Pharmacology and Toxicology: Pharmacodynamics

Study Notes

Pharmacology is the science of the effects of drugs on healthy or sick organisms.
It is the study of the interactions between chemicals and biological systems.

Pharmacodynamics deals with the interactions of chemicals with receptors.
Pharmacokinetics deals with the four stages by which chemicals pass through the body: absorption, distribution, metabolism, and excretion.

Paracelsus said, "All things are poison, and nothing is without poison; the dose alone makes a thing not a poison."
No substance is toxic in itself; it's the dose that makes it toxic.
To assess the risk of toxicity, one needs to know the effective dose during exposure and the dose level at which damage is likely to occur.

Relationship between dose and effect
Emax, EC50, ED50, LD50, and potency (pD2)
Dose-response curves, therapeutic range, therapeutic ratio, and therapeutic index
Receptor theory, types of action, pharmacological receptors, and physiological receptors
Agonists, antagonists, relative intrinsic activity, and types of inhibition

Measurement of effect as a function of concentration
Sigmoid curve, saturation, and hyperbolic curve
Characteristics of a drug that can be read from the concentration-effect curves: Emax and EC50

Depending on the concentration, the intensity of an effect is measured in an individual.
Depending on the dose, the frequency of an effect is studied within a collective.

Therapeutic range: the range of concentrations at which a drug produces a therapeutic effect.
Therapeutic ratio: the ratio of LD50 to ED50.

A drug is a chemical that affects a physiological system by binding specifically to a receptor.
Four main kinds of regulatory proteins are commonly involved as primary drug targets: receptors, ion channels, enzymes, and carrier molecules.
The classic concept of drug actions: the key and lock model, and the occupation theory.

Pharmacological receptors have a dual function: binding a drug with high affinity to form a ligand-receptor complex, and triggering a follow-up response by conformational change.
Simple occupancy model: relates occupancy to response with a direct linear relationship.
Extended occupancy model: introduces a proportionality factor termed the intrinsic activity that allows a partial agonist to produce a reduced response at maximal receptor occupancy.
Induced-fit theory: agonists cause a conformational change in the receptor, which leads to signal transduction, whereas antagonists bind to the receptor but cause no conformational change.### Angiotensin II Receptors
Angiotensin II receptor antagonist, losartan, displaces angiotensin II in the cortex but not in the kidney medulla.
Different IC50 values for losartan in the kidney medulla and adrenal cortex indicate different AT1-receptor subtypes.

[125I]-Sar1-Angiotensin II binding is affected by losartan and CGP 42112 in the kidney medulla and adrenal cortex.
Losartan has a higher affinity for AT1 receptors in the adrenal cortex than in the kidney medulla.

There are four main types of receptors:
- Ligand-gated ion channels (e.g., nicotinic ACh receptor, ionotropic glutamate receptor)
- G-protein-coupled receptors (GPCRs) (e.g., muscarinic ACh receptors, adrenoceptors)
- Receptor protein kinases (e.g., insulin receptor, immunoglobulin E receptor)
- Intracellular (nuclear) receptors (e.g., steroid hormone receptors, vitamin D receptor)

Agonists bind to a receptor to change its conformation, leading to signal transduction.
Agonists have both affinity and "intrinsic activity".
Antagonists bind to a receptor, but do not result in conformational change.
Relative intrinsic activity (α) defines the effect of an agonist or antagonist.

Competitive antagonists compete with agonists for the same receptor.
Non-competitive antagonists bind allosterically to the receptor, altering its conformation.
Functional antagonism: an agonist reverses the effect of a second agonist in the same cell system/organ.
Physiological antagonism: an agonist reverses the effect of a second agonist at a different cell system/organ.
Chemical antagonism: a substance prevents the effect of another substance through, e.g., complex formation.