Pharmacology and Toxicology: Pharmacodynamics

What is Pharmacology?

• 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 and Pharmacokinetics

• 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 and the Concept of Toxicity

• 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.

Objectives of Pharmaco-/Toxicodynamics

• 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

Concentration-Effect Curves

• 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

Dose-Response Relationship

• 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 and Therapeutic Ratio

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

Receptor Theory

• 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.

Drug-Receptor Interaction

• 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.

Radioligand Binding

• [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.

Receptor Types

• 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)

Objectives Pharmaco-/Toxicodynamics

• Relationship between dose and effect
• Emax, EC50, ED50, LD50, potency (pD2)
• Dose-response curves, Therapeutic Range: Therapeutic Ratio, Therapeutic Index

Agonists and Antagonists

• 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.

Types of Antagonists

• 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.