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Last Update: January 29, 2023.


"Did we but know the mechanical affections of the particles of rhubarb, hemlock, opium, and a man...we should be able to tell beforehand that rhubarb will purge, hemlock kill and opium make a man sleepy..." - John Locke: Essay Concerning Human Understanding

Pharmacodynamics is the study of a drug's molecular, biochemical, and physiologic effects or actions. It comes from the Greek words "pharmakon," meaning "drug," and "dynamikos," meaning "power." All drugs produce their effects by interacting with biological structures or targets at the molecular level to induce a change in how the target molecule functions in regard to subsequent intermolecular interactions. These interactions include receptor binding, post-receptor effects, and chemical interactions. Examples of these types of interactions include (1) drugs binding to an active site of an enzyme, (2) drugs that interact with cell surface signaling proteins to disrupt downstream signaling, and (3) drugs that act by binding molecules like tumor necrosis factor (TNF).[1] 

Subsequent to the drug-target interaction occurring downstream, effects are elicited, which can be measured by biochemical or clinical means. Examples of this include the (1) inhibition of platelet aggregation after administering aspirin, (2) reduction of blood pressure after ACE inhibitors, and (3) the blood-glucose-lowering effect of insulin.[2][3] 

While these examples seem obvious, the administration of the preceding drug examples should be kept in mind, so practitioners do not administer these drugs to inhibit platelet aggregation, lower blood pressure, or lower blood glucose but to reduce the risks of cerebrovascular accident, myocardial infarction, and renal and eye complications through the drug's pharmacodynamic effects.[4] It is important for healthcare practitioners they are treating the patient, not the symptom or the lab value.

Pharmacodynamics and pharmacokinetics are the two branches of pharmacology, with pharmacodynamics studying the action of the drug on the organism and pharmacokinetics studying the effect the organism has on the drug.

Pharmacodynamic actions include:

  • Stimulating activity by directly inhibiting a receptor and its downstream effects
  • Depressing activity by direct receptor inhibition and its downstream effects
  • Antagonistic or blocking a receptor by binding to it but not activating it
  • Stabilizing action, where the drug apparently behaves as neither an agonist nor antagonist 
  • Direct chemical reactions (beneficial in therapy and also as an adverse event)

Any of these factors can work both therapeutically as well as precipitate an adverse event.

Issues of Concern

Pharmacodynamic Concepts

A few key concepts and terms are used in the description of pharmacodynamics to describe the extent and duration of a drug's action.

  • Emax is the maximal effect of a drug on a parameter being measured. For example, this could be a measure of platelet inhibition as an ex-vivo test or the maximum lowering of blood pressure.
  • EC50 is the concentration of the drug at a steady state that produces half of the maximum effect
  • Hill coefficient is the slope of the relationship between drug concentration and drug effect. Hill coefficient values above 2 indicate a steep relationship (i.e., small changes in concentration produce significant changes in effect), and hill coefficient values above 3 indicate an almost instantaneous "all or none" effect.[5]

General Mechanisms of Drug Actions

Drugs produce their effects by interacting with biological 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 and proteins of other biologic structures that are 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.[6]

Immediate effects are usually secondary to direct drug effects. 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.[7] Delayed effects can be secondary to direct drug effects. Chemotherapy agents that interfere with DNA synthesis, like cytosine arabinoside, which is used in acute myeloid leukemia, produce bone marrow suppression that occurs several days after administration.

Dosing Principles-Based Upon Pharmacodynamics

Pharmacodynamics emphasizes dose-receptor relationships; these are the interactions between the drug's concentration and its effect.[8] For example, we can examine drug-receptor interactions according to the following formula:

In this equation, L represents the ligand, i.e., drug concentration, R denotes receptor concentrations, and LR is the ligand-receptor complex concentrations.

Other pharmacodynamic concepts include:

Kd: The pharmacologic response depends on the drug binding to its target as well as the concentration of the drug at the receptor site. Kd measures how tightly a drug binds to its receptor. Kd is defined as the ratio of rate constants for association (kon) and dissociation (koff) of the drug to and from the receptors. At equilibrium, the rate of receptor-drug complex formation is equal to the rate of dissociation into its components receptor + drug. The measurement of the reaction rate constants can be used to define an equilibrium or affinity constant (1/Kd). The smaller the Kd value, the greater the affinity of the antibody for its target. For example, albuterol has a Kd of 100 nanomolar (nM) for the beta-2 receptor. 

Receptor Occupancy: From the law of mass action, the more receptors that are occupied by the drug, the greater the pharmacodynamic response, but all receptors do not need to be occupied in order to get a maximal response. This principle is the concept of spare receptors and commonly includes muscarinic and nicotinic acetylcholine receptors, steroid receptors, and catecholamine receptors. Maximal effects are obtained by less than maximal receptor occupancy by signal amplification.

Receptor Up- and Downregulation: Chronic exposure of a receptor to an antagonist typically leads to upregulation, or an increased number of receptors, while chronic exposure of a receptor to an agonist causes downregulation or a decreased number of receptors. [9] Other mechanisms involving alteration of downstream receptor signaling may also be involved in up- or downmodulation without altering the receptor number on the cell membrane.[10] The insulin receptor undergoes downregulation to chronic exposure to insulin. The number of surface receptors for insulin is gradually reduced by receptor internalization and degradation brought about by increased hormonal binding. An exception to the rule is the receptor for nicotine that demonstrates upregulation in receptor numbers upon extended exposure to nicotine, despite nicotine being an agonist, which explains some of its addictive properties.

Effect compartment and indirect pharmacodynamics: A delay between the appearance of the drug in the plasma and its intended effect may be due to multiple factors, including transfer into the tissue or cell compartment in the body or a requirement for the inhibition or stimulation of a signal to be cascaded through intracellular pathways. These effects can be described by either using an effect compartment or using indirect pharmacodynamic response models, which describe the effect of the drug through indirect mechanisms such as inhibition or stimulation of the production or elimination of endogenous cellular components that control the effect pathway.[11]

Clinical Significance

Several issues in drug dosing can be explained in terms of Kd, receptor occupancy, and up/downregulation. Tolerance to a drug, where the effects seem to diminish with continued dosing, frequently occurs with prolonged dosing of opioids. Activation of opioid receptors stimulates the production of intracellular proteins called arrestins. Arrestins bind to the intracellular portion of the opioid receptor, block G-protein signaling, and induce receptor endocytosis. This results in less "signaling" or tolerance. The activity of arrestins, which produce receptor down-regulation, is one of the many pathways that lead to opioid tolerance.[10]

Enhancing Healthcare Team Outcomes

It goes without saying that the goal of pharmacodynamics in a pharmacological therapy setting is to exert positive effects at the least necessary dose that produces the maximum therapeutic effect while minimizing the pharmacodynamics that leads to an adverse event. All interprofessional healthcare team members engaged in the prescribing, dosing, dispensing, or administering of pharmacological therapy must have at least some understanding of pharmacodynamic and pharmacokinetic principles. Obviously, the level of knowledge must be commensurate with the practitioner's clinical function.

However, pharmacologic therapy properly involves an interprofessional team that includes all clinicians who prescribe or order medications (MDs, DOs, NPs, PAs), pharmacists, who without question need to be the subject matter experts regarding pharmacodynamics and their application in drug therapy; clinicians should utilize them as a valuable resource because of this specialization, and nurses, who along with the pharmacists can counsel the patient about their medications, administer them in inpatient and other settings, and are often the main point of contact for patients regarding their drug regimen. With an interprofessional team approach to pharmacotherapy that includes appropriate pharmacodynamic knowledge, patient outcomes can be optimized while adverse events are minimized. [Level 5]

Review Questions


Rang HP. The receptor concept: pharmacology's big idea. Br J Pharmacol. 2006 Jan;147 Suppl 1(Suppl 1):S9-16. [PMC free article: PMC1760743] [PubMed: 16402126]
Cirillo P, Taglialatela V, Pellegrino G, Morello A, Conte S, Di Serafino L, Cimmino G. Effects of colchicine on platelet aggregation in patients on dual antiplatelet therapy with aspirin and clopidogrel. J Thromb Thrombolysis. 2020 Aug;50(2):468-472. [PMC free article: PMC7183388] [PubMed: 32335777]
Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, Yang R, Di W, Wang Z, Li Z, Gao H, Liu L, Zhang G. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020 Dec;9(1):757-760. [PMC free article: PMC7170368] [PubMed: 32228222]
Keller F, Hann A. Clinical Pharmacodynamics: Principles of Drug Response and Alterations in Kidney Disease. Clin J Am Soc Nephrol. 2018 Sep 07;13(9):1413-1420. [PMC free article: PMC6140566] [PubMed: 29769182]
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;22(6):633-48. [PubMed: 19049668]
Ramamoorthy S, Cidlowski JA. Corticosteroids: Mechanisms of Action in Health and Disease. Rheum Dis Clin North Am. 2016 Feb;42(1):15-31, vii. [PMC free article: PMC4662771] [PubMed: 26611548]
Jonsson M, Dabrowski M, Gurley DA, Larsson O, Johnson EC, Fredholm BB, Eriksson LI. Activation and inhibition of human muscular and neuronal nicotinic acetylcholine receptors by succinylcholine. Anesthesiology. 2006 Apr;104(4):724-33. [PubMed: 16571968]
Lees P, Cunningham FM, Elliott J. Principles of pharmacodynamics and their applications in veterinary pharmacology. J Vet Pharmacol Ther. 2004 Dec;27(6):397-414. [PubMed: 15601436]
Dumas EO, Pollack GM. Opioid tolerance development: a pharmacokinetic/pharmacodynamic perspective. AAPS J. 2008 Dec;10(4):537-51. [PMC free article: PMC2628209] [PubMed: 18989788]
Cahill CM, Walwyn W, Taylor AMW, Pradhan AAA, Evans CJ. Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation. Trends Pharmacol Sci. 2016 Nov;37(11):963-976. [PMC free article: PMC5240843] [PubMed: 27670390]
Sharma A, Jusko WJ. Characteristics of indirect pharmacodynamic models and applications to clinical drug responses. Br J Clin Pharmacol. 1998 Mar;45(3):229-39. [PMC free article: PMC1873365] [PubMed: 9517366]

Disclosure: Mark Marino declares no relevant financial relationships with ineligible companies.

Disclosure: Zohaib Jamal declares no relevant financial relationships with ineligible companies.

Disclosure: Patrick Zito declares no relevant financial relationships with ineligible companies.

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Bookshelf ID: NBK507791PMID: 29939568


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