Tolerance may be defined as either (1) the loss of effect over time to the same dose of a drug or (2) the need for more of a drug over time to get the same effect. Tolerance, at first, appears counterintuitive because addition of more of an activating ligand lessens the elicited response.
Recall, however, that receptor number and receptor sensitivity are dynamic and that signaling can adjust based on the conditions of ligand availability. Given that drugs often times act as a replacement for endogenous ligands or alter the response to endogenous ligands, it is possible that drugs may change receptor activity. Tolerance, therefore, is a normal response reflecting the body’s ability to adapt to the presence of a drug.
Tolerance may be pharmacokinetic in origin, but is most often related to drug own metabolism and thus decreases concentration of drug at the site of action. Pharmacodynamic tolerance arises as a result of adaptive changes in receptor sensitivity in response to repeated exposure to a particular drug. The result is usually a decrease or loss of sensitivity to the drug, resulting in a decreased response. Adaptive changes may be related to receptor downregulation, cellular adaptation, or tachyphylaxis (a rapidly decreasing response to a drug after administration of a few doses).
Tolerance to the analgesic effects of morphine is fairly rapid and also is a good example of drug tolerance.