INTRODUCTION TO PHARMACOLOGY
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1 INTRODUCTION TO PHARMACOLOGY Pharmacology is the study of how chemicals interact with the body Endogenous hormones, growth factors, etc Exogenous drugs Two areas of study Pharmacodynamics Interaction of chemicals with receptors or enzymes Pharmacokinetics Absorption, distribution, metabolism, excretion 1
2 Pharmacokinetics What the body does to a drug LADME Liberation Absorption Distribution Metabolism Excretion 2
3 Pharmacokinetics Routes of drug administration Oral Sublingual Intravenous (IV) Intraperitoneal (IP) Intramuscular (IM) Subcutaneous (SC) Rectal Epidural Intracerebroventricular 3
4 Liberation Pharmacokinetics How is a drug released from its delivery vehicle? Pills must dissolve or be broken down Forms of oral medications Tablet Caplet Liquid Liqui-Gel 4
5 Absorption Pharmacokinetics How is a drug absorbed into the tissue or bloodstream? Depends on route of administration Oral absorbed via gastrointestinal tract; goes to liver Sublingual absorbed via blood vessels under the tongue; bypasses the liver IV n/a IP absorbed via peritoneal mucosae IM absorbed via muscle lymphatics & capillaries Bioavailability: how much ingested drug is actually absorbed? 5
6 For an orally-administered medication, absorption can only occur once which of these other processes has occurred? A) Distribution B) Metabolism C) Liberation D) Excretion 6
7 Why does the previous question include the qualifer, For an orally-administered medication? 7
8 Distribution Pharmacokinetics How is a drug distributed to the various fluid compartments or tissues of the body? Plasma vs. interstitial vs. intracellular fluid Adipose tissue vs. lean tissues Distribution is unequal & distinct for each drug Volume of distribution theoretical volume a drug would occupy if it were present in all compartments at the same concentration as in the plasma 8
9 Volume of distribution is based MOSTLY on A) how much blood a patient has. B) how much drug was in a particular pill. C) how soluble a particular drug is in lipids vs. water. 9
10 True or false: The volume of distribution of a drug may be larger than the total volume of the patient. A) True B) False 10
11 Metabolism Pharmacokinetics Is a drug chemically modified by the body? If so Are the metabolites more or less active? Are the metabolites safer or more toxic? Can the metabolites be more easily excreted? Which tissues metabolize the drug? What enzyme systems or other reactions are used to metabolize the drug? 11
12 Metabolism Phase I reactions Pharmacokinetics Liver Cytochrome P450 (cyp450) enzymes E.g., Oxidation, reduction, hydrolysis, (de)cyclization Often produce active metabolites First-pass effect Phase II reactions Liver and kidney Addition of polar functional groups Usually produce non-functional metabolites for excretion E.g., Glucuronidation, glutathione conjugation 12
13 Pharmacokinetics Metabolic clearance of drugs / hormones Metabolized into non-active form Bound to cells & degraded / recycled Excreted These processes are not mutually exclusive Drugs can be metabolized to inactive metabolites, then excreted 13
14 Pharmacokinetics Metabolic clearance of drugs / hormones Rate of removal depends on solubility Peptide hormones Degraded in blood or tissues Cleared rapidly (seconds to minutes) Steroid hormones Bounds to plasma proteins Cleared slowly (minutes to days) 14
15 Drug / Hormone Clearance Metabolic clearance rate (MCR) Rate of disappearance from plasma Infuse at increasing rate until plasma concentration reaches steady-state Infusion rate = rate of disappearance Concentration of hormone in plasma MCR (ml/min) = rate of hormone disappearance (ng/min) Concentration of hormone (ng/ml) 15
16 Pharmacokinetics Excretion / Elimination Urine Feces Breath Skin 16
17 Metabolic clearance rate refers to A) How fast kidneys produce urine. B) How much drug is filtered by the kidneys. C) A theoretical volume of plasma that can be 100% cleared of drug in a particular amount of time. 17
18 Pharmacodynamics What a drug does to the body Drug (ligand)-receptor interactions L + R L R Receptor types membrane vs. intracellular Enzymes & structural proteins can act as drug receptors Signal transduction pathways Enzyme-based biochemical pathways 18
19 Pharmacodynamics Potential actions/roles of drugs Agonist Stimulating action vs. depressing action Full or partial agonist Antagonist Direct beneficial chemical reaction Direct harmful chemical reaction 19
20 Pharmacodynamics Dose-response curves Increased [drug] increased effect EC 50 (effective dose yielding 50% max effect) Curve shifts Upward higher efficacy Leftward higher potency (sensitivity) 20
21 Tension (mn/mm) Tension (mn/mm) Pharmacodynamics LPO AdLib (n=15) NPO AdLib (n=11) NPO FR (n=5) LPO FR (n=8) KCl (mm) NorEpi (nm)
22 A leftward shift of a dose-response curve indicates that a system A) is more senstive to a particular ligand. B) is less sensitive to a particular ligand. C) has a higher concentration of ligand. C) has a lower concentration of ligand. 22
23 Pharmacodynamics Beneficial actions of drugs must be weighed against unintended, harmful effects Side effects Therapeutic window The range of doses which provide benefits without producing toxicity Varies for each drug and may vary between individuals 23
24 True or false: Medications with side effects are not approved by the FDA. A) True B) False 24
25 Measurement of Hormone Concentration Radioimmunoassay Use specific antibody to detect hormone Mix radioactive tracer hormone, antibody and sample together Competitive assay: [Ab] is lower than combined tracer and endogenous [hormone] Remove all unbound mixture, leaving Ab bound to either tracer or endogenous hormone High [endogenous hormone] low tracer Low [endogenous hormone] high tracer 25
26 Measurement of Hormone Concentration Radioimmunoassay Measure radioactivity of remaining sample, compare to standard curve Fig
27 Measurement of Hormone Concentration ELISA (enzyme-linked immunosorbent assay) Coat sample wells with antibody Add test sample Add antibody conjugated to enzyme Add enzyme substrate Fig Color development indicates presence of test substance; concentration determined by dilution factor & comparison to standard curve 27
28 Mouse ICAM-1 ELISA Standard Curve
29 What kind of molecule is used as a molecular tool to measure how much of a particular substance a sample has? A) Protein B) Receptor C) DNA D) Antibody 29
30 RIA standard curves have a negative slope; ELISA standard curves are positive. Why are they different? 30
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