACTION or AREAS OF TRANSIENT STORAGE Particular Sites: FAT EYE BONE MUSCLE LIVER
  66. 66. AFFINITY TISSUES...Guanethidine -binds to heart & skeletal muscle Quinacrine -binds to liver & skeletal muscleTetracycline -binds to bone & enamel Thiopental -binds to adipose tissue
  67. 67. BIOTRANSFORMATIO N
  68. 68. METABOLISM  Parent drug is converted by enzymes into drugLIVER metabolites ready to perform its action then preparing it for excretion
  69. 69. Most Important Intracellular Site of Metabolism  Endoplasmic Reticulum (Microsomes)  Mitochondria (Monoamine Oxidase)  Lysosomes  Cytosol (Alcohol Dehydrogenase & Xanthine Oxidase)
  70. 70. ROLE OFMETABOLISM  It alters the pharmacologic activity, usually decreasing it but sometimes converting the drug to a compound similar or do have greater activity than the original
  71. 71. ROLE OFMETABOLISM Results in metabolites that are more water soluble & less lipid soluble than the parent compound & thus more readily excreted in the urine or processed further by conjugation
  72. 72. 3 DIFFERENT PATTERNS OF ENZYMATICMODIFICATION OF APARENT COMPOUND
  73. 73. Inactive Compound To Active Compound (PRO-DRUG) CONJUGATION 6-Mercaptupurine6- Mercaptupurine REACTION Ribonucleotide
  74. 74. Active Compound 2nd Active Compound Inactive CompoundPHENACETIN ACETAMINOPHEN ACETAMINOPHEN (Oxidation) (Conjugation Rxn) Glucoronide
  75. 75. Active Compound To Inactive Compound Subsequently PENTOBARBITAL TransformedPENTOBARBITAL ALCOHOL Into another Inactive form
  76. 76. CONSIDERATIONS: Most drugs are somewhat LIPOPHYLIC and could remain in the body for prolonged times if not transformed into a more H2O soluble derivatives
  77. 77. CONSIDERATIONS: Drug metabolism usually decreases the activity of the therapeutic agents, but there are important exceptions where active or toxic metabolites are formed
  78. 78. 2 GENERAL TYPES OF CHEMICAL REACTIONNON-SYNTHETICSYNTHETIC
  79. 79. PHASE 1METABOLISM OXIDATION REDUCTION HYDROLYSIS
  80. 80. PHASE 1 METABOLISM Conversion of lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group -OH, -COOH, -NH2
  81. 81. PHASE 1METABOLISM May increase, decrease or leave unaltered the drug’s pharmacologic activity
  82. 82. PHASE 2 METABOLISM CONJUGATION REACTION ENDOGENOUS SUBSTRATE Glucoronic Acid Sulfuric Acid Acetic Acid Amino Acid
  83. 83. CYTOCHROME P-450( Microsomal Mixed FunctionOxidase)  It absorbs light at 450 nm when exposed to Carbon Monoxide (Spectro-photometric Peak )  Most important enzymes in the liver  INHIBITS MIXED FUNCTION OXIDASE ACTIVITY
  84. 84. Liver P450 systems Liver enzymes inactivate some drug molecules  First pass effect (induces enzyme activity)
  85. 85. PHASE 2 METABOLISM results to a more polar & H2O soluble compound that are more often therapeutically inactive
  86. 86. EXCRETION
  87. 87. ORGAN FOR EXCRETION Other Route:  LUNGSKIDNEY  SKIN  BILE  SALIVA  FECES  BREAST MILK
  88. 88. I . KIDNEYMost important route
  89. 89.  3 PROCESSES IMPLICATED IN RENAL SECRETION Glomerular filtration Active secretion Passive reabsorption GF = glomerulus filtering. TR = tubular reabsorption. TS = tubular secretion.
  90. 90. 1. GLOMERULAR FILTRATION Drug enters thekidney through the Renal Arteries
  91. 91. •Free drug flows thruthe capillary slits into the Bowman’s space as part of the Glomerular Filtrate
  92. 92. •DRUG NOT TRANSFERED INTO THE GLOMERULAR FILTRATE LEAVES THE GLOMERULI THRU THEEFFERENT ARTERIOLES W/C DIVIDE TO FORM CAPILLARY PLEXUS SURROUNDING THE NEPHRITIC LUMEN IN THE PROXIMAL TUBULES
  93. 93. •Lipid solubility & pH do not influence thepassage of drug into the glomerular filtrate
  94. 94. 2. Tubular Reabsorption / Active Secretion inthe Proximal Tubule
  95. 95. •Highly ionized acids & bases are actively secreted by tubular cells & clearance can approach RPF of 600 ml/min
  96. 96. GFR = 125 ml / min 20% of theRENAL Plasma FlowRPF = 600 ml / min
  97. 97. Neonates & elderlyhave low GFR & LOW Renal Blood Flow
  98. 98. 3.Tubular Secretion / Passive Re- absorption in the Distal Tubule
  99. 99. •As the drug moves toward the distal convoluted tubule, its concentration increases & exceeds that of the perivascular space. The drug if uncharged, may diffuse out of the nephritic lumen back into the systemic circulation.
  100. 100. •Manipulating the pH of urine to increase theionized form of the drug in the lumen may be used to minimize the amount of back diffusion & increase the clearance of an undesirable drug .
  101. 101. Alkalinization of Urine Na BICARBONATEAcidification of Urine NH4Cl
  102. 102. •When tubular urinary pH is more alkaline thanplasma , weak acids are excreted more rapidly
  103. 103. •When tubular urinary pH is more acidic than plasma, weak acids are excreted more slowly
  104. 104. II . ENTERO-HEPATIC CYCLE
  105. 105. Biliary Excretion
  106. 106. 1.Active secretion of aconjugated drug into the bile
  107. 107. 2. Unconjugated drug liberated in the smallintestine by hydrolysis &free drug reabsorbed into plasma
  108. 108. 3.Some drug escapes reabsorption & appears in feces
  109. 109. III . LUNGS
  110. 110. Blood / Air PartitionCoefficient  LARGE VALUE - slow excretion . Rate of pulmonary circulation limiting  SMALL VALUE - more rapid excretion. Rate of pulmonary ventilation limiting
  111. 111. IV . SKIN
  112. 112. Excretion viasweat & may result in direct irritation or allergic reactions
  113. 113. END OF TOPIC

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