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Pharmacology is the branch of biology concerned with the study of drug action,[1] where a drug can be broadly defined as any man-made, natural, or endogenous (from within the body) molecule which exerts a biochemical or physiological effect on the cell, tissue, organ, or organism (sometimes the word pharmacon is used as a term to encompass these endogenous and exogenous bioactive species). More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.

Pharmacology
Constant tempertature bath for isolated organs Wellcome M0013241.jpg
Diagrammatic representation of organ bath used for studying the effect of isolated tissues
MeSH Unique IDD010600

The field encompasses drug composition and properties, synthesis and drug design, molecular and cellular mechanisms, organ/systems mechanisms, signal transduction/cellular communication, molecular diagnostics, interactions, toxicology, chemical biology, therapy, and medical applications and antipathogenic capabilities. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. 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 biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion (ADME) of chemicals from the biological systems. Pharmacology is not synonymous with pharmacy and the two terms are frequently confused. Pharmacology, a biomedical 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 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 are their distinctions between direct-patient care, for pharmacy practice, and the science-oriented research field, driven by pharmacology.

Contents

EtymologyEdit

The word "pharmacology" is derived from Greek φάρμακον, pharmakon, "drug, poison, spell" and -λογία, -logia "study of", "knowledge of"[2][3] (cf. the etymology of pharmacy).

HistoryEdit

 
A sample of raw opium. Opium has been used as a naturally derived drug since 300 BC. Its major active constituent, morphine, was first isolated in 1804 and acts as an opioid agonist

The origins of clinical pharmacology date back to the Middle Ages, with pharmacognosy and Avicenna's The Canon of Medicine, Peter of Spain's Commentary on Isaac, and John of St Amand's Commentary on the Antedotary of Nicholas.[4] Clinical pharmacology owes much of its foundation to the work of William Withering.[5] Nicholas Culpeper was a 17th century English Physician who translated and used 'pharmacological texts'.

Pharmacology as a scientific discipline did not further advance until the mid-19th century amid the great biomedical resurgence of that period.[6] Before the second half of the nineteenth century, the remarkable potency and specificity of the actions of drugs such as morphine, quinine and digitalis were explained vaguely and with reference to extraordinary chemical powers and affinities to certain organs or tissues.[7] The first pharmacology department was set up by Rudolf Buchheim in 1847, in recognition of the need to understand how therapeutic drugs and poisons produced their effects.[6]

Early pharmacologists focused on natural substances, mainly plant extracts. Pharmacology developed in the 19th century as a biomedical science that applied the principles of scientific experimentation to therapeutic contexts.[8] Today pharmacologists use genetics, 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 preventative care, diagnostics, and ultimately personalized medicine.

Pharmacological research has extensively used the organ bath preparation, where tissue samples are connected to recording devices, such as a myograph, and physiological responses are recorded after drug application.

ContextEdit

Study of pharmacology overlaps with biomedical sciences and study of the effects of drugs on living organisms. Pharmacological research can lead to new drug discoveries, and promote a better understanding of human physiology. Students of pharmacology must have detailed working knowledge of aspects in physiology, pathology and chemistry. Modern pharmacology is highly interdisciplinary and relates to biophysical and computational sciences, and analytical chemistry. Whereas a pharmacy student will eventually work in a pharmacy dispensing medications, a pharmacologist will typically work within a laboratory setting. 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.

DivisionsEdit

 
A variety of topics involved with pharmacology, including neuropharmacology, renal pharmacology, human metabolism, intracellular metabolism, and intracellular regulation
 
The mechanism of action of beta blockers. Pharmacology studies how ligands bind to macromolecules and the effects this causes on a cellular and organism level

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

Systems of the bodyEdit

Pharmacology can also focus on specific systems comprising the body:

  • Related to bodily systems
  • Psychopharmacology, also known as behavioral pharmacology, is the study of the effects of medication on the psyche (psychology), observing changed behaviors of the body and mind, and how molecular events are manifest in a measurable behavioral form. Psychopharmacology is an interdisciplinary field which studies behavioral effects of psychoactive drugs. 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. Another goal of behavioral pharmacology is to develop animal behavioral models to screen chemical compounds with therapeutic potentials. Psychopharmacologists typically animal models to study psychotherapeutic drugs such as antipsychotics, antidepressants and anxiolytics, and drugs of abuse such as nicotine, cocaine and methamphetamine. The field of neuropsychopharmacology investigates drugs in the context of the overlap between the nervous system and the psyche.
  • Pharmacometabolomics, also known as pharmacometabonomics, is a field which stems from metabolomics, the quantification and analysis of metabolites produced by the body.[9][10] It refers to the direct measurement of metabolites in an individual's bodily fluids, in order to predict or evaluate the metabolism of pharmaceutical compounds, and to better understand the pharmacokinetic profile of a drug.[9][10] Alternatively, pharmacometabolomics can be applied to measure metabolite levels following the administration of a pharmaceutical compound, in order to monitor the effects of the compound on certain metabolic pathways(pharmacodynamics). This provides detailed mapping of drug effects on metabolism and the pathways that are implicated in mechanism of variation of response to treatment.[11][12][13][14][15] In addition, the metabolic profile of an individual at baseline (metabotype) provides information about how individuals respond to treatment and highlights heterogeneity within a disease state.[16] All three approaches require the quantification of metabolites found in bodily fluids and tissue, such as blood or urine, and can be used in the assessment of pharmaceutical treatment options for numerous disease states.
  • Pharmacogenomics is the application of genomic technologies to drug discovery and further characterization of older drugs. It investigates drugs in the context of all of an organism's genes. Similarly, pharmacogenetics is clinical testing of genetic variation that gives rise to differing response to drugs. It investigates drugs in the context of particular genes. Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.[17]
  • Pharmacomicrobiomics, first used in 2010, is defined as the effect of microbiome variations on drug disposition, action, and toxicity.[18] Pharmacomicrobiomics is concerned with the interaction between xenobiotics, or foreign compounds, and the gut microbiome. It is estimated that over 100 trillion prokaryotes representing more than 1000 species reside in the gut.[19][20] Within the gut, microbes help modulate developmental, immunological and nutrition host functions.[21] The aggregate genome of microbes extends the metabolic capabilities of humans, allowing them to capture nutrients from diverse sources.[22] Namely, through the secretion of enzymes that assist in the metabolism of chemicals foreign to the body, modification of liver and intestinal enzymes, and modulation of the expression of human metabolic genes, microbes can significantly impact the ingestion of xenobiotics.[23]

Clinical divisions and drug developmentEdit

 
A toxicologist working in a lab
  • Clinical pharmacology is the basic science of pharmacology with an added focus on the application of pharmacological principles and methods in the medical clinic and towards patient care and outcomes.
  • Toxicology is the study of the adverse effects, molecular targets, and characterization of drugs or any chemical substance in excess (including those beneficial in lower doses). Toxicology may be regarded as a separate field to pharmacology. Similarly, pharmacotoxicology and neurotoxicology investigate the toxicity of substances from pharmacological and neurological perspectives.
  • Safety pharmacology specialises in detecting and investigating potential undesirable pharmacodynamic effects of new chemical entities (NCEs) on physiological functions in relation to exposure in the therapeutic range and above.
  • Posology is the study of how medicines are dosed. This depends upon various factors including age, climate, weight, sex, elimination rate of drug, genetic polymorphism and time of administration. It is derived from the Greek words πόσος posos meaning "how much?" and -λογία -logia "study of".[30]
  • Pharmacocybernetics (also known as pharma-cybernetics, cybernetic pharmacy and cyberpharmacy) is an upcoming field that describes the science of supporting drugs and medications use through the application and evaluation of informatics and internet technologies, so as to improve the pharmaceutical care of patients.[31] It is an interdisciplinary field that integrates the domains of medicine and pharmacy, computer sciences (informatics, cybernetics, interactive digital media, human-computer-environment interactions) and psychological sciences to design, develop, apply and evaluate technological innovations which improve drugs and medications management, as well as prevent or solve drug-related problems.
  • Photopharmacology is an emerging approach in medicine in which drugs are activated and deactivated with light. The energy of light is used to change for shape and chemical properties of the drug, resulting in different biological activity. This is done to ultimately achieve control when and where drugs are active in a reversible manner, to prevent side effects and exposure to the environment of antibiotics. Switching drugs 'on' and 'off' is achieved by introducing photoswitches such as azobenzene, spiropyran or diarylethene into the drug. By introducing the photoswitch, the drug has two different states between which can be switched with light. Since both states have a different structure, the activity of the drug is different hence the 'on' and 'off' state of the drug[32][33]

Wider contextsEdit

 
Newspaper headlines from around the world about polio vaccine tests (13 April 1955)

Pharmacology can be studied in relation to wider contexts.

  • Pharmacoenvironmentology or Environmental pharmacology is a new discipline.[34] Focus is being given to understand gene–environment interaction, drug-environment interaction and toxin-environment interaction. There is a close collaboration between environmental science and medicine in addressing these issues, as healthcare itself can be a cause of environmental damage or remediation. Human health and ecology are intimately related. Demand for more pharmaceutical products may place the public at risk through the destruction of species. The entry of chemicals and drugs into the aquatic ecosystem is a more serious concern today. In addition, the production of some illegal drugs pollutes drinking water supply by releasing carcinogens.[35] This field is intimately linked with Public Health fields. Environmental pharmacology studies the environmental effect of pharmaceuticals and personal care products (PPCPs) is currently being widely investigated. PPCPs include substances used by individuals for personal health or cosmetic reasons and the products used by agribusiness to boost growth or health of livestock. More than twenty million tons of PPCPs are produced every year.[36] PPCPs have been detected in water bodies throughout the world. The effects of these chemicals on humans and the environment are not yet known, but to date there is no scientific evidence that they affect human health.[2] This relates to the broader fields of ecology and public health.
  • Ethnopharmacology relates to the ethnic and cultural aspects of pharmacology.

Experimentation and analysisEdit

 
Interactions between proteins are frequently visualized and analyzed using networks. This network is made up of protein–protein interactions from Treponema pallidum, the causative agent of syphilis and other diseases.
  • Theoretical pharmacology is a relatively new and rapidly expanding field of research activity in which many of the techniques of computational chemistry, in particular computational quantum chemistry and the method of molecular mechanics, are proving to be of great value. Theoretical pharmacologists aim at rationalizing the relation between the activity of a particular drug, as observed experimentally, and its structural features as derived from computer experiments. They aim to find structure—activity relations. Furthermore, on the basis of the structure of a given organic molecule, the theoretical pharmacologist aims at predicting the biological activity of new drugs that are of the same general type as existing drugs. More ambitiously, it aims to predict entirely new classes of drugs, tailor-made for specific purposes. Similarly, pharmacometrics are mathematical models of biology, pharmacology, disease, and physiology used to describe and quantify interactions between xenobiotics and patients (human and non-human), including beneficial effects and adverse effects.[37] It is normally applied to quantify drug, disease and trial information to aid efficient drug development, regulatory decisions and rational drug treatment in patients.
  • Experimental pharmacology involves the study of pharmacology through bioassay, to test the efficacy and potency of a drug.

Theory of pharmacologyEdit

 
A trio of dose response curves. Dose response curves are studied extensively in pharmacology

The study of chemicals requires intimate knowledge of the biological system affected. With the knowledge of cell biology and biochemistry increasing, the field of pharmacology has also changed substantially. It has become possible, through molecular analysis of receptors, to design chemicals that act on specific cellular signaling or metabolic pathways by 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. Pharmacokinetics describes the effect of the body on the chemical (e.g. half-life and volume of distribution), and pharmacodynamics describes the chemical's effect on the body (desired or toxic).

Systems, receptors and ligandsEdit

 
The cholinergic synapse. Targets in synapses can be modulated with pharmacological agents. In this case, cholinergics (such as muscarine) and anticholinergics (such as atropine) target receptors; transporter inhibitors (such as hemicholinium) target membrane transport proteins and anticholinesterases (such as sarin) target enzymes

Pharmacology is typically studied with respect to particular systems, for example endogenous neurotransmitter systems. The major systems studied in pharmacology include:

Molecular targets in pharmacology include receptors, enzymes and membrane transport proteins. Receptors are typically categorised based on structure and function. Major receptor types studied in pharmacology include:

PharmacodynamicsEdit

Pharmacological models include the Hill equation, Cheng-Prusoff equation and Schild regression. Pharmacological theory often investigates the binding affinity of ligands to their receptors.

Medication is said to have a narrow or wide therapeutic index or therapeutic 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 require therapeutic drug monitoring (examples are warfarin, some antiepileptics, aminoglycoside antibiotics). Most anti-cancer drugs have a narrow therapeutic margin: toxic side-effects are almost always encountered at doses used to kill tumors.

PharmacokineticsEdit

When describing the pharmacokinetic properties of the chemical that is the active ingredient or active pharmaceutical ingredient (API), pharmacologists are often interested in L-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 the skin, the intestine, the oral 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 development and safety testingEdit

Development of medication is a vital concern to medicine, but also has strong economical and political implications. To protect the consumer and prevent abuse, many governments regulate the manufacture, sale, and administration of medication. In the United States, the main body that regulates pharmaceuticals is the Food and Drug Administration and they enforce standards set by the United States Pharmacopoeia. In the European Union, the main body that regulates pharmaceuticals is the EMA and they enforce standards set by the European 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.[dead link][39] If the chemical structure of a medicinal compound is altered slightly, this could slightly or dramatically alter the medicinal properties of the compound depending on the level of alteration as it relates to the structural composition of the substrate or receptor site on which it exerts its medicinal effect, a concept referred to as the structural activity relationship (SAR). This means that when a useful activity has been identified, chemists will make many similar compounds called analogues, in an attempt to maximize the desired medicinal effect(s) of the compound. This development phase can take anywhere from a few years to a decade or more and is very expensive.[40]

These new analogues need to be developed. It needs to be determined how safe the medicine is for human consumption, its stability in the human body and the best form for delivery to the desired organ system, like tablet or aerosol. After extensive testing, which can take up to 6 years, the new medicine is ready for marketing and selling.[40]

As a result of the long time required to develop analogues and test a new medicine and the fact that 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:[40]

  • Carefully research the demand for their potential new product before spending an outlay of company funds.[40]
  • Obtain a patent on the new medicine preventing other companies from producing that medicine for a certain allocation of time.[40]

Drug legislation and safetyEdit

In the United States, the Food 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 a therapeutic effect or desired outcome.[41]

The safety and effectiveness of prescription drugs in the U.S. is regulated by the federal Prescription Drug Marketing Act of 1987.

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

See alsoEdit

ReferencesEdit

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External linksEdit

Further readingEdit