pharmacodynamics

Pharmacodynamics

The study of the biochemical, physiologic, and molecular effects of drugs

What are applications of pharmacodynamics?

Designing Dosing Regimens

Ceiling effect

Understanding Variability and interactions

Signal transduction

Biochemical mechanism responsible for “transmitting” extracellular signals inside the cell, which lead to activation of target proteins that control metabolic pathways or regulate gene expression

(Cells receive signals via receptors, then relay and amplify these signals inside cell through molecular cascades (pathways) to produce a specific response

How do cells respond to the environment?

Signal → reception → amplification → transduction → response(s)

What are outcomes/purposes to signal transduction?

Protein conformational changes

Covalent protein modifications (PTM)

Altered rates of gene expression

What are the stages of signal transduction?

1. Signal molecule (first messengers, ligand) travels to the cell

2. First messengers binds to a receptor protein and initiates a conformational change in the receptor: activate or deactivate protein, initiate cascade events to relay messages, change activity, gene expression, or function

3. Receptor protein stimulates signalling proteins

4. Second messengers amplify these signals inside signal: free to diffuse, cross talk bnetween pathways exists

5. Second messengers bind to additional signalling proteins

6. Signal is propagated often by a protein kinase cascade

7. Target proteins are affected (activated, inhibited): transcription factors, metabolic enzymes, cytoskeleton proteins, transport proteins

8. Signal is terminated - phosphates

What are examples of conformational changes in receptors?

Membrane receptors stimulus and transfer info across membrane

Most molecules are too polar or too large to cross the membrane, so the stimulus does not enter without membrane receptors

Fat soluble or non-polar molecules (steroid hormones) diffuse across membranes, bind to intracellular receptors

Generally, receptors are membrane proteins with extra- and intracellular domains (except intracellular receptors)

How does solubility determine receptor type?

Lipid-soluble ligands - hydrophobic and can readily diffuse across the cell membrane’s lipid bilayer

Water-soluble ligands - hydrophilic and cannot easily cross the lipid cell membrane

What are examples of water-soluble ligands?

Polypeptide: insulin, amine: epinephrine

What are examples of lipid-soluble ligands?

Steroid: cortisol

Amine: thyroxine

First messengers/ligands

Extracellular signaling molecules that typically bind to receptors on the cell surface rather than directly crossing the hydrophobic cell membrane

How do first messengers help with signal transduction?

First messengers binding to receptors initiates signal transduction - converts the external message into internal signals using second messengers and kinase cascades to amplify the effect within the cell

Why are receptors important in pharmacology?

Drug action

Specificity

Mechanism of action

Therapeutic targets

Personalised medicine

Receptors

Specialised protein, often on a cell surface or inside the cell, that binds specific signaling molecules (ligands) to initiate a biological response

Drug receptors

Protein macromolecules that receive chemical signals (ligands like drugs) to trigger cell responses, with drugs acting as agonists (activating) or antagonists (blocking) to produce therapeutic effects (like pain relief) or side effects, based on their specific binding to these targets

Agonists

Drugs that activate receptors, mimicking the action of natural ligands

Agonists example

Morphine on opioid receptors

Antagonists

Drugs that bind to receptors but do not activate them

Instead, they block the action of natural ligands or agonists from acting

Antagonists example

B-blockers are antagonists that inhibit the action of adrenaline (epinephrine) on B-adrenergic receptors, reducing heart rate and blood pressure

Antagonism

Binds to the orthosteric (agonist) site but causes no activation of the receptor, blocking the effect of the agonist

Antagonism effect on efficacy

Zero

Antagonism key feature

Prevent the agonist from binding

Partial agonism

Binds to the receptor and causes some activation, but cannot elicit a maximal tissue response, even when occupying 100% of available receptors

Partial agonism effect on efficacy

Intermediate

Partial agonism key feature

Acts as an antagonist by blocking the binding site against full agonists

Inverse agonism

Binds to a constitutively active receptor (a receptor active even without a ligand) and shifts the equilibrium toward the inactive (resting) state

Inverse agonism effect of efficacy

Negative

Inverse agonism key feature

Reduces the basal level of receptor activation

What is the inhibition at the receptor level like?

(Highest) full agonist → partial agonist → antagonist → inverse agonist (lowest)

What is the competitive binding like for inhibition at receptor level?

Reversible competitive antagonism

Irreversible competitive antagonism

Reversible competitive antagonism

The antagonist dissociates rapidly, meaning a sufficiently high concentration of agonist can overcome (or surmount) the block to restore the maximal response - most common form

Irreversible competitive antagonism

The antagonist dissociates very slowly or forms covalent bonds with the receptor, making the block insurmountable by increasing the agonist concentration - this lowers the maximum attainable response