Mechanisms of Drug Antagonisms

Question 1

Types of Combined Effects of Drugs

Answer 1

Addition
Potentiation
Antagonism

May be clinically advantageous, neutral, harmful

Question 2

Types of Combined Effects of Drugs

Addition

Answer 2

Combined effect is higher than individual but not higher than sum.

Example: negative heart effects by beta blockers and verapamil

Question 3

Types of Combined Effects of Drugs

Potentiation

Answer 3

Combined effect» sum of individual

Example: central depression by sedatohypnotics and ethanol

Question 4

Types of Combined Effects of Drugs

Antagonist

Answer 4

Combined effect is smaller than that of individual effect

–> Effect of drug is reduced/diminished by another

Question 5

Aim of Antagonist Administration

Answer 5

Decrease effect of endogenous agonist or applied drug

Question 6

Maximal Clinical Effect of Antagonist

Answer 6

Depends on how strongly endogenous agonist stimulates the receptor.

Question 7

Types of Antagonism

Answer 7

Reversible Competitive
Irreversible Competitive
Allosteric
Inhibition of Signal Transduction
Functional
Pharmacokinetic (chemical)

All above are pharmacodynamic

Question 8

Reversible Competitive Antagonism

Answer 8

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

Question 9

Shield Equation

Answer 9

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

Question 10

Irreversible Competitive Antagonism

Answer 10

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

Question 11

Allosteric Antagonism

Answer 11

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)

Question 12

Antagonism by Inhibition of Signal Transduction

Answer 12

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

Question 13

Functional Antagonism

Answer 13

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

Question 14

Pharmacokinetic Antagonism

Answer 14

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

Question 15

Chemical Antagonism

Answer 15

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

Question 16

Constitutive Receptor Activity

Answer 16

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

Question 17

Inverse Agonists

Answer 17

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

Question 18

Two State Model

Answer 18

R R*———> Response

R*: Activated state

Question 19

Two State Model

Explaining Constitutive R Activity and Action of Inverse Agonists

Answer 19

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

Question 20

Margin of Safety

Answer 20

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