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  CHAPTER 3  –  PHARMACODYNAMICS 1 ©RAT PHARMACODYNAMIC CONCEPTS Pharmacodynamics  –  study of biochemical, cellular, and physiological effect of drugs and mechanisms of action Drug receptor or drug target  –  complex with which the drug interacts -   Often on the surface of the cell Acceptors  –  do not cause any change in response but alter pharmacokinetics of a drug’s actions (e.g. albumin)  Therapeutic biologics  –  genetically engineered enzymes and monoclonal antibodies Gene therapy products  –  uses viruses as vectors to replace genetic mutations PHYSIOLOGIC RECEPTORS Physiological receptors  –  drug receptors that serve as receptors for endogenous regulatory ligands Agonists  –  Drugs that bind physiologic receptors and mimic regulatory effects -   Primary agonist  –  binds to the same recognition site as endogenous agonist -   Allosteric (allotopic) agonist  –  bind to a different region on a receptor Antagonists  –  drugs that block or reduce action of agonist -   Syntopic interaction  –  from competition for same overlapping site -   Allosteric antagonism  –  occur by interacting with other sites -   Functional antagonism  –  inhibiting effect of agonist Partial agonist  –  only partially effective as agonist Inverse agonist  –  stabilize receptors with constitutive activity into inactive conformation Partial agonist + Inverse agonist  –  behave as antagonist in the presence of full agonist SPECIFICITY OF DRUG RESPONSES Dissociation constant  –  affinity of drug to its receptor; measurement of strength of reversible interaction Chemical structure  –  determines affinity of drug for its receptor and its intrinsic activity -   Also contributes to drug specificity Drugs w broad specificity -   Enhances clinical utility -   Contribute to adverse side effects Amiodarone  –  one drug that interacts w/ multiple receptors -   For cardiac arrythmias -   Similar structure to thyroid hormone Sotalol  –  prescribes as racemic mixture -   D- and L- enantiomers are equipotent as K channel blockers -   L-enantiomer  –  more powerful potent B-adrenergic antagonist Multiple mechanisms of action depend on: -   Receptor specificity -   Tissue-specific expression of receptors -   Drug access -   Drug concentrations in different tissues -   Pharmacogenetics -   Interactions w/ other drugs Downregulation or desensitization  –  caused by chronic administration of drug -   Chronic use of nitrovasodilators for angina results in complete tolerance, a process nown as tachyphylaxis Drug resistance may also develop because of: -   Pharmacokinetic mechanisms (metabolized rapidly) -   Mechanisms that prevent drug from reaching receptor -   Cancer cells w/ drug-resistant mutations Some effects do not occur by receptor: -   Aluminum and magnesium hydroxide  –  reduce gastric acid chemically -   Mannitol  –  acts osmotically -   Antibiotics, antivirals, antiparasitics  –  targets receptors or cell processes critical for infective agent only Resistance to antibiotics/antivirals can occur by: -   Mutation of target receptor -   ↑  expression of enzymes that degrade or ↑ efflux of drug  -   Development of alternative biochemical pathways STRUCTURE-ACTIVITY RELATIONSHIPS AND DRUG DESIGN Orphan receptor  –  ligands are unknown Chemical structure  –  determines affinity and intrinsic activity of a drug -   Minor modification to molecule may result to major changes -   Therapeutically useful antagonists  –  developed by chemical modification of physiological agonist Pharmacophore  –  use computer analysis to identify chemical properties for optimal action at the receptor QUANTITATIVE ASPECTS OF DRUG INTERACTIONS WITH RECEPTORS Receptor occupancy theory  –   drug’s response emanat es from receptor occupied by the drug -   Basis is the law of mass action Dose-response curve  –  observed effect of a drug as a function of its concentration in the receptor compartment Hormesis  –  drugs that cause low-dose stimulation and high-dose inhibition -   U-shaped relationships (the figure on the left; A)  Affinity, Efficacy, and Potency Drug-receptor reaction is characterized by: 1.   Binding of drug to receptor 2.   Generation of a response L  –  ligand R  –  receptor LR reaction  –  governed by chemical property of affinity LR* - produced in proportion of LR and leads to a response  CHAPTER 3  –  PHARMACODYNAMICS 2 ©RAT -   Illustrates reliance of affinity of L with R on forward association rate and reverse/dissociation rate Potency  –  when two drugs produce equivalent responses, the drug whose dose-response curve lies to the left is more potent Efficacy  –  capacity of drug to activate receptor and generate response -   Full agonist  –  high efficacy -   Partial agonist  –  low intrinsic efficacy -   Antagonist  –  exhibits zero efficacy -   Drug X is more efficacious than drug Y Quantifying Agonism Describe agonist response by determining half-maximally effective concentration (EC50) Can also compare maximal asymptotes in a system -   Advantage: property depends solely on efficacy Drug potency  –  mixed function of affinity and efficacy Quantifying Antagonism  Competitive antagonism  –  drug with affinity for a receptor but lacking intrinsic efficacy competes for agonist for primary binding site -   Characteristic pattern  –  concentration-dependent production of a parallel shift to the right of agonist dose-response curve with no change in maximal response o   Magnitude of rightward shift depends on concentration of antagonist and its affinity -   Will reduce response to zero Partial agonist  –  can compete with full agonist -   Increasing concentrations of partial agonist will inhibit response to a finite level -   Used therapeutically to buffer response -   Vareniciline  –  partial agonist used in smoking cessation therapy o   Blocks effect of high dose nicotine Noncompetitive antagonism  –  an antagonist that dissociates very slowly so that action is prolonged -   Maximal response of agonist will be depressed at some antagonist concentration -   Irreversible antagonist  –  competes for the same binding site o   Same pattern as noncompetitive antagonism Allosteric or allotopic antagonist  –  also produces noncompetitive antagonism -   Binds to a site distinct from primary agonist, changing the affinity of the receptor for agonist Allosteric agonist or coagonist  –  drug binding at allosteric site that potentiates effect of primary agonist Affinity of competitive antagonist (K1)  –  determined in radioligand binding assay or by measuring functional response of a system to a drug -   As more antagonist is added, higher concentration of agonist is needed to produce equivalent response -   Extent of rightward shift  –  measure of affinity of inhibitor  Additivity and Synergism: Isobolograms  Drugs with different mechanisms of actions used in combination may be used to achieve additive and possitve synergistic effects -   Permits use of reduced concentrations Positive synergism  –  superadditive effects of drugs used in combination Negative synergism or subadditive effects  –  efficacy is less Isobologram  –  line connection EC50 of 2 drugs (Figure in the next page) -   Describes concentrations that will achieve half-maximal response when A and B are used in combination  CHAPTER 3  –  PHARMACODYNAMICS 3 ©RAT If A and B are superadditive: -   concentrations of A and B needed needed to achieve response will fall below additive response line If A and B are subadditive: -   concentrations will lie above additive response line PHARMACODYNAMIC VARIABILITY: INDIVIDUAL AND POPULATION PHARMACODYNAMICS Drug responsiveness may change because of: -   disease -   age -   previous drug administration Correlation of drug levels with efficacy and toxicity must be interpreted in the context of pharmacodynamic variability in population -   analyzed by quantal concentration-effect curve Median effective dose (ED50)  –  dose of a drug required to produce a specified effect in 50% of population Median lethal does (LD50)  –  determined in experimental animals LD50/ED50 ratio  –  indication of therapeutic index -   reflects how selective drug is producing its desired effects Therapeutic window  –  range of steady-state concentrations of drug that provides therapeutic efficacy with minimal toxicity Clinical therapeutic index - concentration of drug required to produce toxic effects compared with concentration required for therapeutic effects Population therapeutic window  –  concentrations at which the likelihood of efficacy is high and probability of adverse effects is low -   complemented by monitoring appropriate clinical and surrogate markers for drug effect(s) Drug Interactions and Combination Therapy   Drug interactions may be: -   pharmacokinetic  –  delivery of drug to site of action is altered -   Pharmacodynamic  –  response of the drug target is modified by second drug Combination therapy  –  optimal treatment of many conditions -   Some combinations cause adverse effects: o   Nitrovasodilators  –  vasodilation via NO-dependent elevation of cGMP o   Sildenafil, tadalfil, vardenafil  –  result from inhibition of PDE5 that hydrolyzes CGMP to 5GMP o   Coadministration  –  severe hypotension Warfarin  –  narrow margin between inhibition of clot formation and bleeding complication -   Alterations in dietary vitamin K may affect pharmacodynamics o   Antibiotics that alter intestinal flora    ↓  Vit K   increased effect of warfarin -   NSAIDS - ↑  risk of GI bleeding -   Aspirin  –  increases incidence of bleeding MECHANISM OF DRUG ACTION RECEPTORS THAT AFFECT CONCENTRATIONS OF ENDOGENOUS LIGANDS a-methyltyrosine, cocaine, emphetamine, selegiline  –  acts on adrenergic neurotransmission Vasoactive peptides, lipid-derived autocoids  –  affects synthesis and degradation of circulating mediators DRUG RECEPTORS ASSOCIATED WITH EXTRACELLULAR PROCESSES Many widely used drugs target enzymes and molecules that control extracellular processes: -   Thrombosis, inflammation, immune response -   Coagulation system RECEPTORS UTILIZED BY ANTI-INFECTIVE AGENTS Anti-infective agents target receptors that are microbial proteins -   Key enzymes required by infectious agent but not critical for the host Novel approach  –  genetically engineer vector organism to be resistant to infection (such as CRISPR-Cas9 System) RECEPTORS THAT REGULATE IONIC MILLIEU Receptors are ion pumps expressed only in specialized cells Most diuretics  –  directly affects ion pumps and transporters Esomeprazole  –  H-K ATPAse pump inhibitor in gastric parietal cell -   Reduces gastric secretion by 80-95% INTRACELLULAR PATHWAYS ACTIVATED BY PHYSIOLOGICAL RECEPTORS Signal Transduction Pathways  Largest number of drug receptors are physiological receptors that transduce signals; two major functions: -   Ligand binding -   Message propagation Two functional domains within receptor: -   Ligand binding domain (LBD) -   Effector domain Regulatory actions of receptors may be exerted on: -   Cell target -   Effector protein -   Transducers  –  intermediary cell signaling molecules Second messenger  –  cellular effector protein that is not the ultimate physiologic target -   Convey information and integrate multiple signals Compartmentation  –  constrained diffusion and intracellular actions -   Selective localization of complexes Scaffolds or anchoring proteins  –  proteins designed to localize signaling pathways  CHAPTER 3  –  PHARMACODYNAMICS 4 ©RAT STRUCTURAL AND FUNCTIONAL FAMILIES OF PHYSIOLOGICAL RECEPTORS Receptors for physiological regulatory molecules  –  assigned to functional families that share common mechanisms G Protein-Coupled Receptors  GPCR  –  seven a-helices -   Important regulators of nerve activity in CNS -   Receptors for NTs in the peripheral autonomic NS GPCR subtypes A1, a2, B adrenergic receptors differ in: -   Ligand selectivity -   Coupling to G proteins Terbutaline  –  B2 adrenergic receptor agonist -   Bronchodilator in the treatment of asthma Use of B1-selective antagonist  –  minimizes bronchoconstriction in patients treated for hypertension or angina Receptor dimerization  GPCRS undergo both homo and heterodimerization -   Dimerization  –  regulatesL o   affinity and specificity of G proteins o   sensitivity of receptors to phosphorylation o   binding of arrestin G Proteins  G proteins  –  signal transducers; heterotrimer consisting of: -   a subunit  –  confers specific recognition -   B and Y subunit  –  confer membrane localization by prenylation of Y subunit In the basal state  –   α  subunit is bound to GDP a subunit has 4 families -   Gas  –  activates AC -   Gai  –  inhibits AC -   Gaq  –  activates all forms of PLC β  -   G12/13  –  couple to GEFS (p115RhoGEF for small GTP-binding proteins Rho and Rac) K and Ca channels, P13K  –  some of the effectors of free By dimer Endocytosis of GPCRS in cAMP signaling   prolong signaling and lend “spatial coding” to distal signaling   Second-Messenger Systems Cyclic amp  –  synthesized by AC; mediated by Gas and inhibited by Gia AC has three major targets in most cells: PKA, GEFS termed EPACS, and CREB -   CNG, HCN, cyclic nucleotide regulated PDEs  –  targets in cells w/ specialized function PKA  –  two catalytic (C) subunits reversibly bound to regulatory (R) to form R2C2 -   4 cAMP bind to R2C2   2 per R subunit   R has lower affinity for C   Active C subunits  –  phosphorylate serine and threonine residues -   Isoforms o   a and B isoforms of regulatory subunit o   3 C subunit isoforms  –  Ca, CB, and CY -   Modulated by localization mediated by AKAPs
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