How a chemical finds its target, and what stands in its way
A chemical substance impacts human physiology in specific ways, generally by binding to a particular target protein. Receptors, ion channels, enzymes, and carrier transport proteins are the main target proteins of drugs. These proteins vary in their amount throughout the body, and their distribution depends on body compartment and tissue — some receptors are found only in very specific locations. This confers specificity of effect to the target protein when actuated by a particular chemical (drug) — and, in turn, specificity to the drug itself.
A drug must find its way to its target protein to have an effect. To do this, it must pass a number of obstacles, jump through hoops, slide under barrier rails, and squeeze through narrow passageways — because the body is compartmentalized and barred up, with barriers enforcing different conditions in different places.
Body compartments and their barriers
The compartments are maintained in set conditions by homeostatic mechanisms — mechanisms that allow a certain amount of flux while keeping the internal environment within certain limits. Beyond those limits, physiology breaks down.
There are three main fluid compartments: the intracellular compartment, the interstitial compartment, and the plasma (extracellular) compartment. These are separate and distinct but communicate chemically with one another. Each is maintained under different conditions to the others, yet remain similar enough that communication between compartments remains possible.
- The cell membrane separates the intracellular compartment from the interstitial compartment.
- The capillary wall and its endothelium defines the interstitial compartment from blood plasma.
Capillaries are intima-only vessels, arranged in series and parallel, consisting of little more than a single layer of squamous endothelium (including tight junctions) — their purpose is fluid and chemical exchange. Capillary permeability itself varies meaningfully by tissue, which matters directly for how easily a drug reaches a given site:
- Continuous capillaries (muscle, skin, lung, and — in their most restrictive form — the brain) have tight, closely-joined endothelial cells and are the most selective. The blood–brain barrier is the extreme end of this type, and is the single biggest reason many drugs that work well elsewhere in the body fail to reach the CNS.
- Fenestrated capillaries (kidney glomeruli, endocrine glands, gut mucosa) have small pores that allow larger and more rapid exchange of fluid and small molecules.
- Sinusoidal (discontinuous) capillaries (liver, spleen, bone marrow) have large gaps between endothelial cells, allowing even large molecules and cells to pass — this is part of why the liver is so central to drug and toxin handling.
A drug must enter the body and reach the right compartment to attach to its target protein. Many drugs act on cell surface receptors, so they need to reach the interstitium to access the cell’s outer membrane from the blood plasma. Some drugs act on receptors inside the cell and must also cross the cell membrane itself. Others act on receptors found only on a specific face of polarised epithelial cells — the apical surface (facing a lumen, as in the gut lining or nephron tubule) as distinct from the basolateral surface (facing the interstitium/bloodstream).
Crossing the cell membrane
The most important means by which a drug crosses the cell membrane is passive diffusion. Beyond passive diffusion, chemical and fluid transport can also occur via facilitated diffusion, pressure-driven ultrafiltration, and active transport. (Osmosis can be thought of as the diffusion — or facilitated diffusion — of water specifically.)
A lipid-soluble chemical crosses the cell membrane by passive diffusion, because the membrane is a phospholipid bilayer. Water-soluble (ionic) substances, by contrast, can only cross via transmembrane glycoproteins specifically slotted into the membrane for that purpose — the cell membrane is an effective barrier to the passage of ionised molecules on their own.
The rate of passive diffusion is determined by:
- Molecular size — diffusion rate is commonly taught as inversely related to the square root of molecular size (by analogy with Graham’s Law for gases); some pharmacology texts instead relate it more directly to molecular radius via the Stokes–Einstein relationship. Either way, the practical point holds: smaller molecules diffuse faster.
- Concentration gradient (Fick’s Law) — diffusion across a membrane is proportional to the concentration gradient for that chemical across it.
- Lipid solubility — non-polar substances dissolve freely in lipids, and lipid-soluble molecules diffuse easily through cell membranes, which are fluid at body temperature. A substance’s membrane solubility can be expressed as a partition coefficient: its solubility in the lipid phase relative to the aqueous phase.
- Degree of ionisation (Henderson–Hasselbalch) — the degree of ionisation of a drug in solution depends on its molecular structure and the pH of the solution. The pH at which 50% of a drug’s molecules are ionised is a constant called its pKa. Most drugs are weak acids or weak bases and exist in equilibrium between their un-ionised and ionised forms.
- Protein binding — only the fraction of drug that has dissociated from its transport protein is free to cross the cell membrane. The degree of protein binding therefore governs the proportion of free to bound drug, and it’s the free fraction’s concentration that drives diffusion.
Getting into — and around — the body
A drug first has to enter the body: a tablet is swallowed and the drug crosses the GIT epithelium; an injection delivers it directly into a part of the body accessible by needle and syringe; a drug can be applied to the skin and absorbed through the epidermis; or it can be inhaled. Absorption is the passage of a drug from its site of administration into the systemic circulation.
Once in the blood, the drug circulates around the body and leaches into tissue from the local vascular bed. That vascular bed supplies a flow of drug that raises its concentration in the interstitium, from where the drug moves toward cells — either to act on surface receptors, or to diffuse into the cell and act there. The drug is then said to have been distributed throughout the body. Only the portion of the drug that reaches the tissue containing its target protein is in a position to take its effect.