Pharmacology

• Proteins as drug targets include receptors, ion channels, enzymes, and transporters
• Proteins form the molecular targets for drug action in mammalian cells
• Drugs usually act by binding to one of the four protein targets: receptors, ion channels, enzymes, or carrier molecules (transporters)
• Drugs are chemicals that produce a biological effect when given to a living organism
• Medicines are chemical preparations containing one or more drugs and other components like stabilizers or solvents
• Drugs can come from plants, synthetic chemicals, biologics/biopharmaceuticals, fungi, microorganisms, or animals
• Principles of drug interactions with their targets
• Drugs must have a selective action on a tissue or cell type
• Drug targets must show a high degree of specificity in their interaction with drugs
• Specificity is never absolute, and drugs can interact with more than one protein target, leading to potential side effects
• Quantification of drug action
• Affinity describes the ability of a drug to bind to a receptor (drug target)
• The equilibrium constant (KA) quantifies the affinity of a ligand to a receptor
• The smaller the equilibrium constant, the higher the affinity of the ligand to the receptor
• Relationship between receptor occupancy and effect
• Functional response to a drug (agonist) is quantified, and it may not be directly proportional to receptor occupancy
• Full agonists evoke a maximal response, while partial agonists evoke a response that falls short of the maximum
• The effective dose at which the response is 50% of the maximum (ED50) allows comparison of the potency of different drugs
• Properties of ligand-receptor interactions: Antagonists
• Antagonists have high affinity but zero efficacy, meaning they do not activate the receptor
• Competitive, reversible antagonists bind to the agonist binding site and can inhibit the action of agonists by preventing their binding
• Allosteric modulators
• Alters the action of an agonist by binding to an accessory site on the receptor
• No effect in the absence of an agonist
• Molecular insights into drug-receptor interactions
• Nicotinic ACh receptor is a ligand-gated ion channel
• Acetylcholine (ACh) is a neurotransmitter at the NMJ
• Resting membrane potential of a neurone is about -65 mV, where the inside is more negative than the outside
• Resting membrane potential is essential for normal neuronal function and is maintained by an unequal distribution of ions across the membrane
• Unequal ionic distribution is actively maintained by energy-dependent ion pumps like the Na+/K+ pump
• If the membrane is solely permeable to K+, the resting potential will equal the K+ equilibrium potential
• When an ion channel opens, two forces act on ions: electrical gradient and concentration gradient
• Neuronal membranes contain ion channels that open in response to changes in transmembrane voltage, mediating the generation of action potentials
• Action potentials propagate down the axon through myelinated "saltatory" conduction or unmyelinated conduction
• Local depolarisation of the axon triggers voltage-gated Na+ channels to open, allowing Na+ to flow into the axon down its electrochemical gradient
• This depolarisation leads to the slower opening of voltage-gated K+ channels, causing K+ to flow out of the axon, leading to hyperpolarisation
• After a brief opening, Na+ channels quickly enter an inactive state, while slow closure of K+ channels controls the time before another action potential can be generated
• Communication across a synapse involves the release of a neurotransmitter from the pre-synaptic terminal, which binds to receptors in the postsynaptic membrane, eliciting an electrical signal
• Ca2+ entry into the presynaptic terminal is essential for neurotransmitter release, triggering vesicular exocytosis
• Ligand-gated ion channels activated by neurotransmitters like glutamate mediate excitatory postsynaptic potentials (epsp) in the CNS