Pharmacodynamics: Desensitization and tolerance

Definitions & Key takeaways

Desensitization and tolerance are two related but distinct concepts that describe changes in the body's response to a drug over time. Desensitization refers to a decrease in the response of a receptor to a drug, resulting in a reduced effect of the drug. This can occur due to a decrease in the number of receptors or a change in the way the receptors interact with the drug.

Tolerance refers to a decrease in the effectiveness of a drug over time, requiring the use of higher doses to achieve the same effect. Tolerance can occur due to several mechanisms, such as changes in the number or function of receptors, changes in the way drugs are metabolized, or changes in the way drugs are transported across the blood-brain barrier.

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Introduction0:00–0:42

Pharmacodynamics refers to the mechanisms and effects of medications within the body. Or more simply, it’s what medications do to the body and how they do it.
Alright, so in order to have an effect, most medications have to reach their target cells and bind to a receptor. Receptors are specialized proteins both on the cell membrane and inside the cell, that can bind to a ligand.
Now, that ligand could be an agonist, which is a molecule that binds and activates a receptor. This means the receptor changes its shape or activity, and that gives rise to a signal cascade of intracellular molecules - the second messengers, which ultimately results in some change in the cell’s function.

Desensitization0:42–3:26

Okay, now if we massively expose the receptors to their agonists, we will get a huge downstream signal cascade and cellular response.
But if we continuously or persistently flood that receptor with the same agonist at the same dose, what will happen, is that the ability of the agonist to produce that response will drop.
This is actually a defense mechanism, whereby cells prevent their overstimulation by agonists. If this happens very rapidly, like within a few minutes, it’s called desensitization or tachyphylaxis.
If this happens more gradually, like over the course of days to weeks, it’s called tolerance. Desensitization can occur with the initial dose of a medication, while tolerance typically happens with repeated doses.
Alright, so, there are several mechanisms responsible for these phenomena. First, chronic exposure to agonists cause a decrease in the number of receptors.
The decrease in the number of the receptors could result from the reduced synthesis of new receptors, also known as downregulation.
Also, chronic exposure increases the degradation of preexisting receptors through endocytosis, also known of sequestration or internalization.
This is when the cell swallows up the receptor in vesicles pinching off from the cell membrane and sends them to the lysosome for digestion.
This phenomena can be seen in chronic opioid and other drug users where the target receptors are down regulated, so a higher dose is needed to achieve the same high.
Alternatively, the receptors may be modified where they are “uncoupled” from their intracellular signaling pathway, meaning they can’t activate the secondary messenger proteins anymore.
This type of response is very rapid and mainly causes desensitization. When exposed to high doses of epinephrine, G-protein coupled receptors or GPCRs for short, get phosphorylated by intracellular enzymes, called G protein coupled receptor kinases or GRKs.
The phosphoryl groups then get bound by bulky proteins called arrestins, which prevents the receptor from activating their neighboring guanine nucleotide-binding proteins or G proteins.
At the same time, arrestins tag the receptors for endocytosis, reducing the number of receptors on the cell membrane. In other cases, desensitization or tolerance arises from the exhaustion of intermediate messenger molecules.
Take amphetamine for example; which normally causes the release of amines, like dopamine, serotonin, and noradrenaline from the nerve terminal into the synaptic cleft.
Amine stores are limited though, so continuous amphetamine use can lead to their depletion. As a result, amphetamine can no longer exert the same level of effect on nerve terminals with repeated use in quick succession.

Tolerance3:26–3:51

Another mechanism is the increased metabolic breakdown of the medication. An example is alcohol tolerance, where chronic use causes the body to increase production of enzymes that breaks down ethanol into inactive products.
On the flip side, tolerance to nitrovasodilators like nitroglycerin, is a consequence of their decreased metabolism since their metabolite, nitric oxide, is the substance that causes the vasodilation.

Adaptation3:51–4:12

Lastly, the effects of a medication may be limited because of a physiological adaptation of the body. For example, diuretics like thiazides, which decrease reabsorption of water, could gradually start getting less effective in lowering the blood pressure as the renin- angiotensin- aldosterone system increases its activity to maintain the blood pressure at high levels.

Review4:12–4:38

All right, as a quick recap, desensitization or tachyphylaxis refers to a rapid- onset decrease in the effects of a medication after repeated exposure, whereas tolerance has a gradual onset.
They arise from various mechanisms, including a change in receptors, either downregulation or translocation, exhaustion of messengers, increased metabolic degradation of the medication, and physiological adaptation.
Pharmacodynamics: Desensitization and tolerance | Osmosis