Pharmacology

Pharmacology
Diagrammatic representation of organ bath used for studying the effect of isolated tissues
MeSH Unique ID	D010600

Pharmacologyis thescienceofdrugsandmedications,^[1]including a substance's origin, composition,pharmacokinetics,pharmacodynamics, therapeutic use, andtoxicology. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormalbiochemicalfunction.^[2]If substances have medicinal properties, they are consideredpharmaceuticals.

The field encompasses drug composition and properties, functions, sources, synthesis anddrug design, molecular and cellularmechanisms, organ/systems mechanisms, signal transduction/cellular communication,molecular diagnostics,interactions,chemical biology, therapy, and medical applications and antipathogenic capabilities. The two main areas of pharmacology arepharmacodynamicsandpharmacokinetics. Pharmacodynamics studies the effects of a drug on biological systems, and pharmacokinetics studies the effects of biological systems on a drug. In broad terms, pharmacodynamics discusses the chemicals with biologicalreceptors, and pharmacokinetics discusses theabsorption, distribution,metabolism, andexcretion(ADME) of chemicals from the biological systems.

Pharmacology is not synonymous withpharmacyand the two terms are frequently confused. Pharmacology, abiomedical science, deals with the research, discovery, and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. In contrast, pharmacy, a health services profession, is concerned with the application of the principles learned from pharmacology in its clinical settings; whether it be in a dispensing or clinical care role. In either field, the primary contrast between the two is their distinctions between direct-patient care, pharmacy practice, and the science-oriented research field, driven by pharmacology.

The wordpharmacologyis derived fromGreekwordφάρμακον,pharmakon, meaning "drug" or "poison", together with another Greek word-λογία,logiawith the meaning of "study of" or "knowledge of"^[3][4](cf. theetymology ofpharmacy). Pharmakon is related topharmakos, the ritualistic sacrifice or exile of a humanscapegoator victim inAncient Greek religion.

The modern termpharmaconis used more broadly than the termdrugbecause it includesendogenoussubstances, and biologically active substances which are not used as drugs. Typically it includes pharmacologicalagonistsandantagonists, but alsoenzymeinhibitors (such asmonoamine oxidaseinhibitors).^[5]

The origins ofclinical pharmacologydate back to theMiddle Ages, withpharmacognosyandAvicenna'sThe Canon of Medicine,Peter of Spain'sCommentary on Isaac, andJohn of St Amand'sCommentary on the Antedotary of Nicholas.^[9]Early pharmacology focused onherbalismand natural substances, mainly plant extracts. Medicines were compiled in books calledpharmacopoeias.Crude drugshave been used since prehistory as a preparation of substances from natural sources. However, theactive ingredientof crude drugs are not purified and the substance is adulterated with other substances.

Traditional medicinevaries between cultures and may be specific to a particular culture, such as in traditionalChinese,Mongolian,TibetanandKorean medicine. However much of this has since been regarded aspseudoscience. Pharmacological substances known asentheogensmay have spiritual and religious use and historical context.

In the 17th century, the English physicianNicholas Culpepertranslated and used pharmacological texts. Culpeper detailed plants and the conditions they could treat. In the 18th century, much of clinical pharmacology was established by the work ofWilliam Withering.^[10]Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period.^[11]Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such asmorphine,quinineanddigitaliswere explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues.^[12]The first pharmacology department was set up byRudolf Buchheimin 1847, at University of Tartu, in recognition of the need to understand how therapeutic drugs and poisons produced their effects.^[11]Subsequently, the firstpharmacology departmentinEnglandwas set up in 1905 atUniversity College London.

Pharmacology developed in the 19th century as a biomedical science that applied the principles of scientific experimentation to therapeutic contexts.^[13]The advancement of research techniques propelled pharmacological research and understanding. The development of theorgan bathpreparation, where tissue samples are connected to recording devices, such as amyograph, and physiological responses are recorded after drug application, allowed analysis of drugs' effects on tissues. The development of theligand binding assayin 1945 allowed quantification of thebinding affinityof drugs at chemical targets.^[14]Modern pharmacologists use techniques fromgenetics,molecular biology,biochemistry, and other advanced tools to transform information about molecular mechanisms and targets into therapies directed against disease, defects or pathogens, and create methods for preventive care, diagnostics, and ultimatelypersonalized medicine.

The discipline of pharmacology can be divided into many sub disciplines each with a specific focus.

Pharmacology can also focus on specificsystemscomprising the body. Divisions related to bodily systems study the effects of drugs in different systems of the body. These includeneuropharmacology, in thecentralandperipheral nervous systems;immunopharmacologyin the immune system. Other divisions includecardiovascular,renalandendocrinepharmacology.Psychopharmacologyis the study of the use of drugs that affect thepsyche, mind and behavior (e.g. antidepressants) in treating mental disorders (e.g. depression).^[15][16]It incorporates approaches and techniques from neuropharmacology, animal behavior and behavioral neuroscience, and is interested in the behavioral and neurobiological mechanisms of action of psychoactive drugs.^{[citation needed]}The related field ofneuropsychopharmacologyfocuses on the effects of drugs at the overlap between the nervous system and the psyche.

Pharmacometabolomics, also known as pharmacometabonomics, is a field which stems frommetabolomics, the quantification and analysis ofmetabolitesproduced by the body.^[17][18]It refers to the direct measurement ofmetabolitesin an individual's bodily fluids, in order to predict or evaluate themetabolismofpharmaceuticalcompounds, and to better understand the pharmacokinetic profile of a drug.^[17][18]Pharmacometabolomics can be applied to measuremetabolitelevels following the administration of a drug, in order to monitor the effects of the drug on metabolic pathways.Pharmacomicrobiomicsstudies the effect of microbiome variations on drug disposition, action, and toxicity.^[19]Pharmacomicrobiomics is concerned with the interaction between drugs and the gutmicrobiome.Pharmacogenomicsis the application of genomic technologies todrug discoveryand further characterization of drugs related to an organism's entire genome.^{[citation needed]}For pharmacology regarding individual genes,pharmacogeneticsstudies how genetic variation gives rise to differing responses to drugs.^{[citation needed]}Pharmacoepigeneticsstudies the underlyingepigeneticmarking patterns that lead to variation in an individual's response to medical treatment.^[20]

Pharmacology can be applied within clinical sciences.Clinical pharmacologyis the application of pharmacological methods and principles in the study of drugs in humans.^[21]An example of this is posology, which is the study of how medicines are dosed.^[22]

Pharmacology is closely related totoxicology. Both pharmacology and toxicology are scientific disciplines that focus on understanding the properties and actions of chemicals.^[23]However, pharmacology emphasizes the therapeutic effects of chemicals, usually drugs or compounds that could become drugs, whereas toxicology is the study of chemical's adverse effects and risk assessment.^[23]

Pharmacological knowledge is used to advisepharmacotherapyinmedicineandpharmacy.

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Drug discoveryis the field of study concerned with creating new drugs. It encompasses the subfields ofdrug designanddevelopment.^[24]Drug discovery starts with drug design, which is theinventiveprocess of finding new drugs.^[25]In the most basic sense, this involves the design of molecules that are complementary inshapeandchargeto a given biomolecular target.^[26]After alead compoundhas been identified through drug discovery, drug development involves bringing the drug to the market.^[24]Drug discovery is related topharmacoeconomics, which is the sub-discipline ofhealth economicsthat considers the value of drugs^[27][28]Pharmacoeconomics evaluates the cost and benefits of drugs in order to guide optimal healthcare resource allocation.^[29]The techniques used for thediscovery,formulation, manufacturing and quality control of drugs discovery is studied bypharmaceutical engineering, a branch ofengineering.^[30]Safety pharmacologyspecialises in detecting and investigating potential undesirable effects of drugs.^[31]

The drug discovery cycle

Development of medicationis a vital concern tomedicine, but also has strongeconomicalandpoliticalimplications. To protect theconsumerand prevent abuse, many governments regulate the manufacture, sale, and administration of medication. In theUnited States, the main body that regulates pharmaceuticals is theFood and Drug Administration; they enforcestandardsset by theUnited States Pharmacopoeia. In theEuropean Union, the main body that regulates pharmaceuticals is theEMA, and they enforce standards set by theEuropean Pharmacopoeia.

The metabolic stability and the reactivity of a library of candidate drug compounds have to be assessed for drug metabolism and toxicological studies. Many methods have been proposed for quantitative predictions in drug metabolism; one example of a recent computational method is SPORCalc.^[32]A slight alteration to the chemical structure of a medicinal compound could alter its medicinal properties, depending on how the alteration relates to the structure of the substrate or receptor site on which it acts: this is called the structural activity relationship (SAR). When a useful activity has been identified, chemists will make many similar compounds called analogues, to try to maximize the desired medicinal effect(s). This can take anywhere from a few years to a decade or more, and is very expensive.^[33]One must also determine how safe the medicine is to consume, its stability in the human body and the best form for delivery to the desired organ system, such as tablet or aerosol. After extensive testing, which can take up to six years, the new medicine is ready for marketing and selling.^[33]

Because of these long timescales, and because out of every 5000 potential new medicines typically only one will ever reach the open market, this is an expensive way of doing things, often costing over 1 billion dollars. To recoup this outlay pharmaceutical companies may do a number of things:^[33]

• Carefully research the demand for their potential new product before spending an outlay of company funds.^[33]
• Obtain a patent on the new medicine preventing other companies from producing that medicine for a certain allocation of time.^[33]

Theinverse benefit lawdescribes the relationship between a drugs therapeutic benefits and its marketing.

When designing drugs, theplaceboeffect must be considered to assess the drug's true therapeutic value.

Drug development uses techniques frommedicinal chemistryto chemically design drugs. This overlaps with the biological approach of finding targets and physiological effects.

Pharmacology can be studied in relation to wider contexts than the physiology of individuals. For example,pharmacoepidemiologyconcerns the variations of the effects of drugs in or between populations, it is the bridge betweenclinical pharmacologyandepidemiology.^[34][35]Pharmacoenvironmentologyor environmental pharmacology is the study of the effects of used pharmaceuticals and personal care products (PPCPs) on the environment after their elimination from the body.^[36]Human health and ecology are intimately related so environmental pharmacology studies the environmental effect of drugs andpharmaceuticals and personal care products in the environment.^[37]

Drugs may also have ethnocultural importance, soethnopharmacologystudies the ethnic and cultural aspects of pharmacology.^[38]

Photopharmacologyis an emerging approach inmedicinein which drugs are activated and deactivated withlight. The energy of light is used to change for shape and chemical properties of the drug, resulting in different biological activity.^[39]This is done to ultimately achieve control when and where drugs are active in a reversible manner, to preventside effectsand pollution of drugs into the environment.^[40][41]

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The study of chemicals requires intimate knowledge of the biological system affected. With the knowledge ofcell biologyandbiochemistryincreasing, the field of pharmacology has also changed substantially. It has become possible, through molecular analysis ofreceptors, to design chemicals that act on specific cellular signaling ormetabolic pathwaysby affecting sites directly on cell-surface receptors (which modulate and mediate cellular signaling pathways controlling cellular function).

Chemicals can have pharmacologically relevant properties and effects.Pharmacokineticsdescribes the effect of the body on the chemical (e.g.half-lifeandvolume of distribution), andpharmacodynamicsdescribes the chemical's effect on the body (desired ortoxic).

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Pharmacology is typically studied with respect to particular systems, for example endogenousneurotransmitter systems. The major systems studied in pharmacology can be categorised by theirligandsand includeacetylcholine,adrenaline,glutamate,GABA,dopamine,histamine,serotonin,cannabinoidandopioid.

Molecular targets in pharmacology includereceptors,enzymesandmembrane transport proteins. Enzymes can be targeted withenzyme inhibitors. Receptors are typically categorised based on structure and function. Major receptor types studied in pharmacology includeG protein coupled receptors,ligand gated ion channelsandreceptor tyrosine kinases.

Network pharmacology is a subfield of pharmacology that combines principles from pharmacology, systems biology, and network analysis to study the complex interactions between drugs and targets (e.g., receptors or enzymes etc.) in biological systems. The topology of a biochemical reaction network determines the shape of drugdose-response curve^[42]as well as the type of drug-drug interactions,^[43]thus can help designing efficient and safe therapeutic strategies. The topology Network pharmacology utilizes computational tools and network analysis algorithms to identify drug targets, predict drug-drug interactions, elucidate signaling pathways, and explore the polypharmacology of drugs.

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Pharmacodynamics is defined as how the body reacts to the drugs. Pharmacodynamics theory often investigates thebinding affinityofligandsto their receptors. Ligands can beagonists, partial agonists orantagonistsat specific receptors in the body. Agonists bind to receptors and produce a biological response, a partial agonist produces a biological response lower than that of a full agonist, antagonists have affinity for a receptor but do not produce a biological response.

The ability of a ligand to produce a biological response is termedefficacy, in a dose-response profile it is indicated as percentage on the y-axis, where 100% is the maximal efficacy (all receptors are occupied).

Binding affinity is the ability of a ligand to form a ligand-receptor complex either throughweak attractive forces(reversible) orcovalent bond(irreversible), therefore efficacy is dependent on binding affinity.

Potencyof drug is the measure of its effectiveness,EC₅₀is the drug concentration of a drug that produces an efficacy of 50% and the lower the concentration the higher the potency of the drug therefore EC₅₀can be used to compare potencies of drugs.

Medication is said to have a narrow or widetherapeutic index,certain safety factorortherapeutic window. This describes the ratio of desired effect to toxic effect. A compound with a narrow therapeutic index (close to one) exerts its desired effect at a dose close to its toxic dose. A compound with a wide therapeutic index (greater than five) exerts its desired effect at a dose substantially below its toxic dose. Those with a narrow margin are more difficult to dose and administer, and may requiretherapeutic drug monitoring(examples arewarfarin, someantiepileptics,aminoglycosideantibiotics). Most anti-cancerdrugs have a narrow therapeutic margin: toxic side-effects are almost always encountered at doses used to killtumors.

The effect of drugs can be described withLoewe additivitywhich is one of several common reference models.^[43]

Other models include theHill equation,Cheng-Prusoff equationandSchild regression.

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Pharmacokineticsis the study of the bodily absorption, distribution, metabolism, and excretion of drugs.^[44]

When describing the pharmacokinetic properties of the chemical that is the active ingredient oractive pharmaceutical ingredient(API), pharmacologists are often interested inL-ADME:

• Liberation– How is the API disintegrated (for solid oral forms (breaking down into smaller particles), dispersed, or dissolved from the medication?
• Absorption– How is the API absorbed (through theskin, theintestine, theoral mucosa)?
• Distribution– How does the API spread through the organism?
• Metabolism– Is the API converted chemically inside the body, and into which substances. Are these active (as well)? Could they be toxic?
• Excretion– How is the API excreted (through the bile, urine, breath, skin)?

Drug metabolismis assessed in pharmacokinetics and is important in drug research and prescribing.

Pharmacokinetics is the movement of the drug in the body, it is usually described as 'what the body does to the drug' the physico-chemical properties of a drug will affect the rate and extent of absorption, extent of distribution, metabolism and elimination. The drug needs to have the appropriate molecular weight, polarity etc. in order to be absorbed, the fraction of a drug the reaches the systemic circulation is termed bioavailability, this is simply a ratio of the peak plasma drug levels after oral administration and the drug concentration after an IV administration(first pass effect is avoided and therefore no amount drug is lost). A drug must be lipophilic (lipid soluble) in order to pass through biological membranes this is true because biological membranes are made up of a lipid bilayer (phospholipids etc.) Once the drug reaches the blood circulation it is then distributed throughout the body and being more concentrated in highly perfused organs.

In theUnited States, theFood and Drug Administration(FDA) is responsible for creating guidelines for the approval and use of drugs. The FDA requires that all approved drugs fulfill two requirements:

1. The drug must be found to be effective against the disease for which it is seeking approval (where 'effective' means only that the drug performed better than placebo or competitors in at least two trials).
2. The drug must meet safety criteria by being subject to animal and controlled human testing.

Gaining FDA approval usually takes several years. Testing done on animals must be extensive and must include several species to help in the evaluation of both the effectiveness and toxicity of the drug. The dosage of any drug approved for use is intended to fall within a range in which the drug produces atherapeutic effector desired outcome.^[45]

The safety and effectiveness of prescription drugs in the U.S. are regulated by the federalPrescription Drug Marketing Act of 1987.

TheMedicines and Healthcare products Regulatory Agency(MHRA) has a similar role in the UK.

Medicare Part Dis a prescription drug plan in the U.S.

ThePrescription Drug Marketing Act (PDMA)is an act related to drug policy.

Prescription drugsare drugs regulated by legislation.

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TheInternational Union of Basic and Clinical Pharmacology,Federation of European Pharmacological SocietiesandEuropean Association for Clinical Pharmacology and Therapeuticsare organisations representing standardisation and regulation of clinical and scientific pharmacology.

Systems formedical classificationof drugs withpharmaceutical codeshave been developed. These include theNational Drug Code(NDC), administered byFood and Drug Administration.;^[46]Drug Identification Number(DIN), administered byHealth Canadaunder theFood and Drugs Act;Hong Kong Drug Registration, administered by the Pharmaceutical Service of theDepartment of Health (Hong Kong)andNational Pharmaceutical Product Indexin South Africa. Hierarchical systems have also been developed, including theAnatomical Therapeutic Chemical Classification System(AT, or ATC/DDD), administered byWorld Health Organization;Generic Product Identifier(GPI), a hierarchical classification number published by MediSpan andSNOMED, C axis. Ingredients of drugs have been categorised byUnique Ingredient Identifier.

The study of pharmacology overlaps withbiomedical sciencesand is the study of the effects of drugs on living organisms. Pharmacological research can lead to new drug discoveries, and promote a better understanding of humanphysiology. Students of pharmacology must have a detailed working knowledge of aspects in physiology, pathology, and chemistry. They may also require knowledge of plants as sources of pharmacologically active compounds.^[38]Modern pharmacology is interdisciplinary and involves biophysical and computational sciences, and analytical chemistry. A pharmacist needs to be well-equipped with knowledge on pharmacology for application in pharmaceutical research or pharmacy practice in hospitals or commercial organisations selling to customers. Pharmacologists, however, usually work in a laboratory undertaking research or development of new products. Pharmacological research is important in academic research (medical and non-medical), private industrial positions, science writing, scientific patents and law, consultation, biotech and pharmaceutical employment, the alcohol industry, food industry, forensics/law enforcement, public health, and environmental/ecological sciences. Pharmacology is often taught to pharmacy and medicine students as part of aMedical Schoolcurriculum.

• American Society for Pharmacology and Experimental Therapeutics
• British Pharmacological Society
• International Conference on Harmonisation
• US Pharmacopeia
• International Union of Basic and Clinical Pharmacology
• IUPHAR Committee on Receptor Nomenclature and Drug Classification
• IUPHAR/BPS Guide to Pharmacology

• Foreman JC, Johansen T, Gibb AJ (2009).Textbook of Receptor Pharmacology, Second Edition. CRC Press.ISBN9781439887578.
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• Whalen K (2014).Lippincott Illustrated Reviews: Pharmacology.