Main Phenomena of Repeated Administration
When prescribing a course of treatment, clinicians must consider that the body's response to the same drug transforms over time. Bioavailability, the therapeutic index, and the adverse effect profile can all undergo changes.
Pharmacology identifies several major phenomena associated with repeated administration:
- Cumulation (accumulation);
- Sensitization;
- Habituation (tolerance);
- Drug dependence.
The Process of Cumulation (*Cumulatio*)
Cumulation refers to the accumulation of the drug itself or the effects it produces within the organism. Depending on the substrate of accumulation, the process is divided into two fundamentally different types.
Material Cumulation This phenomenon involves the physical accumulation of the drug in the patient's blood and tissues. With each subsequent dose, the concentration of the substance becomes higher than after the previous administration. This occurs due to several factors:
- Slowed drug metabolism (inactivation).
- Slowed excretion (elimination) from the body.
- Strong binding of molecules to plasma proteins.
- Depot formation in various tissues.
Typical examples of agents prone to material cumulation include certain hypnotics (particularly barbiturates) and cardiac glycosides (digitalis preparations). The clinical significance of this phenomenon is profound: there is a high risk of developing toxic reactions, which necessitates timely dosage adjustments.
Functional Cumulation In this case, the drug's effect becomes enhanced without an increase in its physical concentration in the bloodstream. The mechanism lies in the summation of functional changes in organs and tissues. A classic example is the effect of alcohol. Severe consequences such as delirium tremens (alcohol withdrawal delirium) can manifest at a point when ethanol has already been completely metabolized and is no longer detectable in blood tests. The effect persists and sums up after the toxin has been eliminated. A similar mechanism is characteristic of monoamine oxidase inhibitors (MAO inhibitors).
Habituation or Tolerance (*Tolerantia*)
Tolerance is the gradual decrease in pharmacological response to a drug upon repeated administration at an unchanged dose. Consequently, patients require a progressive increase in dose to achieve the initial therapeutic result.
An important feature of tolerance is that it develops toward both therapeutic and toxic effects. For example, during long-term use of morphine, both analgesia and the depressant effect on the respiratory center decrease in parallel. The timeline for developing such tolerance ranges from several days to many months.
Mechanisms of Tolerance:
- Pharmacodynamic pathway: Occurs at the receptor level. Typical for agonists (receptor stimulators). It involves desensitization—loss of sensitivity of the receptor apparatus—as well as down-regulation—a decrease in the physical density or number of receptors on the cell membrane.
- Pharmacokinetic pathway: Relates to changes in the drug's "fate" within the body. It includes decreased absorption, accelerated elimination, or accelerated biotransformation. For instance, phenobarbital can induce hepatic enzymes, thereby accelerating its own metabolism.
To overcome tolerance, temporary discontinuation or drug rotation (switching to a substance from a different chemical class) is employed. However, when switching drugs, 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 by which an allergic reaction is established. The drug acts as a hapten, binding to plasma proteins. The resulting complex acquires full antigenic properties. In response, the immune system begins to synthesize specific antibodies. Upon re-exposure to the allergenic drug (frequently penicillins, sulfonamides, procaine, or water-soluble vitamins), an allergic response is triggered.
Special Forms of Habituation
- Tachyphylaxis (from Greek tachys — fast). Extremely rapid tolerance that develops when doses are administered at intervals of 10–15 minutes. A prime 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. Norepinephrine release into the synaptic cleft drops, and the hypertensive effect (blood pressure elevation) rapidly wanes.
- Mithridatism. The gradual development of insensitivity to poisons and potent drugs. It occurs during a long-term course beginning with microscopic doses followed by a slow, steady increase. The term references the historical legend of King Mithridates.