Pharmacology for Anaesthesia and Intensive Care

P1: PCX Printer: Yet To Come
9780521704632c03 CUFX213A/Peck 9780521618168 December 27, 2007 13:30

Section IBasic principles

where k 1 is the rate constant for the forward reaction (square brackets indicate con-

centration).

The velocity of the reverse reaction is given by:

V 2 =k 2 ·[LR],

where k 2 is the rate constant for the reverse reaction.

Atequilibrium, the reaction occurs at the same rate in both directions (V 1 =V 2 ),

and the equilibrium dissociation constant, KD,isgiven by the equation:

KD=[L]·[R]/[LR]=k 2 /k 1.

Itsreciprocal, KA,isthe equilibrium association constant and is a reflection of the

strength of binding between the ligand and receptor. Note that these constants do

not have the same units; the units for KDare mmol.l−^1 whereas those for KAare

l.mmol−^1 (when reading pharmacology texts take careful note of which of these two

constants are being described). It was Ariens who first suggested that response is

proportional to receptor occupancy and this was the basis of pharmacodynamic

modelling. However, the situation is not as straightforward as this may imply and we

need to explain the existence of partial agonists and inverse agonists as well as the

phenomenon of spare receptors.

Receptor proteins can exist in a number of conformations that are in equilib-

rium, in particular the active and inactive forms; in the absence of an agonist the

equilibrium favours the inactive form. Antagonists bind equally to both forms of the

receptor and do not alter the equilibrium. Agonists bind to the receptor and push this

equilibrium toward the active conformation. The active conformation then triggers

the series of molecular events that result in the observed effect.

Types of drug–receptor interaction

The two properties of a drug that determine the nature of its pharmacological effect

are affinity and intrinsic activity.


Affinity refers to how well or avidly a drug binds to its receptor – in the analogy

of the lock and key, this is how well the key fits the lock. The avidity of binding is

determined by the KDor KAof the drug.


Intrinsic activity (IA) or efficacy refers to the magnitude of effect the drug has once

bound; IA takes a value between 0 and 1, although inverse agonists can have an IA

between− 1 and 0.

Itis important to distinguish these properties. A drug may have a high affinity, but

no activity, and thus binding will produce no pharmacological response. If such a

drug prevents the binding of a more active ligand, this ligand will be unable to exert

its effect – so the drug is demonstrating receptor antagonism. However, if a drug

binds well but only induces a fractional response, never a full response, then the