What makes a drug work? Understanding “Receptors” (I)
Illustrations and quotations from this post are referenced from Basic & Clinical Pharmacology*.
Imagine you take a pill when you have a headache (perhaps like now when you are trying to understand some pharmacology lol). What happens after you swallow it? How does the pill reduce your headache from your digestive tract to the site of action?
Definition/Nature of a drug
“In the most general sense, a drug may be defined as any substance that brings about a change in biologic function through its chemical actions.”
→ A drug acts “chemically” instead of “physically” by nature to be distinguished from medical devices.
In this article, we will focus on explaining the “target molecule” and the “regulatory” effect of the molecule. Let’s understand our body first.
What is a receptor? The target molecule
The “target molecule” above, is so called “receptors”. You can imagine a receptor as a “bridge” the ingested drug has to bind with in order for it to exert action to our body.
To function as a receptor, an endogenous/exogenous molecule must first be selective in choosing ligands (drug molecules) to bind; and second, it must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered.
Therefore, receptors come in various forms. Table 1 summarizes the four most common types with examples.
The effect of a drug is dependent on several factors, such as affinity of the drug to the receptor and the quantity of the receptors inside the body.
This partly explains why one drug gives different effects to different people as we have different quantity of the receptors.
We can decide however amount of medications we want to ingest, but there is a limitation of the receptors we have. A concentration-effect curve explains the classic hyperbolic relation between the drug concentration and its effect (Figure 2A).
The hyperbolic curve can be obtained by the Formula 1 in Table 2. We can rewrite the formula by replacing the maximal effect (Emax) with the maximum number of drugs bound to the receptors at infinitely high drug concentration (Bmax) at a certain drug concentration (C ). The EC50 is replaced with Kd, equilibrium dissociation constan. In other words, Bmax approximates the number of receptors and Kd approximates the affinity (Figure 2B).
However, Figure 2 only represents one typical scenario where the drug acts as an agonist, exerting the maximal effect of the receptor. As mentioned above, there are various types of “interactions”, and we will talk about these interactions now!
A model of drug-receptor interaction: regulatory effect
Naturally, a receptor has two states, and it changes the conformation/structure when going from one state to the other. In inactive state (Ri), it produces no effect, even when combined with a drug molecule; in the active state (Ra), the receptor would produce some effects in the absence of drug, and this is called constitutive activity, and it produces a higher effect when combined to an agonist.
There are typically 5 types of interactions: full agonists, partial agonists, allosteric agonists/antagonists, antagonists, and inverse agonists.
Full agonists, partial agonists, antagonists, and inverse agonists
Typically, a full agonist has a higher affinity to Ra state and tends to stabilize the conformation, shifting all receptors to the Ra state, and therefore maximizes the effect. A partial agonist also would enhance the effect but with a lesser degree as it evokes a lesser response and does not stabilize Ra as a full agonist does.
On the other hand, an antagonist (or neutral antagonist) fixes the Ri/Ra ratio as in the absence of drugs and thus produce no further effect (so constitutive activity remains) ; however, the presence of an antagonist would prevent the binding of an agonist or a partial agonist to deliver its effect. An inverse agonist, as opposed to a full agonist, stabilizes and maintains a large fraction in the Ri conformation, and therefore does not give extra effect and reduce the constitutive activity. For example, γ-aminobutyric acid (GABA-A) receptors are usually activated to inhibit some brain activities. Benzodiazepines act as GABA-A agonists for sedation purpose but also produce paradoxical anxiety from the inverse-agonist effects [1].
Figure 4 depicts the dose-response relationships of a full agonist, a partial agonist, an antagonist, and an inverse agonist.
Administering antagonists is usually more difficult to control compared to using agonists. Antagonist drugs are further divided into two classes.
1. Competitive antagonist: “In the presence of a fixed concentration of agonist, increasing concentrations of a competitive antagonist progressively inhibit the agonist response”. (and vice versa)
2. Noncompetitive/Irreversible antagonist: “once a receptor is bound by such a drug, agonists cannot surmount the inhibitory effect irrespective of their concentration.”
The distinction between the two types of antagonists can be visually observed in Figure
Allosteric agonists/antagonists
The above mentioned agents bind to the same site on the receptor as the endogenous substances do. Interestingly, a drug can modulate the receptor effects by binding to a different location! These drugs are called allosteric agonists/antagonists, depending on their effects (Figure 6).
In this article, we summarize the nature of receptors and various ways a drug can affect the receptor effect. How exactly a drug “interacts” with a receptor and gives the desired effect is another huge topic: signaling mechanisms. We will cover these mechanisms in the future.
- Khilnani, G., & Khilnani, A. K. (2011). Inverse agonism and its therapeutic significance. Indian journal of pharmacology, 43(5), 492–501. https://doi.org/10.4103/0253-7613.84947
*Katzung B.G.(Ed.), (2017). Basic & Clinical Pharmacology, 14e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2249§ionid=175215158
