Pharmacology Quiz: Key Concepts

Introduction to Pharmacology & Pharmacodynamics

• Course offered by Professor Samuel B. Kombian in the Department of Pharmacology & Toxicology
• Date: April 2024

Aims/Objectives

• Define pharmacology
• Differentiate pharmacodynamics and pharmacokinetics
• Describe drug actions at molecular, cellular, and organ levels
• Explain different drug-receptor interactions
• Describe drug effects over time
• Explain drug safety indices and their measurement

Outcomes/Expectations

• Students should know the definition of pharmacology
• Students should know the types of pharmacological studies
• Students should be able to summarize basic drug actions at molecular and cellular levels
• Students should be able to describe various drug-receptor interactions
• Students should comprehend and interpret dose-response relationships under different conditions
• Students should understand drug effects over time
• Students should understand drug safety indices and their measurement

Pharmacology

• The study of the effects of a drug on physiological and pathophysiological processes
• It's a branch of medical science dealing with characteristics and properties of chemical agents (drugs) used for medicinal purposes
• Derived from Greek: pharmacon (drug); logos (study or discourse)
• Divided into two:
  • Pharmacodynamics
  • Pharmacokinetics

Pharmacodynamics

• Greek: dynamis (power); what the drug does to the body.
• Includes physiological and biochemical effects of drugs and their mechanisms of action at organ system, subcellular, and macromolecular levels.

Pharmacokinetics

• Greek: kinesis (movement); what the body does to the drug.
• Refers to drug movement within the body, including absorption, distribution, binding, storage, biotransformation (metabolism), and excretion (ADME).

Pharmacology: What is a drug?

• An active chemical entity in a medical product for diagnosis, prevention, or treatment/cure of a disease.
• The WHO (1966) definition includes any substance or product used to modify or explore physiological systems or pathological states for the recipient's benefit.
• A drug can be a:
  • Pharmacodynamic agent: Designed to have pharmacodynamic effects on the recipient
  • Chemotherapeutic agent: Designed to inhibit or kill invading parasites/malignant cells with minimal pharmacodynamic effects

Pharmacological Studies

• Molecular (chemical molecules to genes), in vitro (e.g., signal transduction cascades, gene cloning, and expression)
• Cellular (cells and reduced tissue), in vitro and ex vivo (e.g., cancer cell lines, isolated neurons/myocytes, slices)
• Organ (ex vivo), isolate heart, intestines, muscles, lungs
• Whole animal (in vivo), disease models, genetic knock-in/knock-out, chemical lesioning

Other Aspects of Pharmacology: Toxicology

• The study of unwanted, poisonous, and adverse effects of drugs and chemicals. Focuses on detection, prevention, and treatment of poisonings (including household, environmental, industrial, agricultural, and homicidal exposures).
• Includes clinical pharmacology, the scientific study of drugs in humans, covering both old and new drugs. This involves clinical trials to evaluate efficacy and safety, assessing patterns of drug use, adverse effects, and data generation for optimal drug use in 'evidence-based medicine'.

Pharmacotherapeutics

• Applying pharmacological knowledge along with disease knowledge for its prevention, mitigation, or cure.
• Selecting the appropriate drug, dosage, and duration of treatment considering the specific patient's features.
• Subspecialties based on systems or diseases (e.g., Neuropharmacology, Respiratory Pharmacology, GI Pharmacology, Molecular Pharmacology, Cellular Pharmacology, Cardiovascular Pharmacology, Immunopharmacology, Cancer Pharmacology, Pharmacogenetics/genomics)

Introduction to Pharmacodynamics: Cellular level (diagram)

• Shows the internal structures of a cell (Diagram) such as cytosol, centrioles, lysosomes, rough and smooth endoplasmic reticulum, nucleus, microvilli, mitochondria, ribosomes, etc

Introduction to Pharmacodynamics

• The study of drug effects on the living system
• The actions of drugs "when they get there"

Drug Mechanisms: General Principles

• Effects are from non-receptor mechanisms and receptor interactions.
• Drugs primarily interact by binding to protein targets such as enzymes, carrier molecules, ion channels, and receptors.

Non-receptor Mechanisms

• Actions on enzymes:
  • Enzymes are biological catalysts
  • Speed up chemical reactions
  • Drugs altering enzyme activity change the processes the enzyme catalyzes
  • Non-steroidal anti-inflammatory agents (NSAIDs, e.g. ibuprofen, diclofenac), monoamine oxidase inhibitors (e.g., phenelzine).
• Changing physical properties:
  • Mannitol changes osmotic balance, causing osmotic diuresis
  • Lidocaine blocks sodium channels; verapamil blocks calcium channels
• Combining with other chemicals:
  • Antacids, chelation of heavy metals (deferoxamine with iron)
  • Anti-metabolites compete with normal substrates, potentially creating biologically inactive products (e.g., antineoplastic agents like methotrexate competing with folate for dihydrofolate reductase, interfering with thymidylate synthesis and hence DNA synthesis, and antimicrobials like sulfonamides competing with dihydropteroate synthetase, interfering with folic acid synthesis in bacteria).

Receptor Concept

• Macromolecular components in cells (either on the surface or inside the cytoplasm) where drugs interact to produce a response or effect.
• Binding usually results in a conformational change.
• No complete/absolute specificity; selectivity is usually achieved, but often comes with side effects.
• Affinity: A drug's tendency to bind to the receptor
• Intrinsic activity (α): A drug's ability to induce or cause a response (α= +1 to -1)
• Efficacy: A drug's ability to produce a response

Types of Receptors: Channel-linked receptors

• Ligand binds, causes opening/closing of ion channels
• Very fast response (microseconds to milliseconds)
  • Examples: calcium channel blockers (nifedipine, amlodipine); local anesthetics (lidocaine); anticonvulsants (clonazepam, carbamazepine, phenytoin); antiarrhythmics (amiodarone).

Diagram of Ion Channel Receptor

• Depicts ligand binding, opening of channels, ion flow, and change in ion concentration, triggering cellular responses; ligand dissociation, and channel closure

Types of Receptors: G-protein-coupled receptors

• 7-transmembrane receptors
• Contain an intermediate transducing molecule, the G-protein (bound to the inner cell membrane).
• G-protein has three subunits (α, β, γ)
• Ligand binding activates the receptor; GDP on the α subunit is exchanged for GTP.
• Alpha subunit detaches, interacts with other proteins
• Triggers downstream effects (e.g., activating enzymes or changing ion channels) via secondary messenger systems (e.g., cAMP).

G-protein Coupled Receptors (cont'd)

• Alpha subunit with GTP detaches from beta and gamma subunits
• Alpha subunit moves freely along the inner membrane to contact another membrane-bound protein (e.g., adenyl cyclase), which serves as a primary effector.
• The effector protein converts ATP to cAMP
• cAMP activates other proteins or enzymes, acting as a second messenger to cause further effects in the cell

G-protein Coupled Receptor Mechanism

• Diagrams show receptor, G protein, effector protein, and agonist interactions, depicting changes in GDP and GTP status of the G protein during activation and deactivation.

Second Messengers

• Diacylglycerol (DAG), phosphatidylinositols (e.g., inositol 1,4,5-trisphosphate, IP3), calcium (Ca2+), cyclic AMP (cAMP), and cyclic GMP (cGMP) are examples.

Types of Receptors: Enzyme-linked receptors/Kinase-linked receptors

• Transmembrane receptors with intracellular enzyme components (often tyrosine kinases).
• Ligand binding activates the attached enzyme.
• This activates downstream signaling cascades (by adding phosphate groups to proteins; a process called phosphorylation) within the cell, leading to changes in physiological activity.
  • Examples: Growth factors, insulin receptors

Types of Receptors: Intracellular/Nuclear receptors

• Located inside the cell (not on the membrane).
• Ligands are usually lipophilic hormones and other molecules.
• Ligands bind to receptors, the complex moves to the nucleus
• Interaction with DNA to affect gene expression, leading to changes in protein synthesis within the cell.
• Slow-acting drugs as gene transcription takes time to affect physiological function.

Summary Receptor Types

• Visualizing the 4 types of receptors:
  • Agonist-receptor binding activating conductance
  • Agonist activating G-protein; second messenger production
  • Agonist binding resulting in phosphorylation of tyrosine
  • Agonist binding resulting in transcription and translation

Occupancy Theory of Drug Receptors

• A.J. Clark (1926, 1937)
• Drug response (D) corresponds to the occupancy of receptors (R)
• Maximum response when all receptors are occupied.
• Linear relationship between the proportion of occupied receptors and the response observed.

Receptor Interactions: Lock and Key/Induced Fit

• Explains how agonist-receptor interactions work.
• Diagram showing an agonist binding to a receptor (like a lock and key), and the induced fit showing how the shape of the receptor changes to perfectly fit the agonist

Agonists and Antagonists

• Agonists: Substances mimicking endogenous hormone or neurotransmitter actions, binding to receptors to produce a similar response.
• Antagonists: Bind to receptors to block or inhibit endogenous substances or agonists from binding, inhibiting normal cellular functions.
  • Antagonist interactions can be reversible or irreversible, competitive, or non-competitive

Competitive Antagonism

• Reversible: Antagonist and agonist compete for the same receptor site
• Increase in either agonist or antagonist dose displaces the other

Irreversible Competitive Antagonism

• Increasing agonist dose does not displace an antagonist if the antagonist doesn't dissociate from the receptor.

Non-competitive Antagonism

• Antagonist binds to a site different from the agonist, inducing a conformational change in the receptor
• The agonist can't bind; high agonist does not overcome the antagonist

Dose-Response Curves: Potency and Efficacy

• EC50: the dose of a drug required to produce 50% of the maximum effect (a measure of potency).
• Emax: ultimate achievable effect of a drug.
• Potency: Measures the amount of drug needed for a given effect.
• Efficacy: The ability of a drug to produce a response

Therapeutic Index

• The ratio of a drug's lethal dose (LD50) to its effective dose (ED50)
• A TI > 1 is generally desired for a drug to be usable.
• A lower TI indicates a narrower safety margin and increased risk of adverse reactions.

Time Response Relationships

• Latency: Time from administration to the first noticeable effect.
• Duration of response: Length of effect.