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57 Cards in this Set
- Front
- Back
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Define pharmacodynamics
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“Study of intrinsic sensitivity of receptors to a drug and the mechanisms by which these effects occur”
THE ACTIONS OF THE DRUG ON THE BODY |
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How do most drugs behave to cause their effect?
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Most drugs must bind to receptor to cause effect
Drug binding only first step |
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What are the 2 types of drug-receptor interactions?
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Agonist:
Drugs bind and activate receptor Directly (opens channel) or indirectly (linked to coupling or effector molecule) brings about effect Antagonist: Binds and prevents binding by other molecules |
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Duration of a drug depends on when it is terminated.
Termination of drug action at the receptor level results from what? |
1. dissociation of drug from the recepetor
2. inactiviation of coupling molecule 3. Destruction of drug-receptor complex and formation of new receptor (covalent bonding) 4. Desensitization |
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What is the most important mechanism by which drugs exert their pharmacologic effects?
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By the interaction of the drug with a specific protient molecule in the lipid bilayer of cell membranes. This transmembrane macromolecule is a receptor.
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What are receptors?
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They are excitable transmembrane protiens that are responsible for transduction of biologic signals
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What are examples of receptors?
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voltage sensitive ion channels
ligand-gated ion channels transmembrane receptors |
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Inactivation of coupling molecule...explain
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Activated by drug on receptor
Effect of drug may continue after drug is dissociated from receptor |
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What does desensitization mean..how does it work?
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Prevents receptor-effector system from becoming overactivated when exposed to drug for long time
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What do receptors do?
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Must be selective in choosing ligand
Must change its function upon binding in way that alters function of tissue or cell |
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In order for a drug to interact with it’s receptor, a drug must have the appropriate what???
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Size
Electrical Charge Shape Atomic composition |
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What other properties must drugs have?
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Drug must have necessary properties to be transported from its site of administration to its site of action.
Drug should be inactivated or excreted from the body at a reasonable rate so its actions will be of appropriate duration |
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Why do we care about receptors?
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Central focus of pharmacodynamics
Receptor concept important for arriving at therapeutic decisions in clinical practice Determine relationship between dose (concentration) of drug and its effect Responsible for selectivity of drug action Mediate actions of agonists and antagonists |
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To be a receptor in the body, the endogenous molecule must be:
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1) Selective in choosing ligands (drug molecules) to bind
2) Must change its function upon binding so that the function of the biologic system (cell, tissues, etc..) is altered |
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What about the inert binding site?
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Inert binding site
Ex: Plasma albumin - endogenous molecule that can bind a drug molecule, however, will result in no change of biologic function Significance of binding- will affect distribution of drug in the body |
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What are some features of receptors?
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Protein – lipoprotein or glycoprotein
Subunits – subtypes depend on tissue Specificity of binding not absolute – drug may bind to several types of receptors Saturable – finite number of receptors Specific binding of receptor results in signal transduction to intracellular site May require more than one drug molecule to bind to receptor to generate signal |
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More features of receptors?
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Magnitude of signal depends on degree of binding to each site
Drugs can enhance, diminish, or block generation or transmission of signal by binding to receptor Drugs are receptor modulators – do not confer new properties on cells or tissues Receptors must have properties of recognition and transduction Can be up- or down-regulated |
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What is the relationship between drug dosage and response?
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Response usually increases as dose increases
As dose increases, response increment decreases (less response as dose goes up) End-point reached where no further increase in response is seen Occurs as receptors are occupied – maximum effect of drug Can be described by hyperbolic curve |
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Describe the dose concentration-effect curve
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Drug concentration-effect curve
Emax – maximal response that can be produced by the drug EC50 – conc. of drug that produces 50% of maximal effect Responses to low doses of a drug usually in direct prop. to dose As a dose ‘s, it reaches a point at which no in response can be achieved At a low concentration, effect is changing rapidly At a high concentration, effect is changing slowly |
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What is the first step in causing an effect of a drug?
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Coupling of agonist drug to receptor first step in causing effect
Full agonist binds to most receptors and activates them Partial agonist activates only fraction of occupied receptors |
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How is the efficiency of coupling determined?
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Initial conformational change
Biochemical events that transduce receptor occupancy into cellular response Effects of full agonist more efficient than partial agonist |
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What do receptor antagonists do?
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They bind to receptors without activating them
Main effect – prevent agonists (other drugs or endogenous regulatory molecules) from binding and activating Classified as competitive or irreversible antagonists |
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How do competitive antagonists work?
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Said to produce competitive blockade if inhibition can be overcome by increased concentration of agonist (NDMRs)
Progressively inhibit agonist response The degree of inhibition produced by a competitive antagonist depends upon the concentration of antagonist High concentrations prevent response completely Higher concentrations of agonist are required to produce the same effect of agonist alone |
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How do irreversible antagonists work?
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Binds covalently to receptor
Duration of action more dependent upon the rate of turnover of receptor molecules Affinity for receptor so high that receptor unavailable for binding of agonist Covalent bond may be formed Phenoxybenzamine (α-antagonist used to control HTN in pheo) forms covalent bond with α-receptors Effects last for about 48 hours Treatment of overdose is giving vasopressor that doesn’t act via α-receptors |
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What do chemical antagonists do?
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Do not require a receptor
One drug may bind to another drug and inactivate the drug and it’s actions Ex: Protamine (+ charge) will counteract effects of Heparin (- charge) |
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What are the 2 types of agonists?
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1. Full agonists
2. Partial agonists Fails to produce maximal effects even if all receptor sites are occupied. Unable to cause maximum response even at high concentrations – decreased affinity for receptors compared to full agonists Ex: Stadol® (butorphanol) μ antagonist (lowers addiction) and k agonist (analgesic effect) Weak partial agonists can seem to be like competitive antagonists |
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Name the 5 basic transmembrane signaling mechanisms
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1. Lipid soluble ligand crosses membrane to act on intracellular receptor
2. Ligand binds to extracellular receptor site to activate intracellular enzymatic activity on intracellular site 3. Ligand binds to extracellular receptor site to cause activation of tyrosine kinase that’s released from intracellular side. 4. Ligand binds to and regulates opening of ion channel (ligand-gated channel) 5. Ligand binds to cell-surface receptor causing activation of G protein and regulation of intracellular second messenger |
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Describe how the Receptor Tyrosine-Kinase Pathway works
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Ligand binds with receptors
Conformational change in receptor Converts from inactive monomeric state to active dimeric state when they bind with each other in membrane Intracellular receptors brought together causing activation of tyrosine kinase Acts as enzyme to bring about intracellular change Insulin and atrial natriuretic peptide (ANP) exert effect by this method |
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Describe the ligand-gated ion channel
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Ligand binds to and directly regulates the opening and closing of a transmembrane ion channel
Many drugs block or mimic action of endogenous ligands on ion channels |
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What are likely the most importan class of receptors in pharmacology?
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G-protein coupled receptors, because most currently marketed drugs target this receptor.
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Describe G-protein-coupled receptors and the 2nd messenger system
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Ligand (drug) binds to extracellular surface of receptor
Intracellular surface triggers activation of G protein G protein changes activity of enzyme or ion channel (adenylyl cyclase for cAMP) This activation causes change in concentration of intracellular second messenger G-protein receptors described as serpentine receptors Receptor chain “snakes” through membrane seven times Agonist from extracellular fluid binds to site surrounded by transmembrane regions of receptor G-protein released Muscarinic (not nicotinic) ACh receptors |
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To choose drug and determine dose, what 2 things should you know?
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Have to know potency and maximal efficacy in relation to desired effect
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The dose response curve is characterized by what 4 things?
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Potency
Slope Efficacy Individual responses |
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Discuss potency. Where is it on the dose response curve and what things influence it?
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Potency – depicted by location on x-axis & influenced by
Absorption Distribution Metabolism Excretion Affinity for receptor |
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True or False: Increased affinity for receptor moves curve to left?
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True
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Does potency determine the dose of the drug?
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Yes. The more potent, the lower the dose
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What is the "effective dose"? Ed
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Effective dose (ED) is dose necessary to produce desired effect in a given % of patients OR given % of drugs maximal effect
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What is ED50?
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ED50 = dose required to produce desired effect in 50% of patients
ED50 = dose required to produce 50% of maximal effect (used when describing dose-response curves) |
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What does the slope of the dose response curve mean and how can it change?
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Slope – influenced by number of receptors that must be occupied to cause effect
If majority of receptors must be occupied, slope will be steep Steep curve means that small increases in dose cause intense increases in drug effect Steep curve means that difference between therapeutic and toxic concentrations will be small |
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What is the Therapeutic Index and how is it calculated?
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Therapeutic index
Relates dose of drug that produces desired effect to dose that produces undesired effects Ratio of toxic dose (TD50) to effective dose (ED50) Determine TD50 by finding dose required to produce particular toxic effect in 50% of animals studied If death occurs in study, lethal dose (LD) is defined and therapeutic index may include ratio of LD50 to ED50 If therapeutic index is small, less margin for error Small increase in effective dose can lead to toxic dose Prescription of drugs with low therapeutic index depends on gravity of disease treated |
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How can you tell a drug's efficacy on the dose-response curve?
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Efficacy – depicted by plateau & reflects drug’s maximal effect
Once maximal effect reached, increased doses do not increase effect Effectiveness of drug depends on efficacy and ability to reach receptors Side effects of drug may limit dose to less than needed for maximal effect Amount of drug to increase contractility may be limited by its propensity to cause arrhythmias |
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Can patients vary in response to the same drug?
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Yes. Same individual may have different response to same drug during course of treatment
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What is an idiosyncratic response?
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Unusual response
Usually caused by genetic difference in metabolism or immunologic mechanisms such as allergic reactions |
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Is it possible for a hypo or hyper-reactive response to occur?
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Yes
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what is Tolerance?
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Tolerance occurs when response to given dose ↓
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What is tachyphylaxis?
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Tachyphylaxis occurs when response decreases rapidly
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What factors determine the individuals response to drugs?
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Bioavailability
Renal Function Hepatic function Cardiac Function Age of patient |
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Discuss Bioavailability
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How much drug is available to receptor after administration
Absorption depends on physiochemical properties of drug |
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Why is renal function important?
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Important for elimination of unchanged drugs and metabolites
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Why is hepatic function important?
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Hepatic function
No one test to determine liver function as creatinine for kidneys Liver dysfunction leads to Altered protein binding Altered metabolization of drugs Portosystemic shunting Portal HTN → ↓ hepatic blood flow with blood shunted to systemic circulation Along with decreased enzyme activity, see more active drug |
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Why is cardiac function important in an individual's response to drugs?
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Decreased CO causes decreased hepatic blood flow
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What effect can age have on the individual's response to drugs?
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Non-uniform organ maturation in young and non-uniform deterioration in elderly lead to individual responses between groups and among members of same group
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Discuss premature infants and neonates and their specific considerations for responses to drugs
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Metabolic mechanisms poorly developed
Gastric emptying time prolonged until 6-12 months Influences onset of action of PO drugs Total body water increased in newborn – adult values at about 12 months old Renal function greatly reduced in newborn – adult values at 6-12 months |
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Discuss the elderly and their specific considerations for responses to drugs
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Decreased CO
Larger fat content and decreased total body water Increased Vd and vulnerability to cumulative drug effects Decreased protein binding Reduced renal function |
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Individual's responses to drugs are also determined by enzyme activity and genetic differences. Discuss.
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Enzyme activity
Induction from cigarette smoking, chronic alcohol or drug use Acute intoxication inhibits metabolism of drugs Genetic differences Atypical cholinesterase enzyme Malignant hyperthermia Intermittent porphyria |
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If you give drugs concurrently, what might happen to affect the individual's response?
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May see enhanced or diminished effects of one or both drugs
May reflect alterations in absorption, distribution, metabolism or clearance of one drug by another |
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What typical interactions can be anticipated?
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Competition with same plasma protein binding site
Enzyme induction or inhibition by one drug Change in rate of renal excretion from action of one drug |
