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The Differences Between the Four Main Actions a Drug Can Have After Binding to a Receptor

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Receptors are typically glycoproteins located in cell membranes that specifically recognize and bind to ligands

These are smaller molecules (including drugs) that are capable of 'ligating' themselves to the receptor protein. This binding initiates a conformational change in the receptor protein leading to a series of biochemical reactions inside the cell (‘signal transduction’), often involving the generation of ‘secondary messengers’ that is eventually translated into a biological response (e.g. muscle contraction, hormone secretion). Although the ligands of interest to prescribers are exogenous compounds (i.e. drugs), receptors in human tissues have evolved to bind endogenous ligands such as neurotransmitters, hormones, and growth factors.

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Receptors are macromolecules involved in chemical signaling between and within cells; they may be located on the cell surface membrane or within the cytoplasm (see table Some Types of Physiologic and Drug-Receptor Proteins). Activated receptors directly or indirectly regulate cellular biochemical processes (eg, ion conductance, protein phosphorylation, DNA transcription, enzymatic activity). Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands. The binding can be specific and reversible. A ligand may activate or inactivate a receptor; activation may increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes. Few if any drugs are absolutely specific for one receptor or subtype, but most have relative selectivity. Selectivity is the degree to which a drug acts on a given site relative to other sites; selectivity relates largely to physicochemical binding of the drug to cellular receptors. The pharmacologic effect is also determined by the duration of time that the drug-receptor complex persists (residence time). The lifetime of the drug-receptor complex is affected by dynamic processes (conformation changes) that control the rate of drug association and dissociation from the target. A longer residence time explains a prolonged pharmacologic effect. Drugs with long residence times include finasteride and darunavir. A longer residence time can be a potential disadvantage when it prolongs a drug's toxicity. For some receptors, transient drug occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes toxicity. Physiologic functions (eg, contraction, secretion) are usually regulated by multiple receptor-mediated mechanisms, and several steps (eg, receptor-coupling, multiple intracellular 2nd messenger substances) may be interposed between the initial molecular drug–receptor interaction and ultimate tissue or organ response. Thus, several dissimilar drug molecules can often be used to produce the same desired response. Ability to bind to a receptor is influenced by external factors as well as by intracellular regulatory mechanisms. Baseline receptor density and the efficiency of stimulus-response mechanisms vary from tissue to tissue. Drugs, aging, genetic mutations, and disorders can increase (upregulate) or decrease (downregulate) the number and binding affinity of receptors

For example, clonidine downregulates alpha 2 receptors; thus, rapid withdrawal of clonidine can cause hypertensive crisis. Chronic therapy with beta-blockers upregulates beta-receptor density; thus, severe hypertension or tachycardia can result from abrupt withdrawal. Receptor upregulation and downregulation affect adaptation to drugs (eg, desensitization, tachyphylaxis, tolerance, acquired resistance, postwithdrawal supersensitivity).The pharmacologic effect is also determined by the duration of time that the drug-receptor complex persists (residence time). The lifetime of the drug-receptor complex is affected by dynamic processes (conformation changes) that control the rate of drug association and dissociation from the target. A longer residence time explains a prolonged pharmacologic effect. Drugs with long residence times include finasteride and darunavir. A longer residence time can be a potential disadvantage when it prolongs a drug's toxicity. For some receptors, transient drug occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes toxicity. Physiologic functions (eg, contraction, secretion) are usually regulated by multiple receptor-mediated mechanisms, and several steps (eg, receptor-coupling, multiple intracellular 2nd messenger substances) may be interposed between the initial molecular drug–receptor interaction and ultimate tissue or organ response. Thus, several dissimilar drug molecules can often be used to produce the same desired response. Ability to bind to a receptor is influenced by external factors as well as by intracellular regulatory mechanisms. Baseline receptor density and the efficiency of stimulus-response mechanisms vary from tissue to tissue. Drugs, aging, genetic mutations, and disorders can increase (upregulate) or decrease (downregulate) the number and binding affinity of receptors. For example, clonidine downregulates alpha 2 receptors; thus, rapid withdrawal of clonidine can cause hypertensive crisis. Chronic therapy with beta-blockers upregulates beta-receptor density; thus, severe hypertension or tachycardia can result from abrupt withdrawal. Receptor upregulation and downregulation affect adaptation to drugs (eg, desensitization, tachyphylaxis, tolerance, acquired resistance, postwithdrawal supersensitivity).

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Drugs produce their effects by interacting with biologic targets, but the time course of the pharmacodynamic effect is dependent on the mechanism and biochemical pathway of the target. Effects can be classified as direct or indirect and immediate or delayed. Direct effects are usually the result of drugs interacting with a receptor or enzyme that is central to the pathway of the effect. Beta-blockers inhibit receptors that directly modulate cAMP levels in smooth muscle cells in the vasculature. Indirect effects are the result of drugs interacting with receptors, proteins of other biologic structures that significantly upstream from the end biochemical process that produces the drug effect. Corticosteroids bind to nuclear transcription factors in the cell cytosol which translocate to the nucleus and inhibit transcription of DNA to mRNA encoding for several inflammatory proteins. Immediate effects are usually secondary to direct drug effects (Goutelle S, Maurin M, 2008). Neuromuscular blocking agents such as succinylcholine, which consists of two acetylcholine (ACh) molecules linked end to end by their acetyl groups, interact with the nicotinic acetylcholine receptor (nAChR) on skeletal muscle cells and leave the channel in an open state, resulting in membrane depolarization and generation of an action potential, muscle contraction and then paralysis within 60 seconds after administration. Delayed effects can be secondary to direct drug effects. Chemotherapy agents which interfere with DNA synthesis, like cytosine arabinoside which is used in acute myeloid leukemia, produce bone marrow suppression that occurs several days after administration (Liang M, Schwickart M, 2016).

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To summarize, for ligand binding models, the term fractional occupancy is best used to describe the fraction of receptors occupied at a particular ligand concentration. It is stated that the fractional occupancy = occupied binding sites/total binding sites, which means the effect of a drug should depend on the fraction of receptors that are occupied. In the future, network-based systems pharmacology models using ligand binding principles could be an effective way of understanding drug-related adverse effects

This will facilitate and strengthen the development of rational drug therapy in clinical practice.

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Rang HP. The receptor concept: pharmacology's big idea. Br. J. Pharmacol. 2006 Jan;147 Suppl 1:S9-16.

Keller F, Hann A. Clinical Pharmacodynamics: Principles of Drug Response and Alterations in Kidney Disease. Clin J Am Soc Nephrol. 2018 Sep

Goutelle S, Maurin M, Rougier F, Barbaut X, Bourguignon L, Ducher M, Maire P. The Hill equation: a review of its capabilities in pharmacological modelling. Fundam Clin Pharmacol. 2008 Dec

Liang M, Schwickart M, Schneider AK, Vainshtein I, Del Nagro C, Standifer N, Roskos LK. Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development. Cytometry B Clin Cytom. 2016 Mar

Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008

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