Pharmacology Lecture 1: Pharmacodynamics

Drug definition

A chemical substance of known structure (not a nutrient or essential dietary ingredient) that produces a biological effect when administered to a living organism

Synthetic, from plants/animals or product of genetic engineering

MUST be administered, not from body ie. insulin can be a drug or not a drug

Does not need to be medicinal

Medicine definition

Chemical preparation that usually contains 1+ drugs which are administered w/ the intention of producing a therapeutic effect

Usually contains other substances besides the active drug to make them more convenient to use ie. excipients, stabilisers, solvents

Drug principles

Drug molecules must chemically influence 1 or more cell constituents to produce a pharmacological response

Drug molecules must get so close to constituent cellular molecules that they interact chemically to alter the function of the constituent

They must bind to parts of cells & tissues to produce an effect

Pharmacokinetics

What the drug does to the body

Physiological & biochemical processes of the mechanism of action of drugs

ie. dose-response relationship, target binding/affinity & potency & efficacy

Pharmacokinetics

What the body does to the drug

Changes in concentration of drug through physiological processes

Absorption
Distribution
Metabolism
Excretion

Affinity

Strength of association between ligand & receptor

Efficacy

Ability of an agonist to evoke a cellular response

4 types of drug targets

Receptors

Enzymes

Transporters/carrier molecules

Ion channels

Receptors in pharmacology

Any protein molecules that recognise & respond to endogenous chemical signals

Receptor activation

Molecule bound to receptor alters the receptors behaviour towards the cell & causes the tissue to respond

Agonists

Binds to & activates receptor or increases the ability of the endogenous ligand to activate the receptor

Affinity & efficacy

Full agonists possess 100% efficacy

Antagonists

Binds to receptor w/o activating it & blocks the effect of agonists on the receptor

Affinity, no efficacy

Binding curve

Studies drug affinity

Binding capacity (Bmax) = receptor density in tissues

Kd = drug concentration required to bind half of the receptors

Hyperbolic

Dose-response curve

Studies efficacy

Max response a drug can produce

Drug potency (EC50) = dose/concentration needed to get 50% of max response

Sigmoidal

Drug specificity

Drug must have high degree of binding site specificity

Protein drug targets also have ligand binding specificity

No drug acts w/ complete specificity → drug side effects

High dose of lower potency drug = more likely off-target action sites will be affected = side effects

Spare receptors

Spare receptors exist when the max response can be achieved by agonists without engaging all receptors

Orthosteric binding site

Site on protein that binds agonists & competitive antagonists

Triggers direct response in protein

Allosteric binding sites

Site on protein that when bound to influences receptor function

Can increase or decrease agonist affinity for binding site or complex

Allosteric agonist

Binds to allosteric site instead of orthosteric to activate receptor or produce a response

Enzyme-linked receptor mechanism

Receptor is an enzyme in cytoplasmic domain

Ligand binds & causes dimerisation of 2 neighbouring receptors

Dimerised receptors autophosphorylate each other via ATP

SH2 domain proteins bind to phosphorylated receptors & activated

Signal cascade → gene transcription (takes hours)

ie. Tyrosine kinase receptor, insulin receptor, growth factor receptors

Nuclear receptor mechanism

Lipophilic hormones (steroids) diffuse through plasma membrane and binds to receptor (cytoplasmic or nuclear) to form complex

Complex enter nucleus & binds to hormone response element

Activates a specific gene & causes mRNA transcription

Results in new protein being created (can take hours)

ie. sex steroid hormones (oestrogen, testosterone)

Enzyme drug targets

Most of the drugs inhibit enzymes & are competitive

Competitive enzyme inhibitors ie. kinase inhibitors bind ATP pocket of enzyme

Non-competitive inhibitor drugs bind allosterically to cause a conformational change that blocks substrate interaction

Irreversible inhibitor drugs covalently bind to the enzyme & permanently inactivate catalytic function

Transporter drug targets

Inhibits transport of molecules or reuptake by neurotransmitters

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SSRIs = prozac (fluoxetine) & celexa (citalopram)

SNRIs = effexor (venlafaxine) & ultram (tramadol)

Ion channel drug targets

Alters ion channels

Ligands bind directly to channel sites to block or affect gating

Channel indirectly activated via GPCRs

Intracellular signals (Ca2+)