Pharmacodynamics Class Notes PDF

11/6/24 INTRODUCTION TO PHARMACOLOGY: PHARMACODYNAMICS KELLY ELMORE, DNP, APRN-CRNA MARY BALDWIN UNIVERSITY NAP ADVANCED PHARMACOLOGY FOR ANESTHESIOLOGY PRACTICE I SPRING SEMESTER 1 PHARMACOLOGY Goal: prevent, cure, control disease Anesthesi...

11/6/24 INTRODUCTION TO PHARMACOLOGY: PHARMACODYNAMICS KELLY ELMORE, DNP, APRN-CRNA MARY BALDWIN UNIVERSITY NAP ADVANCED PHARMACOLOGY FOR ANESTHESIOLOGY PRACTICE I SPRING SEMESTER 1 PHARMACOLOGY Goal: prevent, cure, control disease Anesthesia: Response to changes in physiologic status Sedation, general anesthesia, amnesia Treat pain Relaxation Prevent complications Safety 2 1  11/6/24 PHARMACOLOGY PharmacoKINETICS PharmacoDYNAMICS Study of what a Study of what the body does to a drug __________________________________________ Relationship between dose and plasma Relationship between effect site concentration and clinical effects concentrations PharmacoBIOPHASICS Affected by drug absorption, ○ Specific area or effect site (biophase) distribution, metabolism, elimination where drug engages with receptor for clinical effect 3 PHARMACOLOGY 4 2  11/6/24 PHYSIOLOGY REVIEW 5 A & P Review Answer The cell membrane is a ________________ bilayer The cell membrane is mostly impermeable to ________ – soluble substances such as ions and glucose Structurally, ion channels, receptors and enzymes are ________________ Oxygen and carbon dioxide move through cell membranes via this mechanism. The sodium-potassium ATPase (pump) moves __(how many?)__ Na ions __(in/out)__ and ___(how many?)___ K ions __(in/out)__ Ion channels transport charged ions across cell membranes causing conduction of electrical signals, known as ____________ _____________ The endoplasmic reticulum makes proteins, lipids and metabolizes carbohydrates. The sarcoplasmic reticulum in the muscle stores and releases what important 2nd messenger? 6 3  11/6/24 THE ACTION POTENTIAL 7 NEURONAL ACTION POTENTIAL Resting membrane potential (slightly polarized) at -70 mV ICF relatively ________________ compared to ECF 8 4  11/6/24 NEURONAL ACTION POTENTIAL Stimulus (e.g., change in nearby membrane potential) initiates process Threshold at –55mV when Na+ voltage-gated channels open ________________________________ 9 NEURONAL ACTION POTENTIAL Membrane potential at +30mV, time-bound Na+ channels close = inactivation K+ voltage-gated channels open as delayed response to original stimulus ________________________________ 10 5  11/6/24 NEURONAL ACTION POTENTIAL Na+/K+ ATPase active K+ channels are slow to close transport of ions _______________________________ RESTING MEMBRANE POTENTIAL 11 ACTION POTENTIAL ABNORMALITIES Calcium Hypocalcemia – prevents Na+ channels from closing between APs ○ Sustained __________________________________ (repetitive fire; e.g., tetany) Hypercalcemia – decreases cell membrane permeability to Na ○ Decreased excitability of membrane 12 6  11/6/24 ACTION POTENTIAL ABNORMALITIES Potassium Hypokalemia – more negative RMP ○ _____________________________________, decreased membrane excitability (e.g., skeletal muscle weakness) Sodium Sodium channel blockade, prevents threshold potential for AP generation (e.g., decreased contractility, altered cardiac conduction) 13 THE SYNAPSE AP from pre-synaptic membrane to post-synaptic membrane across cleft Pre-synaptic membrane Vesicles with neurotransmitter Reuptake pump Voltage-gated ca channels Receives afferent action potential https://www.dana.org/article/qa-neurotransmission-the-synapse/ 14 7  11/6/24 THE SYNAPSE Post-synaptic membrane NT binds receptors Efferent action potential Receptors & structural proteins maintain synaptic homeostasis = postsynaptic density https://www.dana.org/article/qa-neurotransmission-the-synapse/ 15 THE SYNAPSE 16 8  11/6/24 THE SYNAPSE Modulation Change in synaptic function Synaptic signaling, membrane potentials influence depolarization & stimulus response Delay 0.3 - 0.5 ms → NT release, diffusion, binding, ion flow Fatigue Repetitive stimulation of excitatory synapses Reduced post-synaptic response May also be related to depletion of NT stores 17 THE SYNAPSE Post-Tetanic Facilitation Repetitive stimulation of presynaptic terminal Short rest period Synapse _____________________________________ than normal to subsequent stimulation 18 9  11/6/24 THE SYNAPSE Neuronal Responsiveness Changes in pH ○ Alkalosis - increased excitability ○ Acidosis - __________________________________ Changes in PaO2 ○ Hypoxia - decreased excitability 19 RECEPTOR PHARMACOLOGY 20 10  11/6/24 CELL MEMBRANE LIPID BILAYER 21 THE RECEPTOR Protein (or other substance) that binds to an endogenous chemical or drug Properties Sensitivity: concentration required for cellular response Selectivity: structurally compatible, similar chemically Specificity: cellularly-determined response Spectrum of weak à strong bonds formed Locations Membrane (inside, surface of ion channel) Intracellular 22 11  11/6/24 THE RECEPTOR Administration → onset Molecular orientation and receptor attachment Hydrophobic bonding Conformational change Cellular, tissue response 23 THE RECEPTOR Acceptors Endogenous proteins act as alternative drug-binding sites Reduces amount of free drug available Albumin, alpha1-acid GP, beta-globulin 24 12  11/6/24 25 CHEMISTRY APPLICATION 26 13  11/6/24 CHEMISTRY APPLICATION 27 CHEMISTRY APPLICATION 28 14  11/6/24 CHEMISTRY APPLICATION 29 STEREOCHEMISTRY & CHIRALITY Stereochemistry: 3-D molecular structure Chirality: molecules with 3-D asymmetry Enantiomers: mirror imaged molecules which cannot be superimposed 2 enantiomers in equal proportion (50:50) = ___________________ 30 15  11/6/24 STEREOCHEMISTRY & CHIRALITY Isomers Drug properties often depend on stereochemistry Sinister (S) and rectus (R) isomers 31 RECEPTOR STATES Varying receptor conformations (shapes) +/- change with ligand binding +/- pharmacologic effect Active vs Inactive (vs Open) 32 16  11/6/24 RECEPTOR ACTIONS Receptors receive and transduce signals following binding of a ligand Signal _____________________________________ Chemical messengers – cause cellular/tissue response Sends the signal onward Signal amplified Increased cellular response to ligand binding Signal integrated Signal merges with another biochemical pathway https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of- cell-signaling/a/signal-perception 33 RECEPTOR TYPES G-protein coupled receptor Series of intracellular signaling and functions Ligand-gated ion channel Activated by binding of chemical messenger, causing ion movement across membranes Voltage-gated ion channel Activated by changes in electrical membrane potential, causing ion movement 34 17  11/6/24 RECEPTOR TYPES Kinase-linked receptor Series of intracellular signaling and other events such as enzymatic functions Nuclear receptors Sense hormones, other molecules and can regulate genetic expression 35 G PROTEIN-COUPLED RECEPTOR 3 components Receptor protein, G proteins (e.g., α, β), Effector mechanism Activation Extracellular ligand Conformational change GDP → GTP GPRO, 2nd messenger activation Interaction with other intracellular proteins 36 18  11/6/24 G PROTEIN-COUPLED RECEPTOR Effects Activation/stimulation Inhibition/depression Enzyme, ion, or other target 37 ION CHANNELS Ions flow in favor of concentration gradient Na+, Ca2+, Cl- into cells K+ out Na, Ca channels are 'depolarizing' or _______________________________ Cl, K channels are 'hyperpolarizing' or _______________________________ 38 19  11/6/24 ION CHANNELS Activation Membrane depolarization, ligand binding, GPRO activation __________________________________________________________ Channel opens Ion flow 39 LIGAND-GATED ION CHANNELS Fast synaptic transmission between excitable cells Binds ligand (signaling molecule) Conformational change to open (or rarely, close) channel Increased membrane permeability of ion 40 20  11/6/24 LIGAND-GATED ION CHANNELS 41 VOLTAGE-GATED ION CHANNELS Open, close in response to voltage change across membrane Neurons, skeletal muscles, endocrine cells Named for ion which passes through Example: local anesthetic blockade of sodium channels 42 21  11/6/24 CELLULAR RESPONSE Genetic expression Produce some functional product such as a protein Cellular metabolism Enzymatic cells become more or less active Cellular change (from altered molecular activity) Cell migration Cellular function or identity change Apoptosis 43 CELLULAR RESPONSE Variety of possibilities! Increased activity of the system (e.g., propofol & GABA) Decreased activity of the system (e.g., ketamine & NMDA) Chain reaction (e.g., morphine's downstream effect on adenyl cyclase activity in the cell) 44 22  11/6/24 CELLULAR RESPONSE - HOMEOSTASIS Receptor _______regulation Increased number of receptors and _____________________ to agonists Response to specific stimuli (i.e., too little agonist) Goal to increase cellular response 45 CELLULAR RESPONSE - HOMEOSTASIS Receptor ____________regulation Decreased number and sensitivity (physiologic response) of receptors Response to specific stimuli (i.e., excess circulating catecholamines and beta receptors) Goal to __________________________________________________ 46 23  11/6/24 47 DOSE-RESPONSE & RECEPTOR INTERACTION 48 24  11/6/24 DRUG DOSE RESPONSE Dose recommendations based on mean therapeutics in normal, healthy population Individualized therapy required Titration until desired therapeutic response Average drug response Subject variability within a population Consider adverse response 49 GRADED DOSE RESPONSE Change in response with increased dosage Determination of dose which achieves maximal response (plateau) Determination of number of receptors bound before effect occurs (slope) 50 25  11/6/24 QUANTAL DOSE RESPONSE Frequency with which given drug dose produces desired therapeutic response in a population “All-or-nothing” threshold responses Identify effective, toxic, lethal doses and safety margins 51 POTENCY VS. EFFICACY 52 26  11/6/24 POTENCY 53 RECEPTOR PHARMACOLOGY Agonist Antagonist Partial agonist Inverse agonist 54 27  11/6/24 AGONISTS Ionic, hydrogen, London forces Reversible bonding Rare covalent bonding (irreversible) Magnitude of effect related to total number of receptors occupied 55 AGONISTS Receptor ______________________________________ Full agonist produces maximal response from receptor ____________________________________ efficacy! Continuous administration may cause down-regulation of target receptors e.g., Propofol, Fentanyl 56 28  11/6/24 PARTIAL AGONISTS Also known as: agonist-antagonist, mixed agonist-antagonist _____________________________________ receptor ACTIVATION Partial cellular response ____________________________________________ efficacy! 57 PARTIAL AGONISTS Ceiling effect Cannot cause full agonist effect May block effects of full agonist by competing for binding sites Partial opioid agonist to opioid-dependent patient may produce withdrawal symptoms e.g., buprenorphine 58 29  11/6/24 ANTAGONISTS Ionic, hydrogen, and London (Van der Waals) interactions Reversible bonding Block agonist binding Competitive: increased levels of agonist will reverse the antagonism Non-competitive: increased levels of the agonist will not overcome antagonism 59 ADDITION OF AN ANTAGONIST https://www.sciencedirect.com/topics/medicine-and-dentistry/irreversible-antagonist 60 30  11/6/24 ANTAGONISTS _______________________ receptor ACTIVATION No clinical response No efficacy! Continuous administration may cause up-regulation of target receptors e.g., naloxone, flumazenil, vecuronium (competitive with ACh), aspirin (noncompetitive) 61 INVERSE AGONISTS Receptor must have 'constitutive' or an intrinsic (basal) level of activity without any ligand bound to it Inverse agonists 'turn off' this basal activity Binds same receptor as agonist May be blocked by an antagonist __________________________________________ effect of an agonist Negative efficacy! e.g., carvedilol and propranolol (decrease cAMP), antihistamines, naloxone 62 31  11/6/24 ALLOSTERIC MODULATOR Bind a specific allosteric site on the receptor Allosteric = binds to site other than the activating site Do NOT bind the normal agonist site ___________________ the effect of the AGONIST e.g., benzodiazepines 63 DRUG INTERACTIONS Additive effect: clinical response is result of the sum effect of two different drugs given together Antagonistic effect: the effect of one drug prevents or blocks the clinical response of a different drug 64 32  11/6/24 DRUG INTERACTIONS ___________________________________ effect: clinical response is greater than the sum effect of two different drugs given together Potentiation: the effect of one drug is enhanced by a different drug (usually work on different receptors or sites) 65 TACHYPHYLAXIS Progressive decreases in response (efficacy) to a given dose following repeated drug administration ○ ? pharmacokinetic mechanisms – decline in concentrations at target tissues ○ ? pharmacodynamic mechanisms – acute tissue or receptor changes may affect efficacy ○ Local anesthetics, antidepressants, vasopressors (e.g., ephedrine, phenylephrine) 66 33  11/6/24 QUICK REVIEW Which drug is closer to reaching the LD50? On which axis would you find the C50? Which drug is the antagonist? Which drug is more potent? Which axis represents the ability of a drug to produce a clinical response? 67 TRICK(!) REVIEW Which molecule is one half of a racemic mixture? 68 34  11/6/24 MEMORYMASTER KNOWLEDGE CHECK Where is potency depicted on a dose-response curve? How are drug potency and receptor affinity related? Valley Anesthesia.(2023). M em ory M aster: Q uestions and answ ers for the student nurse anesthetist (33rd ed.). P.109 69 MEMORYMASTER KNOWLEDGE CHECK How does a dose-response curve shift for highly potent drugs? What does the slope of a dose-response curve represent? Valley Anesthesia.(2023). M em ory M aster: Q uestions and answ ers for the student nurse anesthetist (33rd ed.). P.109 70 35  11/6/24 MEMORYMASTER KNOWLEDGE CHECK What is efficacy and what part of the dose-response curve reflects this? What is LD50/ED50? Valley Anesthesia.(2023). M em ory M aster: Q uestions and answ ers for the student nurse anesthetist (33rd ed.). P.109 71 MEMORYMASTER KNOWLEDGE CHECK How does a competitive antagonist alter the dose-response curve of an agonist? How does a noncompetitive antagonist alter the dose-response curve of an agonist? What is tachyphylaxis? Valley Anesthesia.(2023). M em ory M aster: Q uestions and answ ers for the student nurse anesthetist (33rd ed.). P.109 72 36  11/6/24 PHARMACOGENETICS & POPULATION VARIABILITY 73 PHARMACOGENETICS Genetically determined variations in response to drugs Pharmacokinetic & dynamic processes e.g., metabolism, interactions, response at target sites Variations in genes may affect response Drug and dosing accuracy, avoid adverse effects 74 37  11/6/24 PHARMACOGENOMICS Variations in genome dictate a specific patient’s response to drugs Identification of response at the level of disease, drug metabolism, drug target DNA sequencing and gene mapping Evidence-based strategy à precision medicine 75 POPULATION VARIABILITY Dosing therapeutics → ”normal” population Population subsets Pediatric, neonatal Obstetric Geriatric Higher BMI Chronic disease Major influences: age, sex, weight, body surface area, metabolic rate, pathologic state, genetics… 76 38  11/6/24 POLYMORPHISMS DNA sequence variation SNPs = one nucleotide exchanged for another in a given position Function or amount of target proteins in biochemical drug pathways CYP450 isoenzymes CYP2D6 – variable enzymatic activity Most occur in genes for metabolizing enzymes Also – enzyme receptor genes, drug transporter genes Variability in absorption, distribution, metabolism, excretion** 77 INDIVIDUAL DRUG RESPONSE - PHARMACODYNAMICS Affects efficacy Genetic-based Rx algorithms Clopidogrel, warfarin Beta blockers, ACE-inhibitors Statins Treatment advances Psychiatric medications ECT 78 39  11/6/24 See the Population OLDER ADULT/GERIATRIC Variability Spotlight!! Decreased _________________________________ Increased fraction of free, unbound, pharmacologically active drug Decreased total body water Decreased volume of distribution for water-soluble drugs Polypharmacy risks 79 OLDER ADULT/GERIATRIC Cellular alterations Age-related changes at receptor level (dose-related adverse effects) Altered cellular responses to drugs Alterations in homeostasis Increased adipose tissue Expanded volume of distribution & accumulation of lipid soluble drugs Decreased muscle mass Limited reservoir capacity 80 40  11/6/24 OLDER ADULT/GERIATRIC Neurophysiology Blood-brain barrier changes Neurotransmitter-receptor alterations Risk for neuroinflammatory response with surgical trauma Increased CNS sensitivity (esp. anesthetics, opioids) High risk for postoperative cognitive decline, delirium _________________________ risk of postoperative nausea & vomiting 81 OLDER ADULT/GERIATRIC Cardiovascular Arrhythmias, reduced cardiac function may affect distribution & response to cardiac drugs Catecholamine receptor down-regulation with age ____________________________________________________ (vessels) reduces response to vasoactive drugs 82 41  11/6/24 OLDER ADULT/GERIATRIC Cardiovascular Reduced or exaggerated (altered) responses to cardiac drugs Reduced response to vascular active medications Some volatile and intravenous anesthetics à myocardial depression, vascular and baroreceptor dysfunction 83 OLDER ADULT/GERIATRIC Respiratory Increased stiffness in chest wall Decline in gas exchange efficiency Higher sensitivity to drug-induced respiratory depression Diminished sensitivity to protective airway reflexes – affects anesthetics 84 42  11/6/24 OLDER ADULT/GERIATRIC Hepatorenal Reduced renal mass, glomerular filtration Impaired excretion and drug elimination Hepatic impairments, decreased blood flow Decreased metabolism of drugs with high hepatic extraction ratios Risks of __________________________________________________ 85 PEDIATRIC/NEONATAL Increased total body water Less circulating plasma proteins in the neonate (peak at 6 months) with decreased binding capacity Dilutional effect Lower plasma concentrations of water-soluble drugs Higher doses per kilogram weight of many drugs required 86 43  11/6/24 PEDIATRIC/NEONATAL Gradual increases & decreases in body fat Increases in neonate until about 6 months Gradual decrease in body fat in children Larger volume of distribution of lipophilic drugs in infants compared to older children Higher plasma concentration of lipid soluble drugs compared to adults 87 PEDIATRIC/NEONATAL Thermoregulation _____________________________________________________________ Limited thermogenesis & unstable thermoregulation Accelerated heat loss – esp. under general anesthesia May delay anesthesia emergence, affect metabolism of some drugs Musculoskeletal Gradual increase in muscle mass – limited reservoir capacity Immature neuromuscular junction – more sensitive to effects of muscle relaxants* 88 44  11/6/24 PEDIATRIC/NEONATAL Neuro (neonatal) Incomplete myelination, diminished nerve conduction Immature blood brain barrier Rapid transmission of nociceptive input (short distances) Sucrose, suckling as analgesics Rapidly maturing CNS 89 PEDIATRIC/NEONATAL Neurological/CNS Risk for prolonged CNS effects of opioids and anesthetics Highest inhalation anesthetic requirements at 6 months, then decreases with age Increased risk for postoperative nausea & vomiting Questionable long-term effects of inhaled anesthetics on the developing brain 90 45  11/6/24 PEDIATRIC/NEONATAL Cardiac Maturing contractile elements, less compliant myocardium Cardiac output dependent on _____________________________________ Drug-induced myocardial depression, bradycardia can be detrimental 91 PEDIATRIC/NEONATAL Respiratory Increased O2 demand ________________________________ the adult alveolar minute ventilation Affects induction and emergence from anesthesia with inhaled agents Higher sensitivity to drug-induced respiratory depression in neonates 92 46  11/6/24 PEDIATRIC/NEONATAL Renal Immature renal function in neonates & infants Gradually increasing glomerular filtration, renal clearance Reduced urine pH in infants Metabolism limitations may lead to reliance on kidneys to excrete Reduced renal excretion of unchanged drugs (neonates) 93 PEDIATRIC/NEONATAL Hepatic Immature hepatic function in neonates Gradually increasing hepatic enzyme expression & capacity Increased liver blood flow in younger peds Increased hepatic drug clearance Possible alteration in metabolism & production of metabolites 94 47  11/6/24 PEDIATRIC/NEONATAL Gastrointestinal Higher gastric pH in neonate with gradual decline Prolonged gastric emptying & decreased intestinal motility _______________________ drug absorption in neonates & infants Gut bacteria may metabolize drugs and reduce absorption 95 OBSTETRIC Increased total body water Decreased plasma proteins (albumin) Dilutional effect Lower plasma concentrations of water soluble drugs Increased fraction of free, unbound, pharmacologically active drugs _____________________________________________________ Larger volume of distribution for lipophilic drugs 96 48  11/6/24 OBSTETRIC Neuromuscular Altered and increased nerve sensitivity Distended epidural veins, decreased epidural and subarachnoid space, decreased CSF volume affect distribution Increased sensitivity to local anesthetics 97 OBSTETRIC Neuromuscular __________________________________________ decreases anesthetic requirements Systemic opioids cross placenta – may cause fetal effects Increased sensitivity to general anesthetics Greater risk of awareness 98 49  11/6/24 OBSTETRIC Cardiovascular Increased blood volume ______________________________________ cardiac output 35 – 50% above baseline during pregnancy 80% immediately post-delivery Dilutional anemia (lower RBC increase relative to plasma) Decreased SVR 99 OBSTETRIC Cardiovascular Altered response to cardiac and vasoactive drugs Greater sensitivity to cardiovascular effects of neuraxial anesthesia Low molecular weight, lipid soluble, unionized, unbound drugs diffuse into fetal circulation easily Plasma drug dilution and acid-base balance minimizes fetal effects 100 50  11/6/24 OBSTETRIC Respiratory Increased O2 consumption at term Increased minute ventilation at term (50%) and delivery (up to 300%) Higher minute ventilation affects induction & emergence of anesthesia with inhaled agents 101 OBSTETRIC Renal Increased renal blood flow and glomerular filtration Dose adjustments may be required for renally eliminated drugs Hemodilution & physiologic anemia 102 51  11/6/24 OBSTETRIC Hepatic Altered hepatic enzyme activity Increased 2D6, 3A4 Decreased cholinesterase Alterations in drug metabolism and duration of action 103 OBSTETRIC Gastrointestinal _________________________________________________ Delayed gastric emptying, decreased GI motility Higher risk nausea/vomiting, regurgitation, aspiration 104 52  11/6/24 SEX-DEPENDENT DIFFERENCES Hormonal differences Differences in muscle mass, body composition Differences in organ blood flow Differences in organ function, enzymatic differences 105 SEX-DEPENDENT DIFFERENCES Pharmacodynamics/drug response Anesthetic considerations Muscle relaxants Propofol Opioids Emergence 106 53  11/6/24 REFERENCES 107 54