Principles of Pharmacology Pharmacokinetics & Pharmacodynamics

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Text of Principles of Pharmacology Pharmacokinetics & Pharmacodynamics

  • Slide 1
  • Principles of Pharmacology Pharmacokinetics & Pharmacodynamics
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  • Pharmacokinetics Movement of drugs in the body Movement of drugs in the body Four Processes Four Processes Absorption Absorption Distribution Distribution Metabolism Metabolism Excretion Excretion Drug concentration at sites of action influenced by several factors, such as: Drug concentration at sites of action influenced by several factors, such as: Route of administration Route of administration Dose Dose Characteristics of drug molecules (e.g., lipid solubility) Characteristics of drug molecules (e.g., lipid solubility)
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  • Drug Absorption Routes of Drug Administration Routes of Drug Administration Oral (per os, p.o.) Oral (per os, p.o.) Inhalation Inhalation vapors, gases, smoke vapors, gases, smoke Mucous membranes Mucous membranes intranasal (sniffing) intranasal (sniffing) sublingual sublingual rectal suppositories rectal suppositories Injection (parenteral) Injection (parenteral) intravenous (IV) intravenous (IV) intramuscular (IM) intramuscular (IM) subcutaneous (SC) subcutaneous (SC) intraperitoneal (IP; nonhumans only) intraperitoneal (IP; nonhumans only) Transdermal Transdermal
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  • DRUG ABSORPTION Lipid solubility Lipid solubility pKa = pH at which 50% of drug molecules are ionized (charged) pKa = pH at which 50% of drug molecules are ionized (charged) Only uncharged molecules are lipid soluble. Only uncharged molecules are lipid soluble. The pKa of a molecule influences its rate of absorption through tissues into the bloodstream. The pKa of a molecule influences its rate of absorption through tissues into the bloodstream. pH varies among tissue sites pH varies among tissue sites e.g., stomach: 3-4, intestines: 8-9 e.g., stomach: 3-4, intestines: 8-9
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  • pKa and Lipid Solubility Image from McKim, 2007, p. 14
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  • Routes of Drug Administration Oral Drug Administration Oral Drug Administration Advantages: Advantages: relatively safe, economical, convenient, practical relatively safe, economical, convenient, practical Disadvantages: Disadvantages: Blood levels are difficult to predict due to multiple factors that limit absorption. Blood levels are difficult to predict due to multiple factors that limit absorption. Some drugs are destroyed by stomach acids. Some drugs are destroyed by stomach acids. Some drugs irritate the GI system. Some drugs irritate the GI system.
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  • Routes of Drug Administration Advantages of Injection Routes Advantages of Injection Routes Absorption is more rapid than with oral administration. Absorption is more rapid than with oral administration. Rate of absorption depends on blood flow to particular tissue site (I.P. > I.M. > S.C.). Rate of absorption depends on blood flow to particular tissue site (I.P. > I.M. > S.C.). Advantages specific to I.V. injection Advantages specific to I.V. injection No absorption involved (inject directly into blood). No absorption involved (inject directly into blood). Rate of infusion can be controlled. Rate of infusion can be controlled. A more accurate prediction of dose is obtained. A more accurate prediction of dose is obtained.
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  • Routes of Drug Administration Disadvantages/Risks of Injection Disadvantages/Risks of Injection A rapid onset of action can be dangerous in overdosing occurs. A rapid onset of action can be dangerous in overdosing occurs. If administered too fast, heart and respiratory function could collapse. If administered too fast, heart and respiratory function could collapse. Drugs insoluble in water or dissolved in oily liquids can not be given I.V. Drugs insoluble in water or dissolved in oily liquids can not be given I.V. Sterile techniques are necessary to avoid the risk of infection. Sterile techniques are necessary to avoid the risk of infection.
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  • Drug Distribution Cell Membranes Cell Membranes Capillaries Capillaries Drug affinities for plasma proteins Drug affinities for plasma proteins Bound molecules cant cross capillary walls Bound molecules cant cross capillary walls Blood Brain Barrier Blood Brain Barrier Tight junctions in capillaries Tight junctions in capillaries Less developed in infants Less developed in infants Weaker in certain areas, e.g. area postrema in brain stem Weaker in certain areas, e.g. area postrema in brain stem Cerebral trauma can decrease integrity Cerebral trauma can decrease integrity Placenta Placenta Not a barrier to lipid soluble substances. Not a barrier to lipid soluble substances.
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  • Termination of Drug Action Biotransformation (metabolism) Biotransformation (metabolism) Liver microsomal enzymes in hepatocytes transform drug molecules into less lipid soluble by-products. Liver microsomal enzymes in hepatocytes transform drug molecules into less lipid soluble by-products. Cytochrome P450 enzyme family Cytochrome P450 enzyme family
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  • Termination of Drug Action Elimination Elimination Two-stage kidney process (filter, absorption) Two-stage kidney process (filter, absorption) Metabolites that are poorly reabsorbed by kidney are excreted in urine. Metabolites that are poorly reabsorbed by kidney are excreted in urine. Some drugs have active (lipid soluble) metabolites that are reabsorbed into circulation (e.g., pro-drugs) Some drugs have active (lipid soluble) metabolites that are reabsorbed into circulation (e.g., pro-drugs) Other routes of elimination: lungs, bile, skin Other routes of elimination: lungs, bile, skin
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  • Termination of Drug Action Kidney Actions Kidney Actions excretes products of body metabolism excretes products of body metabolism closely regulates body fluids and electrolytes closely regulates body fluids and electrolytes The human adult kidney filters approx. 1 liter of plasma per minute, 99.9% of fluid is reabsorbed. The human adult kidney filters approx. 1 liter of plasma per minute, 99.9% of fluid is reabsorbed. Lipid soluble drugs are reabsorbed with the water. Lipid soluble drugs are reabsorbed with the water.
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  • Termination of Drug Action Factors Influencing Biotransformation Factors Influencing Biotransformation Genetic Genetic Environmental (e.g., diet, nutrition) Environmental (e.g., diet, nutrition) Physiological differences (e.g., age, gender differences in microsomal enzyme systems) Physiological differences (e.g., age, gender differences in microsomal enzyme systems) Drug Interactions Drug Interactions Some drugs increase or decrease enzyme activity Some drugs increase or decrease enzyme activity e.g., carbamazepine stimulates CYP-3A3/4 e.g., carbamazepine stimulates CYP-3A3/4 e.g., SSRIs inhibit CYP-1A2, CYP-2C e.g., SSRIs inhibit CYP-1A2, CYP-2C
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  • Drug Time Course Time Course Studies important for Time Course Studies important for predicting dosages/dosing intervals predicting dosages/dosing intervals maintaining therapeutic levels maintaining therapeutic levels determining time to elimination determining time to elimination Elimination Half-Life Elimination Half-Life time required for drug blood levels to be reduced by 50% time required for drug blood levels to be reduced by 50% Approx. 6 half-lives to eliminate drug from body Approx. 6 half-lives to eliminate drug from body With repeated regular interval dosing, steady-state concentration reached in approx. 6 x half-life With repeated regular interval dosing, steady-state concentration reached in approx. 6 x half-life
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  • Therapeutic Drug Monitoring TDM important for clinical decisions TDM important for clinical decisions Plasma levels rough approximation of tissue/receptor concentrations Plasma levels rough approximation of tissue/receptor concentrations TDM goals TDM goals assess medication compliance assess medication compliance avoid toxicity avoid toxicity enhance therapeutic response enhance therapeutic response
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  • Tolerance & Dependence Mechanisms of Tolerance Mechanisms of Tolerance Metabolic (Pharmacokinetic, Dispositional) Metabolic (Pharmacokinetic, Dispositional) Cellular-Adaptive (Pharmacodynamic) Cellular-Adaptive (Pharmacodynamic) Behavioral Conditioning Behavioral Conditioning Dependence Dependence Abstinence Syndrome Abstinence Syndrome Not all addictive drugs produce physical dependence. Not all addictive drugs produce physical dependence. Some nonaddictive therapeutic drugs (e.g. SSRIs) can produce physical dependence. Some nonaddictive therapeutic drugs (e.g. SSRIs) can produce physical dependence.
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  • Pharmacodynamics Drug actions at receptor sites and the physiological/chemical/behavioral effects produced by these actions Drug actions at receptor sites and the physiological/chemical/behavioral effects produced by these actions Studies of drug mechanisms of action at the molecular level Studies of drug mechanisms of action at the molecular level Provides basis for rational therapeutic uses and the design of new, superior therapeutic agents Provides basis for rational therapeutic uses and the design of new, superior therapeutic agents
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  • Drug-Receptor Interactions Receptors found on membrane spanning proteins Receptors found on membrane spanning proteins Continuous series of amino acid loops Continuous series of amino acid loops Ligands (neurotransmitters, drugs) attach inside spaces between coils, held by ionic attractions Ligands (neurotransmitters, drugs) attach inside spaces betwee