Pharmacodynamics and the measurement of drug action

The action of drugs is usually measured by bioassay, which is the measurement of potency or activity of a drug using a biological response, using the principles of drug action and measurement provided in Chapter 3 . It is used when it is necessary to:

  • measure the activity of new/chemically unknown substances in research work or in new drug development,

  • investigate endogenous mediators/transmitters, and

  • measure unwanted actions of drugs.

A clinical trial in which, for example, a new drug is compared with one already in use is a special form of comparative bioassay.

Principles of Bioassay

Most bioassays involve measurements of the responses of isolated tissue or groups of animals. In the usual type of bioassay, the response to the unknown (or test) drug is compared with that of a standard (or control) drug. The response to a drug may be:

  • graded, e.g. the contraction of a smooth muscle, the change in heart rate;

  • all or none (quantal), e.g. the absence or presence of a pinch reflex, the success of maze-running in a stipulated time.

For accurate estimation, a parallel line assay is required (though in many cases this may not be feasible). Often, the effect of a drug (for which we have limited data) will be assessed (especially when compared with another drug or mediator) over several log order of magnitudes of concentration or dose ( in vivo ). This allows estimates of the equivalent concentrations of unknown and standard drugs to be compared for potency. Furthermore, an extensive assay can reveal unforeseen characteristics, for example synergism of receptor activation, selective functionalities at different doses, or polypharmacology. Sometimes pharmacologists will choose half-log (1, 3, 10, 30, 100, etc.) or third-log (1, 2, 5, 10, 20, 50, 100, etc.) intervals because these will provide recordings that are equally spaced on a graph (to improve accuracy of analysis). A more precise understanding of a compound’s pharmacodynamic relationship might lead investigators to use concentrations with an arithmetic interval scaling.

The actions of drugs will be compared using familiar terms, for example the ED 50 (or EC 50 ) or maximal responses (E max ). Other measurements are sometimes also used; for example the ratio ED 75 /ED 25 provides an assessment of the dose-response curve slope (otherwise measured exactly as h , the Hill coefficient: measured at the point of inflection for ED 50 ). It is used in a derivation of the Hill-Langmuir equation (see Chapter 3 ) of the dose-response relationship to quantify the degree of interaction between two ligand binding sites (taken from Page et al. Integrated Pharmacology, 2nd edition, Chapter 5 ):

<SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='E=Emax.[A]h[A]h+(EC50)h’>E=Emax.[A]h[A]h+(EC50)hE=Emax.[A]h[A]h+(EC50)h

Graded responses

Taking the contraction of an isolated strip of smooth muscle as an example, the log of the dose is plotted against the response expressed as the percentage of the maximal response ( Fig. 6.1 ). When two agents act on the same receptor and have the same intrinsic activity (see Chapter 3 ), the log dose–response curves will be parallel and their relative potency (M) can be obtained from the separation of the two curves (log M in Fig. 6.1 ).

Fig. 6.1

Comparison by bioassay of the potency of the unknown (test) drug with standard (control).

Since the concentration–response (C/R) curves are parallel, log M (the potency ratio) is the same at all points of the curve.

All-or-none responses (quantal responses)

In all-or-none situations (usually an in vivo response), the response is expressed as the percentage of individuals giving the all-or-none response. If a parallel log dose–response curve can be obtained, the potency ratio of unknown (or test) drug to control (standard) can be obtained as for a graded response. However, the two drugs may not have identical mechanisms of action and thus will not necessarily have parallel curves. This is the case with comparative bioassays, which seek to compare the biological activity of different drugs, for example to assess whether a new local anaesthetic is more potent than procaine, or whether a new antihypertensive vasodilator acting by a novel mechanism is more or less potent than the calcium antagonist nifedipine.

In comparative assays, a comparison of the ED 50 (the dose which produces the particular outcome in 50% of the population) of each drug can be used to get a rough estimation of its relative potency. Note in this case the shape of the curve is determined by the statistical distribution of sensitivities of the individuals. A small standard deviation will produce a steep log dose–response curve and vice versa. Comparative assays are often used during the development of new drugs and in clinical trials ( Fig. 6.2 ).

Mar 31, 2020 | Posted by in PHARMACY | Comments Off on Pharmacodynamics and the measurement of drug action

Full access? Get Clinical Tree

Get Clinical Tree app for offline access