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117 Cards in this Set
- Front
- Back
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Pharmacology
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Study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes
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Toxicology
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The branch of pharmacology which deals with the undesirable effects of chemicals on living systems, from individual cells to complex ecosystems
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Definition of a Drug
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An agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other animals.
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Nature of Drugs
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Physical
Organic Compounds Inorganic Compounds Acid/Base |
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Physical Drugs
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Solid
Liquid Gaseous |
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Organic Compounds
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Carbohydrates
Proteins Lipids |
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Inorganic Compounds
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Lithium
Iron Heavy Metals |
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Acid/Base Drugs
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pH differences alter the degree of ionization
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Drug size
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Molecular size varies greatly from very small lithium ion MW 7 to very large alteplase [t-PA] a protein of MW 59,050
Molecular weight usually between 100 and 1000 Drugs >1000 will not diffuse readily between compartments |
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Pharmacodynamics
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Study of the mechanism of drug action on living tissue
The response of tissues to specific chemical agents at various sites in the body The effect the drug has on the body |
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Drug Receptor Bonds
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Covalent bonds > ionic bonds > hydrogen bonds > induced dipole interactions
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Agonist
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Bind to and ACTIVATE the receptor which directly or indirectly bring about the effect
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Agonists that INHIBIT binding molecules
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Inhibit molecule responsible for terminating the action of an endogenous agonist
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Antagonist
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Bind to and PREVENT binding by other molecules
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Partial Agonist
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Bind to and ACTIVATE but do not evoke as great of a response as a full agonist
Agonist when no full agonist is present Antagonist when a full agonist present |
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Noncompetitive antagonist
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Allosteric modulators
Bind to a site on the receptor separate from the agonist binding site Reversible if they do not bind covalently |
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Chemical antagonist
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2 drugs bind to each other and one agent is inactivated (ex. heparin and protamine)
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Physiological antagonism
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effect of one agent counteracts the effect of another agent (ex. insulin and hydrocortisone)
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Duration of Drug Action
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Duration of Drug Action
As long as drug occupies receptor Action may persist after dissociation i.e. some coupling molecule is still present in activated form In case of covalent bound dugs, effect persists until drug-receptor complex is destroyed and new receptors made Desensitization mechanism to prevent excessive activation |
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Receptor
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SELECTIVE in choosing ligands (drug molecules)
Must CHANGE ITS FUNCTION upon binding which then alters the biologic (cell, tissue, etc) system |
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Inert Binding Site
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Non-regulatory molecule
Affects the distribution of a drug |
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Drug Receptors
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Regulatory proteins
Enzymes - mostly inhibited by drug binding Transport Proteins- - Na/K ATPase for digitalis glycosides Structural Proteins- Tubulin for Colchicine |
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Concentration-Effect Curves
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E= Emax X C
C + EC50 C is concentration E is the effect observed at C Emax is the maximal response EC50 concentration that produces 50% of max effect |
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Receptor Binding of Agonists
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B= Bmax X C
C + Kd Bmax is the total concentration of receptor sites Kd equilibrium dissociation constant- concentration of free drug at which half maximal binding observed |
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Receptor- Effector Coupling and Spare Receptors
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Coupling- links drug occupancy of receptors and pharmacologic response
Efficiency Initial conformational change Full agonist> partial agonist Biochemical events that convert receptor occupancy into cellular response Linear response Directly related to the number of bound receptors Ion channels Non-linear-increases disproportionately Enzymatic Signal transduction cascades “Spare Receptors” |
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Intracellular Receptors for Lipid-Soluble Agents
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Examples
Steroids and thyroid hormones Regulate gene expression Delayed effects because need to synthesize new proteins Effects persists after agonist is gone |
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Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases
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Initiates in its specific target cells a complex program of cellular events ranging from altered membrane transport of ions and metabolites to changes in the expression of many genes
Down-regulation |
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Cytokine Receptors
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Respond to heterogeneous group of peptide ligands
growth hormone, erythropoietin, interferon |
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Ligand-Gated Channel
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Many drugs mimic or block endogenous ligands that regulate flow of ions through plasma membrane channels
-Acetylcholine -Serotonin -GABA -Glutamate |
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Potency
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ED50 or EC50
Dosage units in terms of therapeutic endpoint |
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Efficacy
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Limit of the dose-response relation on the response axis
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Median Effective Dose (ED50)
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Dose at which 50% of individuals exhibit effect
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Median Toxic Dose (TD50)
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Dose that produces toxic effect in 50% of animals
If the toxic effect is death of the animal, it is the Median Lethal Dose (LD50) |
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Therapeutic Index (TI)
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Relates the dose of a drug required to produce a desired effect to that which produces an undesired effect
TI = TD50 / ED50 You want to TI to be large |
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Variations in Drug Responsiveness
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Idiosyncratic Reaction
Infrequently observed Genetic differences in metabolism Pharmacogenomics Immunologic mechanisms * Hypo- or Hyper-reactive – decreased or increased response Tolerance – decreased response at same dose Tachyphylaxis – response diminishes rapidly after administration of a drug |
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Immunologic (Allergic)
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Anaphylaxis from β-lactam antibiotics
Hypotension after protamine Dermatitis from sulfonamides Hypotension after succinylcholine Quinine-induced thrombocytopenia |
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Idiosyncratic (“Pseudoallergic”)
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Shock after radiocontrast media
Opiate-related urticaria Hemolytic anemia due to primaquine Flushing during vancomycin infusion Isoniazid hepatitis |
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Causes of Altered Drug Responsiveness
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Concentration that reaches receptor is altered
-Pharmacokinetics -Multidrug resistance (MDR) genes - Actively transport drug from cytoplasm Varied concentration of an endogenous receptor ligand |
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Upregulation
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An increase in the number of receptors on the surface of target cells, making the cells more sensitive to a hormone or another agent.
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Downregulation
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An decrease in the number of receptors on the surface of target cells, making the cells less sensitive to a hormone or another agent.
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Causes of Altered Drug Responsiveness-Alterations in Number or Function of Receptors
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Antagonist can increase the number of receptors in a critical cell or tissue by preventing down-regulation cased by an endogenous agonist
Agonist decreases the number of receptors by drug-induced down-regulation Change in receptor number can be caused by hormones Genetic factors |
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Causes of Altered Drug Response- Changes in Components of Response Distal to Receptor
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Patient characteristics that may limit the clinical response
Age General Health MOST importantly the severity and pathophysiologic mechanism responsible for the disease |
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Clinical Selectivity: Therapeutic vs. Toxic Effects of Drugs
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No drug causes only a single, specific effect
Drugs are SELECTIVE not SPECIFIC They bind to one or a few types of receptors more tightly than others These receptors control discrete processes, resulting in distinct effects Measure Selectivity Compare binding affinities of a drug to different receptors Compare ED50 for different effects of a drug in vivo Beneficial or therapeutic vs. toxic effects (“side effect”) |
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Therapeutic and Toxic effects Mediated by the Same Receptor-Effector
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Serious drug toxicity caused by a direct pharmacologic extension of the therapeutic actions of the drug
Avoiding toxicity Measure therapeutic effects Combination therapy Do not give drug Not a strong therapeutic indication Alternative therapy available |
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Beneficial and Toxic Effects Mediated by Same Receptors BUT in Different Tissues or by Different Effector Pathways
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Drugs produce both desired and adverse effects by acting on a single receptor type in different tissues
Avoiding toxicity Use lowest effective dose Adjunctive drugs acting on different receptor mechanisms Dosage form targeting receptor sites (aerosol) |
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Pharmacokinetics
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DAME
The actions of the body on the drug Absorption Distribution Metabolism Elimination/Clearance/Excretion |
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Pharmacokinetic Principles-Permeation
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Aqueous diffusion
Driven by concentration gradient Fick’s Law Flux (molecules per unit time)= (C1-C2) X [Area X Permeability coefficient / Thickness] Influenced by electrical fields |
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Permeation: Ionization of Weak Acids and Bases
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Weak acid= Neutral molecule than can reversibly dissociate into an anion and a proton
C8H7 O2COOH C8H7 O2COO- + H+ Aspirin Weak base=Neutral molecule that can form a cation by combining with a proton C12H11CIN3NH3+ C12H11CIN3NH2+ H+ Pyrimethamine |
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Permeation: Ionization of Weak Acids and Bases
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Henderson-Hasselbach Equation
Log (Protonated)/(Unprotonated) = pKa- pH |
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Pharmacokinetic Principles-Permeation: Special carriers/ pumps
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Too large or too insoluble
Peptides, amino acids, glucose Saturable and inhibitable Expel foreign molecules |
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Absorption-Dosage Forms
Oral (PO) |
Route: by mouth
Form: tablets, capsules, liquids |
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Absorption-Dosage FormsSublingual (SL)
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Route: under the tongue
Form: tablets, troches, lozenges |
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Absorption-Dosage Forms
Epicutaneous |
Route: skin surface
Form: ointments, creams, lotions, powders, aerosals |
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Absorption-Dosage Forms
Transdermal |
Route: skin surface
Form: patch, discs, solutions |
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Absorption-Dosage Forms
Conjunctival |
Route: conjunctiva
Form: ointment, contact lens inserts, solution |
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Absorption-Dosage Forms
Intranasal |
Route: nose
Form: solution, spray, inhalant, ointment |
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Absorption-Dosage Forms
Aural |
Route: ear
Form: solution, suspension |
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Absorption-Dosage Forms
Intrarespiratory |
Route: lungs
Form: solutions, powder, aerosal |
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Absorption-Dosage Forms
Rectal (PR) |
Route: rectum
Form: ointment, solution, suppositories, foam |
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Absorption-Dosage Forms
Vaginal |
Route: vaginal
Form: solution, ointment, foam, inserts, tablet, suppositories |
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Absorption-Dosage Forms
Intraurethral |
Route: urethra
Form: solution, suppositories |
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Absorption-Dosage Forms
Parenteral (IV, IA, ID, SC/SQ, IM) |
Route: vein, artery, dermal, subcutaneous, muscle
Form: injection |
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Bioavailability (F)
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Amount of drug that is absorbed by route X compared with the amount of drug that is absorbed after IV administration
IV 100 (by definition)Most rapid onset, IM 75 to ≤ 100 Rectal 30 to <100 Less first pass effect than oral Inhalation 5 to <100 Often very rapid onset Transdermal 80 to ≤ 100 Usually slow absorption, lacks first pass effect, prolonged duration of action Large Volumes often feasible, pain SC 75 to ≤ 100 Smaller volumes than IM, pain PO 5 to <100 Most convenient, first pass effect may be significant |
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Dissolution
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Physico-chemical properties of drug
Crystal size and form Excipients Special dosage forms (Sustained release (SR), enteric coated (EC)) pH (stomach and small intestine) |
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Gastric emptying rate
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Stability of drug at acid pH
Solution or solid dosage forms (liquids and smaller particles empty more quickly) Affected by: food: antacids; drugs (opiates, anticholinergics, metoclopramide); disease (autonomic neuropathy). |
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Intestinal motility
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Dissolution of slowly soluble drugs (digoxin, SR)
Chemical degradation or metabolism by microflora |
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Drug interactions in gut lumen
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Chelation (tetracyclines with divalent metal ions)
Adsorption (anion exchange resins) Food interactions |
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Passage through the gut wall
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Physico-chemical characteristics of the drug
Metabolism by enzymes in the intestinal endothelium |
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Rate of Absorption
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Site
Drug formulation Zero order: absorption rate independent of drug remaining Gastric emptying Controlled release drug formulation First order: absorption rate proportionate to the concentration |
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Volume of Distribution (Vd)
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Vd (L) = Amount of drug in body (mg)/ Concentration of drug in plasma/blood (mg/L)
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Compartment and Volume
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Water
Total body water (0.6L/kg) Extracellular (0.2L/kg) Blood (0.08 L/kg); plasma (0.04 L/kg) Fat (0.2- 0.35 L/kg) Bone (0.07 L/kg) |
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Vd-Calculating Ideal Body Weight (IBW)
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Males:
50 + (2.3)(height in in >60) Females: 45 + (2.3)(height in in >60) |
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***Protein Binding
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Free drug = unbound drug =typically chemically active
Bound drug typically chemically inactive Albumin - Low in many disease states alpha 1-acid glycoprotein - Increased during inflammatory reactions Capacity-limited protein binding - Protein binding is saturated at higher concentrations Increasing dosing rate/amount leads to higher unbound drug Total drug concentration will increase less rapidly than the dosing rate would suggest as protein binding approaches saturation at higher concentrations |
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Protein Binding-Effect of decreased plasma concentration
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In cases where there is decreased albumin (3.5 to 5.5mg/dL) you must calculate the corrected phenytoin concentration by adjusting for the decreased protein
C (calc) = [C (observed)/ 0.2 Albumin conc]+ 0.1 C= concentration |
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Pharmacokinetics-Clearance (CL)
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CL (ml/min) = Rate of elimination (mg/min)/
Drug Concentration (mg/ml) |
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Half-Life (t1/2)
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Time required for drug concentration to decrease by one-half
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First-Order Kinetics- Clearance and Elimination
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Elimination Rate (mg/hr) = CL (L/hr) X C (mg/L)
Elimination rate is not saturable, a constant FRACTION of drug is lost per unit of time CL = Dose/AUC (of time-concentration profile after a dose) |
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Non-linear Kinetics-Clearance and Elimination
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“concentration-dependent”
ex. phenytoin, aspirin, ethanol Rate of Elimination = Vmax X C / Km + C |
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Non-linear Pharmacokinetics
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Rate of Elimination = Vmax X C / Km + C
C= Substrate Concentration Vmax = maximum velocity at high substrate concentrations Km= substrate concentration at half of Vmax and is a measure of the affinity of the substrate for the enzyme Clint= Rate of Elimination = Vmax / Km + C If C is very small compared to Km, then: Clint= Vmax / Km |
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Hepatic Extraction Ratio
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Extraction of drugs by liver determined by
Fraction of drug unbound in plasma Intrinsic activity of the drug metabolizing enzymes Liver blood flow |
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First-Pass Effect
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Variability in drug response
Drug Interactions Liver Disease Alternative routes of administration |
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Elimination- Renal
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“Cockroft-Gault eq” estimates Creatinine Clearance(CrCl)
CrCl (ml/min) = (140 – Age) x Wt* (Kg)/ 72 x SCr (mg/dl) For females = multiply overall value by 0.85 Wt* = use actual body weight, but if ABW is greater than 20% above IBW then use IBW Serum Creatinine (SCr) < 1mg/dl recommended that you round up to 1mg/dl |
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Excretion/Elimination
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Bile (major route of excretion)
Breast Milk Tears Urine Saliva Sweat |
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Steady State (ss)
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At steady state, the dosing rate (“rate in”) must equal the rate of elimination (“rate out”)
Dosing rate ss = Rate of Elimination ss |
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Maintenance Dose (MD)
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Depends on drug’s CL
Dosing Rate ss = CL X TC Intermittent dosing MD = (dosing rate/Fx) X Dosing interval |
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Loading Dose (LD)
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LD = Vd X target concentration (TC)
Useful in drugs with long t1/2 |
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Therapeutic Drug Monitoring
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Using serum levels to predict a therapeutic response based on population studies and avoid toxicity
Timing of Samples Allow for absorption and distribution Should be at steady state Draw peak and/or trough values Determine actual elimination rates, then calculate new dose For agents that follow first-order kinetics: C = CO x e –k( t) C = concentration at time t CO = initial concentration k = elimination rate constant t = change in time |
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Drug Screening
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Biologic Assays
- Molecular – cellular- organ system- whole animal Define Mechanism of Action (MOA) and Selectivity Lead Compound |
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Types of Safety Tests
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Acute toxicity
Subacute toxicity Chronic toxicity Effect on reproductive performance Carcinogenic potential Mutagenic potential Investigative toxicology |
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Preclinical Safety &Toxicity Testing Goals
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Identify potential for human toxicities
Design tests to further define toxic mechanisms Predict the specific and the most relevant toxicities to be monitored in clinical trials |
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“No-effect” Dose
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the max dose at which a specified toxic effect is not seen
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Minimum Lethal Dose
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the smallest dose that is observed to kill ANY experimental animal
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Median Lethal Dose (LD50)
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dose that kills approx 50% of the animals
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Limitations in Preclinical Safety & Toxicity Testing
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Time-consuming (2-6 yrs) and expensive
Large number of test animals Increase cell and tissue culture in vitro methods Extrapolation of data from animals to humans are reasonably predictive for many but not all toxicities For statistical reasons, rare adverse effects are unlikely to be detected |
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Evaluation in Humans
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Careful Design and Execution
Variable Natural History of Most Diseases Large subject population Crossover design Concomitant Diseases and other Risk Factors Subject and Observer Bias Placebo Response= “I shall please” Double-Blind Design |
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Clinical Trials
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Notice of Claimed Investigational Exemption for a New Drug (IND)
Declaration of Helsinki http://www.fda.gov/oc/health/helsinki89.html Interdisciplinary Institutional Review Board (IRB) Approval of Plans and Ethics |
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Phase 1 Clinical Trial
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non-blinded
25-50 Max tolerated dose, show if humans and animals show significantly different responses, PK measures If toxic drug, then used in people with disease |
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Phase II Clinical Trial
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100-200
Determine Efficacy in people with target disease |
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Phase III Clinical Trial
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double-blind and crossover
thousands Minimize errors due to placebo effects, variable course of disease used in target disease Expensive, certain toxic effects may first become apparent |
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Phase IV Clinical Trial
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Monitor safety
Importance of reporting toxicity Drug induced effects may have very small incidence such as 1 in 10,000 or less Some side effects only seen after chronic dosing Phase 4 has no fixed duration |
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New Drug Application (NDA)
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Apply for permission to market agent if phase 3 results meet expectations
Application contains hundreds of volumes Averages about 5,000 patients |
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FDA review and Approval
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Months to years
Expedited in special cases |
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Rational Prescribing
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Make a SPECIFIC diagnosis
Consider Pathophysiology of diagnosis Select a SPECIFIC therapeutic objective Select a drug of choice Labeled & Unlabeled Uses Patient Characteristics Clinical Presentation Determine the appropriate dosing regimen Duration of therapy Identify monitoring parameters EDUCATE patient |
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What a health care provider should know about medications:
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Usual dose
Route of administration Indications for use Significant side effects and adverse reactions Contraindications Major drug interactions Appropriate assessment, planning, implementation and evaluation |
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Compliance/Adherence
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Fails to obtain medications
Does not take as prescribed Prematurely discontinues Takes medication inappropriately |
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Prescription (Rx)
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Prescriber’s orders in patient’s chart
Written/Electronic order to which the pharmacist refers when dispensing Medication container with a label affixed |
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Drug Name
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Chemical Name – N-4-hydroxyphenyl acetamide
Generic/nonproprietary name - acetaminophen Trade/brand/proprietary name – Prilosec, Zocor Prescription/legend drug Rx only - morphine, lisinopril Non-prescription/over-the-counter (OTC) drug - Loratadine (Claritin), loperamide (Imodium) |
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Reduce Medication Errors
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Write legibly or use E-prescribing
81% errors occur during prescribing, 14% transcribing, 3% dispensing Do not write in cursive Use pre-printed order sets Use TALL man lettering (acetaZOLamide vs acetaHEXamide) Ongoing education about medication Bar code medication administration (2004 FDA regulation) Unit of use dispensing (no bulk bottles) Remove dangerous medications from general areas Label all devices clearly Have patients ask questions |
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Schedule I Drugs
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Abuse: highest
no accepted medical use (LSD, Rohypnol) |
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Schedule II Drugs
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Abuse: high
accepted medical use, risk of physical/psychological dependence (morphine, amphetamines) |
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Schedule III Drugs
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abuse: less abuse potential than I or II
accepted medical use, moderate/low physical but high psychological dependence (Vicodin, anabolic steroids) |
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Schedule IV Drugs
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abuse: Less than III
accepted medical use, limited physical/psychological dependence (Ambien, oral phenobarbital) |
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Schedule V Drugs
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abuse: Less than III
accepted medical use, limited physical/psychological dependence (Ambien, oral phenobarbital) |
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Controlled Substances - California
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Provider needs a DEA number
C III – V may have 5-refills in a 6-month period C II has NO refills, order may NOT be sent over telephone, may fax (followed by special form) Require special Prescription forms No more triplicate form; now need the new controlled substance form for ANY controlled substance Approved Security Prescription Printers Prescribers must order the new tamper-resistant forms from pre-approved security prescription printer companies. |
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Who May Prescribe in California?
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Physicians, Dentists, Podiatrists
Veterinarians Physician’s Assistant - under protocol Pharmacists – under protocol + clinical training Nurse Practitioner – in collaboration with or under supervision of a physician Optometrists – limited to certain agents affecting the eyes Licensed Naturopaths-may issue non C-II drugs |
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PA Prescribers
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May prescribe under written formulary and protocols under physician supervision
Transmit the physician’s order to a pharmacy Cannot transmit any prescription for a drug not specified in the protocol or any controlled substance without a patient-specific order from a supervising physician Supervising physician must within 7 days, review, countersign, and date the medical record of any patient for whom a schedule II controlled substance drug order has been issued California Controlled Substances Act Register with DEA |
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Elements Essential for Proper Medication Administration
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“Five Rights”
Right patient Right drug Right dose Right route of administration Right time of administration |
