Basic Principles of Pharm 751 Canvas.pptx
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Basic Principles of Pharmacolo gy Terry C. Wicks, DNP, CRNA Traditional thinking characterized receptor states Receptor as binary: Theory Effect is produced by ligand binding Effect is absent when not bound by the ligand An agonist binds to and...
Basic Principles of Pharmacolo gy Terry C. Wicks, DNP, CRNA Traditional thinking characterized receptor states Receptor as binary: Theory Effect is produced by ligand binding Effect is absent when not bound by the ligand An agonist binds to and activates a receptor. An antagonist binds to the receptor without activating the receptor Receptors probably fluctuate between active and inactive conformations, spending various proportions of time between the two states. Ligands may alter the relative time spent in each state Competitive antagonism: increasing concentration of the antagonist Receptor progressively inhibits the response to the Theory: agonist Noncompetitive antagonism: antagonist Variations administration prevents receptor activation on the even when exposed to high concentrations of the agonist Theme Covalent bonding Allosteric inhibition Partial agonists/agonist-antagonists: activate the receptor less completely than full agonists-can reduce agonist effects. Inverse agonists “turn off” the constituent activity of the receptor Receptors: may increase (up regulate) or Receptor decrease (down regulate) in response to Basics specific stimuli May exist on the surface of a cell (membrane bound) or within cytoplasm of a cell May respond to ligand or alterations in polarity of adjacent cell membranes May either allow something into or out of a cell Cause a process to start, accelerate, decelerate, or stop a cellular activity (usually protein or enzyme mediated) Pharmacokineti cs of Injected Drugs Determines the concentration in the plasma or effect site: Absorption, distribution, metabolism and elimination… Important Hyperreactiv Cellular Terms to e tolerance Learn Hyporeactive Additive effect Hypersensiti Synergistic ve effect Tolerance Agonist Tachyphylaxi Antagonist s Distribution Initial distribution (within 1 minute) mixing within the central compartment Venous blood volume of the arm Great vessels Heart Lung Upper aorta Highly fat-soluble drugs may be vigorously taken up by the lung: Lidocaine Propranolol Opioids IV injection delivers drugs to the vessel rich Initial group (1). Distribution Highly perfused tissues Lungs, heart, brain, kidneys Non-polar molecules (lipid soluble) will be preferentially taken up by fat. High lipid solubility implies a large volume of distribution. Drug concentrations in the various compartments (2) will be reflected in the calculated volume of distribution (Vd). Pharmacologic effects may or may not reflect the current or steady state concentration in the various compartments. Acidic drugs tend to bind to albumin Protein Basic drugs tend to bind to alpha1 Binding acid glycoprotein Protein binding parallels lipid solubility (hydrophobic drugs are more likely to bind to plasma proteins or fat) Only free fractions can cross cell membranes Bound fractions are not available for hepatic extraction nor glomerular filtration Changes in plasma protein concentration will have a greater pharmacodynamic influence on highly protein bound drugs Generally, metabolism converts active lipid soluble drugs to water soluble pharmacodynamically inactive Metabolis drugs. m of Drugs Phase I reactions are mediated by CP450, and non- CP450 enzymes and mono-oxygenase enzymes. Phase I Reactions: increase drug polarity Oxidation (cytochrome P450) Reduction (cytochrome P450) Hydrolysis (non-cytochrome) Phase II Reactions: Conjugation: ties the agent to a polar compound, increasing its water solubility ability to be excreted: glucuronosyltransferase, glutathione-S-transferase, N- acetyl-transferase Hepatic microsomal enzyme activity: located in the hepatic smooth ER The rate of metabolism for most anesthetic Hepatic drugs is proportional to drug concentration Clearance To quantify the process: R = Q(Cin-Cout) Where: R = rate of clearance Q = Liver blood flow Cin = Concentration flowing into the liver Cout = Concentration flowing out of the liver If the liver could completely extract the drug from afferent flow, clearance would equal liver blood flow. Clearance Clearance is the volume of plasma cleared of a drug per unit of time. The fraction of inflowing drug extracted by the liver is the extraction ratio Cinflow-Coutflow/Cinflow For drugs with an extraction ratio of nearly one, a change in hepatic blood flow produces a nearly proportional change in clearance (flow limited) For drugs with a low extraction ratio clearance is nearly independent of the rate of liver blood flow (capacity limited) Renal Renal excretion Glomerular filtration includes:Passive tubular Active tubular secretion reabsorption Clearance GFR and protein binding determine the amount of drug entering the renal tubular lumen Renal tubular secretion is an active transport process Tubular reabsorption is generally passive and most prominent for lipid soluble drugs Initial volume of Volume of distribution = dose Distributio of drug administered/plasma n concentration prior to elimination beginning (Vdi) After achieving a steady state Vdss. Highly lipid soluble drugs have large calculated Vd. Nonionized Ionized Effects of Drug Pharmacologi cal effect Active Inactive Ionization Solubility Lipids Water Cross lipid barriers Yes No Renal excretion No Yes Hepatic metabolism Yes No Oral Routes of Oral administrati transmucosal on Transdermal Rectal Parenteral SQ IM IV # of Fraction Percent Half- remaini Eliminat Simple Times ng ed Pharmaco- 0 1 0 kinetic 1 1/2 50 Model 2 1/4 75 3 1/8 87.5 4 1/16 93.8 5 1/32 96.9 t½ alpha=distribution half time 6 1/64 98.4 t1/2 First beta=elimination Order Kineticshalf time Key Elimination half-time: Time necessary Concepts for the plasma drug concentration to decrease by 50% during the elimination phase: Directly proportional to the Vd Inversely proportional to the Cl Elimination half-life: Time to eliminate half the drug from the body after rapid IV injection. First Order v. Zero Order Kinetics Three Compartme Initially drug flows from the central compartment to the two other compartments nt Model After rapid equilibration, the concentration in the central compartment falls below that of the rapid equilibration compartment and the flow of drug is reversed When the concentration in the central compartment falls below the concentration of the other two decreases in plasma concentration are dependent on elimination Determinants of Distributio Tissue Uptake Determinants of Tissue Storage Capacity n After Blood flow Systemic Concentration Solubility Absorption gradient Tissue mass Blood brain barrier Binding to Physicochemical macromolecules properties of the pH drug: Ionization Lipid solubility Protein binding Effect-site The plasma is almost never the effect site (biophase) Equilibratio Effect-site equilibration may be short: n Remifentanil Alfentanil Thiopental propofol Effect-site equilibration may be longer: Fentanyl Sufentanil Midazolam Dosing intervals should be adjusted to reflect effect-site equilibration Context Sensitive Half-time Potency and Determinants of potency Absorption Efficacy Distribution Metabolism Excretion Receptor affinity For drugs with very different time courses the relative potency depends on the time of measurement Efficacy is a measure of the intrinsic ability to produce a given physiologic or clinical effect Dose Response Curve The ED50 is the dose Effective required to produce Dose & the desired effect in 50% of patients. Lethal Dose The LD50 is the dose required to produced death in 50% of patients (or other animals). The therapeutic index is the ratio between the LD50 and ED50 or LD50/ED50. Drug May be pharmacokinetic or pharmacodynamic Interactio Drug response may be: ns Increased Decreased Drug interactions increased with the number of drugs administered Impair absorption Compete for protein binding sites Induce or inhibit enzyme systems Alter the rate of renal excretion Stereochemistry Enantiomers are mirror images of one another. 3-dimensional asymmetry is based on the chiral center. Enantiomers often have different pharmacokinetic and pharmacodynamic properties. Presence of equal portions of S and R enantiomers are referred to as racemic mixtures. Individual Individual variability: drug response varies greatly among patients; from little or no Variability response to toxicity Pharmacokinetic variability: Bioavailability Renal function Hepatic function Cardiac function Patient age Pharmacodynamic variability Enzyme activity Genetic differences Individual Drugs excreted unchanged by the kidneys Variability tend to have smaller pharmacokinetic differences than metabolized drugs. Systemic clearance of drugs with low hepatic extraction ratios are highly susceptible to small changes in metabolic rate. Administration of inhalation agents alter hepatic, circulatory and renal function and may alter drug pharmacokinetics. Administering drugs in high doses may mask interpatient variability.
