1.1 Pharmacology- Student Review.pdf

1.1 Pharmacology- Student Review Page 1: !"Section I: Pharmacology Review #"Mechanisms of Anesthesia #"IV Sedative-Hypnotics #"Exam (20% of grade) !"Section II: Uptake and Distribution #"Inhaled Anesthetics #"Exam (20% of grade) cumulative (< 20%) !"Section III: Physiology of Pain #"Opioids #"Local...

1.1 Pharmacology- Student Review Page 1: !"Section I: Pharmacology Review #"Mechanisms of Anesthesia #"IV Sedative-Hypnotics #"Exam (20% of grade) !"Section II: Uptake and Distribution #"Inhaled Anesthetics #"Exam (20% of grade) cumulative (< 20%) !"Section III: Physiology of Pain #"Opioids #"Local Anesthetics #"Exam (20% of grade) cumulative (< 20%) !"Section IV: Neuromuscular blockers #"Exam (20%) cumulative (< 20%) !"Section V: Chemotherapy and Antibiotics #"Adjunct drugs #"Review of Organ System Effects #"Final Exam (20%) cumulative (100%) Page 3: !"GABA is the primary inhibitory neurotransmitter in the brain. #"Activation of the GABAA receptor results in influx of chloride and hyperpolarization of the cell. !"Efficacy of a drug is the maximal response when all receptor sites are occupied, and is a function of the nature of the drug as a full, partial, or inverse agonist. !"The primary mechanism of termination of action of a bolus dose of an anesthetic induction agent is redistribution to the vessel intermediate group. !"Volume of distribution is the dosage divided by the initial plasma concentration of the drug, and is a model used to explain the measured concentration in the central compartment following a given dose. It does not represent actual volume. !"Clearance of the high hepatic extraction ratio drugs is dependent on liver blood flow, while that of the low hepatic extraction ratio drugs is more dependent on enzymatic activity. Page 4: !"Glomerular filtration rate is considered the best measure of renal function, and creatinine clearance is the most reliable measure of GFR. !"The pharmacokinetics of most anesthetic drugs can be adequately described by a two or three compartment model. !"When a sedative-hypnotic drug is delivered into the central circulation, equilibration with the effect site is so rapid as to be indistinguishable from a pharmacokinetic standpoint. The lag between peak plasma concentration and peak effect (hysteresis or biophase or k) is a pharmacodynamic effect. !"The volume of distribution at time of peak effect (Vdpe) provides a more useful guideline for determining proper bolus dosing. !"The context-sensitive decrement-time provides us useful information about termination of effect following a drug infusion of a given duration. !"Wide interpatient variability exists (much of which is unpredictable) emphasizing the need to individualize drug infusion. Page 6: !"Receptor Types #"G Protein-Coupled #"Ion Channels #"Ligand-gated #"Excitatory #"Inhibitory #"Voltage-gated #"G Protein-gated #"Other-gated !"The Synapse !"Receptor Theory Page 7: !"Cell Surface Receptors #"Bind an extracellular molecule (ligand) and convert this input into a change in intracellular behavior !"Intracellular Receptors !"Examples #"Steroid receptors in nucleus regulate transcription of genes #"Cytosolic receptors of phosphodiesterase inhibitors increase cAMP concentration Page 8: !"Cell Surface Receptors #"Three types $"G protein-coupled receptors $"Largest family of receptors $"Acts through activation or inhibition of an: $"Enzyme $"Ion channel $"Other target $"Ion channel $"Ligand-gated $"Voltage-gated $"G protein-gated $"Other-gated $"Enzyme-linked transmembrane $"Typically a tyrosine kinase that phosphorylates an intracellular second messenger $"E.g. Insulin receptor increases expression of GLUT Page 9: !"G PROTEIN-COUPLED RECEPTORS #"Consists of a protein linked to 7 transmembrane spanning domains #"Coupled to specific G proteins #"There are many types of Gα,β and γ proteins #"Binding activates the Gα protein which then activates or inhibits an: $"Enzyme $"Ion channel $"Other target Page 10: !"G PROTEIN-COUPLED RECEPTORS #"Ligand binding results in a conformational change in the receptor #"Allows substitution of GTP for GDP on the Gα protein #"GTP bound Gα protein acts as a second messenger where GTP hydrolyzed back to GDP releasing energy to affect the target protein #"GDP bound Gα returns and binds to the receptor Page 11: !"Neurotransmitters and Anesthesia-Related Drugs Which Target G Protein-Coupled Receptors #"Opioids - µ receptor $"Endogenous and exogenous #"Norepinephrine $"Excitatory and inhibitory in CNS $"Descending inhibitory pathways in spinal cord $"VLPO sleep-wake cycle #"Adrenergic drugs #"Dopamine $"Primary catecholamine in CNS $"Excitatory and inhibitory #"Atropine and glycopyrollate – muscarinic Ach receptor #"Substance P $"Neurokinin-1 receptor in spinal cord #"Antihistamines $"Histamine important in TMN sleep-wake cycle #"Adenosine $"Some antiemetics $"Via dopamine and serotonin receptors Page 12: !"ION CHANNEL RECEPTORS #"Resting membrane potential ~ -70mV #"When ion channels open ions flow in or out based on their concentration gradients #"Na+, Cl-, and Ca++ have higher extracellular concentrations #"K+ has a higher intracellular concentration #"Na+ and Ca++ entry depolarizes the cell #"Cl- entry hyperpolarizes the cell #"K+ exits the cell to repolarize it following a depolarization Page 13: !"LIGAND-GATED ION CHANNELS #"Excitatory $"Glutamate receptors $"NMDA, AMPA, Kainate $"Nicotinic acetylcholine receptors $"CNS and neuromuscular junction $"Serotonin #"Inhibitory $"GABA $"Glycine Page 14: !"EXCITATORY LIGAND-GATED ION CHANNELS #"Glutamate – primary excitatory neurotransmitter in CNS $"Important in learning, memory, and central pain transduction #"Glutamate receptors $"Non-selective cation channels $"Inotropic Glutamate Receptors $"NMDA $"Associated with neuropathic pain and opioid tolerance $"Blocked by ketamine $"AMPA $"Both associated with rapid synaptic transmission, synaptic plasticity, and long-term potentiation $"Kainate $"Metabotropic Glutamate Receptors $"G protein-coupled Page 15: !"EXCITATORY LIGAND-GATED ION CHANNELS #"NAChr $"Non-selective cation channels $"Acetylcholine acts as an excitatory stimulus at CNS NAChr producing arousal $"Produces muscular contraction at the NMJ NAChr #"Serotonin $"Excitatory $"Non-selective cation channel Page 16: !"INHIBITORY LIGAND-GATED ION CHANNELS #"GABA (γ – Aminobutyric Acid) Receptor $"Primary inhibitory neurotransmitter in brain $"Composed of 5 subunits (2 α , 2 β, 1 γ) $"When two GABA molecules bind the receptor a Cl- channel opens, hyperpolarizing the cell $"Actions of IV anesthetic drugs on GABAA receptor $"Benzodiazipines $"Increase sensitivity of receptor to endogenous GABA $"Propofol, Etomidate, Thiopental $"Increase sensitivity of receptor to GABA $"At high concentrations can directly open the Cl - channel Page 17: !"INHIBITORY LIGAND-GATED ION CHANNELS #"Glycine Receptor $"Spinal cord $"Glycine is the primary inhibitory neurotransmitter $"Operates via a chloride channel #"Brain $"Glycine receptors in the brain modulated by multiple anesthetic agents, but currently no defined anesthetic effect related to this #"A couple notes: $"Absorption of glycine containing irrigant during TURP may produce a transient blindness $"Strychnine and tetanus toxin antagonize the inhibitory effect of glycine, producing activation of the EEG and potentially seizures Page 18: !"VOLTAGE-GATED ION CHANNELS #"Open in response to changes in voltage across the cell membrane #"Important function in transmission of impulses in neurons and skeletal muscle #"Typically named for the ion that traverses the channel when depolarization occurs #"Examples important in anesthesia: $"Voltage Page 19: !"G protein-gated ion channels #"Ion channels activated by a G protein-coupled receptor from the interior of the cell #"Best studied are the G protein regulated inwardly rectifying potassium channels (GIRKs) #"K+ flows with the electrical, rather than the concentration, gradient #"Activated by the Gβγ rather than Gα #"Multiple receptors coupled to GIRKs $"Muscarinic M2 in heart $"α2 adrenergic $"A1 adenosine $"D2 dopamine $"GABAB $"etc Page 20: !"Other-gated ion channels #"Many other ion channels which respond to: $"Ions $"Second messengers $"Tissue injury Page 21: !"The synapse Page 22: !"The synapse #"Synaptic modulation $"Resting postsynaptic transmembrane potential ~ -70mV in CNS $"Further modulated by postsynaptic excitatory and inhibitory potentials #"Synaptic delay $"0.3 – 0.5 millisecond consisting of: $"Neurotransmitter release $"Diffusion of NT to postsynaptic receptor $"Change in permeability and ion flux due to receptor activation #"Synaptic fatigue $"Decreased postsynaptic firing following rapid, repetitive firing $"Presumably exhaustion of NT #"Posttetanic facilitation $"Rapid firing of an excitatory stimulus followed by a rest period leads to increased response at the postsynaptic neuron #"Other factors $"Neuronal excitability increased by alkalosis $"Hypoxia decreases neuronal excitability Page 23: !"Receptor theory #"Agonists are characterized by: $"Efficacy $"Maximal response when all receptor sites are occupied $"Reflects the agonist's ability to activate the receptor $"Full agonist = high efficacy $"Partial agonist = low efficacy $"Potency $"Defined by the dose (or concentration) needed to produce a defined effect ED50 or (EC50) Page 24: !"Receptor theory #"Antagonists $"Competitive antagonist $"Binds at the orthosteric site but doesn't activate the receptor $"Binding of the agonist and competitive antagonist is mutually exclusive $"Can be overcome by large doses of agonist $"Noncompetitive antagonist $"Binds at an allosteric site $"Can bind whether the orthosteric site is bound by an agonist or not $"Agonist binding is not affected, but receptor activation is blocked $"Can not be overcome by large doses of agonist Page 25: !"Receptor theory #"Serial binding-activation vs. Allosteric receptor activation models #"Allosteric receptor activation models $"Allow for receptor activation in the absence of agonist (Constitutive activity) $"Receptors fluctuate between multiple conformations and ligand binding may favor a particular state over another $"Provide a better understanding of partial and inverse agonists #"Partial agonist $"Binds a receptor but does not favor an active state as much as the full agonist $"Even if 100% of receptors are bound, less than 100% will be in an active state #"Inverse agonist $"Binds the receptor, but favors an inactive state by binding to the inactive receptor more strongly than an active receptor Page 26: !"Receptor theory (Serial binding-activation model) #"Agonist #"Agonist + Antagonist #"R* + R* #"Bound, activated #"Bound, R receptor inactive #"Unbound, inactive #"Unbound, inactive receptor Page 27: !"Receptor theory (Allosteric receptor activation model) #"A Agonist #"B Partial agonist #"80% 20% agonist #"0% 100% #"50% 50% #"R R* R R* #"Inactive Active #"Inactive Active receptor receptor #"R R* #"C Antagonist #"D Inverse agonist #"20% 80% #"100% 0% #"Inactive Active receptor receptor #"R R* R R* #"Inactive Active #"Inactive Active receptor receptor receptor receptor Page 28: !"Receptor theory - additional concepts #"Spare receptors $"Exist in the presence of a maximal tissue response in the absence of 100% receptor binding by an agonist $"E.g. Neuromuscular transmission $"Very high density of NACHRs in critical muscles like diaphragm $"Usually only a small fraction of receptors must be activated to produce contraction $"Important in differential blockade of muscle groups with the NDPMRs #"Signal amplification $"G protein activation by the GPCRs lasts much longer than the actual binding of ligand at the receptor and may activate multiple second messengers #"Signal damping $"Diminished response to repeated drug administration $"Multiple mechanisms $"Receptor desensitization $"Downregulation $"Depletion of neurotransmitters $"Transcriptional changes Page 29: !"Pharmacokinetics #"Absorption #"Distribution #"Volume of Distribution #"Protein Binding #"Elimination $"Metabolism $"Hepatic Clearance $"Renal Clearance Page 30: !"Absorption #"Most drugs are weak acids or weak bases #"At physiologic pH they exist in non-ionized or ionized forms #"The non-ionized form can diffuse across cell membranes #"Blood-brain barrier #"Renal tubular epithelium #"GI epithelium #"Hepatocytes #"Placenta #"To render a drug more water soluble: $"Basic drugs come in an acidic solution $"Acidic drugs come in a basic solution Page 31: !"Review of pKa #"log protonated = pKa – pH unprotonated #"For a weak acid, the protonated form is non-ionized HA A- + H+ #"So, the greater the pKa than the pH, the more protonated, non-ionized form is present #"For a weak base, the protonated form is ionized HB+ B + H+ #"So, the greater the pKa than the pH, the more protonated, ionized form is present Page 32: !"pKa examples #"Local anesthetics (weak bases) $"Mepivacaine (pKa = 7.6) $"Bupivacaine (pKa = 8.1) #"Opioids (weak bases) $"Sufentanil (pKa = 8.0) $"Alfentanil (pKa = 6.5) Page 33: !"Absorption #"Lipid soluble $"Easily absorbed from the GI tract $"Pharmacologically active $"Reabsorbed in the renal tubules $"Metabolized by the liver #"Poorly lipid soluble $"Poorly absorbed from the GI tract $"Pharmacologically inactive $"Excreted by the kidneys $"Reduced hepatic metabolism Page 34: !"Absorption #"Ion trapping $"Only the non-ionized portion of drug equilibrates across a lipid membrane $"This can result in varying concentration of drug in compartments with different pHs $"Examples: $"A basic drug in the stomach becomes highly ionized and concentrated $"A basic drug which crosses the placenta in an unionized form becomes ionized in the more acidic fetal circulation $"Drug continues to cross into the fetal circulation because only the nonionized portion is equilibrating, so concentration of the drug occurs $"In a compromised (acidotic) fetus this mechanism is compounded Page 35: !"Absorption #"Routes of Administration $"Intravenous $"Absorption not really an issue $"Oral $"Principle site of absorption is small intestine due to the large surface area $"First-pass effect (GI tract portal vein liver systemic circulation) $"Oral transmucosal $"Sublingual, buccal, nasal drains to the SVC $"Bypasses the liver Page 36: !"Absorption #"Routes of Administration $"Transdermal $"Rate-limiting step is absorption through the stratum corneum, the thickness of which varies widely throughout the body $"Available in transdermal preparations $"NTG, fentanyl, scopolamine, clonidine, estrogen and progesterone $"Rectal $"Unpredictable response $"Irritation of the rectal mucosa $"Subcutaneous and intramuscular Page 37: Distribution !"Drug is distributed to various tissues relative to tissue perfusion !"Most rapid equilibration occurs in highly perfused tissues (brain, heart, lungs, kidneys) !"Less well perfused and higher volume tissues equilibrate at a slower rate (intermediate, muscle, fat, bone) Page 38: Distribution !"V1: Central compartment !"V2: Rapidly equilibrating compartment (vessel intermediate) !"V3: Slowly equilibrating compartment (vessel poor group) !"E: Effect !"k12, k21, k13, k31, k10, k1e, ke0 Page 39: Distribution (Propofol and Remifentanil) !"Propofol: V1 = 16 L, V2 = 32 L, V3 = 205 L, Cl2 = 1.8, Cl3 = 0.67, Clo = 205 L, Remifentanil: V2 = 5.1, V1 = 9.8, V3 = 5.4, Cl2 = 2.05, Cl3 = 0.077, Clo = 2.61 Page 40: Distribution (Redistribution) !"Following a bolus dose of an anesthetic induction agent, high concentrations of drug are rapidly attained in the central compartment (effect site) !"Drug is redistributed to other compartments due to blood flow, lipid solubility, and clearance !"Redistribution to other tissues, primarily muscle, is the primary mechanism of termination of action of a bolus dose of induction agent Page 41: Distribution (Redistribution) !"Drug is distributed by concentration gradients and equilibrium coefficients !"Brain concentration exceeds blood concentration, causing drug to move back into the plasma and continue being distributed to other tissues !"Accumulation of drug in adipose tissue can occur with repeated boluses or infusion of a lipid soluble drug !"Propofol has slower return of drug from fat, resulting in low brain concentration and no delayed awakening Page 42: Volume of Distribution !"Vd = Amount of drug administered / Initial drug plasma concentration !"Volume of distribution is a model to explain the concentration of drug in the central compartment (blood) !"Affinity of the drug for various tissues, mass of tissue, and volume of distribution are factors affecting drug distribution Page 43: Volume of Distribution !"Factors affecting volume of distribution include lipid solubility, protein binding, pH, actual volume change, tissue composition, age, obesity, and perfusion !"Loading dose is calculated using Vd x Target concentration Page 44: Protein Binding !"Most drugs are protein bound to some extent !"Only free drug can cross cell membranes and bind receptors !"Lipophilic drugs more avidly bind plasma proteins and lipids in fatty tissue !"IV sedative-hypnotics are generally highly protein bound Page 45: Protein Binding !"Concentration of plasma proteins can be decreased by significant hepatic disease, age, pregnancy, renal failure !"Changes in plasma protein concentrations have the greatest effect on highly protein bound drugs Page 46: Elimination !"Elimination consists of metabolism (oxidation, reduction, conjugation, hydrolysis, glucuronidation) and clearance (hepatic, renal) Page 47: Metabolism !"Cytochrome P450 enzymes are primarily located in the liver and responsible for the metabolism of the majority of drugs !"Enzyme induction or inhibition can affect drug metabolism and drug effect Page 48: Metabolism !"Phase I reactions increase drug polarity and are dependent on CYP450 enzymes (oxidation, reduction, conjugation) !"Phase II reactions increase water solubility of the drug and involve transferase enzymes (glucuronidation) Page 49: Hepatic Clearance !"Rate of metabolism in the liver is determined by the difference between the concentration entering and exiting the liver, multiplied by the blood flow through the liver !"Hepatic extraction ratio is the fraction of drug entering the liver that is removed !"Clearance is the amount of blood cleared of drug per unit time Page 50: Hepatic Clearance !"High hepatic extraction ratio (HER) drugs have high capacity for metabolism and clearance is dependent on liver blood flow !"Low HER drugs have limited capacity for metabolism and clearance is dependent on enzymatic capacity !"Enzyme induction or inhibition affects metabolism of low HER drugs more Page 51: Hepatic Extraction Ratio !"Changes in liver blood flow and enzyme activity affect hepatic extraction ratio !"Extraction ratio is higher with higher liver blood flow and enzyme activity Page 52: Hepatic Extraction Ratios of Common Drugs !"Low HER drugs: Methohexital, Metoprolol, Midazolam, Morphine, Vecuronium, Naloxone, Methadone, Phenytoin, Propranolol, Theophylline, Sufentanil, Thiopental, Lidocaine, Verapamil, Warfarin, Meperidine !"Intermediate HER drugs: Bupivacaine, Diltiazem, Lorazepam, Etomidate, Fentanyl, Ketamine !"High HER drugs: Alfentanil, Diazepam, Propofol Page 53: Renal Clearance !"Renal clearance involves glomerular filtration, tubular secretion, and tubular reabsorption !"Glomerular filtration is dependent on GFR and free fraction of drug !"Tubular secretion is an active process, while tubular reabsorption is a passive process Page 54: Renal Clearance !"GFR is considered the best measure of renal function !"Creatinine Clearance is the most reliable measure of GFR #"Calculated value: Creatinine clearance(ml/min) = (140-age) x lean body mass (kg) / Plasma creatinine(mg/dl) x 72 #"Measured value: Creatinine Clearance(ml/min) = Urinary creatinine conc. (mg/100ml) / Plasma creatinine conc. (mg/100ml) X Urine Volume(ml/min) !"Normal values: #"Female: 85 – 125 ml/min #"Male: 95 – 140 ml/min !"Decreases with age Page 55: Zero and First-Order Processes Physiologic Models !"Compartment Models #"One Compartment #"Multi Compartment !"Hysteresis – Combined PK/PD Model !"Stochastic Dosing Guidelines !"Bolus Dosing Maintenance !"Context Sensitive Decrement-time !"Target-controlled Infusions !"Closed-loop Infusions !"Response Surface Models !"PHARMACOKINETIC MODELS Page 56: Zero- and First-Order Processes !"Zero-order process #"Rate of change is constant #"A fixed amount of drug is removed per unit time dx = k dt !"First-order process #"Rate of change is proportional to the amount of drug present dx = k x dt Page 57: Physiologic Models !"Involves measurement (at multiple times) the concentration of drug in each tissue !"Complex, inefficient, and generally provide no better information than grouping tissues into hypothetical compartments !"Termination of effect of a bolus dose of anesthetic induction agents results from: #"Redistribution of drug from brain to muscle, with almost no effect from: #"Metabolism of drug #"Redistribution to the vessel-poor tissues Page 58: Compartment Models !"Group the individual organs of the physiologic models into compartments based on perfusion !"The pharmacokinetics of most anesthetic drugs can be adequately described by a two or three compartment model !"Assumptions: #"Clearance only occurs from the central compartment #"Distribution and elimination of the drug is a linear, first-order process #"Time invariant Page 59: Two Compartment Model !"Dose A+B !"Cp(t) = Ae-at + Be-Bt !"Central #"k21 #"V1 !"Peripheral Compartment #"k12 #"B !"Elimination Phase Slope = ke !"Distribution Phase Slope = a !"Time after IV Injection Page 60: Three Compartment Model !"Dose !"Deep #"K31 #"Central $"k21 $"Shallow Compartment $"k12 $"ke !"BARASH Page 61: Three Compartment Model !"Rapid !"Intermediate !"Slow !"Minutes since bolus injection !"MILLER Page 62: Three Compartment Model !"Propofol #"V3 #"V2 #"V1 #"Cl2 #"Cl3 #"Clo !"Remifentanil #"V2 #"V1 #"V3 #"Cl2 #"Cl3 #"Clo Page 63: Hysteresis !"Fentanyl !"Alfentanil !"Arterial level !"EEG level !"Infusion !"Time (min) !"FLOOD Page 64: Hysteresis - Combined PK/PD Model !"Dose !"Deep #"K31 #"Central $"K21 $"Shallow Compartment $"K13 $"k12 $"ke !"Effect-Site Compartment !"Ke0 !"BARASH Page 65: Hysteresis / Biophase - Combined PK/PD Model !"Drug administration !"ke0 !"V2 !"K12 !"V1 !"K13 !"V3 !"Rapidly equilibrating Central !"Slowly equilibrating compartment !"K21 compartment !"K31 compartment !"K1e !"K10 !"Effect site !"Time (min) !"MILLER Page 66: Stochastic Models !"Mathematical technique sometimes labeled non-compartmental !"Make the same assumptions we discussed with compartmental models !"Varies primarily by incorporation of the concept of mean residence time (MRT) !"Fails to adequately describe the redistribution of drug from effect site to less wellperfused tissues, and then ultimately back to the central compartment for clearance Page 67: Dosing Guidelines !"Bolus Dosing !"V1 (volume of the central compartment) !"V2 (volume of the vessel-intermediate group) !"V3 (volume of the vessel-poor group) !"Vdss (sum of all the above at steady state) !"Vdpe (volume of distribution at the time of peak effect following a bolus dose) Page 68: Dosing Guidelines !"Volume of Distribution at the Time of The Time to Peak Effect and t 1/2 keo Peak Effect. following a Bolus Dose !"V1 !"Vdpe !"Time to Peak Drug pe Drug (L) (L) Drug Effect (min) t 1/2 keo (min)" !"Fentanyl !"Alfentanil !"Sufentanil !"Remifentanil !"Propofol !"Thiopental !"Midazolam !"Etomidate !"FLOOD Page 69: Dosing Guidelines !"Maintenance infusion rate = CT × V1 × (k10 + k12e −k21t + k13e −k31t) !"Target concentration !"Central compartment volume !"Clearance from the central compartment !"Redistribution between the central and peripheral compartments !"At steady state t = ∞, and the equation becomes CT V 1 k 10 !"Bottom Line !"We give more at the start to account for redistribution out of the central compartment to the peripheral compartments !"Once steady state is achieved the infusion rate to maintain a given concentration essentially matches the amount being cleared Page 70: Dosing Guidelines !"If you just start an infusion, the initial rate must be much higher to maintain the target concentration at the effect site in the face of redistribution to other tissues !"In practice, we often give a bolus dose (based on the Vdpe) which covers some of the initial redistribution !"While the infusion rate will still have to be higher initially than at steady state, this reduces the difference to some extent Page 71: Context Sensitive Decrement-Time !"Context-sensitive half-time !"The time required for the drug concentration to decrease by 50% following termination of a steady state infusion !"Increases with increased duration of the infusion !"Due to increased distribution of drug in the peripheral compartments over time !"Context-sensitive decrement-time !"Allows the substitution for 50% of any decrement which may prove more valuable !"MACAWAKE = The drug concentration where 50% of patients follow commands Page 72: Context Sensitive Decrement-Time !"Midazolam !"Alfentanil !"Propofol !"Fentanyl !"Thiopental !"Sufentanil !"Dexmedetomidine !"Remifentanil !"MILLER Note Isoconcentration Nomograms and Infusion Dosing Schemes (Page 73) !"Isoconcentration nomogram #"Plasma concentration achieved over time with various infusion rates are plotted using a pharmacokinetic model #"A desired plasma concentration is selected and a horizontal line is drawn at that concentration #"Vertical lines indicate when to reduce infusion rate to maintain the desired plasma concentration Bolus and Infusion Dosing Scheme (Page 74) !"BET scheme #"B = bolus #"E = infusion rate to compensate for elimination #"T = decreasing rate over time to compensate for distribution to peripheral tissues Target Controlled Infusions (Page 75) !"Depend on pharmacokinetic and pharmacodynamics models !"Equation: CT × V1 × (k10 + k12e −k21t + k13e −k31t) !"Factors to account for: #"Desired concentration and plasma volume #"Elimination rate #"Distribution changes between central and peripheral compartments over time !"Available in several countries, but not currently in the United States !"Use pharmacokinetic parameters derived from population studies !"Results in up to 30% error due to individual patient variation Target Controlled Infusions - Other Uses (Page 76) !"Patient controlled postoperative analgesia: Alfentanil !"Patient controlled sedation: Propofol !"Mechanism: #"Establish an infusion rate #"Patient demand dose increases the rate slightly #"Lack of subsequent patient demand allows the rate to slowly fall to the initial infusion rate Closed-Loop Infusions (Page 77) !"Experimental, not available commercially for anesthetic purposes !"Drug delivery is controlled by "output" from the patient !"Processed EEG (e.g., BIS) and auditory evoked potentials are used !"Change in patient "output" results in: #"Change in drug delivery rate #"Change in pharmacokinetic model !"Limited usefulness due to inadequate definitions of anesthesia and inadequate monitoring of anesthetic depth Response Surface Models (Page 78) !"Designed to look at the net effect of combining two drugs, which may be additive, synergistic, or antagonistic !"Components: #"Concentrations of the two drugs #"Desired effect !"Probability isoboles are typically at 5%, 50%, and 95% Individual Variability (Page 79) !"Variation in plasma concentrations using the same dosing regimen: up to 2-fold !"Variation in plasma concentration required to achieve the same effect: up to 5-fold !"Causes: #"Genetic factors (alteration in CYP450 enzymes) - most important determinant of metabolic rate #"Disease processes #"Changes in receptor numbers and sensitivity #"Alterations induced by inhaled anesthetics Pharmacodynamics (Page 80) !"Concentration-Response Relationships !"Potency and Efficacy !"Effective and Lethal Dose !"Interpatient Variability Concentration-Response Relationships (Page 81) !"Potency: Dose required to produce a given effect !"Efficacy: The maximum effect the drug can produce !"Factors affecting concentration-response relationships: #"Partial agonist #"Presence of a competitive antagonist #"Presence of a non-competitive antagonist Effective and Lethal Dose (Page 82) !"ED50: Dose required to produce a specific effect in 50% of patients !"LD50: Dose producing death in 50% of patients !"Therapeutic index: Ratio of LD50/ED50 !"Greater the ratio, the safer the drug !"LD1/ED99 Interpatient Variability (Page 83) !"Variation in plasma concentrations using the same dosing regimen: at least 2-fold !"Variation in plasma concentration required to achieve the same effect: at least 5-fold !"Other factors in dosing decisions: #"Hemodynamic consequences of drug administration #"Delay in onset of desired effect #"Random inter-individual variability Sources (Page 84) !"Flood Stoelting's Pharmacology and Physiology in Anesthetic Practice 6th edition. 2022 !"Barash Clinical Anesthesia 8th edition. 2017 !"Evers Anesthetic Pharmacology 2nd edition. 201