Drug-receptor interaction Flashcards
Types of drug-receptor interaction
Agonism (3), antagonism (4)
Agonists
* Full agonists
* Partial agonists
* Inverse agonists
Antagonists: exhibit affinity but no intrinsic activity
* Reversible: competitive
* Reversible: non-competitive
* Reversible: allosteric modulators (often grouped with non-competitive)
* Irreversible
Formulas relating binding of ligand to its receptor, and the rate of the forward and reverse reactions
Law of mass action
Binding of ligand (L) to receptor (R) (reversible):
L + R <-> LR
Law of mass action states that the rate of a reaction is proportional to the concentrations of the reacting components
Velocity of forward reaction, V1 = k1.[L].[R]
Velocity of reverse reaction, V2 = k2.[LR]
k1 = rate constant for forward reaction, k2 = rate constant for reverse reaction
Equilibrium dissociation constant, equilibrium association constant
Formula, units
Because at equilibrium, V1=V2..
Equilibrium dissociation constant, KD = [L].[R]/[LR] = k1/k2
* units are mmol/L
Equilibrium association constant, KA = 1/KD
* units are L/mmol
Equilibrium between receptor active and inactive forms in:
* Absence of agonist
* Presence of antagonist
* Presence of agonist
* Presence of partial agonist
* Presence of inverse agonist
Receptor proteins can exist in a number of conformations that are in equilibrium, in particular their active and inactive forms
- Absence of agonist: equilibrium favours inactive form
- Presence of agonist: equilibrium is pushed towards active form
- Presence of antagonist: NO CHANGE to equilibrium as antagonist binds equally to active and inactive forms
- Presence of partial agonist: equilibrium between active and inactive receptor forms can never be entirely in favour of the active conformation.
- Presence of inverse agonist: equilibrium shifted towards inactive receptors
Affinity vs intrinsic activity
Drug affinity and intrinsic activity determine the nature of its pharmacological effects.
Affinity = how well or avidly a drug binds to its receptor
* ‘How well key fits in the lock’
* Avidity of binding is determined by equilibrium dissociation constant (KD) or equilibrium association constant (KA, or 1/KD)
Intrinsic activity (IA) or efficacy = the magnitude of effect the drug has once bound
* Takes a value between 0 and 1, or -1 and 0 for inverse agonists
Receptor affinity and intrinsic activity of
* Agonist
* Antagonist
* Partial agonist
* Inverse agonist
- Agonist: significant receptor affinity and full intrinsic activity (IA =1)
- Antagonist: singificant receptor affinity but no intrinsic activity (IA = 0)
- Partial agonist: significant receptor affinity but only fractional intrinsic activity (0<IA<1)
- Inverse agonist: can be full or partial, with -1<IA<0
Full agonists
Definition, IA and affinity, Relationship between potency and KD
Drugs able to generate a maximal response from a receptor
High affinity, intrinsic activity =1
Potency of the drug is determined by equilibrium dissociation constant KD: lower the KD, higher the potency
Note for may drugs, the ED50 (dose producing 50% maximum response) corresponds to the KD
Partial agonists
Definition, effects
Definition
* Have intrinsic activity 0<IA<1: such that drug occupies receptors , but produces a submaximal effect compared with the full agonist
* Fail to achieve a maximal effect even with full receptor occupancy
Effects
* Link between activation of receptor and effect is only a fraction of that seen with full agonists
* May act as agonists or antagonists:
* If used alone: agonists
* If combined with full agonist: produce additive effects at low doses of the full agonist, but this switches to competitive antagonism as the dose of the full agonist increases (because full agonist needs to displace partial agonist to have maximum effect)
Inverse agonists
Mechanism of action, example
- Drug binds and exerts an effect opposite to that of the endogenous agonist
- May have high or moderate affinity. Intrinsic activity -1<IA<0
Due to constitutive action of receptors:
* Some receptors can show a low level of activity in the absence of a ligand, since probability of taking up an active conformation is small but measurable
* Inverse agonists bind to these receptors and reduce the indidence of the active conformation responsible for this constitutive activity -> therefore appear to exert opposite effect to agonist
Example: ketanserin is an inverse agonist at 5HT2c receptors
Competitive antagonists
- Effect of antagonist may be overcome by increasing concentration of agonist
- Relative amounts of each (and relative affinity) determine the ratios of receptor occupation
Examples
* Non-depolarising muscle relaxants: compete with ACh for cholinergic binding sites on the nicotinic ACh receptor at the NMJ
* Beta-blockers: compete with noradrenaline at beta-adrenergic receptor sites in the heart
Dose ratio and pA2 value for competitive antagonists
Dose ratio = the extent of the right shift along the x-axis of the log[dose] vs response curve in the presence of a competitive antagonist, i.e. the factor by which agonist concentration bmust be increased to produce equipvalent responses in the presence and absence of a competitive inhibitor (at a given concentration).
pA2 value = the negative logarithm of the concentration of the antagonist required to produce a dose ratio of 2
* used to compare the efficiency of competitive antagonistm for different antagonists at a given receptor
Bowman’s principle with regards to non-depolarising neuromusclar blockers
Non-depolarising neuromuscular blockers are competitive inhibitors of acetylcholine at cholinergic binding site at nicotinic receptor at the NMJ
- Bowman’s principle: weaker antagonists have more rapid onset of action: because given in higher dose for same amximal effect-> more molecules tavailable to occupy receptors
- e.g. rocuronium has 1/5 potency of vecuronium, thus given at 5x dose for same effect
Non-competitive antagonists and allosteric modulators
Binding site, effect of increasing [agonist]
Non-competitive antagonists
* Do not bind to same site as agonist
* Classically do not alter binding of agonist, but prevent receptor activation through conformational distortion. NB recept classifications group competitive antagonists and negative allosteric modulators together - because most non-competitive inhibitors (when investigated carefully) do not alter agonist binding
* Action cannot be overcome by increasing agonist concentration
* Examples: Ketamine is a non-competitive antagonist of glutamate at NMDA receptors in the CNS
Allosteric modulation of receptor binding
* Bind to sites distant from agonist receptor site, but alter binding characteristics of agonist
* May reduce (negative allosteric modulator) or increase (positive allosteric modulator) effects of given dose of agonist without haveing any effects of their own
* Example: effect of benzodiazepines on activity of GABA at GABAa receptor complex
Irreversible antagonists
Binding site, effect of increasing [agonist], examples (2)
May bind at
* Same site as agonist
* Distant site
Increasing agonist concentration does not overcome the blockade
Examples:
* Phenoxybenzamine irrevesibly binds to alpha-adrenoceptors, antagonising catecholamines
* Clopidogrel is metabolised to active metabolite which binds irreversibly to Gi-protein coupled ADP Py2Y12 receptors
Effect of spare receptors at the neuromuscular junction
Dose response curve in presence of irreversible inhibitors
ACh binding to ACh receptors at NMJ -> depolarisation of the motor end plate
* Only fraction of these receptors need to be occupied to produce a maximal pharmacological effect: small qualntity of ACh can produce a maximal response
* ‘Spare receptors’ provide some protection against failure of transmission in the presence of toxins.
In presence of irreversible inhibitors:
* Small dose of irreversible inhibitor: log[dose] vs response curve is shifted to the right (higher fraction of the remaining receptors not bound by the inhibitor must be occupied to produce the original response)
* When >3/4 receptors occupied by irreversible antagonist: whatever dose of ACh, maximum response cannot occur -> shape of curve changes so both maximum response and slope are reduced
