Site of effect: local and resorptive
Depending on where exactly the drug begins to work and contact tissues, local and resorptive actions are distinguished.
Local action develops directly in the area of substance application. The drug interacts with sensory nerve endings on the skin or mucous membranes. Typical examples include the use of ointments, lotions, patches, gargles, as well as eye and ear drops, or performing surface anesthesia. It is important to remember that even with local administration, a portion of the substance may be absorbed into the blood, leading to an unforeseen systemic effect, or the drug may trigger reflex reactions.
Resorptive action (from Latin resorbeo — to absorb) occurs only after the drug enters the systemic circulation and is distributed throughout the body. This can be achieved by absorption of the substance into the vascular bed or by direct intravenous administration.
Direct, indirect, and reflex action
Drugs can alter the function of organs and systems in three different ways depending on the proximity of the target:
- Direct (primary) action implies direct contact of the drug with the tissue of the target organ. For instance, cardiac glycosides directly bind to cardiomyocytes, exerting a cardiotonic effect (increasing the force of myocardial contractions).
- Indirect (secondary) action is a cascade of physiological changes that occurs as a consequence of a primary effect on another organ. For example, the improvement of diuresis under the influence of cardiac glycosides occurs not due to their direct effect on the kidneys, but thanks to increased cardiac output and elimination of circulatory failure.
- Reflex action is realized through the nervous system. The drug excites receptors, the signal is transmitted via the reflex arc to the central nervous system, from where a stimulating or inhibitory command is sent to distant organs. One can affect exteroceptors of the skin (mustard plasters cause irritation and a subsequent trophic effect in internal organs) or vascular interoceptors (intravenous administration of lobeline excites carotid sinus chemoreceptors, which stimulates the respiratory and vasomotor centers).
Therapeutic goal and selectivity
In clinical practice, the effects of the same drug are strictly divided into desirable and undesirable, and the focus of their action is also evaluated.
- Main (primary) action is the result for which the drug is used in a specific disease. It depends on the context of the pathology. For example, phenytoin in a patient with epilepsy is used for its main anticonvulsant effect, while in arrhythmia against the background of glycoside intoxication, its main effect is antiarrhythmic.
- Side effect includes any additional changes that occur when taking a drug in therapeutic doses. Most often they are undesirable and may become the reason for discontinuing therapy. Classical examples: ulcerogenic action of acetylsalicylic acid (formation of ulcers on the gastric mucosa) or ototoxicity (hearing impairment) when taking aminoglycosides such as gentamicin.
- Selective action means that the substance acts predominantly on a specific organ. Oxytocin works on the uterine myometrium, cardiac glycosides on the myocardium, and hypnotics on central nervous system structures.
Localization in the nervous system and bond strength
Based on the localization of action in the nervous system, central action (direct action on the brain and spinal cord, as with general anesthetics or antidepressants) and peripheral action (action on peripheral nerves, synapses, or tissues) are distinguished. For example, curariform muscle relaxants relax skeletal muscle by blocking neuromuscular synapses, while vasodilators relax vascular smooth muscle. Drugs with central action may produce peripheral side effects (the antipsychotic chlorpromazine blocks peripheral $\alpha$-adrenoceptors, lowering blood pressure).
At the cellular level, voltage-gated ion channels frequently serve as targets (they open upon membrane depolarization, unlike ligand-gated receptors). Drugs can block ion influx or activate currents.
According to the nature of the chemical bond with the target molecule, two types of action are distinguished:
- Reversible: the drug binds via weak bonds (hydrogen, ionic, van der Waals). The complex dissociates through competition for the binding site or natural dissociation.
- Irreversible: strong covalent bonds are formed. For example, acetylsalicylic acid irreversibly acetylates the active center of the enzyme cyclooxygenase (COX). The effect ceases only after the synthesis of new enzyme molecules by the organism.
Briefly: answers to topical questions
What factors determine the onset rate of the resorptive action of a drug?
The onset rate of resorptive action (absorption rate) is primarily determined by the route of administration. This process is also influenced by the following factors:
- Physicochemical properties — lipophilic nonpolar compounds are absorbed best, and for solid forms, the use of water-soluble salts accelerates the process.
- Particle size and quantity — micronization increases the contact area and accelerates absorption.
- Blood flow intensity — tissue vascularization (e.g., subcutaneous adipose tissue), which can be altered by massage, compresses, or vasoconstrictors (adrenaline).
- Tissue permeability — can be increased by the administration of the enzyme hyaluronidase.
- Diffusion rate — is a limiting factor in the aqueous environment of the intestine.
What are the main cellular targets for drugs besides ion channels?
Besides ion channels, the main cellular targets for drugs include receptors, enzymes, and transport systems.
- Receptors — specific structures with which drugs bind (e.g., P2Y12 purinergic receptors for thienopyridines).
- Enzymes — substances can act as their inhibitors (e.g., cyclooxygenase, MAO-A, proton pump).
- Transport proteins — carrier proteins whose blockade disrupts the transport of substances across the membrane (e.g., blockade of neurotransmitter reuptake).
- Ion pumps — active ion transport systems (e.g., $Na^+$-$K^+$-ATPase, which is blocked by cardiac glycosides).
Which drugs exert an irreversible action through the formation of covalent bonds?
Irreversible action through the formation of covalent bonds with the target molecule has been confirmed for:
- Acetylsalicylic acid — irreversibly acetylates the active center of cyclooxygenase.
- Thienopyridines (ticlopidine, clopidogrel) — active metabolites covalently bind to cysteine residues of platelet P2Y12 receptors.
- Phenoxybenzamine — forms a strong covalent bond with $\alpha_1$- and $\alpha_2$-adrenoceptors.
What types of adverse drug reactions are distinguished besides the classical side effect?
In addition to the classical side effect occurring with the use of therapeutic doses, the following adverse reactions are distinguished:
- Toxic reactions — can occur when maximum therapeutic doses are exceeded or be associated with direct chemotherapeutic action.
- Allergic reactions — are associated with an effect on the immune system and usually require a sensitization period.
- Idiosyncrasy — a genetically determined aberrant reaction to a drug, capable of occurring upon first contact.
- Drug intolerance — an unpredictable reaction independent of dose.
- Organotropic reactions — damage to specific organs.
Which groups of receptors are excited during the reflex action of drugs?
During the reflex action of drugs, the following are excited:
- Exteroreceptors are receptors of the skin and mucous membranes. For example, mustard plasters irritate the skin, causing a trophic effect in internal organs.
- Interoreceptors include, in particular, the chemoreceptors of the carotid sinus vessels. When administered intravenously, lobeline excites them, leading to stimulation of the respiratory and vasomotor centers.
- Gastric receptors are affected by reflex-acting emetics and expectorants.
The pair of «Direct and Indirect action» is easily remembered using the example of falling dominoes: direct action is the strike against the first tile, and indirect action is the fall of all subsequent pieces as a result of this initial push.
Class and exam questions
How does local drug action differ from resorptive action?
Local action develops directly in the zone of contact between the drug and the tissue (on the skin or mucous membranes), whereas resorptive action manifests only after the substance is absorbed into the systemic circulation and distributed throughout the body.
Can the same action be both the main effect and a side effect?
Yes, this depends on the goal of therapy. For example, the ability of a drug to depress the CNS is the main effect for hypnotics, but acts as a side effect (drowsiness) when taking certain antihistamines.
How does the body recover after irreversible drug action?
With irreversible action, the substance binds to the target (enzyme or receptor) via strong covalent bonds that cannot be broken. Function is restored only thanks to the physiological turnover of proteins — when the body synthesizes new target molecules.
What else to study on this topic
- Mechanisms of voltage-gated ion channels
- The role of the blood-brain barrier in realizing central action
- Interaction of drugs with interoreceptors and exteroreceptors
- Ulcetogenic action and ototoxicity: mechanisms of typical side effects
- Processes of physiological protein turnover in irreversible binding
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