Pharmacodynamic Principles - Module 2 (2024)

Module 2: Pharmacodynamic Principles  Copyright ©2024 by The Michener Institute of Education at UHN 222 St. Patrick Street Toronto, Ontario, Canada M5T 1V4 This material...

Module 2: Pharmacodynamic Principles  Copyright ©2024 by The Michener Institute of Education at UHN 222 St. Patrick Street Toronto, Ontario, Canada M5T 1V4 This material has been prepared and developed by The Michener Institute of Education at UHN. Reproduction of any part of this material, written, audio, visual or electronic, in any form, without the written consent of The Michener Institute is forbidden. Pharmacology  Pharmacodynamics Pharmacodynamics is the study of a drugs mechanism of action (MOA) by which the drug produces its physiologic effect (mechanism of drug effect) What the drug does to the body  Pharmacodynamics Drug binds to This initiates a Activation of a Alteration in it’s target signal second an intracellular receptor or transduction messenger process enzyme pathway molecule Effect of Drug  Drug Receptors Drugs produce their effects by interacting with specific cell molecules called receptors or a drug target Receptors/drug targets may be membrane proteins (most), cytoplasmic enzymes, or a nucleic acid Formation of drug-receptor complex leads to biologic response  Drug Receptors While many classes and subtypes of receptors/drug targets exist, there are two general types: Generalized: Molecules such as enzymes and DNA which are essential to cells normal function/replication Specialized: Molecules that have evolved specifically for intercellular communication (these are the primary targets of most drugs in clinical use) Drug receptors/drug targets exhibit molecular recognition by possessing molecular domains that are spatially and energetically favourable for binding specific drug molecules  Receptor/Drug Binding Most drugs are small molecules which interact with receptors via different chemical bonds The weaker the bonds between receptor and drug complex the more reversible the drug effect and vice versa  Relative Strength of Bonds Between Receptors and Drugs Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition, Golan  Drug-Receptor Interactions Most often drugs bind to their receptor by forming ionic, hydrogen, hydrophobic, or Van der Waals bonds These weaker bonds are reversible and enable the drug to dissociate from the receptor as tissue concentrations of the drug declines (E.g. Ibuprofen) If covalent bonds form this complex is relatively permanent and effects of the drug at this site are irreversible (E.g. ASA)  Receptors Receptors naturally exist Agonist activation (ligand binds to receptor) results in signal transduction Protein (most commonly but not exclusively) Different tissue distributions  Receptors Drug binding is usually reversible and stereoselective (some drugs may possess several forms or “stereoisomers” which have the same composition but different spatial orientations) Quantitative Relationship, magnitude of signal depends on degree of binding Specificity of binding not absolute, leading to nonspecific effects  Receptors May require more than one drug molecule to activate receptor Receptors are saturable because of their finite number Signal can be amplified by intracellular mechanisms Drugs can enhance, diminish, or block signal generation or transmission (Agonist versus Antagonist) Can be up regulated or down regulated  Receptors: Quantitative Relationship There is a correlation between drug concentration and the physiologic response This response is determined by the affinity of the drug for the receptor Affinity is the measure of the binding constant of the drug for the receptor (strength of the drug-receptor complex) and attraction of the drug to the receptor The number of receptors [R] occupied by a drug depends of the drug concentration [D] and the drug-receptor association and dissociation rate constants k1 and k2  Receptors: Quantitative Relationship The ratio of k2/k1 is known as the KD and represents the drug concentration required to saturate 50% of the receptors The lower the KD is, the greater is the drugs affinity for the receptor A high affinity (low KD) means that a lower concentration of drug is needed to occupy 50% of receptor sites RT = total # of receptors RT = [R] + [DR] KD = equilibrium dissociation constant  Receptors: Quantitative Relationship [DR] = drug bound to receptors If KD is low, binding affinity is high [D] = concentration of free (unbound) drug [DR]max KD = the concentration of free drug at which half-maximal binding is [DR] observed (characterizes the binding affinity of receptor for drug) KD [DR]max = total concentration of [D] receptor sites (at high concentration of drug)  Receptors: Quantitative Relationship In addition to affinity the correlation between drug concentration and physiologic response is also influenced by the number of receptors available for binding Although not always the case, more receptors generally can produce a greater response  Receptors: Specificity Specificity of drug action is determined by the characteristic of the receptor Binding of drugs to receptors often exhibits stereospecificity (only one of the stereoisomers will bind with the receptor) Specificity of drug action is determined by the distribution of receptors in the tissues  Receptors: Agonist versus Antagonist Molecules that bind to a receptor and activate it (produce the biologic response) are called agonists Molecules that bind to a receptor but do not activate it are called antagonists Antagonists block or reverse the clinical effect of agonists Antagonists produce no effect of their own at a receptor Molecules that bind to a receptor distinct from that which normally binds an endogenous agonist are called allosteric modulators Occupation of these sites can either increase or decrease the response to the agonist (positive or negative) and some allosteric modulators can act as allosteric agonists in themselves  Receptors: Agonist versus Antagonist Allosteric modulators bind to different sites than agonists therefore interactions are not competitive in nature  Receptors: Agonist versus Antagonist Agonist: Affinity for receptor Intrinsic activity when bound to receptor Antagonist: Affinity for receptor No intrinsic activity when bound to receptor Can be either competitive or noncompetitive  Types of Drug Receptors 1. Ligand/Voltage-Gated Ion Channels 2. G-Protein-Coupled Receptors (GPCRs) 3. Enzyme-Linked Receptor -Tyrosine Kinase (RTKs) 4. Nuclear Hormone Receptors  Types of Drug Receptors G-Protein- Enzyme Linked Ligand-Gated Nuclear Hormone Coupled Receptor - Ion Channel Receptor Receptor Tyrosine Kinase Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition, Golan Types of Drug Receptors  Ligand/Voltage-Gated Ion Channels These are complex membrane transport proteins At ligand-gated ion channels drugs can bind at the same site as the endogenous ligand and directly compete for the receptor site At voltage-gated channels there is no endogenous ligand and ion channel is controlled solely by membrane voltage potential which then opens or closes ion channel  Ligand/Voltage-Gated Ion Channels ROC=receptor operated channel VOC=voltage operated channel  Ligand-Gated Ion Channels Watch: https://www.khanacademy.org/test-prep/mcat/organ- systems/biosignaling/v/ligand-gated-ion-channels  G-Protein-Coupled Receptors (GPCRs) Most abundant receptor in the human body Most currently marketed drugs target this type of receptor (40%-60%) A large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses  G-Protein-Coupled Receptors (GPCRs) Receptors consist of a single subunit with a single binding site and 7 transmembrane spanning domains  G-Protein-Coupled Receptors (GPCRs) Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition, Golan Watch: https://www.khanacademy.org/test-prep/mcat/organ-systems/biosignaling/v/g-protein-coupled-receptors  Enzyme Linked Receptor: Tyrosine Kinase (RTKs) Composed of a single transmembrane protein containing an extracellular ligand binding domain, one transmembrane spanning segment, and an intracellular domain with tyrosine kinase (or other enzyme) activity Enzyme Linked Receptor: Tyrosine Kinase (RTKs) Binding of a ligand to the extracellular domain causes dimerization of the receptor and stimulates a tyrosine kinase (or other enzyme) activity within the intracellular domain Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition, Golan Enzyme Linked Receptor: Tyrosine Kinase (RTKs) Binding of a ligand to extracellular domain causes dimerization of receptor and stimulates a tyrosine kinase (or other enzyme) activity within intracellular domain Enzyme Linked Receptor: Tyrosine Kinase (RTKs) Watch: https://www.khanacademy.org/test-prep/mcat/organ- systems/biosignaling/v/enzyme-linked-receptors  Nuclear Hormone Receptors These receptors are in cytoplasm or nucleus If they bind their ligand in the cytoplasm, they are then translocated to the nucleus These receptors are usually ligand-activated transcription factors (increase or decrease transcription of particular genes) Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 2nd Edition, Golan  Nuclear Hormone Receptors Aldosterone is an example of a hormone that acts on nuclear receptor Watch: https://youtu.be/wJk7nRccLbc  Receptors Speed of transduction (cellular actions of drugs) and onset of tissue response is determined by receptor type and by mechanism of transduction Enzyme Nuclear Ligand-Gated G-Protein- Linked Hormone Ion Channel Coupled Receptor Receptor Receptor  Receptors Receptor activation is very specific with little cross reactivity between endogenous compounds and other receptors other than their own However, there are families of receptors with multiple receptor subtypes which are distributed throughout the tissues Receptors can undergo dynamic changes with respect to their density (number per cell) and their affinity for drugs and other ligands  Receptor Regulation Continuous or repeated exposure to agonists initially causes desensitization by producing temporary changes of the receptor itself which decreases affinity (KD) between the receptor and the ligand Continuous or repeated exposure to agonists eventually causes down-regulation (a decrease in the number of receptors by internalizing the receptor or regulating the receptor gene) These situations describe drug tolerance Continuous or repeated exposure to antagonists initially causes supersensitivity by producing temporary changes of the receptor itself which increases affinity (KD) between the receptor and the ligand Continuous or repeated exposure to antagonists eventually causes up-regulation (an increase in the number of receptors by decreasing internalization or regulating the receptor gene) Receptor Regulation  Drug Tolerance Drug tolerance is seen when the same dose of drug given repeatedly loses its effect or when greater doses are needed to achieve a previously obtained effect  Receptor Regulation and Drug Tolerance Pharmacodynamic tolerance (cellular tolerance) describes adaptations to chronic drug exposure at the tissue and receptor level Receptor down-regulation is most commonly responsible for this type of tolerance  Receptor Regulation and Drug Tolerance Pharmacokinetic tolerance (metabolic tolerance) also describes adaptations to chronic drug exposure however this can occur at remote tissues as well as those at the receptor level This type of tolerance is caused by an up-regulation of the enzymes that metabolize the drug  Drug Dependence Dependence occurs when a patient needs a drug to “function normally” Clinically dependence is detected when cessation of a drug produces withdrawal symptoms Dependence can be physical (chronic use of laxatives leads to dependence on laxatives to have a normal bowel movement) Dependence may also have a strong psychological component  Withdrawal Withdrawal occurs when a drug is no longer administered to a dependent patient Symptoms of withdrawal are often the opposite of the effects achieved by the drug (e.g., cessation of laxative) However, in some cases the symptoms of withdrawal are complex and appear unrelated to the drugs’ effects (e.g., alcohol, morphine)  Cross Tolerance/Cross Dependence Occurs when tolerance or dependence develops to different drugs which are chemically or mechanistically related E.g. Methadone relieves the symptoms of heroin withdrawal because patients have developed a cross dependence to these two drugs  Drugs Which Possess Unconventional (Non-Receptor) Mechanisms of Action Disruption of Structural Proteins E.g. Colchicine for gout Enzymes E.g. Streptokinase for thrombolysis Covalently Link to Macromolecules E.g. Cyclophosphamide for cancer React Chemically with Small Molecules E.g. Antacids for increased acidity Bind Free Molecules or Atoms E.g. Drugs for heavy metal poisoning  Drugs Which Possess Unconventional (Non-Receptor) Mechanisms of Action Nutrients E.g. Vitamins, minerals Exert Actions Due to Physical Properties E.g. Mannitol (osmotic diuretic), laxatives Antigens E.g. Vaccines Unknown Mechanisms of Action E.g. General anesthetics  Dose-Response Relationships The relationship between the concentration of a drug at the receptor site and the magnitude of the response is called the concentration-response relationship Realistically it is often difficult to know the concentration of the drug at the active site so it is often necessary to work with the dose-response relationship (dose is adjusted based on patient size and weight)  Dose-Response Relationships Dose-response curves are plotted on semi-log scales rather than linear scales to make comparisons easier Dose-response curves can be described in terms of a graded (continuous) response or a quantal (all or none) response When plotted When plotted linearly, semi-log, a relationship sigmoidal graph displays a shape indicating misleading the true exponential graph relationship shape  Dose-Response Relationships There is a correlation between drug concentration and the physiologic response This response is determined by the affinity of the drug for the receptor Affinity is the measure of the binding constant of the drug for the receptor (strength of the drug-receptor complex)  Dose-Response Relationships The ratio of k2/k1 is known as the KD and represents the drug concentration required to saturate 50% of the receptors The lower the KD is, the greater is the drugs affinity for the receptor  Agonists An agonist is a compound that binds to a receptor and produces the biologic response An agonist can be a drug or the endogenous ligand for the receptor In this case the drug is a full agonist The effect reaches 100% of the maximum possible effect  Partial Agonists A partial agonist produces the biologic response but cannot produce 100% of the biologic response even at high doses When partial agonist is administered with full agonist, the partial agonist may act as an antagonist by preventing the full agonist from binding to the receptor and reducing its effect  Efficacy Efficacy is the maximal response a drug can produce Efficacy is not directly related to receptor affinity Agonists have both affinity and efficacy Antagonists have affinity but lack efficacy  Potency Potency is a measure of the dose that is required to produce a response Potency is often expressed as the dose of a drug required to achieve 50% of the desired therapeutic effect. This is known as the ED50 (effective dose) Potency is largely determined by the affinity of a drug for its receptor The potency of a drug is inversely proportional to the ED50 of a drug  Spare Receptors The KD represents the drug concentration required to saturate 50% of the receptors The ED 50 is the drug concentration required to achieve 50% of the desired therapeutic effect  Spare Receptors Spare Receptors (unoccupied receptors): Maximal response may be achieved by an agonist even if a fraction of receptors are unoccupied Maximal drug response may not require binding of all receptors (spare receptors may exist) Therefore, sensitivity of a cell to an agonist concentration depends on affinity of receptor for drug AND the total receptor concentration (with more receptors available, the chance of binding is greater)  Spare Receptors If KD = ED50 = No spare receptors If KD > ED50 = There are spare receptors (half the maximum effect was reached before half the receptors were bound) If KD < ED 50 = This would indicate some sort of cellular or tissue damage inhibiting effect  Spare Receptors Spare Receptors: (unoccupied receptors): It is said that there are spare receptors if the concentration of drug that produces 50% of the maximum effect (ED50) is less than the concentration of free drug at which 50% of maximum binding is observed (KD) Reasons for having spare receptors: 1. The effect resulting from the drug-receptor binding may last less than the binding itself 2. Allows for the # of receptors to exceed the # of effector molecules available which helps ensure the “effect” E.g. Acetylcholine receptors at neuromuscular junctions  Therapeutic Index Therapeutic index is a measure of a drug’s (relative) safety Lethal dose (LD50) is dose that kills 50% of animals that receive it In clinical practice this is generally replaced by TD50 referencing the adverse effect that ultimately limits use Effective dose (ED50) is the dose required to achieve 50% of a desired therapeutic effect Therapeutic Index = Lethal Dose50 / Effective Dose50  Therapeutic Index Drugs with higher therapeutic index are safer than those with lower therapeutic index Therapeutic index is not the same as therapeutic window Therapeutic window (therapeutic range) is the range of doses that will elicit the desired response in a population The margin of safety is the range between therapeutic (effective doses) and lethal (or toxic) doses and is reflected by the therapeutic index  Antagonists Antagonists block or reverse the effect of agonists Antagonists produce no effect of their own at a receptor (binding of an antagonist to a receptor on its own does not produce a biologic effect)  Competitive Antagonists A competitive antagonist competes for the same receptor sites as an agonist If the agonist wins there is a response If the antagonist wins there is no response  Competitive Antagonists Competitive antagonists make an agonist look less potent by shifting dose-response curve to right Same maximal effect is achieved but takes higher doses to do so Competitive antagonists are said to be surmountable because the antagonism can be overcome by high doses of agonists  Non-Competitive Antagonists Non-competitive antagonists bind to a site other than the agonist binding domain Upon binding they induce a conformational change in the receptor such that the agonist no longer recognizes this domain Non-competitive antagonists reduce the maximal response that an agonist can produce Even high doses of agonist cannot overcome this antagonism Non-competitive antagonists are considered to be insurmountable Non-Competitive Antagonists  Non-Competitive Antagonists A noncompetitive antagonist causes maximum efficacy to decrease Potency is minimally affected Spare receptors may initially mask effect of a noncompetitive antagonist Competitive vs. Non-Competitive Antagonists Watch: https://www.youtube.com/watch?v=nFfPAklivHU  Inverse Agonists Inverse agonists have opposite effects from those of full agonists They are not the same as antagonists which block effects of both agonists and inverse agonists Some level of intrinsic (baseline) activity at receptor in absence of agonist must exist (eg. baseline conductance at ion channels) Agonists: Summary Inverse Agonists and Antagonism  Antagonism In addition to pharmacologic antagonism there is also physiological antagonism and antagonism by neutralization  Physiological Antagonism Two agonists in unrelated pharmacological reactions cause opposite effects Physiological effects cancel one another out E.g. Albuterol (agonist at beta-2 receptors leads to bronchodilation effect) vs Ach (agonist at muscarinic receptors leads to bronchoconstriction effect) on bronchial smooth muscle.  Antagonism by Neutralization Two drugs bind to one another and when combined both drugs become inactive Also known as “Chemical Antagonism”  Drug Interactions Drug interactions occur when one drug alters the pharmacological effect of another drug. The pharmacological effect of one or both drugs may be increased or decreased, or a new and unanticipated adverse effect may be produced. Types of Drug Interactions: Addition Synergism Potentiation Antagonism  Types of Drug Interactions Addition: The response elicited by combined drugs is equal to the combined responses of the individual drugs 1+1=2  Types of Drug Interactions Synergism: The response elicited by combined drugs is greater than the combined responses of the individual drugs 1+1=3  Types of Drug Interactions Potentiation: A drug which has no effect enhances the effect of a second drug 0+1=2  Types of Drug Interactions Antagonism: A drug (the antagonist) which has no inherent activity inhibits the effect of another drug 0+1=0