Pharmacodynamics (Drug Targets)

Drug Definitions and Concepts

• A drug is a natural or synthetic chemical introduced to the body from the outside that causes a physiological response.
• Ligand: something that binds to a biological target.
• Endogenous ligand: a natural chemical produced by the body to bind to the biological target.
• Drug: an exogenous ligand that generates a physiological response.

Mechanism of Action and Effects

• Mechanism of action: the biochemical interaction by which a drug causes its effects.
• Resultant cellular biological, physiological, and clinical effects (“mode of action”).
• The relationship of concentration and effect.

Examples of Drugs and Their Targets

• Atorvastatin & simvastatin: high cholesterol, enzyme target.
• Omeprazole & lansoprazole: gastric acid, transporter target.
• Levothyroxine: hypothyroidism, receptor target.
• Amlodipine: hypertension, ion channel target.
• Ramipril: thromboembolism, enzyme target.
• Bisoprolol: hypertension, receptor target.
• Colecalciferol (Vit.D): calcium metabolism, receptor target.
• Aspirin: thromboembolism, enzyme target.
• Metformin: diabetes, enzyme target.
• Salbutamol: asthma/COPD, receptor target.

Ligands and Receptors

• Specific ligands: much more effective at a target than others (> 100x more potent).
• Selective ligands: mild-moderate greater effectiveness at a target than others.
• Non-selective ligands: minimal difference in effectiveness between multiple targets.
• Key “detecting” elements of cellular communication: endocrine, paracrine, juxtacrine, autocrine.

Receptor Superfamilies

• 4 superfamilies: G-protein coupled, Ligand-gated ion channels, Kinase linked receptors, Nuclear receptors.
• G-protein coupled receptors: largest receptor family, 865 known human GPCRs.
• Ligand-activated receptors; single polypeptide, 7 TM domains.
• Linked to intracellular effectors: G-proteins.
• Activate enzymatic signalling cascade – metabotropic; slow (induction 100+ ms; initial effects for seconds – minutes).

G-Protein Coupled Receptors (GPCRs)

• 3 types of GPCRs: Gs, Gi, Gq.
• Gs: stimulates Adenylate Cyclase, increases cAMP.
• Gi: inhibits Adenylate Cyclase, decreases cAMP.
• Gq: activates Phospholipase, increases Calcium.

Ligand Gated Ion Channels

• Ligand binds to receptor, channel in receptor opens allowing ion movement across membrane.
• Ionotropic, very fast – neurotransmission.
• Examples of ligand-gated ion channels: nicotinic acetylcholine receptors, NMDA glutamate receptors, GABAA receptors, P2X receptors.

Enzyme-Linked and Nuclear Receptors

• Often activated by signalling molecules like cytokines, hormones.
• Usually involved in regulation of cell processes and gene expression.
• Slow induction of effects, very long lasting effects (gene regulation).
• Enzyme-linked: e.g. receptor tyrosine kinase (RTK), receptor serine/threonine kinase (RSTK).
• Nuclear receptors: steroid hormones bind to receptor proteins and goes to nucleus, then binds to specific regions of the DNA, MRNA is produced/codes for specific proteins.

Ion Channels

• Usually selective for either: cations (K+, Na+, Ca2+) or anions (Cl-, rare others).
• Cation channels may be selective for a specific ion, or if non-specific, are usually permeable to all three.
• Ligand-gated channels: leak channels, voltage-gated channels.
• Voltage-gated ion channels: e.g. voltage-gated sodium channel (Na+ channel).

Tolerance, Withdrawal, and Desensitisation

• Tolerance: the drug may become less effective (“refractory”).
• Withdrawal: removal of the drug may cause a reverse rebound as the body has adjusted to a new baseline with drug.
• Desensitisation: the reduction of activity of a drug target in response to a drug.
• Target desensitisation may be acute, rapid, and transient (“tachyphylaxis”) or long-term due to chronic administration; often a basis of tolerance.