PEDRO AMORIM, MD Department of Anesthesiology, Intensive Care and Emergency Medicine Hospital Santo António Centro Hospitalar do Porto University of Porto PORTUGAL pamorim@vianw.pt
Drug Pharmacology Any exogenous non-nutritive substance that affects bodily functions This happens through physical interactions (antacids), changes in enzymatic activity or binding to molecular structures in or on the cell, that affect cellular function Pharmacokinetics Pharmacodynamics
Pharmacodynamics Pharmacodynamics for anesthesiologists taking the EDA diploma exams References/sources of information?
Professors Jennie Hunter and Ronald Miller
Pharmacodynamics Pharmacodynamics describes the relationship between plasma drug concentration and pharmacologic effect. Simply stated: pharmacokinetics describes what the body does to the drug, whereas pharmacodynamics describes what the drug does to the body
outline transduction of biologic signals (receptor theory and structure) developments in molecular pharmacology clinical evaluation of drug effects
Drug Receptor a component of a cell that interacts selectively with an extracellular compound to initiate a cascade of biochemical events that culminate in the pharmacologic effects of the compound receptors are now recognized as discrete excitable proteins
binding between drug and receptor (1) the quantitative relationship between a given dose of a drug and the resulting effect (2) the selectivity of a given drug's activity and effect (3) the pharmacologic activity of receptor agonists, antagonists, and inverse agonists Receptors therefore serve to mediate and amplify the effect of a drug on the biologic system
Claude Bernard (1813-1878) receptor theory ligated vessels leading to one hind limb of a frog while leaving nerve input intact. He then administered intravenous curare. Pinching the paralyzed hind limb produced reflex movements in the opposite unparalyzed vessel-ligated hind limb. These experiments and others demonstrated for the first time the separation between the sensory and motor nervous systems and also revealed that circulating substances produce selective effects on organ systems, a concept important in the development of receptor theory.
drug receptor interaction law of mass effect Combination of drug (ligand) and receptor depends on the concentrations of each The amount of drug-receptor complex formed determines the magnitude of the response
Pharmacokinetics involves the use of many formulas Pharmacodynamics also involves using some formulas
binding of a ligand Binding of a ligand, L, to its receptor, R, follows the laws of mass action and can be summarized by the relationship [L] + [R] K OFF K ON [LR] kon is the rate constant for binding of the ligand to the receptor koff is the rate constant for the dissociation of the ligand from the receptor [L] is the concentration of the ligand [R] is the concentration of the unbound receptor [LR] is the concentration of the bound receptor Note that the units for kon are time-1. units of [L] -1. The units of L are typically nanomoles per liter. The units for koff are time-1.
The rate of formation of [LR] is: At steady state, which is nearly instantaneous, the net rate of formation is 0, and thus [L] [R] kon = [LR] koff.
dissociation constant - Kd The term Kd, or dissociation constant, defines the characteristics of ligand/receptor interactions at equilibrium.
Drug binding Strength, duration and type of drug receptor interaction represent the affinity: Size and shape of drug molecule Types, number and spatial arrangement of binding sites (stereochemistry) Intramolecular forces between drug and binding sites: Van de Walls forces = weak bonds andn transient reversible effects Hydrogen bonds = intermidiate and transient reversible Covalent bonds = strong and long-lasting or irreversible
drug binding Binding of drugs involves mostly weak bonds The drug-receptor complex is not static Continuous association and dissociation of the drug The equilibrium dissociation constant Kd is a measure of this process Kd also represents the drug concentration necessary to bind 50% of the total receptor population
Free energy maps Ligand receptor interactions can be studied by energy free maps Binding affinities between propofol and HES were evaluated by binding free energy approximation (HGb, kj.mol-1) Aura Silva, Pedro Amorim et al
Selectivity of drug responses The cell responds only to the drugs that exhibit affinity for the receptors it expresses The greater the extent a drug molecule exhibits affinity for only one receptor, the more selective the drug s actions with lower potential for side effects The higher the affinity the lower the amount of drug necessary to exert an effect
Selectivity of drug responses Few drugs are entirely specific for one receptor Selectivity is relative As the concentration of drug increases it will combine with receptors for which it has lower affinity Off target side effects are generated Example: Beta- adrenergic receptor agonists and cardiovascular selectivity (asthma patients )
Tissue distribution of receptors
RECEPTOR AGONISTS AND ANTAGONISTS Drugs that are agonists mimic endogenous hormones or neurotransmitters when bound to a receptor. This effect may be excitatory or inhibitory.
RECEPTOR AGONISTS AND ANTAGONISTS Full agonist - completely activates a receptor Partial agonist - partially activates a receptor, even at very high concentrations Neutral antagonist - has no activity of its own Inverse agonist - superantagonists because they decrease receptor responses to less than the baseline
Flumazenil, Bretanazil, Flumazenil and RO 19-4063
Drug-receptor occupancy curves law of mass action Relationship is not linear but parabolic (Linear scale)
Drug-receptor occupancy curves law of mass action Logarithmic scale
Drug-receptor occupancy curves law of mass action Logarithmic scale
Dose-response relationships it is necessary to understand the relationship between the amount of drug given and the anticipated effect in the patient This relationship is described quantitatively by the dose-response curve There are two basic types of dose-response curve: Graded Quantal
Dose-response curves - relationships Measure an effect that is continuous such that, in theory, any value is possible in a given range (0% through 100%). Have a sigmoidal shape similar to the drug receptor occupancy curves, because the biologic response to a drug is determined by the interaction of a drug with a receptor or molecular target Exhibit a dose beyond which no further response is achieved (maximal effect; Emax) Emax is a measure of the pharmacologic efficacy of the drug Show the dose that produces 50% of the Emax (ED50). ED50 is an index of the potency of the drug Agonists with higher potency will have lower ED50 values
Dose-response curves - relationships The relationship between the drug-receptor binding event and the ultimate biologic effect is complex Quite often in experimental settings, the KD (concentration causing 50% receptor occupancy) does not correspond to a 50% maximal response from the test tissue or organism In many cases half-maximal tissue responses are obtained at drug concentrations below the KD, suggesting that amplification of drug response occurs.
potency from a therapeutic perspective, potency is often defined in terms of the dose-versus-response relationship. However, from a pharmacologic perspective, potency is best described in terms of the concentration versus-response relationship potency should be defined in terms of a specific drug effect (e.g., 50% of maximal effect). This is particularly important if the two drugs have different Hill coefficients or efficacies (Emax)
efficacy Efficacy is a measure of the intrinsic ability of a drug to produce a given physiologic or clinical effect The scale used to describe intrinsic efficacy at a given receptor ranges from 0 to 1 Efficacy is 1.0 for full agonists, 0 for neutral antagonists, and between 0 and 1.0 for partial agonists In contrast, the term potency refers to the quantity of drug that must be administered to produce a specific effect
graded dose-response curves A is the most potent (less ED 50) B & C equipotent (same ED 50) B more efficacy (higher Emax)
Quantal dose-response curves Quantify responses for variables that are all or none For example seizure or no seizure Describe the relationship between drug dosage and the frequency with which a biologic effect occurs For example, in individuals administered an anticonvulsant medication, the percentage of individuals not experiencing a convulsive episode at any given dose is plotted in cumulative fashion Represent a cumulative frequency distribution for a given response Provide an ED50 value that reflects the dose of drug at which 50% of the patients respond also called the median effective dose Provide an Emax value that is the dose at which all of the patients respond to the drug.
Quantal dose-response curves % patients responding vs log drug dose
Therapeutic Index Therapeutic index (TI) or therapeutic ratio is the ratio of the LD50 and ED50 Large values of Therapeutic Index are desirable because they indicate that the doses that produce death are much greater than those that produce a therapeutic effect
Therapeutic window Therapeutic window is a loosely defined term that generally refers to the range of doses that produce therapeutic effects with minimal toxic effects It can be viewed as the lack of overlap between the quantal dose-response curves for therapeutic and toxic or lethal effects There are several indices of the degree of this overlap.
safety Certain safety factor: The certain safety factor is the dose of drug that produces a lethal effect in 1% of the population (LD 1 ), divided by the dose that produces a therapeutic effect in 99% of the population (ED 99 ). So: (LD 1 /ED 99 ) Protective index: The protective index is calculated as the dose for an undesirable effect in 50% of patients (TD50) divided by the ED50 for the desired effect (TD50/ED50)
Lethal dose
Potency and efficacy and variability
Drug receptors Receptors are ubiquitous in the cell, being present in cell membranes, cytoplasm, intracellular organelle membranes, and the nucleus The overall physical structure of a receptor depends on the type of receptor and its location Cytoplasmic and nuclear receptors bind ligands that readily traverse cell membranes These ligands must therefore contain significant hydrophobic (lipophilic) components.
Drug receptors - anesthetics The receptors of most interest to anesthesiologists are located on the cell membrane They include membrane receptors, ligand-gated ion channels, and voltage-gated ion channels Receptors on the cell membrane bind water-soluble ligands that are typically unable to cross lipid bilayers and mediate a cellular response via intermediary proteins (e.g., G protein coupled receptors) or by causing changes in ion flux (e.g., ligand-gated ion channels).
Membrane associated drug targets in anesthesia
Guanine Nucleotide (G) Protein Coupled Receptors G protein coupled receptors are the most abundant type of receptor known Extracellular amino terminus containing glycosylation sites, an intracellular carboxyl terminus, fatty acid attachment (usually via palmitoylation or myristoylation of a carboxylterminal cysteine residue), three extracellular loops, and four intracellular loops.
G protein coupled receptors (two-dimensional version of receptor structure ) with seven transmembrane domains, an extracellular amino (NH2) terminus (with associated glycosylation sites [Y]), an intracellular carboxyl (COOH) terminus, palmitoylated cysteine residue (the crooked line extending into the membrane), three extracellular loops, and four intracellular loops
Schematic of the three-dimensional structure of the β2- adrenergic receptor (a prototypical G protein coupled receptor)
Ion channels Some anesthetic drugs target voltage-gated ion channels. These receptors mediate neural signaling by modulating ion permeability in electrically excitable membranes in response to changes in membrane potential Voltage-gated ion channels such as the sodium channel have charged regions that span the cell membrane The formation of ion pairs between many positive and negative charges helps stabilize the ion-conducting pore Local anesthetics work by blocking voltage-gated sodium channels
Ligand gated ion channels The ligand-gated ion channel is a combination of a classic receptor protein and an ion channel Ligand gated ion channels permit certain drugs to directly alter membrane potentials Many anesthetic drugs act on ligand-gated ion channels, such as the nicotinic acetylcholine receptor and the GABAA receptor.
The GABA receptor the neurotransmitter GABA binds to its receptor within the GABAA ligand-gated ion channel complex and causes the intracellular flux of chloride ions This action results in hyperpolarization of the membrane potential, a hallmark of inhibitory neurotransmission Drugs binding to other sites on the GABAA receptor facilitate the action of the endogenous ligand GABA
GABA receptor
Ion pumps Another type of excitable membrane protein is the ion pump. The sodium-potassium ATPase pump is perhaps the most familiar ion pump to the anesthesiologist because it is inhibited by digitalis Action potentials activate sodium channels, thereby allowing sodium to flux intracellularly along a combined chemical and electrical gradient The sodium-potassium-atpase pump then rapidly pumps sodium out of the cell in exchange for potassium, thereby returning the cell to its original cation composition and electrical gradient Digitalis acts by inhibiting the sodium-potassium- ATPase pump
Second messengers Binding of a ligand to a receptor does not instantly produce its clinical effects. Instead, a series of rapid biochemical events couples receptor binding to ultimate clinical effects These biochemical events are called second messengers Many membrane receptors couple to their second messenger through G proteins, which are intermediate regulatory molecules. Coupling of G proteins to receptor-hormone complexes requires energy in the form of guanosine triphosphate (GTP).
β-adrenergic receptor signal transduction cascade. βar, β-adrenergic receptor; ATP, adenosine triphosphate; camp, cyclic adenosine monophosphate; Gsα, α subunit of the stimulatory G protein (Gs); βγ, stimulatory G protein, βγ-subunit
Stimulation of receptors and second messengers ultimately leads to physiologic effects in a given tissue The physiologic effects produced depend on the presence of specific receptor subtypes, G proteins, and second messengers within that tissue. An example of the wide-ranging cardiovascular effects produced by norepinephrine
Actions at different receptors Anesthesia is the practice of applied drug interactions General anesthesia is, at a minimum, a combination of hypnosis, immobility, and antinociception Potentiation or synergism may occur and we use them intentionally
Effect of fentanyl on MAC of Isoflurane
Synergism of propofol and alfentanil Influence of alfentanil on the concentration of propofol associated with a 50% probability of response to intubation and incision, as well as a 50% probability of awakening at the end of surgery
Summary of drug interactions in humans and animals for hypnosis (loss of consciousness in humans, loss of righting reflex in animals) and immobility (loss of movement response to noxious stimulation). The numbers in each cell refer to the number of papers supporting the finding
MOLECULAR PHARMACOLOGY Molecular pharmacology takes advantage of the finding that all proteins, including excitable membrane proteins, are encoded in the human genome as nucleic acids Every amino acid present in a protein is encoded by a specific combination of three nucleotides in DNA Therefore, the DNA sequence that encodes a receptor protein can be determined Encoding DNA sequences (i.e., genes) can be inserted into special cells that will express (manufacture, assemble, and deliver to the appropriate location in the cell) the receptor protein in high quantity.
MOLECULAR PHARMACOLOGY By changing (mutating) nucleotide sequences, an abnormal (synthetic or designer ) receptor can be created Naturally occurring human receptor variants have been investigated and tested for alterations in pharmacologic properties PHARMACOGENOMICS New investigational drugs can be rapidly screened for effects on a spectrum of native and variant receptors
Clinical Evaluation of Drug Effects Once pharmacologic agents have exerted their actions on a molecular level, stimulated their targets, and produced a physiologic effect, it is important to evaluate the effect on the whole organism Dose-response curves, efficacy, potency, the median effective dose (ED50), the median lethal dose (LD50), and the therapeutic index
Clinical Evaluation of Drug Effects PATIENT VARIABILITY Genetic factors Biologically active genetic polymorphisms have been found in numerous receptors, second messenger systems, and ion channels Physiologic factors Age Liver function Proteins/albumin Disease states
Drug Interactions Pharmacokinetic Interactions Pd Drug-Time Interaction: Desensitization Pd Drug-Time Interaction: Increased Receptor Sensitivity Pd Drug-Drug Interactions
Anesthesia Pharmacodynamics How do we assess what the drug does to the body? How do we administer drugs? The way we were taught! In a per kilogram of weight basis!!! We use the concept of the average patient We do that for opioids We do that for inhaled anesthetics with MAC We do that for propofol
the average patient does not exist! BHU - Varanasi, 2013
We assess the patient clinically and with monitors BHU - Varanasi, 2013
Pharmacodynamic assessement of anesthesia How do we assess adequacy of hypnosis? In individual patients? Is it important to measure anesthetic plasma drug s concentrations in real time? Can we measure plasma concentrations in real time? We can measure expired end-tidal concentrations of inhalational anesthetics and calculate MAC! What about intravenous anesthetics?
propofol anesthesia
PHARMACODYNAMICS in ANESTHESIA Is it useful to measure real time concentrations? Should we guide anesthesia administration based on desired or recommended plasma concentrations? It makes more sense to use pharmacodynamic parameters! To use monitors that use variables that represent the effect!
BHU - Varanasi, 2013 EEG based indexes like the BIS
Or State Entropy and Response Entropy BHU - Varanasi, 2013
How do we assess analgesia adequacy? Can we use objective monitors? Can we measure pain? We can objectively measure the balance between nociceptive stimuli and antinociceptive drugs?
Closed Loop Anesthesia - Analgesia BHU - Varanasi, 2013
Analgesia / Nociception Index ANI: Analgesic Nociceptive Index Mathieu JEANNE, MD, PhD Anesthesia & Intensive Care Cic-It 807 Inserm University Hospital Lille, France
ANESTHESIA Bringing pharmacokinetics and pharmacodynamics together With modern Pk modeling With modern Pd monitors With modern drugs The anesthesiologist can become A SURFER!
Closed Loop Anesthesia - Ngai Liu Combining hypnosis and analgesia closed loop control BHU - Varanasi, 2013
Thank You