c Growth factors: Fibroblast growth factors comprise the largest family of growth factor ligands at 23 members. The natural alternate splicing of four fibroblast growth factor receptor (FGFR) genes results in the production of over 48 different isoforms of FGFR. Vascular endothelial growth factor (VEGF) is one of the main inducers of endothelial cell proliferation and permeability of blood vessels; The platelet‐derived growth factors PDGF‐A and ‐B have been recognized as important factors regulating cell proliferation, cellular differentiation, cell growth, development, and many diseases including cancer. Neurotrophins are critical to the functioning of the nervous system. Angiopoietins are protein growth factors required for the formation of blood vessels (angiogenesis). Others include epidermal growth factor (EGF) and hepatocyte growth factor (HGF).
Figure 1.12. Concentration–response curve of an agonist in (a) linear (b) log scale.
Figure 1.13. Concentration–response curves of a partial agonist and a full agonist both of which have a similar affinity towards the receptor.
Small molecule drugs are selective rather than specific, which means that they rarely produce a single effect. Even if a drug were to act on a single receptor, this receptor may be ubiquitously expressed and may be present in organs where the drug is not intended to act. Alternatively, the targeted receptor may exist in other isoforms which, when affected, can produce adverse effects. Additionally, drugs may act on several receptor classes. A primary effect is the desired therapeutic effect. Secondary effects include all other effects besides the desired effect and may be either beneficial (which is rare) or harmful. With appropriately designed PK and PD studies, one can potentially interpret and predict the outcome of primary and secondary effects. PD involves a study of the relationships between plasma drug concentrations, receptor occupancy, receptor activation and the pharmacological effect, aided by the biochemical and physiological mechanisms of drug action. For drugs which have low membrane permeability or which are substrates of drug transporters, target tissue concentrations rather than plasma concentrations should correlate well with the observed pharmacological effect.
1.5.2 Functional Adaptation Processes
One of the perils of drug development is the occurrence of time‐dependent modulations in pharmacological activity upon repeat administration of certain drugs, arising from functional adaptation processes such as desensitization and sensitization.
1.5.2.1 Desensitization, Tolerance, and Tachyphylaxis
Receptor‐mediated responses to drugs often desensitize with time. This reduced response to an agonist, which is usually reversible upon cessation of treatment, is called desensitization. A second exposure to the agonist after a lapse usually restores response. Agonists that desensitize receptors due to conditioning mechanisms can trigger tolerance and addiction. Some examples of addictive medicines are tranquilizers and sedatives (sleeping pills). Many of these belong to a group of similar substances called benzodiazepines, which allosterically potentiate GABA type A receptor (Sieghart, 1994). Desensitization is often used to suggest a reduced response by any mechanism – receptor phosphorylation, uncoupling, antagonistic metabolites, or negative physiological feedback that occurs over a relatively short period of time, while tolerance is reserved for reduced responsiveness developing over longer periods, usually because of receptor downregulation. Tachyphylaxis is a rapidly developing desensitization after just one or two administrations of the drug.
Figure 1.14. Target classes. (a) G‐protein‐coupled receptor (GPCR) (b) tyrosine kinase (c) nuclear receptor and (d) ion channel.
Most receptors can undergo agonist‐induced regulation. When an agonist occupies a receptor, it can result in a series of events that can lead to internalization of the receptor. The signals for internalization include phosphorylation of the receptor, which sets the stage for adapter molecules to bind to the receptor. The agonist is then removed, and the receptor is targeted for cycling back to the cell membrane or is trafficked into a degradation pathway. Cycling of the receptor is associated with resensitization of the receptor, while degradation results in a loss of total receptor density. When receptor density is decreased, it is usually associated with a shift to the right in the dose‐effect curve for agonists. An example of desensitization is the high affinity, desensitized, closed state of the nicotinic acetylcholine receptors (nAChRs), induced by chronic exposure to acetylcholine (ACh) or nicotinic drugs, leading to a gradual decrease in the rate of opening of K+, Na+, and sometimes Ca2+ cationic channels (milliseconds to minutes).
Sensitization has the opposite effect of tolerance, where an increase in drug effect is observed after repeated administration of certain drugs. When the body tries to return to homeostasis following a sudden discontinuation of a drug, the receptors which are deprived of their AGONISTs/blockers become hypersensitive to an agent that targets it, causing a further exacerbation of the symptoms/conditions that triggered the use of the drug in the first place. This rebound effect can be minimized by a gradual rather than a sudden discontinuation of the drug. Several anxiolytics and hypnotics have a rebound effect. For example, benzodiazepine withdrawal can cause severe anxiety and insomnia, worse than the original insomnia or anxiety disorder. Other examples causing rebound effects include sedatives like lunesta and ambien, the short acting hypnotic, triazolam (due to its high potency and ultra‐short half‐life), stimulants such as methylphenidate or dextroamphetamine antidepressants such as SSRIs, and alpha‐2 adrenergic agents such as clonidine and guanfacine. Rebound on drug withdrawal can be a factor in the chronic use of medications and drug dependence, with patients taking the medications only to ward off withdrawal or rebound withdrawal effects.
Time‐dependent changes in drug action arising from desensitization, sensitization, and rebound cause a loss of consistency in the concentration–effect relationship with increasing number of doses, leading to the serious consequences of reduced efficacy or increased toxicity with time which can be disastrous for drugs with narrow therapeutic window.
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints
The pharmacological effect of a drug or the response that it evokes in a species can be quantified using a biomarker (biological marker). A biomarker is an indicator of some biological or pathogenic processes and may be a protein, metabolite, DNA or RNA measured in blood, urine or soft tissues. The nature of biomarkers depends on whether they are meant for early screening assays such as binding or cell‐based assays, or whether they are used later in the value chain in in vivo/ex vivo preclinical or clinical development. They can provide great predictive value if they reflect the mechanism of drug action (target‐site drug exposure, drug–target interaction, target activation, signal transduction, homeostatic feedback mechanisms in normal and disease populations) and if the biomarker levels needed to reach the desired pharmacological effect
