Full agonists, partial agonists and inverse agonists (2022)

This chapter is relatedto one of theaimsof SectionC(i) from the2017CICM Primary Syllabus, whichexpects theexam candidate to"define and explain dose-effect relationships of drugs, including dose-response curves with reference to...partial agonists, mixed agonist-antagonists and inverse agonists". It is another topic in pharmacodynamics which seems important, enjoys extensive testing in the world of anaesthetic basic science exams, and has been ignored completely in the CICM primaries (at least among the publically available written papers).

For the purposes of passing some future viva or written SAQ, one can safely limit oneself to reading the end parts ofMark von Zastrow's chapter (Ch.2) fromBasic and Clinical Pharmacology (14th ed., or whatever the most recent edition is). No detail beyond this is required. If one is able to get a hold of a copy, the concise definitions and examples fromNeubig et al (2003) are also excellent.

In summary:

  • Agonist:A ligand that binds to a receptor and alters the receptor state resulting in a biological response
    • A full agonistreaches the maximal response capability of the system
    • A partial agonistdoes not reach themaximal response capability of the system even at full receptor occupancy.
      • A partial agonist acts as an antagonist in the presence of a full agonist (if they compete for the same receptors)
    • An inverse agonistis aligand that by binding to receptors reduces the fraction of them in an active conformation.
    • An allosteric modulatorincreases (or decreases) the actions of a primary agonist while having no effect on its own.
  • Spare receptors are said to exist wherevera full agonist can cause a maximum response when occupying only a fraction of the total receptor population.

    Agonist drugs

    The International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (Neubig et al, 2003) give an "official" definitionas

    (Video) Agonist, Partial Agonist, Antagonist and Inverse Agonist for Receptors

    "Agonist:A ligand that binds to a receptor and alters the receptor state resulting in a biological response"

    Which sounds a lot like the definition of drug effect (as in effect that's what it is). There is a number of different definitions, and generally they are all either an echo of the statement above, or an attempt to explain the concept with an example. It would be unexpected to encounter the need to define "agonist" in an exam scenario, as the meaning of the term is intuitively understood by most, and the task of defining it is more of a test of English language control, which probably does not belong in a higher-order medical college examination. One would be more likely to be asked to describe what the differences are between different types of agonists.

    Allosteric and orthosteric effects

    An allosteric modulator is:

    "A ligand that increases or decreases the action of an (primary or orthosteric) agonist or antagonist by combining with a distinct (allosteric or allotopic) site on the receptor macromolecule."

    In short, classic direct binding to the receptor is "orthosteric", and binding somewhere to the side of it is "allosteric". The definition of the orthosteric site appears to be somewhat arbitrary, but generally it is the site where the endogenous ligan likes to bind. Allosteric modulators can have a positive or negative effect on the receptor-agonist interaction, i.e. these can be agonists or antagonists, but the main part of the definition is that they do not interfere with the binding site of some "primary" agonist ligand. In fact, these drugs do not need to have any effect whatsoever on the interaction of the primary agonist and the receptor; their main effect may be as a competitive antagonist of other drugs which might want to bind to the same allosteric site.

    Full agonists

    A full agonist is a drug which is capable of producing a maximum response that the target system is capable of:

    (Video) Agonists VS partial agonists VS inverse agonists VS antagonists

    "When the receptor stimulus induced by an agonist reaches the maximal response capability of the system (tissue), then it will produce the system maximal response and be a full agonist in that system."

    There is no obligation for this full agonist effect to happen at full receptor occupancy.Neubig et al(2003) go on to explain that this might happen for different drugs at different doses, different concentrationsor different fractions of the total receptor pool. For instance, the diagram below has several full agonists with different potencies.

    Full agonists, partial agonists and inverse agonists (1)

    So, if the agonist drug can exert a maximal systemic response at some sub-total receptor occupancy, some receptors must be around which remain unbound even at maximal effect. These are the spare receptors.

    Spare receptors

    This nomenclature is obviously something of a pharmacological fantasy, as the organism has not been keeping a surplus ofreceptors just to have them on hand as a reserve. According to the IUP,

    "A pharmacological system has spare receptors if a full agonist can cause a maximum response when occupying only a fraction of the total receptor population. Thus not all of the receptors in the tissue are required to achieve a maximal response with some high efficacy agonists"

    (Video) Full Agonist | Partial Agonist | Inverse Agonist || Junaid Asghar PhD

    It would be inaccurate to say that these receptors are completely superfluous, in excess to physiologicalrequirements, or inactive. All receptors contribute. If you knock out some of these "spare" receptors with an irreversible antagonist, the full agonist drug will still be able to achieve the maximal response in the system, but it will be acting at a reduced potency (i.e. a higher concentration will be required).

    Partial agonists

    A partial agonist can never achieve the maximal response that the system is capable of, because its efficacy is lower than that of a full agonist. To borrow a longer, more wordy definition from the IUP,

    [A partial agonist] "in a given tissue, under specified conditions, cannot elicit as large an effect (even when applied at high concentration, so that all the receptors should be occupied) as can another agonist acting through the same receptors in the same tissue"

    In short, themaximal efficacyof this drug is lower than the maximal efficacy of a drug which is a full agonist of this system (and this is obviously dependent on the system, and probably on the experimental setup which tests the effect).

    Full agonists, partial agonists and inverse agonists (2)

    This maximal efficacy thing is related to several possible mechanisms. Perhaps the partial agonist occupies all the receptors (i.e. achieved full receptor occupancy), and interacts with them in a manner identical to the full agonist, but for some of the receptorsit inexplicably fails to activate the ligand binding site or secondary messenger system. The obvious extension of this is where the drug, while binding avidly to the receptors, somehow fails to activate any of them - in which case it is said to be an antagonist. Alternatively, a drug may be a partial agonist because it produces a different distinct structural change in the receptor - for example, an ion channel might open incompletely with a partial agonist, with ionic conductance reduced thereby. The latter effect is observed in the effect of different partial agonists on the acetylcholine receptor (Mukhtasimova & Sine, 2018).

    (Video) Agonist, Partial Agonist, Antagonist and Inverse agonist شرح مبسط

    Obviously, if a partial agonist drug is used at the same time as a full agonist, and they both act on the same receptors, then the partial agonist will act as an antagonist, competing with the full agonist for a finite number of binding sites. Of the binding sites occupied by the partial agonist, some will not be activated, which reduces the total drug effect. A maximal system response can still be achieved, however - unless the partial agonist binds to the receptor in some sort of irreversible manner, it can be displaced from the receptor by a sufficiently high concentration of full agonist. Thus, the efficacy of the full agonist is not affected, but its potency is reduced.

    Full agonists, partial agonists and inverse agonists (3)

    This can extend naturally into biological systems which have some baseline of endogenous receptor-ligand activity which exists in the absence of drugs (which - let's face it- is virtually any biological system). In such cases, a drug may have an inverse agonist effect by its competition with an endogenous agonist ligand.

    Inverse agonists

    An inverse agonist is a ligand which, by binding to a receptor, produces theoppositeof the effect which would be produced when an agonist binds to the same receptor. IUP defines it as

    "A ligand that by binding to receptors reduces the fraction of them in an active conformation...if some of the receptors are in the active form in the absence of a conventional agonist".

    Though it can also decrease the available fraction of active receptors by preferentially binding to receptors which are in their inactive state (thereby reducing the total possible pool of receptors). In short, these antagonist drugs - when given in the absence of any other drug - will have the opposite effect to the normal expected effect of receptor activation, because of some baseline resting level of autonomous receptor activity. A drug like this is said to have "negative efficacy" - whereas the maximum efficacy of a full agonist is said to be 100%, the efficacy of an inverse agonist is less than 0% (i.e. -10% of -20%). An inverse agonist's oppositional activity can be reduced in magnitude by a competitive "neutral" antagonist which also binds the receptors but does nothing with them once attached.

    (Video) Agonist vs Antagonist vs Partial agonist vs Inverse Agonist for beginners@Biology Lectures

    Full agonists, partial agonists and inverse agonists (4)

    An excellent example of this is offered by Barbara Plevry (2004) in terms of the effects of various drugs on the GABA receptor. Benzodiazepines are agonists which increase the effect of GABAby acting as allosteric modulators of the GABA receptor, and they produce anxiolysis and an antiepileptic effect.β-carboline derivatives (eg. norharmane) are also allosteric modulators, but they act as inverse agonists of the GABA receptor, and they reduce the effect of GABA thereby causing anxiogenesis and seizures. Flumazenil is a "neutral" antagonist which reverses both the sedating effects of benzodiazepines and proconvulsant effects ofβ-carboline.

    FAQs

    What is a full partial and inverse agonist? ›

    A drug that binds to and activates a receptor. Can be full, partial or inverse. A full agonist has high efficacy, producing a full response while occupying a relatively low proportion of receptors. A partial agonist has lower efficacy than a full agonist.

    What is the difference between a full agonist and a partial agonist? ›

    A full agonist is a drug whose efficacy5 is sufficient that it produces a maximal response when less than 100% of receptors are occupied. A partial agonist has lower efficacy, such that 100% occupancy elicits only a submaximal response.

    What is the difference between agonist and inverse agonist? ›

    An agonist increases the activity of a receptor above its basal level, whereas an inverse agonist decreases the activity below the basal level. The efficacy of a full agonist is by definition 100%, a neutral antagonist has 0% efficacy, and an inverse agonist has < 0% (i.e., negative) efficacy.

    What is full inverse agonist? ›

    An inverse agonist is a ligand that binds to the same receptor-binding site as an agonist and not only antagonizes the effects of an agonist but, moreover, exerts the opposite effect by suppressing spontaneous receptor signaling (when present). From: Encyclopedia of Neuroscience, 2009.

    What drugs are partial agonists? ›

    Some currently common drugs that have been classed as partial agonists at particular receptors include buspirone, aripiprazole, buprenorphine, nalmefene and norclozapine. Examples of ligands activating peroxisome proliferator-activated receptor gamma as partial agonists are honokiol and falcarindiol.

    What is inverse agonist explain by using examples? ›

    a ligand that binds to a receptor and produces the opposite pharmacological effect that would be produced by an agonist or by the natural ligand. For example, if agonism of the receptor led to sedation, an inverse agonist might cause wakefulness.

    Is inverse agonist same as antagonist? ›

    An inverse agonist is a drug that binds to the same receptor as an agonist but brings about an opposite response to that of the agonist while an antagonist is a drug that binds to a receptor that will disrupt the interaction and the function of both the agonist and inverse agonist at the receptor.

    What are types of agonist? ›

    Types of Agonists. There are several types of agonists, which include endogenous, exogenous, physiological, superagonists, full, partial, inverse, irreversible, selective, and co-agonists. Each type of agonist exhibits different characteristics and mediates distinct biological activity.

    How do you identify a partial agonist? ›

    A most unambiguous method to determine the KB for a partial agonist consist in to irreversibly block or inactivate a sufficient fraction of the receptor population so that the partial agonist no longer produces a response but that still permit to observe the effects of a full agonist.

    What does a partial agonist do? ›

    Partial agonists bind to and activate a receptor, but are not able to elicit the maximum possible response that is produced by full agonists. The maximum response produced by a partial agonist is called its intrinsic activity and may be expressed on a percentage scale where a full agonist produced a 100% response.

    Why are inverse agonists important? ›

    Inverse agonists bind with the constitutively active receptors, stabilize them, and thus reduce the activity (negative intrinsic activity). Receptors of many classes (α-and β-adrenergic, histaminergic, GABAergic, serotoninergic, opiate, and angiotensin receptors) have shown basal activity in suitable in vitro models.

    Why antihistamines are inverse agonist? ›

    Thus, H1-antihistamines are not receptor antagonists but are inverse agonists in that they produce the opposite effect on the receptor to histamine[14]. Consequently, the preferred term to define these drugs is "H1-antihistamines" rather than "histamine antagonists."

    Is acetylcholine a full or partial agonist? ›

    Both ACh and 5-methylfurmethide are full agonists but ACh has a higher intrinsic activity than 5-methylfurmethide.

    Is atropine an inverse agonist? ›

    Atropine behaves as an inverse agonist on calcium currents (ICa) in frog ventricular cells (reproduced with permission from Hanf et al., 1993). Organ bath preparations have also been used to detect inverse agonism (Noguera et al., 1996).

    Which beta blockers are inverse agonists? ›

    Each of these (betaxolol, bisoprolol, carvedilol, ICI 118,551, metoprolol, nadolol, propranolol, sotalol, and timolol) decreased constitutive cAMP accumulation and are thus inverse agonists (Fig.

    Is naloxone an inverse agonist? ›

    Naloxone has been shown to act as an inverse agonist at the mu receptor in vitro, stimulating cAMP levels and inhibiting GTPγS binding in morphine-pretreated, but not untreated, tissue (Liu and Prather, 2001; Raehal et al, 2005; Wang et al, 2001, 2004, 1994).

    Is naloxone a partial agonist? ›

    Our data indicate that naloxone is a partial agonist on the mu- and kappa-opioid receptors.

    Is methadone a full agonist? ›

    Methadone is a medication used to treat Opioid Use Disorder (OUD). Methadone is a long-acting full opioid agonist, and a schedule II controlled medication.

    Is benzodiazepine an inverse agonist? ›

    When the benzodiazepine inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester) occupies the benzodiazepine recognition site on the GABAA receptor complex, the inhibitory action of gamma-aminobutyric acid (GABA) is attenuated.

    Is Benadryl an inverse agonist? ›

    Diphenhydramine is a first-generation H1 antihistamine that acts as an inverse agonist at H1 receptors. 19 It penetrates through the blood brain barrier, but it is not a substrate for the P-glycoprotein efflux pump.

    How do you remember the agonist and antagonist? ›

    The muscle that is contracting is called the agonist and the muscle that is relaxing or lengthening is called the antagonist. One way to remember which muscle is the agonist – it's the one that's in 'agony' when you are doing the movement as it is the one that is doing all the work.

    What is the difference between agonist and antagonist medications? ›

    Agonists are drugs with both affinity (they bind to the target receptor) and intrinsic efficacy (they change receptor activity to produce a response). Antagonists have affinity but zero intrinsic efficacy; therefore they bind to the target receptor but do not produce a response.

    Is histamine a full agonist? ›

    Methylhistaprodifen (MH) and 2-(3-TFMP) histamine are full agonists at the H1 receptors expressed by PO/AH neurons.

    How does a partial agonist become an antagonist? ›

    Obviously, if a partial agonist drug is used at the same time as a full agonist, and they both act on the same receptors, then the partial agonist will act as an antagonist, competing with the full agonist for a finite number of binding sites.

    Can a drug be both an agonist and antagonist? ›

    Buprenorphine or Buprenex is another example of a mixed agonist-antagonist medicine that is growing in use due to its ability to produce good pain relief, its potential for reduced risk of respiratory depression, and its ability for use as a maintenance drug for opioid-dependent patients.

    Can a partial agonist act as full agonist? ›

    Partial agonists have a lower intrinsic activity at receptors than full agonists, allowing them to act either as a functional agonist or a functional antagonist, depending on the surrounding levels of naturally occurring neurotransmitter (full agonist).

    Which antipsychotics are partial agonists? ›

    Dopamine receptor partial agonists (DRPAs; aripiprazole, brexpiprazole, and cariprazine) constitute a novel class of antipsychotics.

    Do inverse agonists have intrinsic activity? ›

    As agonists have intrinsic efficacy (the ability to increase the activity of a receptor), inverse agonists are said to have negative intrinsic efficacy (the ability to decrease the activity of a receptor).

    Is loratadine an inverse agonist? ›

    Pharmacodynamics. Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1 receptors.

    Is chlorpheniramine an inverse agonist? ›

    Chlorphenamine acts primarily as a potent H1 antihistamine. It is specifically a potent inverse agonist of the histamine H1 receptor. The drug is also commonly described as possessing weak anticholinergic activity by acting as an antagonist of the muscarinic acetylcholine receptors.

    Is antihistamine an agonist or antagonist? ›

    H1-antihistamines

    Most antihistamines are inverse agonists at the H1 receptor, but it was previously thought that they were antagonists. Clinically, H1-antihistamines are used to treat allergic reactions and mast cell-related disorders.

    What type of agonist is acetylcholine? ›

    Nicotinic Agonists

    A nicotinic agonist is a drug that mimics, in one way or another, the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). Nicotinic acetylcholine receptors are receptors found in the central nervous system, the peripheral nervous systems, and skeletal muscles.

    Is nicotine an agonist or antagonist? ›

    Nicotine is a nonselective nicotinic receptor agonist, acting at nicotinic receptors of the autonomic ganglia, at the neuromuscular junction, and in the brain.

    What are ACh receptor agonists? ›

    A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.

    Is propranolol an inverse agonist? ›

    Different β-blockers have differing potencies as inverse agonists that are unrelated to their β-blocking potency. Thus, propranolol is a potent inverse agonist whereas pindolol is not and this may relate to the different tendency of these two agents to induce asthma.

    Is naltrexone an inverse agonist? ›

    Naltrexone is also a partial inverse agonist, and this property is exploited in treatment of opioid addiction, as a sustained course of low-dose naltrexone can reverse the altered homeostasis which results from long-term abuse of opioid agonist drugs.

    Is pilocarpine an agonist or antagonist? ›

    Pilocarpine is a prototypical drug used to treat glaucoma and dry mouth and is classified as either a full or partial muscarinic agonist.

    What is full agonist in pharmacology? ›

    An agonist is a drug that activates certain receptors in the brain. Full agonist opioids activate the opioid receptors in the brain fully resulting in the full opioid effect. Examples of full agonists are heroin, oxycodone, methadone, hydrocodone, morphine, opium and others.

    What is an antagonist drug example? ›

    An antagonist is a drug that blocks opioids by attaching to the opioid receptors without activating them. Antagonists cause no opioid effect and block full agonist opioids. Examples are naltrexone and naloxone. Naloxone is sometimes used to reverse a heroin overdose.

    What are types of agonist? ›

    Types of Agonists. There are several types of agonists, which include endogenous, exogenous, physiological, superagonists, full, partial, inverse, irreversible, selective, and co-agonists. Each type of agonist exhibits different characteristics and mediates distinct biological activity.

    Is naloxone an inverse agonist? ›

    Naloxone has been shown to act as an inverse agonist at the mu receptor in vitro, stimulating cAMP levels and inhibiting GTPγS binding in morphine-pretreated, but not untreated, tissue (Liu and Prather, 2001; Raehal et al, 2005; Wang et al, 2001, 2004, 1994).

    Is acetylcholine a full or partial agonist? ›

    Both ACh and 5-methylfurmethide are full agonists but ACh has a higher intrinsic activity than 5-methylfurmethide.

    Is benzodiazepine an inverse agonist? ›

    When the benzodiazepine inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester) occupies the benzodiazepine recognition site on the GABAA receptor complex, the inhibitory action of gamma-aminobutyric acid (GABA) is attenuated.

    Is inverse agonist same as antagonist? ›

    An inverse agonist is a drug that binds to the same receptor as an agonist but brings about an opposite response to that of the agonist while an antagonist is a drug that binds to a receptor that will disrupt the interaction and the function of both the agonist and inverse agonist at the receptor.

    What is the meaning of partial agonist? ›

    Partial agonists have a lower intrinsic activity at receptors than full agonists, allowing them to act either as a functional agonist or a functional antagonist, depending on the surrounding levels of naturally occurring neurotransmitter (full agonist).

    Is histamine a full agonist? ›

    Methylhistaprodifen (MH) and 2-(3-TFMP) histamine are full agonists at the H1 receptors expressed by PO/AH neurons.

    Is atropine an inverse agonist? ›

    Atropine behaves as an inverse agonist on calcium currents (ICa) in frog ventricular cells (reproduced with permission from Hanf et al., 1993). Organ bath preparations have also been used to detect inverse agonism (Noguera et al., 1996).

    Are antihistamines inverse agonists? ›

    Thus, H1-antihistamines are not receptor antagonists but are inverse agonists in that they produce the opposite effect on the receptor to histamine[14]. Consequently, the preferred term to define these drugs is "H1-antihistamines" rather than "histamine antagonists."

    Is naltrexone an inverse agonist? ›

    Naltrexone is also a partial inverse agonist, and this property is exploited in treatment of opioid addiction, as a sustained course of low-dose naltrexone can reverse the altered homeostasis which results from long-term abuse of opioid agonist drugs.

    What type of agonist is acetylcholine? ›

    Nicotinic Agonists

    A nicotinic agonist is a drug that mimics, in one way or another, the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). Nicotinic acetylcholine receptors are receptors found in the central nervous system, the peripheral nervous systems, and skeletal muscles.

    Is methadone a full agonist? ›

    Methadone is a medication used to treat Opioid Use Disorder (OUD). Methadone is a long-acting full opioid agonist, and a schedule II controlled medication.

    Is nicotine an agonist or antagonist? ›

    Nicotine is a nonselective nicotinic receptor agonist, acting at nicotinic receptors of the autonomic ganglia, at the neuromuscular junction, and in the brain.

    Is flumazenil an inverse agonist? ›

    Competitive antagonist and inverse agonist of the benzodiazepine receptor. Moderate lipid solubility, 50% protein bound. t1/2β < 1 hour - may require infusion.

    Which drug is a benzodiazepine antagonist? ›

    Flumazenil is a competitive benzodiazepine antagonist that reverses the effects of benzodiazepines.

    Which statement is true for inverse agonist? ›

    True statement regarding inverse agonists is:
    1)Binds to receptor and causes opposite action
    2)Binds to receptor and causes intended action
    3)Binds to receptor and causes submaximal action
    4)Binds to receptor and causes no action
    5)NULL

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