Pharmacodynamics: Molecular Mechanisms of Drug Action

Pharmacodynamics: Molecular Mechanisms of Drug Action

• Pharmacodynamics is the study of the effects of drugs on the function of living systems.
• It involves the interaction between a drug and components of the organism.

Drug Action

• Most drugs exert their effects by binding to protein targets such as receptors, ion channels, enzymes, and transporters.
• A drug must bind to a target to produce an effect.

Receptors

• Receptors are proteins that allow a chemical agent (drugs, hormones, neurotransmitters) to initiate a change in cell function.
• Receptors are the cell's 'sensing elements' and provide molecular communication between the chemical agent and the transduction process.
• Different cell types have different receptor profiles, which determines the hormones and neurotransmitters to which the cell responds.

Agonists and Antagonists

• Agonists mimic the actions of endogenous ligands and bind to the receptor to produce a response.
• Antagonists block the actions of endogenous ligands and bind to the receptor to prevent a response.

Ligand Selectivity

• Receptors show ligand selectivity, meaning each receptor type is activated by a small number of substances.
• Receptor activation requires a good 3-D "fit" between the agonist and receptor.

Selectivity of Drugs

• Useful drugs show selectivity, binding only to certain receptors to produce a specific response.
• Selectivity is reciprocal, meaning each drug only binds to certain receptors and each receptor recognises only certain drugs.

Limitations of Selectivity

• Selectivity is not absolute, as most drugs act on more than one receptor.
• Increasing the dose of a drug can activate other receptors, leading to adverse effects.

Drug-Induced Responses

• Drugs act by binding to specific drug targets, such as receptors, to produce a response.
• Agonist binding requires intermolecular forces between the agonist and receptor and is usually reversible.
• The strength of agonist binding is determined by the forward and backward rate constants.

Receptors and Other Drug Targets

• A drug will not work unless it is bound to a protein target, such as receptors, ion channels, enzymes, or transporters.
• Receptors are sub-divided into 4 major types or superfamilies: ion channel receptors, G protein-coupled receptors, enzyme-linked receptors, and nuclear receptors.

Ion Channel Receptors

• Located in the cell membrane
• Collection of proteins form a central pore/channel
• Ions cannot cross the cell membrane without binding of an agonist
• Examples: nicotinic acetylcholine receptor
• Characteristics:
  • Mechanism of signal transduction: binding of an agonist alters ion channel structure, allowing ions to flow into the cell
  • Receptor location: cell membrane
  • Effector protein: channel
  • Time scale of action: milliseconds, very fast
  • Agonist: ACh (acetylcholine)
  • Antagonist: pancuronium (used to produce paralysis during anaesthesia)

G Protein-Coupled Receptors

• Also located in the cell membrane
• 7 transmembrane domains
• Examples: adrenoceptors, muscarinic acetylcholine receptors
• Characteristics:
  • Mechanism of signal transduction: binding of an agonist activates a G protein, which in turn activates an effector protein
  • Receptor location: cell membrane
  • Effector protein: enzyme or channel
  • Time scale of action: seconds, fast
  • Agonist: salbutamol (relieves bronchospasm in asthma)
  • G proteins link GPCRs to effector proteins that generate intracellular second messengers

Enzyme-Linked Receptors

• Also located in the cell membrane
• Examples: insulin receptor, receptors for cytokines, growth factors
• Characteristics:
  • Mechanism of signal transduction: binding of an agonist activates a linked enzyme
  • Receptor location: cell membrane
  • Effector protein: enzyme (e.g. kinase)
  • Time scale of action: minutes, slow
  • Agonist: insulin (used to reduce blood glucose levels)

Nuclear Receptors

• Located in the intracellular compartment
• Examples: glucocorticoid receptor, other steroid hormone receptors
• Characteristics:
  • Mechanism of signal transduction: binding of an agonist activates gene transcription
  • Receptor location: intracellular
  • Effector protein: gene transcription
  • Time scale of action: hours, very slow
  • Agonist: glucocorticoid (prednisolone, an anti-inflammatory agent)

Protein Targets for Drug Action

• Receptors: agonists bind to and activate receptors, while antagonists bind to but do not activate receptors
• Ion channels: blockers physically plug the ion channel, while modulators bind to accessory sites and modulate channel activity
• Enzymes: substrate analogues competitively inhibit the enzyme, while some drugs act as false substrates for enzymes
• Transporters: specific carrier proteins transport ions and small organic molecules across cell membranes, and some drugs inhibit transporters or act as false substrates.