Pharmacodynamics
Encyclopedia
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect. One dominant example is drug-receptor interactions as modeled by
where L=ligand (drug), R=receptor (attachment site), reaction dynamics
that can be studied mathematically through tools such as free energy
maps. Pharmacodynamics is often summarized as the study of what a drug
does to the body, whereas pharmacokinetics
is the study of what the body does to a drug. Pharmacodynamics is sometimes abbreviated as "PD", while pharmacokinetics can be referred to as "PK".
There are 7 main drug actions:
General anesthetics were once thought to work by disordering the neural membranes, thereby altering the Na+ influx. Antacid
s and chelating agents combine chemically in the body. Enzyme-substrate binding is a way to alter the production or metabolism of key endogenous
chemicals, for example aspirin
irreversibly inhibits the enzyme prostaglandin synthetase (cyclooxygenase)
thereby preventing inflammatory
response. Colchicine
, a drug for gout, interferes with the function of the structural protein tubulin
, while Digitalis
, a drug still used in heart failure, inhibits the activity of the carrier molecule, Na-K-ATPase pump. The widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their normal action (agonist), blocked action (antagonist), or even action opposite to normal (inverse agonist).
In principle, a pharmacologist would aim for a target plasma
concentration of the drug for a desired level of response. In reality, there are many factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown and excretory clearance. Genetic
factors may exist which would alter metabolism or drug action itself, and a patient's immediate status may also affect indicated dosage.
between the amount that gives an effect (effective dose
) and the amount that gives more adverse effects than desired effects. For instance, medication with a small pharmaceutical window must be administered with care and control, e.g. by frequently measuring blood concentration of the drug, since it easily loses effects or gives adverse effects.
where L=ligand, R=receptor, square brackets [] denote concentration. The fraction of bound receptors is
This expression is one way to consider the effect of a drug, in which the response is related to the fraction of bound receptors. The fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear. This explains the so called receptor reserve phenomenon i.e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response.
Often the response is determined as a function of log[L] to consider many orders of magnitude of concentration. However, there is no biological or physical theory which relates effects to the log of concentration. It is just convenient for graphing purposes. It is useful to note that 50% of the receptors are bound when [L]=Kd .
The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion. The curve toward the left represents a higher potency (potency arrow does not indicate direction of increase) since lower concentrations are needed for a given response. The effect increases as a function of concentration.
where L=ligand (drug), R=receptor (attachment site), reaction dynamics
Reaction dynamics
Reaction dynamics is a field within physical chemistry, studying why chemical reactions occur, how to predict their behavior, and how to control them...
that can be studied mathematically through tools such as free energy
Thermodynamic free energy
The thermodynamic free energy is the amount of work that a thermodynamic system can perform. The concept is useful in the thermodynamics of chemical or thermal processes in engineering and science. The free energy is the internal energy of a system less the amount of energy that cannot be used to...
maps. Pharmacodynamics is often summarized as the study of what a drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
does to the body, whereas pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
is the study of what the body does to a drug. Pharmacodynamics is sometimes abbreviated as "PD", while pharmacokinetics can be referred to as "PK".
Effects on the body
The majority of drugs either (a) mimic or inhibit vital processes of endo- or ectoparasites and microbial organisms.There are 7 main drug actions:
- stimulating actionStimulationStimulation is the action of various agents on nerves, muscles, or a sensory end organ, by which activity is evoked; especially, the nervous impulse produced by various agents on nerves, or a sensory end organ, by which the part connected with the nerve is thrown into a state of activity.The word...
through direct receptor agonismAgonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
and downstream effects - depressing actionDepression (physiology)Depression in physiology and medicine refers to a lowering, in particular a reduction in a particular biological variable or the function of an organ...
through direct receptor agonismAgonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
and downstream effects (ex.: inverse agonistInverse agonistIn the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
) - blocking/antagonizing action (as with silent antagonistsReceptor antagonistA receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
), the drug binds the receptor but does not activate it - stabilizing action, the drug seems to act neither as a stimulant or as a depressant (ex.: some drugs possess receptor activity that allows to stabilize general receptor activation, like buprenorphineBuprenorphineBuprenorphine is a semi-synthetic opioid that is used...
in opioid dependent individuals or aripiprazoleAripiprazoleAripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
in schizophrenia, all depending on the dose and the recipient) - exchanging/replacing substances or accumulating them to form a reserve (ex.: glycogenGlycogenGlycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
storage) - direct beneficial chemical reaction as in free radical scavenging
- direct harmful chemical reaction which might result in damage or destruction of the cells, through induced toxic or lethal damage (cytotoxicityCytotoxicityCytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
or irritationIrritationIrritation or exacerbation, in biology and physiology, is a state of inflammation or painful reaction to allergy or cell-lining damage. A stimulus or agent which induces the state of irritation is an irritant...
)
Desired activity
The desired activity of a drug is mainly due to one of the following:- Cellular membrane disruption
- Chemical reactionChemical reactionA chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...
with downstream effects - Interaction with enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
proteins - Interaction with structural proteins
- Interaction with carrier proteins
- Interaction with ion channelIon channelIon channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s - Ligand binding to receptorsReceptor (biochemistry)In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
:- HormoneHormoneA hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
receptors - Neuromodulator receptors
- NeurotransmitterNeurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
receptors
- Hormone
General anesthetics were once thought to work by disordering the neural membranes, thereby altering the Na+ influx. Antacid
Antacid
An antacid is a substance which neutralizes stomach acidity.-Mechanism of action:Antacids perform a neutralization reaction, increasing the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous...
s and chelating agents combine chemically in the body. Enzyme-substrate binding is a way to alter the production or metabolism of key endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
chemicals, for example aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
irreversibly inhibits the enzyme prostaglandin synthetase (cyclooxygenase)
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
thereby preventing inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
response. Colchicine
Colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
, a drug for gout, interferes with the function of the structural protein tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
, while Digitalis
Digitalis
Digitalis is a genus of about 20 species of herbaceous perennials, shrubs, and biennials that are commonly called foxgloves. This genus was traditionally placed in the figwort family Scrophulariaceae, but recent reviews of phylogenetic research have placed it in the much enlarged family...
, a drug still used in heart failure, inhibits the activity of the carrier molecule, Na-K-ATPase pump. The widest class of drugs act as ligands which bind to receptors which determine cellular effects. Upon drug binding, receptors can elicit their normal action (agonist), blocked action (antagonist), or even action opposite to normal (inverse agonist).
In principle, a pharmacologist would aim for a target plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
concentration of the drug for a desired level of response. In reality, there are many factors affecting this goal. Pharmacokinetic factors determine peak concentrations, and concentrations cannot be maintained with absolute consistency because of metabolic breakdown and excretory clearance. Genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
factors may exist which would alter metabolism or drug action itself, and a patient's immediate status may also affect indicated dosage.
Undesirable effects
Undesirable effects of a drug include:- Increased probability of cell mutationMutagenIn genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...
(carcinogenCarcinogenA carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
ic activity) - A multitude of simultaneous assorted actions which may be deleterious
- Interaction (additive, multiplicative, or metabolic)
- Induced physiological damage, or abnormal chronic conditions
Therapeutic window
The therapeutic window is the amount of a medicationMedication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
between the amount that gives an effect (effective dose
Effective dose
Effective dose may refer to:*Effective dose the dose of pharmacologic agent which will have a therapeutic effect in some fraction of the population receiving the drug...
) and the amount that gives more adverse effects than desired effects. For instance, medication with a small pharmaceutical window must be administered with care and control, e.g. by frequently measuring blood concentration of the drug, since it easily loses effects or gives adverse effects.
Receptor binding
The binding of ligands (drug) to receptors is governed by the law of mass action which relates the large-scale status to the rate of numerous molecular processes. The rates of formation and un-formation can be used to determine the equilibrium concentration of bound receptors. The equilibrium dissociation constant is defined by:
where L=ligand, R=receptor, square brackets [] denote concentration. The fraction of bound receptors is
This expression is one way to consider the effect of a drug, in which the response is related to the fraction of bound receptors. The fraction of bound receptors is known as occupancy. The relationship between occupancy and pharmacological response is usually non-linear. This explains the so called receptor reserve phenomenon i.e. the concentration producing 50% occupancy is typically higher than the concentration producing 50% of maximum response.
Often the response is determined as a function of log[L] to consider many orders of magnitude of concentration. However, there is no biological or physical theory which relates effects to the log of concentration. It is just convenient for graphing purposes. It is useful to note that 50% of the receptors are bound when [L]=Kd .
The graph shown represents the conc-response for two hypothetical receptor agonists, plotted in a semi-log fashion. The curve toward the left represents a higher potency (potency arrow does not indicate direction of increase) since lower concentrations are needed for a given response. The effect increases as a function of concentration.
Multicellular pharmacodynamics
The concept of pharmacodynamics has been expanded to include Multicellular Pharmacodynamics (MCPD). MCPD is the study of the static and dynamic properties and relationships between a set of drugs and a dynamic and diverse multicellular 4 dimensional organization. It is the study of the workings of a drug on a minimal multicellular system (mMCS), both in vivo and in silico. Networked Multicellular Pharmacodynamics (Net-MCPD) further extends the concept of MCPD to model regulatory genomic networks together with signal transduction pathways, as part of a complex of interacting components in the cell.Freeware
- ADAPT
- PottersWheelPottersWheelPottersWheel is a MATLAB toolbox for mathematical modeling of time-dependent dynamical systems that can be expressed as chemical reaction networks or ordinary differential equations . It allows the automatic calibration of model parameters by fitting the model to experimental measurements...
(MATLAB toolbox for kinetic modeling and parameter estimation, free for academic usage) - SBPKPD.org (Systems Biology Driven Pharmacokinetics and Pharmacodynamics) - web-based tool for simulation and fitting of PK and PD.
See also
- Dose-response relationshipDose-response relationshipThe dose-response relationship, or exposure-response relationship, describes the change in effect on an organism caused by differing levels of exposure to a stressor after a certain exposure time...
- PharmacokineticsPharmacokineticsPharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
- ADMEADMEADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism...
- Antimicrobial pharmacodynamicsAntimicrobial pharmacodynamicsAntimicrobial pharmacodynamics is a term used to describe the relationship between concentration of antibiotic and its ability to inhibit vital processes of endo- or ectoparasites and microbial organisms...
- Pharmaceutical companyPharmaceutical companyThe pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
- Schild regressionSchild regressionSchild regression analysis, named for Heinz Otto Schild, is a useful tool for studying the effects of agonists and antagonists on the cellular response caused by the receptor or on ligand-receptor binding....
- Pharmacodynamics analysis service
External links
- Vijay. (2003) Predictive software for drug design and development. Pharmaceutical Development and Regulation 1 ((3)), 159-168.
- Werner, E., In silico multicellular systems biology and minimal genomes, DDT vol 8, no 24, pp 1121-1127, Dec 2003. (Introduces the concepts MCPD and Net-MCPD)
- Dr. David W. A. Bourne, OU College of Pharmacy Pharmacokinetic and Pharmacodynamic Resources.