“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 regards 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). 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) the reduction of blood pressure after ACE inhibitors, and (3) the blood-glucose-lowering effect of insulin. 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.
There are a few key concepts and terms used in the description of pharmacodynamics that describe the extent and duration of a drug's action.
Emax is the maximal effect of a drug on a parameter that is 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 coefficients above 2 indicate a steep relationship (i.e., small changes in concentration produce large changes in effect), and hill coefficients above 3 indicate an almost instantaneous "all or none" effect.
General Mechanisms of Drug Actions
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. 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 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
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 while erlotinib has a Kd of 0.35 nM for the estimated glomerular filtration rate (EGFR) receptor indicating that erlotinib has approximately 300 times the receptor interaction than albuterol.
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 is the concept of spare receptors and occurs commonly to include 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. 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. 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 drug in the plasma and its intended effect may be due to multiple factors to include 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.
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.
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