A Rational Way of Taking Medication Can Improve Therapeutic Efficacy

Treatment of the vast majority of diseases requires drugs to enter cells to exert their effect. So how do drugs get into cells? This requires understanding the several common ways substances enter cells.

Through observation and experiment, biologists have found that substances enter cells mainly by passive transport, active transport, and endocytosis. Passive transport is further divided into simple diffusion and facilitated diffusion; active transport into primary and secondary active transport; and endocytosis into phagocytosis and pinocytosis.

Simple diffusion is a physical phenomenon in which substances cross the membrane from the high-concentration side of the plasma membrane (cell membrane), through the gaps between the lipid molecules, toward the low-concentration side; simple diffusion requires no mediator. Because the cell membrane is a bilayer of liquid lipids, simple diffusion mainly transports lipid-soluble small molecules, such as the oxygen we inhale and the carbon dioxide we exhale when breathing.

Some lipid-soluble small-molecule drugs can also be transported into cells this way, such as diethyl ether used for anesthesia. Simple diffusion applies to a very small range; only very few lipid-soluble small substances can be transported this way, and clinically very few drugs rely on simple diffusion, so this is not discussed further here.

Endocytosis is the process by which extracellular macromolecules or masses of material such as bacteria, dead cells and cell debris are wrapped by the cell membrane and enter the cell in the form of vesicles; this process is also called internalization. The vesicles entering the cell are then handled by lysosomes. The drugs we use clinically basically do not enter cells by this route, so this is not discussed further here either.

Both facilitated diffusion and active transport require a mediator, namely membrane proteins. Drugs entering cells through membrane proteins basically bind to receptors on the cell membrane. Receptors are proteins in cells that receive and transduce information; receptors in the cell membrane are called membrane receptors, while those in the cytoplasm and nucleus are called cytoplasmic and nuclear receptors. Receptors are the key to a drug's action; without the action of receptors, cells are insensitive to the drug.

However, when a drug is used for too long, the number of receptors becomes over-consumed, fewer and fewer receptors remain, and the effect of continuing to use the drug is greatly reduced. This produces what we commonly call drug resistance. Whether Western or Chinese medicine, most drugs need to bind to receptors to enter cells and exert their effect; therefore, both Western and Chinese medicines develop resistance after long use.

But once a drug has developed resistance, it is not absolutely useless: receptors do not suddenly drop to zero, and the weakening of the drug's therapeutic effect is a gradual process. Moreover, after cells have adapted to a certain drug, suddenly stopping it produces great side effects, which in severe cases may even be life-threatening. For example, after long-term use of hormonal drugs, abrupt complete discontinuation makes the patient very unwell. The best measure is to gradually reduce the dosage until finally stopping. During this period, one may try switching to other drugs to produce new effects. This is the same principle as drug rehabilitation, which also requires a step-by-step process.

Cancer patients using certain anti-cancer drugs (such as oral chemotherapy drugs, targeted drugs, or certain Chinese medicines) may also experience this resistance. Resistance in cancer patients is related not only to the reduction of drug receptors but also to the evolution of cancer cells. However, abrupt cessation can also lead to an explosive rebound of the tumor. Rational, step-by-step dose reduction, together with timely switching of regimens and adopting alternatives, can better control the speed of tumor progression and prolong the patient's survival.