Pharmacology Lecture 3: Pharmacodynamics

Pharmacodynamics

• Describes the actions of a drug on the body, which is achieved by interacting with specialized target macromolecules called receptors.
• The drug-receptor complex initiates alterations in biochemical and/or molecular activity of a cell through a process called signal transduction.

Fundamentals of Drug Action

• Activation: a drug molecule stimulates a process or selectively accelerates it, e.g. caffeine causes CNS stimulation and increased alertness.
• Inhibition: a drug molecule inhibits a process or selectively deaccelerates it, e.g. aspirin inhibits cyclooxygenase, thereby inhibiting the formation of prostaglandins.
• Complexation: a drug molecule makes a complex with the target site, making it inactive by sequestration, e.g. deferoxamine chelates iron.
• Neutralization: a drug molecule binds to the target site and neutralizes the action of the existing molecule directly through a chemical reaction or physical interaction, e.g. antacids (sodium bicarbonate, magnesium hydroxide) or physical interaction (polyvalent anti-snake venom).

Signal Transduction

• Drugs act as signals, and receptors act as signal detectors.
• A drug is termed an "agonist" if it binds to a site on a receptor protein and activates it to initiate a series of reactions that ultimately result in a specific intracellular response.
• "Second messenger" or effector molecules are part of the cascade of events that translates agonist binding into a cellular response.

Major Receptor Families

• Transmembrane ligand-gated ion channels: the channel is usually closed until the receptor is activated by an agonist, which opens the channel for a few milliseconds, e.g. cholinergic nicotinic receptor is stimulated by acetylcholine.
• Transmembrane G protein–coupled receptors: the extracellular portion of this receptor contains the ligand-binding site, and the intracellular portion interacts with a G protein when activated, e.g. α and β adrenoceptors.
• Enzyme-linked receptors: this family of receptors undergoes conformational changes when activated by a ligand, resulting in increased intracellular enzyme activity, e.g. growth factors and insulin receptors possess tyrosine kinase activity.
• Intracellular receptors: the receptor is entirely intracellular, and the ligand (e.g. steroid hormones) must have sufficient lipid solubility to diffuse into the cell to interact with the receptor.

Signaling Mechanisms for Drug Effect

• Transmembrane diffusion of drug to bind to an intracellular receptor.
• Transmembrane enzyme receptor, whose outer domain provides the receptor function and inner domain provides the effector mechanism.
• Transmembrane receptors that, after activation by an appropriate ligand, activate separate mobile protein tyrosine kinase molecules (Janus Kinases or JAKs), which phosphorylate (signal transducer and activators of transcription or STAT) molecules that regulate transcription.
• Transmembrane channels that are gated open or closed by the binding of a drug to the receptor site.
• G-Protein coupled receptors, which utilize a coupling protein to activate a separate effector molecule.

Response of Drug-Receptor Interaction

• If a drug has affinity for the receptor, and if it is in close proximity of the receptor site, receptor-occupancy takes place.
• This drug-receptor coupling leads to a variety of responses depending upon the nature of the drug molecule.
• Agonist: a drug that resembles the natural transmitter or hormone, may activate the concerned receptor and result in response, so an agonist has “affinity” as well as “intrinsic activity”.
• Antagonist: a drug that binds to the receptor but does not activate it.
• Partial agonist: a drug that binds to the receptor and activates it, but not to the same extent as the natural transmitter or hormone.
• Inverse agonist: a drug that binds to the receptor and reduces its activity.

Structure-Activity and Receptor Classes

• Structure-activity relationship: the same receptor type may mediate two effects, a competitive antagonist will inhibit both responses of the agonist.
• Stereoselectivity: drug molecules have more than one 3-dimensional configuration, and biological activity for each is different.
• Receptor classes: there are multiple receptor subtypes for each endogenous ligand, e.g. Ach(5), NA(5), H(3), 5-HT(4).

Quantitative Variation in Drug Response

• Response to drugs vary from animal to animal, human to human due to normal biological variation.
• Response may change quantitatively in the same individual during the course of therapy.
• Up and down regulation of receptors: upregulation (i.e., increase in the number) of receptors occurs when the activity of the receptor is lower than usual, e.g. administration of beta-blockers upregulates β-adrenoreceptors.
• Desensitization and tachyphylaxis: change in receptors, loss of receptors, or exhaustion of mediators.
• Tolerance: a gradual decrease in responsiveness (in vivo) to a drug, taking days or weeks to develop.
• Factors influencing drug response: age, sex, pregnancy, diseases (e.g. hepatic or renal dysfunction), and genetic factors.

Dose-Response Relationships

• Graded dose–response relations: as the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect).
• Potency: a measure of the amount of drug necessary to produce an effect, measured by the concentration of drug producing 50% of the maximum effect (EC50).
• Efficacy: the magnitude of response a drug causes when it interacts with a receptor, dependent on the number of drug–receptor complexes formed and the intrinsic activity of the drug.
• Maximal efficacy of a drug (Emax) assumes that the drug occupies all receptors, and no increase in response is observed in response to higher concentrations of drug.

Signal Transduction

• When activated, a receptor phosphorylates tyrosine residues on itself and other specific proteins.

Major Receptor Families

• Intracellular receptors: differ from other three families in that the receptor is entirely intracellular, and the ligand (e.g., steroid hormones) must have sufficient lipid solubility to diffuse into the cell to interact with the receptor.

Signaling Mechanisms for Drug Effect

• Five major signaling mechanisms are recognized:
  • Transmembrane diffusion of drug to bind to an intracellular receptor.
  • Transmembrane enzyme receptor, whose outer domain provides the receptor function and inner domain provides the effector mechanism.
  • Transmembrane receptors that, after activation by an appropriate ligand, activate separate mobile protein tyrosine kinase molecules (Janus Kinases or JAKs), which phosphorylate (signal transducer and activators of transcription or STAT) molecules that regulate transcription.
  • Transmembrane channels that are gated open or closed by the binding of a drug to the receptor site.
  • G-Protein coupled receptors, which utilize a coupling protein to activate a separate effector molecule.

Response of Drug-Receptor Interaction

• If a drug has affinity for the receptor, and if it is in close proximity of the receptor site, receptor-occupancy takes place, leading to a variety of responses depending on the nature of the drug molecule.
• Types of drug responses:
  • Agonist: a drug that resembles the natural transmitter or hormone, may activate the concerned receptor and result in a response, so an agonist has both affinity and intrinsic activity.
  • Antagonist: a drug that has affinity to receptors without intrinsic activity.
  • Partial agonist: a drug that has affinity but very low intrinsic activity.
  • Inverse agonist: a drug that produces actions specifically opposite to those of an agonist.

Combined Use of Drugs

• Synergism: occurs when two drugs have similar actions and are additive, or when one drug increases the action of another.
• Antagonism: occurs when two drugs have opposite actions, resulting in reduced biological activity.

Therapeutic Index (Safety Margin)

• The therapeutic index is a measure of the range of effective doses (up to ED max) and the range of toxic doses (from minimal toxic dose upward) in humans.
• A wide margin of safety indicates a high therapeutic index, while a narrow margin of safety indicates a low therapeutic index.

Mechanism of Drug Action

• Mechanisms of drug action include:
  • On cell membrane: action of receptors of agonists and antagonists, action on enzymes and pumps, action on ion channels, and physico-chemical interaction.
  • On intracellular constituents: action on cytosolic or nuclear receptors, enzymes, DNA or RNA, and transport carrier molecules.
  • Outside the cell: chemical interaction, physical mechanisms, and antimicrobial action.

Structure Activity and Receptor Classes

• Structure-activity relationship: the same receptor type may mediate two effects, a competitive antagonist will inhibit both responses of the agonist.
• Stereoselectivity: drug molecules have more than one 3-dimensional configuration, with biological activity for each being different.
• Receptor classes: multiple receptor subtypes exist for each endogenous ligand.

Quantitative Variation in Drug Response

• Response to drugs varies from animal to animal, human to human due to normal biological variation, and may change quantitatively in the same individual during the course of therapy.
• Factors contributing to quantitative variation in drug response:
  • Up and down regulation of receptors.
  • Desensitization and tachyphylaxis.
  • Tolerance: a gradual decrease in responsiveness to a drug, requiring either raising the dose or substituting a different drug.
  • Drug resistance: used in the field of chemotherapy during antimicrobial therapy or chemotherapy of malignancy.

Adverse Drug Reactions (Toxicity)

• Measurement of pre-clinical toxicity: extensive toxicity testing is done in various animal species to determine acute toxicity, subacute and chronic toxicity, effects on reproduction, carcinogenicity, and mutagenicity.
• Definitions of commonly used terms:
  • Side effects: some reaction due to excess of normal, predictable, dose-related, pharmacodynamic effects seen in therapeutic doses.
  • Secondary effects: super infection or vitamin deficiency during chemotherapy.
  • Intolerance: low threshold to pharmacological action of a drug, inability to tolerate the adverse effects of a medication.
  • Iatrogenic diseases: drug-induced diseases.

Adverse Drug Reactions ADR (Toxicity)

• Factors influencing ADR:
  • Drugs.
  • Patients: age, sex, pregnancy, and other factors.
  • Diseases: hepatic dysfunction, renal dysfunction, and others.
  • Genetic factors.

Dose-Response Relationships

• Graded dose-response relations:
  • As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect).
  • Potency: a measure of the amount of drug necessary to produce an effect, determined by the concentration of drug producing 50% of the maximum effect (EC50).
  • Efficacy: the magnitude of response a drug causes when it interacts with a receptor, dependent on the number of drug-receptor complexes formed and the intrinsic activity of the drug.