Clinical pharmacodynamics

Desensitization refers to the common situation where the biological response to a drug diminishes when it is given continuously or repeatedly. It may be possible to restore the response by increasing the dose (or concentration) of the drug but, in some cases, the tissues may become completely refractory to its effect. The term tachyphylaxis is used to describe desensitization that occurs very rapidly, sometimes with the initial dose. The term tolerance is conventionally used to describe a more gradual loss of response to a drug that occurs over days or weeks. There is no clear distinction but the different scales imply that different mechanisms may be involved. Rapid development implies the depletion of chemicals that may be necessary for the pharmacological actions of the drug (e.g. a stored neurotransmitter released from a nerve terminal) or receptor phosphorylation. Slower development implies changes in receptor numbers or the development of counter-regulatory physiological changes that offset the actions of the drug (e.g. accumulation of salt and water in response to vasodilator therapy) or reduction of target receptor numbers.

The term refractoriness is often used to describe a state where there is lack of responsiveness to a drug. Drug resistance is a term normally reserved to describe the loss of effectiveness of an antimicrobial or cancer chemotherapy drug. In addition to these pharmacodynamic causes of diminished effectiveness, reduced response may be the consequence of a reduction in the plasma and tissue drug concentrations that result from the same drug dose, because of alterations in the way the drug is handled (its ‘pharmacokinetics’).

Where desensitization to a drug arises because of established chemical, hormonal and physiological changes that offset the actions of the drug, discontinuation may mean that these changes themselves cause ‘rebound’ withdrawal effects (e.g. nitrates, opioids, benzodiazepines).

Normal physiology depends on the structure and function of cells and tissues, which are composed of complex molecules and biochemical processes. The pathophysiology underlying the progression of most diseases involves disordered activity of one or more of these cells. Drugs are exogenous molecules that are intended to restore the activity of the endogenous systems to normal by increasing or decreasing the activity of key regulatory pathways. They do this by exerting effects on cells and tissues, either by initiating new events or blocking the actions of endogenous substances, to exert a biological effect. These biological responses include changing the ion content of cells, promoting secretion of hormones, reducing the electrical signalling by excitable cells, reducing contractile activity, stimulating the synthesis of new proteins, and many others. Most of these responses result from interactions between a drugs and endogenous receptors.

Receptors are glycoproteins situated in the cell membrane (or at an intracellular site) that specifically recognise and bind ligands - smaller molecules capable of 'ligating' themselves to the receptor protein. The ligands of interest in pharmacology are exogenous compounds (i.e. drugs), receptors in human tissues have evolved to bind endogenous ligands such as neurotransmitters, hormones, and growth factors. When ligands bind to receptors they initiate a conformational change in the receptor protein that eventually transmits a biochemical signal into the cell (signal transduction), sometimes involving a secondary messenger, which is ultimately translated into a biological response (e.g. muscle contraction, hormone secretion). Drug-receptor complex formation is reversible with the biological response being proportional to the fraction of receptors bound.

When the relation between drug dose (X-axis) and drug response (Y-axis) is plotted on a linear scale, the resulting curve is usually hyperbolic. Clinical responses that might be plotted in this way include change in heart rate, blood pressure, gastric pH or blood glucose. Non-clinical (biochemical) responses can also be plotted in this way including enzyme activity, accumulation of an intracellular second messenger, membrane potential, secretion of a hormone, or contraction of a muscle. 

If the drug dose is plotted on a base 10 logarithmic scale, this produces a sigmoidal dose-response curve. This representation is more useful because it expands the dose scale in the region where drug response is changing rapidly and compresses the scale at higher doses where large changes have little effect on response. Note that, in reality, it is ligand concentration (and resulting receptor occupation) that affects response - the term ‘dose-response curve’ assumes that the drug dose and ligand concentration are closely linked.

Drug dose-response involves the principles of pharmacokinetics and pharmacodynamics and can be used to determine the required dose and frequency to achieve the desired response, for example the desired drug effect. Multiple factors can cause variation in dose-response curves: population differences, patient-related factors and measurement methodologies for example, but repeated measurements carried out under identical conditions can help establish the pharmacologic profile of the drug being evaluated. The dose-response relationship is important because the concentration of a drug at its site of action controls its effect, with caveats as mentioned above..

Box 2 shows how drug profiles can be compared based on their plotted dose-response curves.