Repeated administration of medicines

Main phenomena of repeated administration

When prescribing a course of treatment, the physician must take into account that the body's reaction to the same medicinal substance transforms over time. Bioavailability, the therapeutic index, and the adverse effect profile may all undergo changes.

Pharmacology distinguishes several main phenomena accompanying repeated administration:

• Cumulation (accumulation);
• Sensitization;
• Habituation (tolerance);
• Drug dependence.

The process of cumulation (Cumulatio)

Cumulation is the accumulation of the medicinal substance itself in the body or the effects it induces. Depending on the accumulation substrate, the process is divided into two fundamentally different types.

Material cumulation The essence of the phenomenon lies in the physical accumulation of the drug in the patient's blood and tissues. With each subsequent administration, the concentration of the substance becomes higher than in the previous administration. This occurs for a number of reasons:

1. Delayed metabolism (inactivation) of the drug.
2. Slow excretion (elimination) from the body.
3. Strong binding of molecules to plasma proteins.
4. Formation of depots in various tissues.

Typical examples of agents prone to material cumulation include certain hypnotic drugs (specifically barbiturates) and cardiac glycosides (digitalis preparations). The clinical significance of this phenomenon is immense: there is a high risk of toxic reactions, which invariably requires timely dosage adjustment.

Functional cumulation In this case, there is an enhancement of the drug's action, but without an increase in its physical concentration in the bloodstream. The mechanism lies in the summation of changes in the functions of organs and tissues. A classic example is the effect of alcohol. Severe consequences in the form of delirium tremens (alcohol psychosis) can manifest at a time when ethanol has already been completely metabolized and is no longer detectable in the blood by laboratory tests. The effect persists and sums up after the toxin is eliminated. A similar mechanism is characteristic of monoamine oxidase inhibitors (MAO inhibitors).

Habituation or tolerance (Tolerantia)

Tolerance is the gradual decrease in the pharmacological response to a drug upon its repeated use at an unchanging dose. As a consequence, to achieve the initial therapeutic result, the patient requires a progressive increase in dose.

An important feature of tolerance is that it develops toward both therapeutic and toxic effects. For example, with prolonged use of morphine, both analgesia (pain relief) and the depressant effect on the respiratory center decrease in parallel. The timeline for the development of such habituation varies from a few days to many months.

Mechanisms of habituation development:

• Pharmacodynamic pathway: implemented at the receptor level. Characteristic of agonists (receptor stimulators). Desensitization occurs — loss of sensitivity of the receptor apparatus, as well as down-regulation — a decrease in the physical density or number of receptors on the membrane.
• Pharmacokinetic pathway: associated with changes in the "fate" of the substance inside the body. Includes decreased absorption, accelerated excretion, or accelerated biotransformation. For example, phenobarbital is capable of inducing hepatic enzymes, thereby accelerating its own metabolism.

To overcome tolerance, temporary discontinuation of the agent or drug rotation (substitution with a substance from another chemical group) is employed. However, when substituting, one must remember the phenomenon of cross-tolerance: if the new substance acts on the same enzymes or receptors, tolerance will persist even if the chemical structure of the drugs differs.

Tachyphylaxis, mithridatism, and sensitization

Sensitization This is the process of forming an allergic reaction. The medicinal substance, acting as a hapten, binds to blood plasma proteins. The resulting complex acquires full antigenic properties. In response, the immune system begins to synthesize specific antibodies. Upon repeated administration of the allergen drug (often penicillins, sulfonamides, procaine, or water-soluble vitamins), an allergic response is triggered.

Special forms of habituation

1. Tachyphylaxis (from Greek tachys — fast). Very rapid habituation occurring with administrations at intervals of 10–15 minutes. A vivid example is ephedrine, which acts indirectly by stimulating the release of norepinephrine. With frequent use, the stores of this neurotransmitter in sympathetic nerve endings are simply depleted. The release of norepinephrine into the synaptic cleft drops, and the hypertensive effect (increase in blood pressure) rapidly weakens.
2. Mithridatism. Gradual development of insensitivity to poisons and potent drugs. It arises during a prolonged course starting with microscopic doses followed by their slow but steady increase. The term refers to the historical legend of King Mithridates.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of physical and mental drug dependence
• Processes of hepatic microsomal enzyme induction using barbiturates as an example
• Down-regulation phenomenon: decrease in receptor density on cell membranes
• Changes in bioavailability via various repeated administration routes
• Combined drug use and specific features of their interaction

Other topics in "General Pharmacology"

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