General Principles of Pharmacology

G protein-coupled receptors are the largest and most pharmacologically important family of drug targets. They are membrane proteins with seven transmembrane segments that, when activated by a drug or endogenous ligand, couple to intracellular G proteins and initiate a cascade of intracellular signaling. The response takes seconds to minutes and is amplified through second messenger systems. An enormous range of drugs act at G protein-coupled receptors, including beta-blockers, opioids, antihistamines, and many others. Muscarinic receptors in the heart and smooth muscle are a familiar example: their activation by acetylcholine or muscarinic agonists slows the heart rate and contracts smooth muscle through G protein-mediated intracellular signaling.

Ligand-gated ion channels are membrane proteins that open an ion-conducting pore directly upon ligand binding, without any intermediary signaling step. The response is almost instantaneous — measured in milliseconds — making these receptors the primary targets at fast synapses in the nervous system. The nicotinic acetylcholine receptor at the neuromuscular junction is the prototypical example: when acetylcholine binds, the channel opens and sodium ions flow in, depolarizing the muscle membrane and triggering contraction. Drugs that act at ligand-gated ion channels include neuromuscular blocking agents and benzodiazepines, which enhance the effect of gamma-aminobutyric acid at its ion channel receptor in the brain.

Enzyme-linked receptors are transmembrane proteins that have enzymatic activity on their intracellular side. The most common type is the receptor tyrosine kinase, which phosphorylates target proteins inside the cell when activated by a growth factor or cytokine binding to its extracellular domain. The response develops over minutes to hours. Insulin receptors are enzyme-linked receptors: insulin binding activates the receptor’s kinase domain, triggering a cascade of phosphorylation events that ultimately promotes glucose uptake into cells. Several cancer drugs target specific receptor tyrosine kinases that are overactive in tumor cells.

Nuclear receptors are intracellular proteins that act as transcription factors when activated by their ligands. Because they regulate gene expression, the response develops slowly — over hours to days — and persists long after the drug has been eliminated from the body. The ligands for nuclear receptors must be lipophilic enough to cross the cell membrane and reach the receptor in the cytoplasm or nucleus. Glucocorticoids, thyroid hormones, sex steroids, and vitamin D all act through nuclear receptors. This mechanism explains why corticosteroid anti-inflammatory effects take hours to develop and why abrupt discontinuation after prolonged use can cause serious problems: the drug has been suppressing gene expression, and the body needs time to restore normal transcriptional activity.

Not all drugs act through receptors. Many important drug classes target enzymes, ion channels directly, or membrane transporters. Angiotensin-converting enzyme inhibitors block the enzyme that converts angiotensin I to angiotensin II, reducing blood pressure. Proton pump inhibitors covalently inactivate the hydrogen-potassium adenosine triphosphatase enzyme in the stomach, blocking acid secretion. Statins inhibit the enzyme that controls cholesterol synthesis. Local anesthetics block voltage-gated sodium channels directly. Antidepressants of the selective serotonin reuptake inhibitor class block the transporter that removes serotonin from the synapse. In each case the drug produces its effect not by activating or blocking a receptor, but by interfering with a specific enzyme, channel, or transporter function.

Potency refers to the dose or concentration of a drug required to produce a given effect. A more potent drug produces its effect at a lower dose than a less potent drug. On a dose-response curve, a more potent drug has its curve shifted to the left — the effect begins at lower concentrations. Potency determines how many milligrams of a drug need to be prescribed, but it says nothing about the maximum effect the drug can produce.

Efficacy refers to the maximum effect a drug can produce, regardless of dose. A drug with high efficacy produces a large maximum response. A drug with low efficacy produces a small maximum response no matter how high the dose is pushed. The distinction matters clinically: a highly potent drug is not necessarily a highly efficacious one. Morphine has higher efficacy as an analgesic than codeine, meaning it can control severe pain that codeine cannot, regardless of what dose of codeine is used. Aspirin has higher potency as an anti-inflammatory than acetaminophen (it works at lower doses), but both have similar ceiling effects for fever reduction.

The therapeutic index is the ratio of the dose that produces toxicity to the dose that produces the desired therapeutic effect. A large therapeutic index means there is a wide margin between the dose needed for efficacy and the dose that causes harm — the drug is relatively safe to use across a range of doses. A small (narrow) therapeutic index means that therapeutic and toxic doses are close together, leaving little room for dosing error.

Narrow therapeutic index drugs require careful dosing, patient-specific adjustment, and often therapeutic drug monitoring. Digoxin, warfarin, lithium, phenytoin, and aminoglycoside antibiotics are classic examples. For these drugs, a dose that is just right for one patient may be subtherapeutic for another and toxic for a third, because of individual differences in pharmacokinetics. Recognizing a drug as having a narrow therapeutic index is a signal to monitor closely, adjust carefully, and check drug levels when indicated.