Pharmacodynamics Mechanism of Action PDF

INTRODUCTION TO PHARMACODYNAMICS **Introduction** Pharmacokinetics (PK) studies the fate of drugs in the animal whereas pharmacodynamics (PD) studies the action of drugs from its interaction with receptors, to the effect on animal populations. Pharmacokinetic/pharmacodynamic (PK/PD) integration co...

INTRODUCTION TO PHARMACODYNAMICS **Introduction** Pharmacokinetics (PK) studies the fate of drugs in the animal whereas pharmacodynamics (PD) studies the action of drugs from its interaction with receptors, to the effect on animal populations. Pharmacokinetic/pharmacodynamic (PK/PD) integration consists of describing and explaining the time course of the drug effect (PD) via the time course of its concentration in the plasma (PK). Pharmacodynamics (sometimes described as what a drug does to the body) is the study of the biochemical, physiologic, and molecular effects of drugs on the body and involves [receptor binding](https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacodynamics/drug%E2%80%93receptor-interactions) (including receptor sensitivity), post-receptor effects, and [chemical interactions](https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacodynamics/chemical-interactions). It is the relationship between drug concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects. The effect of a drug present at the site of action is determined by that drug\'s binding with a receptor. Pharmacodynamics, with [pharmacokinetics](https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/overview-of-pharmacokinetics) (what the body does to a drug, or the fate of a drug within the body), helps explain the relationship between the [dose and response](https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacodynamics/dose-response-relationships), ie, the drug\'s effects. The pharmacologic response depends on the drug binding to its target. The concentration of the drug at the receptor site influences the drug's effect. A drug's pharmacodynamics can be affected by physiologic changes due to; A disorder or disease, Aging process, Other drugs. **Disorders** that affect pharmacodynamic responses include genetic mutations, thyrotoxicosis, malnutrition, myasthenia gravis, Parkinson disease, and some forms of insulin-resistant diabetes mellitus. These disorders can change receptor binding, alter the level of binding proteins, or decrease receptor sensitivity. **Aging** tends to affect pharmacodynamic responses through alterations in receptor binding or in post-receptor response sensitivity (see table Effect of Aging on Drug Response). **Pharmacodynamic drug--drug** interactions result in competition for receptor binding sites or alter post-receptor response. Mechanism of drug action \| Pharmacodynamics In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. **Types of Drug Targets** Most drugs act via an interaction with certain proteins either of the host or of the pathogen.  [**Figure 4.2**](https://veteriankey.com/mechanism-of-drug-action-and-pharmacokineticspharmacodynamics-integration-in-dosage-regimen-optimization-for-veterinary-medicine/#figureanchor4-2) Mechanisms of drug action. For most drugs, the drug action is mediated by some biological interaction with a macromolecule of the cell, often a protein. Different proteins are involved as drug targets and the term receptor is only used when the interaction triggers a cascade of events for signal transmission. Four types of protein are targeted by drugs: *enzymes, carriers, ion channels,* and *receptors*. The term receptor should be reserved for regulatory proteins that play a role in intercellular communication. Thus, enzymes, ion channels, and carriers are not usually classified as receptors. **Drug Receptor and Ligand as Agonist or Antagonist** A receptor is a molecule or a polymeric structure on the surface of or inside a cell that specifically recognizes and binds an endogenous compound. Binding sites are three-dimensional structures, forming pockets or grooves on the surface of protein that allow specific interactions with compounds known as *ligands*, which are molecules of complementary shape to the protein binding site (lock and key analogy). Receptors possess an effector system (also termed signal-transduction pathways). In this they differ from *acceptors* which are molecules without signal-transduction pathways (e.g., serum albumin), characterized by a binding process that is not followed by a physiological response. Endogenous neurotransmitters, such as hormones, act as molecular messengers and are endogenous ligands. Drugs may be viewed as exogenous ligands. After attachment to a receptor site, a drug may produce a cascade of biochemical events that result in drug action. A drug is said to be an *agonist* when it produces a measurable physiological or pharmacological response characteristic of the receptor (contraction, relaxation, secretion, enzyme activation, etc.). If a drug binds to the same site as the endogenous ligand, the drug is said to be a *primary agonist,* in comparison to an *allosteric agonist* which binds to a different region of the receptor. Most anesthetic drugs allosterically modulate GABA~R~ and disrupt corresponding physiological circuits. A *full agonist* produces a maximal effect under a given set of conditions whereas a *partial agonist* produces only a submaximal effect regardless of the amount of drug applied. For opioid receptors, morphine and fentanyl are full agonists, able to initiate strong analgesia, while buprenorphine is a partial agonist (Lees et al., 2004b). Even if buprenorphine is unable to achieve the same level of analgesia provided by a maximally effective dose of full agonists, it may be preferred for postsurgical analgesia because its effect is of long duration and adverse effects are minimal. In contrast to an agonist, some drugs may be unable to trigger any action on their own, after attachment to a receptor site, but are able to block the action of other agonists. These "silent drugs" are termed *antagonists*; most drugs used in therapeutics are receptor antagonists and prevent the action of natural agonists (neurotransmitters, hormones, etc.). Some drugs may be both agonist and antagonist, for example butorphanol, a central-acting opioid analgesic, is mainly an antagonist at the *mu* receptor but is an agonist at the *kappa* receptor. Two forms of antagonism can be distinguished: *competitive* and *noncompetitive antagonism*. In competitive antagonism, antagonists act on the same receptor as the agonist**;** this is said to be reversible when it can be surmounted by increasing the concentration of the agonist. Examples of therapeutic agents acting by competitive antagonism are atropine (an antimuscarinic agent) and propranolol (a beta blocker). In irreversible (competitive) antagonism, a net displacement of the antagonist from its binding site cannot be achieved by increasing the agonist concentration and, operationally, it resembles noncompetitive antagonism. This occurs when the antagonist is bound covalently and irreversibly to its receptor binding site. Although there are few drugs of this type, irreversible antagonists are used as experimental probes for investigating receptor function. *Noncompetitive antagonism* refers to the situation where a drug blocks the cascade of events, normally leading to an agonist response, at some downstream point. This occurs with Ca^2+^ channel blockers, such as nifedipine, which prevent the influx of calcium ions through the cell membrane and nonspecifically block any agonist action requiring calcium mobilization, as in smooth muscle contraction. The concept of *physiological antagonism* refers to the interaction of two drugs whose opposing actions on a physiological system tend to cancel each other out. For example, histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump. Antagonists were viewed solely as "silent ligands" until the discovery of the so-called inverse agonists. An inverse agonist is a drug that acts at the same receptor as that of an agonist, yet produces an opposite effect (see Section Drug Receptor Theories: from the Occupancy Theories to the Two-State Model for the mechanism of inverse agonist action). [Figure 4.3](https://veteriankey.com/mechanism-of-drug-action-and-pharmacokineticspharmacodynamics-integration-in-dosage-regimen-optimization-for-veterinary-medicine/#figure4-3) summarizes the spectrum of activities that ligands can display. **Drug Affinity, Efficacy and Potency** The concentration--effect relationship is determined by two features of the drug--receptor interaction, namely drug *affinity* and drug *efficacy*. The affinity of a drug is its ability to bind to a receptor. Affinity is determined by the chemical structure of the drug and minimal modification of the drug structure may result in a major change in affinity. This is exploited to discover new drugs. Affinity determines the concentration of drug required to form a significant number of drug--receptor complexes that in turn are responsible for drug action. The numerical representation of affinity for both an agonist and an antagonist is the *constant of affinity,* denoted by Ka (dimension M^−1^, i.e., liter per mole). A Ka of 10^7^M^−1^ means that one mole of the ligand must be diluted in 10^7^ liters of solvent to obtain a concentration of the free ligand able to saturate half the maximal binding capacity of the system. The reciprocal of Ka is the equilibrium *dissociation constant* of the ligand--receptor complex, denoted by Kd (dimension M i.e., mole per liter). A Kd of 10^−7^M means that a free ligand concentration of 10^−7^ mole per liter is required to saturate half the maximal binding capacity of the system. The lower the Kd value of a drug, the higher the affinity for its receptor. Radioactive receptor ligands (radioligands) or fluorescent probes are used to accurately determine receptor affinity. The relationship between bound and free ligand may be described by a hyperbolic equation corresponding to the Michaelis Menten equation: numbered Display Equation Where *B~max~* (a parameter) represents the maximal binding capacity (the total number of receptors), *Free* is the molar concentration of the free ligand, *Bound* is the bound ligand concentration and *Kd* (a parameter) is the equilibrium constant of dissociation. In pharmacology, potency or biological potency is a measure of a drug\'s biological activity expressed in terms of the dose required to produce a pharmacological effect of given intensity. A highly potent drug (e.g., [fentanyl](https://en.wikipedia.org/wiki/Fentanyl), [clonazepam](https://en.wikipedia.org/wiki/Clonazepam), [risperidone](https://en.wikipedia.org/wiki/Risperidone), [benperidol](https://en.wikipedia.org/wiki/Benperidol), [bumetanide](https://en.wikipedia.org/wiki/Bumetanide)) evokes a given response at low concentrations, while a drug of lower potency (e.g. [morphine](https://en.wikipedia.org/wiki/Morphine), [alprazolam](https://en.wikipedia.org/wiki/Alprazolam), [ziprasidone](https://en.wikipedia.org/wiki/Ziprasidone), [haloperidol](https://en.wikipedia.org/wiki/Haloperidol), [furosemide](https://en.wikipedia.org/wiki/Furosemide)) evokes the same response only at higher concentrations. Higher potency does not necessarily mean greater [effectiveness](https://en.wikipedia.org/wiki/Effectiveness) or more [side effects](https://en.wikipedia.org/wiki/Adverse_drug_reaction). **Drug Specificity and Selectivity** The drug receptor interaction is responsible for the *specificity* and *selectivity* of drug action. When the drug acts only on a single target (enzyme, receptor, etc.), it is said to be specific. *Specificity* is linked to the nature of the drug--receptor interaction and more precisely to the macromolecular structure of the receptors (or enzymes). As receptors are generally proteins, the diversity in three-dimensional shape required for ligand specificity is provided by the polypeptide structure. The recognition of specific ligands by receptors is based on the complementarity of the three-dimensional structure of the ligand and a binding pocket on the macromolecular target. The shapes and actions of receptors are currently being investigated by X-ray crystallography and computer modeling. Most drugs can display activity towards a variety of receptors and are more often selective than specific. For example, histamine antagonists produce several effects, such as sedation and prevention of vomiting, which do not depend on histamine antagonism. *Selectivity* is related to the concentration range. The drug may be specific at a low concentration if it activates only one type of target, whereas several targets may be involved simultaneously (activated, inhibited, etc.) if the drug concentration is increased. This is the case with NSAIDs and inhibition of the different subtypes of cyclooxygenases (COX-1 vs. COX-2 isoenzymes). Cortisol possesses both glucocorticoid and mineralocorticoid properties and cortisol at pharmacological dose causes unwanted side effects, such as fluid--electrolyte imbalance, which is the reason why it cannot be used as an anti-inflammatory drug. This is due to the close structural relationship of the nuclear glucoreceptor (GR) and the mineralocorticoid receptor (MR).