Mechanisms of Drug Antagonisms Flashcards
Types of Combined Effects of Drugs
Addition
Potentiation
Antagonism
May be clinically advantageous, neutral, harmful
Types of Combined Effects of Drugs
Addition
Combined effect is higher than individual but not higher than sum.
Example: negative heart effects by beta blockers and verapamil
Types of Combined Effects of Drugs
Potentiation
Combined effect» sum of individual
Example: central depression by sedatohypnotics and ethanol
Types of Combined Effects of Drugs
Antagonist
Combined effect is smaller than that of individual effect
–> Effect of drug is reduced/diminished by another
Aim of Antagonist Administration
Decrease effect of endogenous agonist or applied drug
Maximal Clinical Effect of Antagonist
Depends on how strongly endogenous agonist stimulates the receptor.
Types of Antagonism
Reversible Competitive Irreversible Competitive Allosteric Inhibition of Signal Transduction Functional Pharmacokinetic (chemical)
All above are pharmacodynamic
Reversible Competitive Antagonism
Agonists and Antagonist bind reversibly to same site-> compete with each other for receptor
Outcome of competition determined by
Concentration of Agonist and Antagonist
Affinity (Kd) of Agonist and Antagonist
Examination in vitro:
Conc-occupancy curve or resp curve taken for agonist
Agonist washed out
Antagonist applied at given concentration
Respective curve for agonist is taken again in + of Anta.
–> parallel rightward shift of conc-occupancy and conc-response curves of agonist; no change in maxima
–> Reflects: chance for agonist binding is higher if higher conc +
==> Antagonism is surmountable
Degree of Antagonism= degree of rightward shift
In + of antagonist: need higher conc of agonist req for given occupancy or effect
Shield Equation
Describes reversible competitive antagonism
r= c’Ag/cAg = (cAnt+KdAnt)+1
r: concentration ratio
c’Ag: conc of agonist required for given effect in presence of the antagonist
cAg: conc of agonist required for given effect in absence of antagonist
cAnt: conc of antagonist
KdAnt: affinity of antagonist
if r=2: conc and Kd of antagonist are equal-> twofold right shift produced
pA2: negative log of Kd value of antagonist
Higher pA2= higher affinity
Irreversible Competitive Antagonism
Bind to same site within receptor
Antagonist is very strong (often covalent)-> doesn’t dissociate
Conc-occupation curve for agonist is depressed (decreased binding maximum) but location (Kd) remains
Rightwards shift if number of receptors is decreased
If there is a receptor reserve for agonist-> maximum of curve stays the same
Antagonism is initially surmountable until receptor reserve is exhausted, then-> insurmountable
Long duration of action as new Rs must be produced
Drugs rarely used in clinical practice as dose adjustment is difficult and poor plasma level-effect correlation
Examples
Ticlopidine, Clopidogrel at P2Y12 Purinoreceptors
Allosteric Antagonism
Pharmacodynamic Antagonism
Antagonist binds to receptor at an allosteric site-> no competition
Induces change in function of R-> impairs agonist binding, R activation, or early step in signal transduction
Saturation of allosteric binding site may limit antagonism
Examples
Benzo-type drugs decrease affinity of GABA for GABA-
A Receptors
Drugs blocking ion channel part of ionotropic R
(ketamine-NMDA R; tubocurarine- Ggl N R)
Antagonism by Inhibition of Signal Transduction
Pharmacodynamic Antagonism
Antagonist is membrane permeable-> inhibits step of signal transduction pathway
Can diminish effect of numerous agonists using common signalling mech.
No competition between antagonist and agonist
Doesn’t necessarily block all agonist effects
Examples
Amiloride
Sirolimus inhibiting IL-2
Functional Antagonism
Pharmacodynamic Antagonism
Two agonists act on own receptors (located on same cell)
Produce opposite effects
Both are agonists but interaction is antagonistic
Example
ACh induced bronchoconstriction on M3 R is inhibited by adrenaline induced bronchodilation via beta2
Insulin induced hypoglycaemia can be antagonised by glucagon evoked glycogenolysis in liver
Pharmacokinetic Antagonism
Non competitive
Antagonist modifies pharmacokinetics of affected drug -> decreased conc at site of action-> decreased effect
Affected drug not necessarily an agonist
Possible Mechs
Inhibition: Extent or rate of absorption
Laxatives reduce oral bioavailability
Atropine diminishes rate of gastric emptying-> delay
of intestinal drug absorption
Enhanced metabolic inactivation: Enzyme inducers
Enhanced excretion:
Example: Furosemide-> forced diuresis
Chemical Antagonism
Also Pharmacokinetic
Antagonist directly binds to molecules of affected drug via salt/complex formation or precipitation
–> direct neutralisation
Handled separately from pharmacokinetic mech as may take place outside body
Examples
Sugammadex can bind steroidal muscle relaxants
Protamine can bind heparin
EDTA can bind divalent cations
Di- or trivalent cations can form chelates with
tetracyclines or fluoroquinolones
Constitutive Receptor Activity
In vitro! Spont. activity in vivo not typical
Special circumstances-> R can be agonist independent
Signalling event/cellular response can be detected in absence of endo or exogenous agonist
Can be induced in vitro: high degree R up regulation
Receptor mutants
Inverse Agonists
Bind to R at same site as agonists or antagonists
Evoke response opposite of agonist
In systems with no constitutive activity: behave like competitive antagonists ‘just’ occupying binding site
Many drugs were thought to be competitive antagonists but are actually inverse agonists
Examples All H1 and H2 R Antagonists Metoprolol Clorpromazine Haloperidol Clozapine
Bind preferentially to inactive R conformation
Agonists bind preferentially to active R conformation
Antagonists bind equally to both
Two State Model
R R*———> Response
R*: Activated state
Two State Model
Explaining Constitutive R Activity and Action of Inverse Agonists
According to this:
Proteins exist in two states: inactive and spont. active
Two conformations can be converted to each other; there is an equilibrium between them
Agonists bind preferentially to active R conformation-> they shift equilibrium in favour of active-> more R in active-> higher system activity
Inverse Agonists preferentially bind to inactive R conformation–> shift equilibrium in favour of inactive-> more R in inactive-> lower system activity
Antagonists have equal affinity for both conformations–> don’t alter equilibrium-> # of active R doesn’t change
Margin of Safety
TD50/ED50
TD50: dose causing level of toxic effect in 50% of pop
ED50: dose prod. desired therapeutic effect in 50% of pop
if=1–> TD50=ED50–> highly toxic drug at normal th level
Therapeutic Window
Min toxic plasma level - min therapeutic plasma level
Therapeutic index doesn’t equal therapeutic window; exception: animal experiments
Toxic effects can limit drug therapy
