Pharmacology for Anaesthesia and Intensive Care

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

Section IBasic principles

Such drugs are called allosteric modulators and may either reduce (negative allosteric

modulators) or enhance (positive allosteric modulators) the activity of a given dose of

agonist without having any discernible effects of their own. An example of a positive

allosteric modulator is the effect of benzodiazepines on the activity of GABA at the

GABAAreceptor complex.

Irreversible

Irreversible antagonists may either bind irreversibly to the same site as the ago-

nist or at a distant site. Whatever the nature of the binding site, increasing agonist

concentration will not overcome the blockade. A clinical example is that of phenoxy-

benzamine that irreversibly binds to and antagonizes the effects of catecholamines

atα-adrenoceptors. Aspirin is also an irreversible inhibitor; it causes cross-linking

of the COX-1 enzyme in platelets rendering it inactive for the lifetime of the platelet.

Asingle 75 mg dose is sufficient to block all platelet COX-1 and so return of normal

function requires new platelet formation. This is why aspirin should be stopped 7–10

days before surgery where surgical bleeding must be minimized.

Spare receptors

The neuromuscular junction contains ACh receptors, which when occupied by ACh

cause depolarization of the motor end plate. However, only a fraction of these recep-

tors needs to be occupied to produce a maximal pharmacological effect. Occupancy

of only a small proportion of the receptors ensures that a small quantity of ACh

produces a maximal response. As a result there are ‘spare receptors’, which provide

some protection against failure of transmission in the presence of toxins. This can

be demonstrated as follows: if a small dose of an irreversible inhibitor is given then a

proportion of the receptors are bound by the inhibitor and rendered unavailable so

the log[dose] versus response curve for acetylcholine is shifted to the right because

ahigher fraction of the remaining receptors must be occupied to produce the orig-

inal response. If a further irreversible antagonist is used more receptors are made

unavailable and results in a further right-shift of the log[dose] versus response curve.

When more than three-quarters of the receptors are occupied by irreversible antag-

onist then whatever the dose of ACh, a maximum response cannot occur and the

shape of the curve changes so that both the maximum response and the slope is

reduced.

Tachyphylaxis, desensitization and tolerance

Repeated doses of a drug may lead to a change in the pharmacological response,

which may be increased or decreased for the same dose.

Tachyphylaxis

Tachyphylaxis is defined as a rapid decrease in response to repeated doses over a short

time period. The most common mechanism is the decrease of stores of a transmitter