Principles of Substance Classification
The main criterion by which receptor-acting drugs are classified is intrinsic activity.
- If a substance binds to a receptor (has affinity, or affinity) and is able to activate it, it is called an agonist.
- If a substance binds but has no intrinsic activity, it is an antagonist.
Agonists (mimetics) alter the conformation of the receptor. This triggers a cascade of intracellular biochemical reactions, ultimately leading to a pharmacological effect.
Types of agonists
Agonists are classified by the strength of their stimulating effect on the receptor:
- Full agonists. They possess maximal intrinsic activity and are capable of producing the maximum possible effect for a given system. For example, acetylcholine fully opens ion channels upon binding to nicotinic receptors.
- Partial agonists. Their intrinsic activity is below the maximum. Even if they occupy all available receptors, the effect will be weaker than that of a full agonist (e.g., buprenorphine).
- Inverse agonists. They act on spontaneously (constitutively) active receptors, shifting them from the active state to the inactive state.
Mechanisms of action of antagonists
Antagonists (or blockers) have affinity but lack intrinsic activity. Their role is to occupy the receptor and prevent endogenous ligands (hormones, neurotransmitters) or exogenous agonists from binding.
The effect of antagonists is secondary: they eliminate the action of the natural stimulant, so the observed effect is often opposite to that of the agonist. For instance, acetylcholine causes bradycardia, whereas the antagonist atropine blocks its action, resulting in an increased heart rate.
Antagonism has two main types:
- Competitive. Substances compete for the same binding sites. Who wins depends on concentration and affinity. The effect is reversible (overcomable) — adding more agonist will displace the antagonist. This property is utilized in antidote therapy (e.g., physostigmine in atropine poisoning).
- Non-competitive. The antagonist binds to a different (allosteric) site on the receptor or forms a strong covalent bond with it. The receptor changes conformation and cannot respond to the agonist. This type of antagonism is insurmountable: increasing the agonist dose does not restore the maximal effect.
Special types of interaction
Pharmacology distinguishes substances with a mixed type of action — agonist-antagonists. They selectively interact with different receptor subtypes of the same system. For example, butorphanol blocks $\mu$-opioid receptors while stimulating $\kappa$-opioid receptors. This helps reduce adverse effects compared to full agonists.
Partial agonists also exhibit interesting behavior. Competing with full agonists for binding sites, they displace the latter. Because the intrinsic activity of a partial agonist is lower, the net effect decreases. Thus, functionally they can act as antagonists.
Briefly: answers to topical questions
Which drugs serve as examples of non-competitive antagonists?
An example of a non-competitive antagonist is ketamine.
- Ketamine is a phencyclidine derivative that acts as a non-competitive NMDA receptor antagonist and is used for general anesthesia.
The mechanism of action of non-competitive antagonists is that they bind not to the active site, but to allosteric sites of the macromolecule, or form stable covalent bonds with the receptor. This induces a conformational change in the receptor, causing it to lose the ability to interact with the agonist. Increasing the agonist concentration does not fully restore the effect in this case.
What types of drug antagonism exist besides receptor antagonism?
Besides receptor antagonism, there is direct and indirect functional antagonism, as well as physical and chemical antagonism.
- Physical antagonism is based on the physical interaction of substances (adsorption), resulting in the formation of inactive or poorly absorbed complexes (e.g., adsorption of toxins on activated charcoal).
- Chemical antagonism is a chemical reaction between substances resulting in the formation of inactive compounds. Drugs of this type are called antidotes (e.g., sodium thiosulfate, protamine sulfate).
What is drug synergism and what types does it include?
Synergism is the unidirectional action of drugs in which the combined pharmacological effect exceeds the effects of each component individually.
There are two main variants of this interaction:
- Summation (additive effect) — the effect of the combination equals the simple arithmetic sum of the effects of each component. It occurs when substances act on the same substrates.
- Potentiation — one substance significantly enhances the action of another, and the final effect exceeds the sum of the effects of the individual components. This allows for lower dosages of toxic drugs.
Which intracellular reaction cascades are triggered by agonists upon binding to G-protein-coupled receptors?
When agonists bind to G-protein-coupled receptors, enzymes are activated that trigger the formation of second messengers and protein phosphorylation.
Main intracellular cascades:
- Adenylyl cyclase system — the G-protein activates adenylyl cyclase, which hydrolyzes ATP to form cAMP. The accumulation of cAMP activates cAMP-dependent protein kinases, which phosphorylate cellular proteins.
- Inositol triphosphate system — the G-protein activates phospholipase C, which cleaves membrane phospholipids into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 opens calcium channels of the endoplasmic reticulum, and the released calcium along with DAG activates protein kinase C.
An effect on guanylyl cyclase with the formation of cGMP is also possible.
Class and exam questions
What is the difference between an agonist and an antagonist?
Both have affinity for the receptor, but the agonist possesses intrinsic activity and stimulates the receptor, whereas the antagonist lacks intrinsic activity and merely blocks the receptor.
Can the effect of a non-competitive antagonist be overcome?
No, non-competitive antagonism is insurmountable. Even an infinite increase in the agonist dose will not achieve a 100% effect, as some receptors are rendered permanently inactive.
Why can a partial agonist act as an antagonist?
If a partial agonist displaces a full agonist from receptors, the overall pharmacological effect of the system decreases because the intrinsic activity of the partial agonist is lower.
What else to study on this topic
- Graphical analysis of the dose-response relationship
- Examples of competitive antagonism in antidotal therapy
- Characteristics of inverse agonist action
- Pharmacological profile of agonist-antagonist drugs
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