Principles of Drug Action
Drug action is the study of how drugs affect the function of cells, tissues, organs or organisms. Drugs can alter or inhibit the activity of specific molecules, such as receptors, enzymes, ion channels, transporters or DNA. Drugs can also interact with each other and produce synergistic or antagonistic effects. In this blog post, we will explore some of the basic principles and mechanisms of drug action.
Receptors as Drug Targets
Receptors are proteins that act as recognition sites for endogenous ligands, such as neurotransmitters, hormones, inflammatory mediators, etc. Receptors are located on the cell surface or inside the cell, and they can trigger different cellular responses when activated by their ligands. Many drugs act by binding to receptors and either mimicking or blocking the action of the endogenous ligands. A drug that binds to a receptor and activates the cellular response is called an **agonist**. A drug that binds to a receptor and prevents the activation by the endogenous ligand is called an **antagonist**.
Receptors are not rigid structures, but they can change their shape depending on the binding of ligands or drugs. Receptors can have different conformations that correspond to different levels of activity. When an agonist binds to a receptor, it stabilizes the active conformation and enhances the cellular response. When an antagonist binds to a receptor, it stabilizes the inactive conformation and reduces or abolishes the cellular response. The binding of drugs to receptors is usually reversible and depends on the concentration and affinity of the drugs.
Receptors can also have different subtypes that have different functions and distributions in the body. For example, there are four subtypes of adrenergic receptors (alpha-1, alpha-2, beta-1 and beta-2) that mediate different effects of adrenaline and noradrenaline on various organs. Drugs can have different selectivity for different receptor subtypes, which can result in different therapeutic effects and side effects. For example, beta-1 blockers are used to treat hypertension and heart failure by reducing the cardiac output and heart rate, while beta-2 blockers can cause bronchoconstriction and hypoglycemia by inhibiting the relaxation of bronchial smooth muscle and the stimulation of glycogenolysis.
Receptors can also be modulated by other factors, such as co-agonists, allosteric modulators, inverse agonists or partial agonists. A **co-agonist** is a molecule that enhances the effect of an agonist by binding to a different site on the same receptor. For example, glycine is a co-agonist of glutamate at NMDA receptors in the brain. An **allosteric modulator** is a molecule that binds to a site on the receptor that is distinct from the orthosteric site (the site where the endogenous ligand binds) and alters the affinity or efficacy of the orthosteric ligand or drug. For example, benzodiazepines are allosteric modulators of GABA at GABA-A receptors in the brain. An **inverse agonist** is a molecule that binds to a receptor and stabilizes an inactive conformation that has lower activity than the basal state of the receptor. For example, rimonabant is an inverse agonist of cannabinoid receptors in the brain and peripheral tissues. A **partial agonist** is a molecule that binds to a receptor and produces a submaximal response compared to a full agonist. For example, buprenorphine is a partial agonist of opioid receptors in the brain and spinal cord.
Enzymes as Drug Targets
Enzymes are proteins that catalyze specific biochemical reactions in the body. Enzymes are essential for many physiological processes, such as metabolism, synthesis, degradation, signaling, etc. Enzymes can also be involved in pathological processes, such as inflammation, infection, cancer, etc. Drugs can act by inhibiting or inducing enzymes and affecting their activity or expression.
Enzyme inhibitors are drugs that bind to enzymes and reduce their catalytic activity. Enzyme inhibitors can be classified into two types: **competitive inhibitors** and **non-competitive inhibitors**. Competitive inhibitors bind to
Enzyme inhibitors are drugs that bind to enzymes and reduce their catalytic activity. Enzyme inhibitors can be classified into two types: **competitive inhibitors** and **non-competitive inhibitors**. Competitive inhibitors bind to the same site as the substrate and compete with it for binding. The inhibition can be overcome by increasing the substrate concentration. Non-competitive inhibitors bind to a different site than the substrate and change the shape of the enzyme, making it less active. The inhibition cannot be overcome by increasing the substrate concentration.
Enzyme inhibitors can have therapeutic effects by blocking the synthesis or degradation of certain molecules or by interfering with the metabolism of other drugs. For example, aspirin is a competitive inhibitor of cyclooxygenase (COX) enzymes, which are involved in the synthesis of prostaglandins, thromboxanes and leukotrienes. By inhibiting COX enzymes, aspirin reduces inflammation, pain, fever and platelet aggregation. Another example is allopurinol, a competitive inhibitor of xanthine oxidase, which is involved in the degradation of purines. By inhibiting xanthine oxidase, allopurinol reduces the production of uric acid and prevents gout.
Enzyme inducers are drugs that increase the activity or expression of enzymes and enhance their metabolism or synthesis of certain molecules. Enzyme inducers can act by binding to enzymes and increasing their catalytic efficiency or by stimulating the transcription of genes that encode for enzymes. Enzyme inducers can have therapeutic effects by increasing the elimination or activation of certain drugs or by stimulating the production of endogenous substances. For example, phenobarbital is an inducer of cytochrome P450 (CYP) enzymes, which are involved in the metabolism of many drugs. By inducing CYP enzymes, phenobarbital increases the clearance of drugs such as warfarin, phenytoin and oral contraceptives and reduces their efficacy. Another example is rifampicin, an inducer of UDP-glucuronosyltransferase (UGT) enzymes, which are involved in the conjugation of bilirubin. By inducing UGT enzymes, rifampicin increases the excretion of bilirubin and treats jaundice.
Ion Channels as Drug Targets
Ion channels are proteins that form pores in the cell membrane and allow the movement of ions across the membrane. Ion channels are essential for many physiological processes, such as nerve conduction, muscle contraction, hormone secretion, etc. Ion channels can be classified into two types: **voltage-gated ion channels** and **ligand-gated ion channels**. Voltage-gated ion channels open or close in response to changes in the membrane potential. Ligand-gated ion channels open or close in response to binding of ligands, such as neurotransmitters, hormones or drugs.
Drugs can act by modulating the opening or closing of ion channels and affecting the membrane potential or the intracellular concentration of ions. Drugs can act on ion channels by directly binding to them or by influencing their gating mechanisms. Drugs can have different effects on ion channels, such as blocking, activating, stabilizing or prolonging their opening or closing.
Drugs that act on ion channels can have therapeutic effects by altering the excitability or conductivity of cells or by affecting the function of organs that depend on ion fluxes. For example, lidocaine is a blocker of sodium channels, which are involved in the generation and propagation of action potentials in neurons and cardiomyocytes. By blocking sodium channels, lidocaine reduces nerve pain and cardiac arrhythmias. Another example is diazepam, an activator of GABA-A receptors, which are ligand-gated chloride channels that mediate inhibitory neurotransmission in the brain. By activating GABA-A receptors, diazepam increases chloride influx and hyperpolarizes neurons, causing sedation, anxiolysis and anticonvulsant effects.
