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Drug antagonism

  • An antagonist is a drug that has affinity for a receptor but no efficacy.
  • Several types of antagonism:
    • Competitive (or surmountable) antagonism – the most common [involves blocking receptors]
    • Non-competitive (or irreversible) antagonism – rare, mostly enzyme inhibitors [involves blocking receptors]
    • Physiological antagonism [functional antagonism – involves two agonists with mechanisms that oppose each other]
    • Chemical antagonism
    • Pharmacokinetic antagonism

Competitive antagonism

  • Agonists and antagonists compete for the same receptor sites, as they both bind specifically to a particular type or receptor, except the antagonist does NOT activate the receptor and the agonist DOES
    • Flip-flop back and forth (competing dynamically based on affinity and probability)
  • Occurs because receptors are each only able to bind one molecule at a time
  • Maximal effect is unchanged (i.e. antagonism is surmountable – by increasing the concentration of agonist high enough)
    • If you increase the agonist conc then they’re more likely to bind (probability). This is because the rate of dissociation of the antagonist molecules is sufficiently high that a new equilibrium is rapidly established on addition of the agonist. (Irreversible, or non-equilibrium, competitive antagonism occurs when the antagonist dissociates very slowly, or not at all, from the receptors, with the result that no change in the antagonist occupancy takes place when the agonist is applied).
    • Note that an agonist cannot evict a bound antagonist molecule
  • Parallel shift to the right of the log(concentration)-response curve
    • Increasing dose of antagonist shifts the curve further and further to the right, but the gradient and maximum remain the same. The dose ratio (the ratio by which the agonist concentration has to be increased in the presence of the antagonist in order to restore a given level of response) increases linearly with the concentration of the antagonist (such that on a log(concentration) – response curve, the curves representing 1, 1, 10, 100, … , 10^k will be equally spaced)
    • At any given agonist concentration, the agonist occupancy will be reduced in the presence of the antagonist.
  • Agonists and antagonists compete at the high affinity receptor sites
  • The agonist can activate the receptor but the antagonist cannot
  • The dose-response curve of the agonist is shifted to the right
  • A high enough dose of agonist can overcome the antagonist
  • Salient features
    • Shift of the agonist log concentration-effect curve to the right, without change of slope or maximum
    • Linear relationship between agonist dose ratio and antagonist concentration
    • Evidence of competition from binding studies

Non-competitive antagonism

  • Irreversible antagonists bind irreversibly to the receptor
  • They cause a change in the receptor so that the agonist can no longer bind
    • E.g. covalent bond
    • Virtually the same as removing the receptor
  • A maximum effect is no longer produced
    • No matter how high you increase the agonist, you can’t get back to the same maximum
    • Except in the case of spare receptors
  • Non-competitive antagonists bind covalently to the receptor and do NOT wash out.
  • Reduced maximum of the curve
  • Changed slope of the curve

Physiological antagonism

  • Occurs when 2 agonists act on different receptors to produce opposite effects (hence follow different receptor mechanisms). The opposing actions of the two drugs in the body tend to cancel each other out.
  • The drugs have different mechanisms of action (they target different receptors)
  • Eg bronchoconstriction due to histamine can be treated with adrenaline, which acts as a vasodilator
  • Most often used if:
    • There isn’t an available receptor site
    • The full mechanism is not known
  • E.g. alcohol vs caffeine.

Chemical antagonism

  • Two substances combine in solution and, as a result, the effect of the active drug is lost
  • Examples:
    • Chelating agents that bind to heavy metals to reduce their toxicity**Neutralising antibodies against protein mediators

Pharmacokinetic antagonism

  • Antagonist effectively reduces the concentration of the active drug at its site of action
  • Mechanisms:
    • Increase the rate of metabolic degradation of the active drug
    • Reduce the rate of absorption of the (orally consumed) active drug from the GI tract
    • Increase the rate of renal excretion of the drug


Agonists in vivo – the concept of tone

  • The effect of an antagonist relies solely on blocking the action of an agonist which is already producing a certain effect
  • Hence there must be an agonist-induced tone.
  • Adding an antagonist to a receptor system which doesn’t have an agonist in it produces no response at all.
  • E.g. acetylcholine slows down heart rate; atropine blocks acetylcholine to give an increased heart rate
  • organ bath with heart; add atropine -> No response (as there is no agonist)

Partial agonists

  • The ability of a drug molecule to activate the receptor is actually a graded rather than an all-or-nothing property
  • Agonists bind to a receptor = response
  • Antagonists bind to a receptor = no response
  • Full agonists bind to receptors and very efficiently give a response (they give the maximal response)
  • Partial agonists are less “efficacious” (give a submaximal response, even at 100% occupacy)
    • Never achieve a maximum effect (even when all receptors are occupied)
    • Also act as a competitive antagonist
      • When you give it with a full agonist, it can bind and prevent the full agonist from binding to produce a maximum effect
    • There is thus a concept of efficacy – the “strength” of the agonist-receptor complex in evoking a response of the tissue
  • The dose response curve for a partial agonist therefore does not reach the maximal response obtained for a full agonist.
  • Binds well, but produces a weak response.
  • Efficacy describes the tendency of the drug-receptor complex to adopt the active (AR*), rather than the resting (AR) state. It is a quantitative value. A drug with zero efficacy (e=0) has no tendency to cause receptor activation, and causes no tissue response. A drug with maximal efficacy (e=1) is a full agonist, while partial agonists lie in between.

Inverse agonists

  • Some receptors are constitutively active, even in the absence of any agonist (they produce a basal response without any stimulation). This is called constitutive activation.
  • An inverse agonist restores the receptor to its inactive state.
  • It produces a response, even though it’s a negative response.
  • Hence it has negative efficacy
  • Constitutive activation can be bad if there is an overexpression of receptors (because, if some fraction of receptors is always active, then a large number of receptors will be active if there are a large number of expressed receptors). In this case is it useful to have inverse agonists.
    • They are distinguished from competitive antagonists, because (unlike competitive antogonists), they can affect the level of activation by themselves (without the presence of another agonist)

The two-state receptor model

  • Consider our original concepts of affinity and efficacy:

A + R --> AR --> AR* -> Response

(affinity) (efficacy)
  • Now consider the idea that all receptors R (in the absence of any ligand) exist in some equilibrium with their activated state R* (which produces responses): R <--> R*
    • Note: 1) For most “normal” receptors, the equilibrium constant for this reaction is close to zero, and so very little response occurs with zero occupancy of receptors. 2) Receptors exhibiting constitutive activation have a slightly higher equilibrium constant, and so some response is produced even with zero occupancy.
  • Under this model, we can see that:
    • Inverse agonists have a higher affinity for R than R*, and so bind R (removing them from the system) and shift the equilibrium to the left: deactivating receptors and reducing response.
    • Agonists have a higher affinity for R* than R, and so bind R*, shifting the equilibrium to the right: activating receptors and increasing response
    • Antagonists have equal affinity for R and R*, and so do not affect the equilibrium on their own, but instead competes for binding locations on receptors and so reduces the binding of other ligands (hence shifting the dose-response curve of their agonists)
  • Note that this model is incomplete: receptors are not actually restricted to two distinct states
    • Their different conformations may be preferentially stabilised by different ligands, and may produce different functional effects by activating different signal transduction pathways.

Spare receptors

  • Many full agonists are capable of eliciting maximal responses at very low occupancies
  • The link between response and occupancy has a reserve capacity
  • These systems have spare receptors or a receptor reserve
  • This does not imply a functional subdivision in the receptor pool, just that the receptor pool is larger than that required to evoke a maximal response
  • This means that a given number of agonist-receptor complexes (corresponding to a given level of builogical response) can be reached with a lower concentration of hormone or neurotransmitter than if fewer receptors were provided.
    • Economy of hormone/transmitter secretion at the expense of increased receptor expression
  • The effect of spare receptors on log(concentration)-response curves of non-competitive antagonists
    • The distinction between reversible and irreversible competitive antagonism is more difficult to see:
    • If the agonist occupancy required to produce a maximal biological response is very small (say 1%) then it is possible to block irreversibly a very large proportion (say 99%) of the receptors without reducing the maximal response. The effect of a lesser degree of antagonist occupancy will be to produce a parallel shift of the log concentration-effect curve that is indistinguishable from reversible competitive antagonism (up to a point, after which the reduced slope and maximum characteristic of non-competitive antagonists will become apparent).

Summary of efficacies

  • Full agonist = positive efficacy (e=1)
  • Partial agonist = smaller positive efficacy (0<e<1)
  • Inverse agonist = negative efficacy (e<0)
  • Antagonist = no efficacy (e=0)

Potentiation of agonists

  • This is the decreased inactivation of an agonist. Agonists don’t stay there forever (they’re metabolised by an enzyme or re-uptaken)
  • Potentiation reduces this metabolism or re-uptake, and results in a higher concentration of the agonist, and hence a greater response.
  • Examples:
    • Enzyme-regulated: Acetylcholine in the presence of anticholinesterase (neostigmine; physostigmine)
      • Inhibit enzyme -> less metabolism of the agonist -> higher concentration of agonist -> higher response
    • Reuptake-regulated: Noradrenaline in the presence of an uptake blocker (cocaine, tricyclic anti-depressants) (reuptake back into nerve terminals)
      • Inhibit uptake -> higher concentration of the agonist -> higher response
  • Increased concentration -> Increased response.

Quantitative and quantal response

  • Quantitative response: is measured in gradual steps e.g. fall in blood pressure
    • Everything so far has been measureable e.g. contraction of muscle
  • Quantal response: is all or none
    • Responders or non-responders
    • What percentage of the population responds?
    • (E.g. how many muscles contracted?)
    • Helps measure variation amongst subjects/species
  • Quantal dose-response curves
    • Here, ED_50 = dose at which 50% of individuals respond
    • Dose versus percentage of individuals responding.
    • Graph is of the percentage of people requiring that dose to achieve the specified effect.
    • [See slide 45]
    • LD_50: Lethal dose 50
      • Dose at which 50% of the population is dead
      • Important for measuring safety
      • The further the ED and LD curves are apart, the better (safer = further effect versus lethality)

Therapeutic ratio

  • Therapeutic ratio = (LD50)/(ED50)
    • Smaller = more dangerous
    • Bigger = safer
    • Problems:
      • to know what the lethal dose for this is
      • Ignores toxic effects that occur before death
      • Animal data doesn’t always correlate well with humans
    • E.g.
      • Digoxin: 2 (2x ED50 is deadly!)
      • Barbiturate: 10 (average)
    • Valium: almost infinite (can’t overdose, but can become dependent)
  • Toxic ratio = (TD50)/(ED50)
    • Where TD50 = toxic dose 50 for a given side effect.
    • Problems:
      • No defined endpoint as there are an array of effects
      • Toxic ratio is defined differently for different symptoms
  • Risk vs benefit
    • Drugs that are unsafe (or have a narrow safety margin) are only used when the consequence of not using it is death
    • The narrower the toxic ratio, the more accurately you need to titrate your doses to a particular amount for each patient; especially if the genetic variability of response is great.

Tolerance and desensitisation

  • Tolerance: the same dose of drug, on repeated administration, produces less effect.
    • Especially occurs in drugs that act on the CNS (e.g. opioids for pain – always use lowest dose). On PNS, tolerance is less likely.
    • Tachyphylaxis: tolerance that develops very rapidly – “rapidly diminishing response to successive doses of a drug, rendering it less effective. The effect is common with drugs acting on the nervous system”.
    • Is a drug effect – level phenomenon
  • Desensitisation: Less effect is produced the longer the agonist remains in contact with the receptor (hence remember to wash out agonists in your studies).
    • Is a receptor – level phenomenon
  • Causes of desensitisation/tolerance:
    • Changes in receptors (e.g. phosphorylation)
    • Receptors no longer able to be bound to
    • Recovery = days
  • Down-regulation of receptors
    • Internalisation – receptors no longer available on surface (due to endocytosis of patches of the cell membrane, a process that depends on receptor phosphorylation)
    • Reduced expression – receptors no longer made
    • Recovery = weeks
  • Depletion of mediators
    • E.g. amphetamine: noradrenaline is stored in synapse. These stores may run out. Hence a bigger dose does nothing as more of it has to be synthesised.
  • Increased metabolic breakdown
    • The more frequently you give it, the faster it is broken down
    • E.g. alcohol
  • Physiological adaptation
    • A drug’s effect iis nullified by a homeostatic response
    • Presumably associated with altered gene expression resulting in changes in the levels of various regulatory molecules.
    • E.g. side effects of nausea or drowsiness may subside although the drug administration is continued.
  • NB: Desensitisation and tachyphylaxis are synonymous

Practice exam questions

  • Define agonist and antagonist
  • Distinguish between affinity, efficacy and potency
  • Define ED50 (remember there are 2 definitions)
  • What are the main features of competitive antagonism?
  • What is a partial agonist?
  • What is a therapeutic ratio?

The role of pharmacodynamics in pharmacology

  • Pharmacodynamics provides information regarding dose/dosage regimen vs response
  • Factors affecting pharmacodynamics together with pharmacokinetics are considered when a dose is individualised for special populations such as the elderly (reduced metabolism), or for when drugs have a low therapeutic ratio
  • Useful tool for introducing new indications, new dosages or new treatment populations contributing to valuable information for drug development
  • Frequency and amount of dose matter.
  • Wrong dose:
    • No effect, or
    • Toxic side effects (or death)
  • Take into account the drug metabolism
  • Things to consider when prescribing:
    • Is the drug necessary? (Don’t need antibiotics in viral infections etc)
    • Use as few drugs as possible for as short a time as possible, at the lowest dose possible
    • Regularly review drug therapy; assess its effectiveness and safety
    • Provide medication charts, particularly for multiple drugs or the elderly
    • Non-compliance:
      • There is no guarantee a patient will take the drug
      • Explain the consequences and why they have to take it
      • Make it easier for them to comply.
      • Be aware of non-compliance