Pharmacology

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Pharmacology

  1. 1. PharmacologyFrom Wikipedia, the free encyclopediaJump to: navigation, searchA variety of topics involved with pharmacology, including neuropharmacology, renalpharmacology, human metabolism, intracellular metabolism, and intracellular regulation.Pharmacology (from Greek φάρμακον, pharmakon, "poison" in classic Greek; "drug" in modernGreek; and -λογία, -logia "study of", "knowledge of") is the branch of medicine and biologyconcerned with the study of drug action,[1] where a drug can be broadly defined as any man-made, natural, or endogenous (within the cell) molecule which exerts a biochemical and/orphysiological effect on the cell, tissue, organ, or organism. More specifically, it is the study ofthe interactions that occur between a living organism and chemicals that affect normal orabnormal biochemical function. If substances have medicinal properties, they are consideredpharmaceuticals. The field encompasses drug composition and properties, interactions,toxicology, therapy, and medical applications and antipathogenic capabilities. The two mainareas of pharmacology are pharmacodynamics and pharmacokinetics. The former studies theeffects of the drugs on biological systems, and the latter the effects of biological systems on thedrugs. In broad terms, pharmacodynamics discusses the chemicals with biological receptors, andpharmacokinetics discusses the absorption, distribution, metabolism, and excretion of chemicalsfrom the biological systems. Pharmacology is not synonymous with pharmacy and the two termsare frequently confused. Pharmacology, a biomedical science, deals with how drugs interactwithin biological systems to affect function. It is the study of drugs, of the reactions of the bodyand drug on each other, the sources of drugs, their nature, and their properties. In contrast,pharmacy, a health services profession, is concerned with application of the principles learnedfrom pharmacology in its clinical settings; whether it be in a dispensing or clinical care role. Ineither field, the primary contrast between the two are their distinctions between direct-patientcare, for pharmacy practice, and the science-oriented research field, driven by pharmacology.Dioscorides De Materia Medica is often said to be the oldest and most valuable work in thehistory of pharmacology.[2] The origins of clinical pharmacology date back to the Middle Ages inAvicennas The Canon of Medicine, Peter of Spains Commentary on Isaac, and John of StAmands Commentary on the Antedotary of Nicholas.[3] Clinical pharmacology owes much of itsfoundation to the work of William Withering.[4] Pharmacology as a scientific discipline did not
  2. 2. further advance until the mid-19th century amid the great biomedical resurgence of that period.[5]Before the second half of the nineteenth century, the remarkable potency and specificity of theactions of drugs such as morphine, quinine and digitalis were explained vaguely and withreference to extraordinary chemical powers and affinities to certain organs or tissues.[6] The firstpharmacology department was set up by Rudolf Buchheim in 1847, in recognition of the need tounderstand how therapeutic drugs and poisons produced their effects.[5]Early pharmacologists focused on natural substances, mainly plant extracts. Pharmacologydeveloped in the 19th century as a biomedical science that applied the principles of scientificexperimentation to therapeutic contexts.[7]DivisionsClinical pharmacologyThe basic science of pharmacology, with added focus on the application of pharmacologicalprinciples and methods in the real worldNeuropharmacologyEffects of medication on nervous system functioning.PsychopharmacologyEffects of medication on the brain; observing changed behaviors of the body and read the effectof drugs on the human brain.PharmacogeneticsClinical testing of genetic variation that gives rise to differing response to drugs.PharmacogenomicsApplication of genomic technologies to new drug discovery and further characterization of olderdrugs.PharmacoepidemiologyStudy of effects of drugs in large numbers of people.Toxicology
  3. 3. Study of harmful or toxic effects of drugs.Theoretical pharmacologyStudy of metrics in pharmacology.PosologyHow medicines are dosed. It also depends upon various factors like age, climate, weight, sex,and so on.PharmacognosyA branch of pharmacology dealing especially with the composition, use, and development ofmedicinal substances of biological origin and especially medicinal substances obtained fromplants.Behavioral pharmacologyBehavioral pharmacology, also referred to as psychopharmacology, is an interdisciplinary fieldwhich studies behavioral effects of psychoactive drugs. It incorporates approaches andtechniques from neuropharmacology, animal behavior and behavioral neuroscience, and isinterested in the behavioral and neurobiological mechanisms of action of psychoactive drugs.Another goal of behavioral pharmacology is to develop animal behavioral models to screenchemical compounds with therapeutic potentials. People in this field (called behavioralpharmacologists) typically use small animals (e.g. rodents) to study psychotherapeutic drugssuch as antipsychotics, antidepressants and anxiolytics, and drugs of abuse such as nicotine,cocaine, methamphetamine, etc.Environmental pharmacologyEnvironmental pharmacology is a new discipline.[8] Focus is being given to understand gene–environment interaction, drug-environment interaction and toxin-environment interaction. Thereis 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 andecology is intimately related. Demand for more pharmaceutical products may place the public atrisk through the destruction of species. The entry of chemicals and drugs into the aquaticecosystem is a more serious concern today. In addition, the production of some illegal drugspollutes drinking water supply by releasing carcinogens.[9] More and more biodegradability ofdrugs are needed.Scientific backgroundThe study of chemicals requires intimate knowledge of the biological system affected. With theknowledge of cell biology and biochemistry increasing, the field of pharmacology has also
  4. 4. changed substantially. It has become possible, through molecular analysis of receptors, to designchemicals that act on specific cellular signaling or metabolic pathways by affecting sites directlyon cell-surface receptors (which modulate and mediate cellular signaling pathways controllingcellular function).A chemical has, from the pharmacological point-of-view, various properties. Pharmacokineticsdescribes the effect of the body on the chemical (e.g. half-life and volume of distribution), andpharmacodynamics describes the chemicals effect on the body (desired or toxic).When describing the pharmacokinetic properties of a chemical, pharmacologists are ofteninterested in LADME: Liberation - disintegration (for solid oral forms {breaking down into smaller particles}), dispersal and dissolution Absorption - How is the medication absorbed (through the skin, the intestine, the oral mucosa)? Distribution - How does it spread through the organism? Metabolism - Is the medication converted chemically inside the body, and into which substances. Are these active? Could they be toxic? Excretion - How is the medication eliminated (through the bile, urine, breath, skin)?Medication is said to have a narrow or wide therapeutic index or therapeutic window. Thisdescribes 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 widetherapeutic index (greater than five) exerts its desired effect at a dose substantially below itstoxic dose. Those with a narrow margin are more difficult to dose and administer, and mayrequire therapeutic drug monitoring (examples are warfarin, some antiepileptics, aminoglycosideantibiotics). Most anti-cancer drugs have a narrow therapeutic margin: toxic side-effects arealmost always encountered at doses used to kill tumors.Medicine development and safety testingDevelopment of medication is a vital concern to medicine, but also has strong economical andpolitical implications. To protect the consumer and prevent abuse, many governments regulatethe manufacture, sale, and administration of medication. In the United States, the main body thatregulates pharmaceuticals is the Food and Drug Administration and they enforce standards set bythe United States Pharmacopoeia. In the European Union, the main body that regulatespharmaceuticals is the EMEA and they enforce standards set by the European Pharmacopoeia.The metabolic stability and the reactivity of a library of candidate drug compounds have to beassessed for drug metabolism and toxicological studies. Many methods have been proposed forquantitative predictions in drug metabolism; one example of a recent computational method isSPORCalc.[10] If the chemical structure of a medicinal compound is altered slightly, this couldslightly or dramatically alter the medicinal properties of the compound depending on the level ofalteration as it relates to the structural composition of the substrate or receptor site on which itexerts its medicinal effect, a concept referred to as the structural activity relationship (SAR). This
  5. 5. means that when a useful activity has been identified, chemists will make many similarcompounds called analogues, in an attempt to maximize the desired medicinal effect(s) of thecompound. This development phase can take anywhere from a few years to a decade or more andis very expensive.[11]These new analogues need to be developed. It needs to be determined how safe the medicine isfor human consumption, its stability in the human body and the best form for delivery to thedesired 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.[11]As a result of the long time required to develop analogues and test a new medicine and the factthat of every 5000 potential new medicines typically only one will ever reach the open market,this is an expensive way of doing things, costing millions of dollars. To recoup this outlaypharmaceutical companies may do a number of things:[11] Carefully research the demand for their potential new product before spending an outlay of company funds.[11] Obtain a patent on the new medicine preventing other companies from producing that medicine for a certain allocation of time.[11]EducationThe study of pharmacology is offered in many universities worldwide in programs that differfrom pharmacy programs. Students of pharmacology are trained as biomedical researchers,studying the effects of substances in order to better understand the mechanisms which might leadto new drug discoveries, for example, or studying biological systems for the purpose of re-defining drug mechanisms or discovering new mechanisms against which novel therapies can bedirected (or new pathways for the sake of a more complete picture of its biochemistry). Inaddition, students of pharmacology must have detailed working knowledge of those areas inwhich biological or chemical therapeutics play a role. These may include (but are not limited to):biochemistry, molecular biology, genetics, chemical biology, physiology, chemistry,neuroscience, and microbiology. Whereas a pharmacy student will eventually work in apharmacy dispensing medications or some other position focused on the patient, apharmacologist will typically work within a laboratory setting.Pharmacological GlossaryDefinitions of commonly used pharmacological terms
  6. 6. Term Description A drug that binds to and activates a receptor. Can be full, partial or inverse. A full agonist has high efficacy, producing a full response while occupying a relatively low proportion of receptors. A partial agonist has lower efficacy than a full agonist. It produces sub-maximal activationAgonist even when occupying the total receptor population, therefore cannot produce the maximal response, irrespective of the concentration applied. An inverse agonist produces an effect opposite to that of an agonist, yet binds to the same receptor binding-site as an agonist. A drug that binds to a receptor at a site distinct from the active site. Induces a conformational change in the receptor, which alters the affinityAllosteric Modulator of the receptor for the endogenous ligand. Positive allosteric modulators increase the affinity, whilst negative allosteric modulators decrease the affinity. A drug that attenuates the effect of an agonist. Can be competitive or non-competitive, each of which can be reversible or irreversible. A competitive antagonist binds to the same site as the agonist but does not activate it, thus blocks the agonist’s action. A non-competitive antagonistAntagonist binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor. A reversible antagonist binds non-covalently to the receptor, therefore can be “washed out”. An irreversible antagonist binds covalently to the receptor and cannot be displaced by either competing ligands or washing. The maximum amount of drug or radioligand, usually expressed as picomoles (pM) per mg protein, which can bind specifically to theBmax receptors in a membrane preparation. Can be used to measure the density of the receptor site in a particular preparation. Used to determine the Ki value from an IC50 value measured in a competition radioligand binding assay:Cheng-Prusoff Equation Where [L] is the concentration of free radioligand, and Kd is the dissociation constant of the radioligand for the receptor.Competitive Antagonist See Antagonist
  7. 7. A reduction in response to an agonist while it is continuously present atDesensitization the receptor, or progressive decrease in response upon repeated exposure to an agonist. The molar concentration of an agonist that produces 50% of theEC50 maximum possible response for that agonist. In vitro or in vivo dose of drug that produces 50% of its maximumED50 response or effect. Describes the way that agonists vary in the response they produce when they occupy the same number of receptors. High efficacy agonists produce their maximal response while occupying a relatively lowEfficacy proportion of the total receptor population. Lower efficacy agonists do not activate receptors to the same degree and may not be able to produce the maximal response (see Agonist, Partial).Ex vivo Taking place outside a living organism. Half-life (t½) is an important pharmacokinetic measurement. The metabolic half-life of a drug in vivo is the time taken for its concentration in plasma to decline to half its original level. Half-life refers to theHalf-life duration of action of a drug and depends upon how quickly the drug is eliminated from the plasma. The clearance and distribution of a drug from the plasma are therefore important parameters for the determination of its half-life.i.a. Intra-arterial route of drug administration (see Useful Abbreviations). In a functional assay, the molar concentration of an agonist or antagonist which produces 50% of its maximum possible inhibition. In a radioligandIC50 binding assay, the molar concentration of competing ligand which reduces the specific binding of a radioligand by 50%.i.c. Intracerebral route of drug administration (see Useful Abbreviations). Intracerebroventricular route of drug administration (see Usefuli.c.v. Abbreviations). In vitro or in vivo dose of a drug that causes 50% of the maximumID50 possible inhibition for that drug.
  8. 8. i.d. Intradermal route of drug administration (see Useful Abbreviations).i.g. Intragastric route of administration (see Useful Abbreviations).i.m. Intramuscular route of drug administration (see Useful Abbreviations).Inverse Agonist See Agonist Taking place in a test-tube, culture dish or elsewhere outside a livingIn vitro organism.In vivo Taking place in a living organism.i.p. Intraperitoneal route of drug administration (see Useful Abbreviations).Irreversible Antagonist See Antagonisti.t. Intrathecal route of drug administration (see Useful Abbreviations).i.v. Intravenous route of drug administration (see Useful Abbreviations). The equilibrium dissociation constant for a competitive antagonist: theKB molar concentration that would occupy 50% of the receptors at equilibrium. The dissociation constant for a radiolabeled drug determined byKd saturation analysis. It is the molar concentration of radioligand which, at equilibrium, occupies 50% of the receptors. The inhibition constant for a ligand, which denotes the affinity of the ligand for a receptor. Measured using a radioligand competition bindingKi assay, it is the molar concentration of the competing ligand that would occupy 50% of the receptors if no radioligand was present. It is calculated from the IC50 value using the Cheng-Prusoff equation.Negative Allosteric Modulator See Allosteric ModulatorNeutral Antagonist See Silent Antagonist The proportion of radioligand that is not displaced by other competitiveNon-Specific Binding ligands specific for the receptor. It can be binding to other receptors or proteins, partitioning into lipids or other things.
  9. 9. Measure of the potency of an antagonist. It is the negative logarithm ofpA2 the molar concentration of an antagonist that would produce a 2-fold shift in the concentration response curve for an agonist.pD2 The negative logarithm of the EC50 or IC50 value.pEC50 The negative logarithm of the EC50 value.pIC50 The negative logarithm of the IC50 value.pKB The negative logarithm of the KB value.pKd The negative logarithm of the Kd value.pKi The negative logarithm of the Ki value.p.o. Oral (by mouth) route of drug administration (see Useful Abbreviations).Positive Allosteric Modulator See Allosteric ModulatorPotency A measure of the concentrations of a drug at which it is effective.s.c. Subcutaneous route of drug administration (see Useful Abbreviations). The proportion of radioligand that can be displaced by competitiveSpecific Binding ligands specific for the receptor. A drug that attenuates the effects of agonists or inverse agonists, producing a functional reduction in signal transduction. Effects onlySilent Antagonist ligand-dependent receptor activation and displays no intrinsic activity itself. Also known as a neutral antagonist. In the periphery of the body (not in the central nervous system – seeSystemic Useful Abbreviations).t½ Biological half-life; (see Half-life).Latin AbbreviationsAbbreviation Meaning Latinad.lib. freely as wanted ad libitum
  10. 10. aq. water Aquab.i.d. twice a day bis in diecap. capsule capulac with bar on top with Cumdiv. divide divideeq.pts. equal parts equalis partisgtt. a drop Guttah. hour Horano. number numeroO. pint octariusp.r.n. as occasion requires pro re nataq.s. a sufficient quantity quantum sufficiatq4h every 4 hours quaque 4 horaq6h every 6 hours quaque 6 horaq1d every day quaque 1 dieq1w every weekq.i.d. four times a day quater in dies.i.d. once a day semel in die
  11. 11. Sig., S. write on the label Signastat. immediately statimtab. a tablet tabellat.i.d. three times a day ter in dieWeights and measures used in prescribing and toxicology The Metric SystemWeight1 picogram (pg) 10-12 gram1000 picograms 1 nanogram (ng) or 10-9 gram1000 nanograms 1 microgram (ug) or 10-6 gram1000 micrograms 1 milligram (mg) or 10-3 gram1000 milligrams 1 gram (g)1000 grams 1 kilogram (kg)Volume1000 milliliters (ml) 1 liter (L)Be able to interconvert all of these valuesPrefixes for volumes correspond to those for weight.IMPORTANT: Know that 1 part per million (ppm) is a frequently used term in toxicology and drugresidue discussions. For example, the following are 1 ppm:1 mg / kg, 1 mcg/g. An analogy is "Percent" that represents 1 part per hundred, i.e., 1 g/100 g = 1%w/w. The expression "w/w" indicates that the amount of both substances is on a weight basis. It is
  12. 12. assumed that ppm is w/w unless otherwise specified. The Apothecaries SystemWeight20 grains (gr) 1 scruple ( )3 scruples 1 dram( ) = 60 grains8 drams 1 ounce ( ) = 480 grainsVolume60 minims (m) 1 fluid dram ( )8 fluid drams 1 fluid ounce ( )16 fluid ounces 1 pint (O.)Know eqivalents in bold faced typedConversion Equivalents Approximate Exact1 milligram 1/60 grain 1/65 grain1 gram 15 grains 15.432 grains1 kilogram 2.2 pounds* 2.2 pounds*1 milliliter 15 minims 16.23 minims
  13. 13. 1 liter 1 quart 1.06 quarts or 33.8 fluid ounces1 grain 60 milligrams 65 milligrams1 dram 4 grams 3.88 grams1 ounce 30 grams 31.1 grams1 pound* 450 grams 454 grams1 minim 0.06 milliliter 0.062 milliliter1 fluid dram 4 milliliters 3.7 milliliters1 fluid ounce 30 milliliters 29.57 milliliters1 pint 500 milliliters 473 milliliters1 quart 1000 milliters 946 milliliters1 drop 1 minim1 teaspoonful 5 milliliters1 dessertspoonful 8 milliliters1 tablespoonful 15 millilitersKnow equivalents in bold faced type.Note: Where possible, use suitable units rather than decimal fractions, e.g., 10 mg not 0.010 g. When adecimal fraction is used the decimal point must be preceded by a zero, e.g., 0.5 not .5.* = avoirdupois pound (the one used in the USA!)Conversion factors for obtaining approximate equivalentsTo convert To Multiply by
  14. 14. gr/lb mg/lb 60 gr/lb mg/kg 143 mg/lb gr/lb 0.015 mg/lb mg/kg 2.2 mg/kg gr/lb 0.007 mg/kg mg/lb 0.45Know conversions in bold typeface Pharmaceutical Abbreviations | Abbreviations in product information leaflets and literature Acronyms | GSources of Drugs August 7, 2011 9:45 am Many drugs were discovered long ago by trial and error. Some were good and are still used today like the opium from the poppy tree, digitalis from the foxglove plant, etc. Discovery of medicinal plants was largely by chance and when tribal people looked for food they discovered various roots, leaves, and barks. The people ate, and, by trial and error, they learned about healing effects of these plants. They also learned about toxic effects. Today, there is a synthetic version of drugs to conserve their sources, for resource effectiveness, better dosage and control. We would learn about these sources of drugs in this lesson.Sources of Drugs 1. Primitive Medicine; Folklore, witchcraft, dreams, trances etc. Also from observing the reaction of some animals to particular herbs. Through primitive medicine quinine was discovered from Africa; used for malaria and limejuice for Ascorbic acid/Vitamin C and this is used for scurvy and gum bleeding. 2. Plants; Roots, bark, sap, leaves, flowers, seeds were sources for drugs e.g. Reserpine from Rauwolfia Vomitora, Digitalis from foxglove, opium from the poppy plant. 3. Animal sources; gave us hormones for replacement in times of deficiencies e.g. Insulin from the pancreases of pigs and cattle, Liver extracts for anemia etc 4. Minerals; including acids, bases and salts like potassium chloride 5. Natural; OCCURRING SUBSTANCES like proteins
  15. 15. 6. Happy Chance; Discovery is by chance not by any premeditated effort. 7. Synthesis of Substances; from natural products in the laboratory.Currently most drugs are synthetics produced in the laboratories with few from naturalextractions.Drugs are obtained from six major sources: 1. Plant sources 2. Animal sources 3. Mineral/ Earth sources 4. Microbiological sources 5. Semi synthetic sources/ Synthetic sources 6. Recombinant DNA technology1. Plant Sources:Plant source is the oldest source of drugs. Most of the drugs in ancient times were derived fromplants. Almost all parts of the plants are used i.e. leaves, stem, bark, fruits and roots.Leaves:a. The leaves of Digitalis Purpurea are the source of Digitoxin and Digoxin, which are cardiacglycosides.b. Leaves of Eucalyptus give oil of Eucalyptus, which is important component of cough syrup.c. Tobacco leaves give nicotine.d. Atropa belladonna gives atropine. Flowers: 1. Poppy papaver somniferum gives morphine (opoid) 2. Vinca rosea gives vincristine and vinblastine 3. Rose gives rose water used as tonic.Photo of Papaver somniferum by Evelyn Simak
  16. 16. Fruits: 1. Senna pod gives anthracine, which is a purgative (used in constipation) 2. Calabar beans give physostigmine, which is cholinomimetic agent.Seeds: 1. Seeds of Nux Vomica give strychnine, which is a CNS stimulant. 2. Castor oil seeds give castor oil. 3. Calabar beans give Physostigmine, which is a cholinomimetic drug.Roots: 1. Ipecacuanha root gives Emetine, used to induce vomiting as in accidental poisoning. It also has amoebicidal properties. 2. Rauwolfia serpentina gives reserpine, a hypotensive agent. 3. Reserpine was used for hypertension treatment.Bark: 1. Cinchona bark gives quinine and quinidine, which are antimalarial drugs. Quinidine also has antiarrythmic properties. 2. Atropa belladonna gives atropine, which is anticholinergic. 3. Hyoscyamus Niger gives Hyosine, which is also anticholinergic.Stem:Chondrodendron tomentosum gives tuboqurarine, which is skeletal muscle relaxant used ingeneral anesthesia.2. Animal Sources: 1. Pancreas is a source of Insulin, used in treatment of Diabetes. 2. Urine of pregnant women gives human chorionic gonadotropin (hCG) used for the treatment of infertility. 3. Sheep thyroid is a source of thyroxin, used in hypertension. 4. Cod liver is used as a source of vitamin A and D. 5. Anterior pituitary is a source of pituitary gonadotropins, used in treatment of infertility. 6. Blood of animals is used in preparation of vaccines. 7. Stomach tissue contains pepsin and trypsin, which are digestive juices used in treatment of peptic diseases in the past. Nowadays better drugs have replaced them.3. Mineral Sources:i. Metallic and Non metallic sources: 1. Iron is used in treatment of iron deficiency anemia.
  17. 17. 2. Mercurial salts are used in Syphilis. 3. Zinc is used as zinc supplement. Zinc oxide paste is used in wounds and in eczema. 4. Iodine is antiseptic. Iodine supplements are also used. 5. Gold salts are used in the treatment of rheumatoid arthritis.ii. Miscellaneous Sources: 1. Fluorine has antiseptic properties. 2. Borax has antiseptic properties as well. 3. Selenium as selenium sulphide is used in anti dandruff shampoos. 4. Petroleum is used in preparation of liquid paraffin.4. Synthetic/ Semi synthetic Sources:i. Synthetic Sources:When the nucleus of the drug from natural source as well as its chemical structure is altered, wecall it synthetic.Examples include Emetine Bismuth Iodideii. Semi Synthetic Source:When the nucleus of drug obtained from natural source is retained but the chemical structure isaltered, we call it semi-synthetic.Examples include Apomorphine, Diacetyl morphine, Ethinyl Estradiol, Homatropine, Ampicillinand Methyl testosterone.Most of the drugs used nowadays (such as antianxiety drugs, anti convulsants) are syntheticforms.5. Microbiological Sources: 1. Penicillium notatum is a fungus which gives penicillin. 2. Actinobacteria give Streptomycin. 3. Aminoglycosides such as gentamicin and tobramycin are obtained from streptomycis and micromonosporas.6. Recombinant DNA technology:Recombinant DNA technology involves cleavage of DNA by enzyme restriction endonucleases.The desired gene is coupled to rapidly replicating DNA (viral, bacterial or plasmid). The newgenetic combination is inserted into the bacterial cultures which allow production of vast amountof genetic material.
  18. 18. Advantages: 1. Huge amounts of drugs can be produced. 2. Drug can be obtained in pure form. 3. It is less antigenic.Disadvantages: 1. Well equipped lab is required. 2. Highly trained staff is required. 3. It is a complex and complicated technique.Relevant Terms in Drug Intake, Absorption, Metabolismand Elimination Bioavailability; This is the proportion of administered drug, which reaches the circulation. Drugs given IV have high bioavailability whilst those given orally have to pass through the portal circulation so have lower bioavailability. Absorption; For the oral route this denotes how drugs pass through the stomach walls, intestines before entering the systemic circulation through the portal vein.The other routes of IV, IM, Subcutaneous, Sublingual, Inhalation, Rectal etc. get absorbed cells membranes and tissues. First-Pass; Drugs absorbed from the G.I. tract pass through the portal vein before the general circulation. They are metabolized and some get removed leaving only a proportion. Removal of the drug as passes through the liver is known as the first-pass. Drugs with high first-pass are inactive when swallowed e.g. glycerol dinitrate. They need to be given by other routes like IM, Sublingual or IV. Distribution; Movement of drugs from the blood to the tissues and cells Elimination or Excretion; Movement of the drug and its metabolites out of the body Metabolism; This is the process of breaking down the drugs by the liver and elimination of the foreign and undesirable compounds from the body Drug effects; this is the action of the drug which could be: 1. Efficacy; which is the drugs ability to produce a desired chemical change in the body 2. Tolerance refers to when the effects get lessened than desired due to abuse and the dosage must be increased. 3. Adverse or side effects are undesired. They are unpleasant and/or harmful. 4. Local effect is when drug does not get into the blood stream. The action is at the site of application. 5. Systemic is when effect is throughout the body because the drug is absorbed into the bloodstream and distributed.Classification
  19. 19. Medications can be classified in various ways,[3] such as by chemical properties, mode or routeof administration, biological system affected, or therapeutic effects. An elaborate and widelyused classification system is the Anatomical Therapeutic Chemical Classification System (ATCsystem). The World Health Organization keeps a list of essential medicines.A sampling of classes of medicine includes: 1. Antipyretics: reducing fever (pyrexia/pyresis) 2. Analgesics: reducing pain (painkillers) 3. Antimalarial drugs: treating malaria 4. Antibiotics: inhibiting germ growth 5. Antiseptics: prevention of germ growth near burns, cuts and woundsTypes of medications (type of pharmacotherapy)For the gastrointestinal tract (digestive system) Upper digestive tract: antacids, reflux suppressants, antiflatulents, antidopaminergics, proton pump inhibitors (PPIs), H2-receptor antagonists, cytoprotectants, prostaglandin analogues Lower digestive tract: laxatives, antispasmodics, antidiarrhoeals, bile acid sequestrants, opioidFor the cardiovascular system General: β-receptor blockers ("beta blockers"), calcium channel blockers, diuretics, cardiac glycosides, antiarrhythmics, nitrate, antianginals, vasoconstrictors, vasodilators, peripheral activators Affecting blood pressure (antihypertensive drugs): ACE inhibitors, angiotensin receptor blockers, α blockers, calcium channel blockers Coagulation: anticoagulants, heparin, antiplatelet drugs, fibrinolytics, anti-hemophilic factors, haemostatic drugs Atherosclerosis/cholesterol inhibitors: hypolipidaemic agents, statins.For the central nervous systemSee also: Psychiatric medication and Psychoactive drugDrugs affecting the central nervous system include: hypnotics, anaesthetics, antipsychotics,antidepressants (including tricyclic antidepressants, monoamine oxidase inhibitors, lithium salts,and selective serotonin reuptake inhibitors (SSRIs)), antiemetics, anticonvulsants/antiepileptics,anxiolytics, barbiturates, movement disorder (e.g., Parkinsons disease) drugs, stimulants(including amphetamines), benzodiazepines, cyclopyrrolones, dopamine antagonists,antihistamines, cholinergics, anticholinergics, emetics, cannabinoids, and 5-HT (serotonin)antagonists.For pain and consciousness (analgesic drugs)
  20. 20. See also: AnalgesicThe main classes of painkillers are NSAIDs, opioids and various orphans such as paracetamol.For musculo-skeletal disordersThe main categories of drugs for musculoskeletal disorders are: NSAIDs (including COX-2selective inhibitors), muscle relaxants, neuromuscular drugs, and anticholinesterases.For the eye General: adrenergic neurone blocker, astringent, ocular lubricant Diagnostic: topical anesthetics, sympathomimetics, parasympatholytics, mydriatics, cycloplegics Anti-bacterial: antibiotics, topical antibiotics, sulfa drugs, aminoglycosides, fluoroquinolones Antiviral drug Anti-fungal: imidazoles, polyenes Anti-inflammatory: NSAIDs, corticosteroids Anti-allergy: mast cell inhibitors Anti-glaucoma: adrenergic agonists, beta-blockers, carbonic anhydrase inhibitors/hyperosmotics, cholinergics, miotics, parasympathomimetics, prostaglandin agonists/prostaglandin inhibitors. nitroglycerinFor the ear, nose and oropharynxsympathomimetics, antihistamines, anticholinergics, NSAIDs, steroids, antiseptics, localanesthetics, antifungals, cerumenolytiFor the respiratory systembronchodilators, NSAIDs, anti-allergics, antitussives, mucolytics, decongestantscorticosteroids, Beta2-adrenergic agonists, anticholinergics, steroidsFor endocrine problemsandrogens, antiandrogens, gonadotropin, corticosteroids, human growth hormone, insulin,antidiabetics (sulfonylureas, biguanides/metformin, thiazolidinediones, insulin), thyroidhormones, antithyroid drugs, calcitonin, diphosponate, vasopressin analoguesFor the reproductive system or urinary systemantifungal, alkalising agents, quinolones, antibiotics, cholinergics, anticholinergics,anticholinesterases, antispasmodics, 5-alpha reductase inhibitor, selective alpha-1 blockers,sildenafils, fertility medicationsFor contraception
  21. 21. Hormonal contraception Ormeloxifene SpermicideFor obstetrics and gynecologyNSAIDs, anticholinergics, haemostatic drugs, antifibrinolytics, Hormone Replacement Therapy(HRT), bone regulators, beta-receptor agonists, follicle stimulating hormone, luteinisinghormone, LHRHgamolenic acid, gonadotropin release inhibitor, progestogen, dopamine agonists, oestrogen,prostaglandins, gonadorelin, clomiphene, tamoxifen, DiethylstilbestrolFor the skinemollients, anti-pruritics, antifungals, disinfectants, scabicides, pediculicides, tar products,vitamin A derivatives, vitamin D analogues, keratolytics, abrasives, systemic antibiotics, topicalantibiotics, hormones, desloughing agents, exudate absorbents, fibrinolytics, proteolytics,sunscreens, antiperspirants, corticosteroidsFor infections and infestationsantibiotics, antifungals, antileprotics, antituberculous drugs, antimalarials, anthelmintics,amoebicides, antivirals, antiprotozoalsFor the immune systemvaccines, immunoglobulins, immunosuppressants, interferons, monoclonal antibodiesFor allergic disordersanti-allergics, antihistamines, NSAIDsFor nutritiontonics, electrolytes and mineral preparations (including iron preparations and magnesiumpreparations), Parental nutritional supplements, vitamins, anti-obesity drugs, anabolic drugs,haematopoietic drugs, food product drugsFor neoplastic disorderscytotoxic drugs, therapeutic antibodies, sex hormones, aromatase inhibitors, somatostatininhibitors, recombinant interleukins, G-CSF, erythropoietinFor diagnostics
  22. 22. contrast mediaFor euthanasiaSee also: Barbiturate#Other non-therapeutical usDrug actionFrom Wikipedia, the free encyclopediaJump to: navigation, search This article does not cite any references or sources. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (August 2009)The action of drugs on the human body is called pharmacodynamics, and what the body doeswith the drug is called pharmacokinetics. The drugs that enter the human tend to stimulatecertain receptors, ion channels, act on enzymes or transporter proteins. As a result, they cause thehuman body to react in a specific way.There are two different types of drugs: Agonists - they stimulate and activate the receptors Antagonists - they stop the agonists from stimulating the receptorsOnce the receptors are activated, they either trigger a particular response directly on the body, orthey trigger the release of hormones and/or other endogenous drugs in the body to stimulate aparticular response.Contents 1 Short Note on Receptors o 1.1 Ionic Bonds o 1.2 Hydrogen bonds 2 How shape of Drug Molecules affect drug action o 2.1 Potency o 2.2 The specificity of drugs o 2.3 Affinity 3 References 4 External links
  23. 23. Short Note on ReceptorsThe drugs interact at receptors by bonding at specific binding sites. Most receptors are made upof proteins, the drugs can therefore interact with the amino acids to change the conformation ofthe receptor proteins.These interactions are very basic, just like that of other chemical bondings:Ionic BondsMainly occur through attractions between opposite charges. For example, between protonatedamino (on salbutamol) or quaternary ammonium (e.g. acetylcholine), and the dissociatedcarboxylic acid group. Similarly, the dissociated carboxylic acid group on the drug can bind withamino groups on the receptor.This type of bonds are very strong, and varies with so it could act over large distances.Cation-π interactions can also be classified as ionic bonding. This occurs when a cation, e.g.acetylcholine, interacts with the negative π bonds on an aromatic group of the receptor.Ion-dipole and dipole-dipole bonds have similar interactions, but are more complicated and areweaker than ionic bonds.Hydrogen bondsRefer to the attraction between Hydrogen atoms and polar functional groups e.g. The Hydroxyl (-OH) group. Only act over short distances, and are dependent on the correct alignment betweenfunctional groups.Of course, drugs not only just act on receptors. They also act on ion channels, enzymes and celltransporter proteins.Receptors are located on all cells in the body. The same receptor can be located on differentorgan, and even on different types of tissues. There are also different subtypes of receptor whichellicit different effects in response to the same agonist, e.g.There are two types of Histamine receptor; H1 and H2, activation of H1 subtype causescontraction of smooth muscle whereas activation of the H2 receptors stimulates gastric secretion.It is this phenomenon that gives rise to drug specificity.How shape of Drug Molecules affect drug action
  24. 24. When talking about the shape of molecules, the scientists are mainly concerned with the 3Dconformation of drug molecules. There are many isomers of a particular drug, and each one willhave their own effects. This effect is not only what the drug activates, but also changes thepotency of each drug.PotencyPotency is a measure of how much a drug is required in order to produce a particular effect.Therefore, only a small dosage of a high potency drug is required to induce a large response. Theother terms used to measure the ability of a drug to trigger a response are: Intrinsic Activity which defines: o Agonists as having Intrinsic Activity = 1 o Antagonists as having Intrinsic Activity = 0 o and, Partial Agonist as having Intrinsic Activity between 0 and 1 Intrinsic Efficacy also measures the different activated state of receptors, and the ability for a drug to cause maximum response without having to bind to all the receptors.The specificity of drugsDrug companies invest significant effort in designing drugs that interact specifically withparticular receptors[citation needed], since non-specific drugs can cause more side effects.An example is the endogenous drug acetylcholine (ACh). ACh is used by the parasympatheticnervous system to activate muscarinic receptors and by the neuromuscular system to activatenicotinic receptors. However, the compounds muscarine and nicotine can each preferentiallyinteract one of the two receptor types, allowing them to activate only one of the two systemswhere ACh itself would activate both.AffinityThe specificity of drugs cannot be talked about without mentioning the affinity of the drugs. Theaffinity is a measure of how tightly a drug binds to the receptor. If the drug does not bind well,then the action of the drug will be shorter and the chance of binding will also be less. This can bemeasured numerically by using the dissociation constant KD. The value of KD is the same as theconcentration of drug when 50% of receptors are occupied.The equation can be expressed as KD =But the value of KD is also affected by the conformation, bonding and size of the drug and thereceptor. The higher the KD the lower the affinity of the drug.References
  25. 25. External linksBASIC PHARMACOLOGYHow Do Drugs Work?What Are Receptors?Basic PharmacokineticsCorrelating Blood Levels with Effects of ImpairmentHow Do Drugs Work?Did you ever wonder how aspirin knows to go to your head when you have a headache and toyour elbow when you have "Tennis Elbow"? Or how one or two small aspirins containing only325-650 mg of active drug can relieve a headache or ease the inflammation of a strained muscleor tendon in a 195 lb. athlete?The answer to the first question is that drugs are distributed throughout the body by the bloodand other fluids of distribution (see distribution below). Once they arrive at the proper site ofaction, they act by binding to receptors, usually located on the outer membrane of cells, or onenzymes located within the cell.What Are Receptors?Receptors are like biological "light switches" which turn on and off when stimulated by a drugwhich binds to the receptor and activates it. For example, narcotic pain relievers like morphinebind to receptors in the brain that sense pain and decrease the intensity of that perception. Non-narcotic pain relievers like aspirin, Motrin (ibuprofen) or Tylenol (acetaminophen) bind to anenzyme located in cells outside of the brain close to where the pain is localized (e.g., hand, foot,low back, but not in the brain) and decrease the formation of biologically-active substances
  26. 26. known as prostaglandins, which cause pain and inflammation. These "peripherally-acting" (actoutside of the central nervous system (CNS)) analgesics may also decrease the sensitivity of thelocal pain nerves causing fewer pain impulses to be sensed and transmitted to the brain forappreciation.In some instances, a drugs site of action or "receptor" may actually be something which resideswithin the body, but is not anatomically a part of the body. For example, when you take anantacid like Tums or Rolaids, the site of action is the acid in the stomach which is chemicallyneutralized. However, if you take an over-the-counter (OTC) medication which inhibits stomachacid production instead of just neutralizing it (e.g., Tagamet (cimetidine) or Pepsid-AC(famotidine)), these compounds bind to and inhibit recptors in the stomach wall responsible forproducing acid.Another example of drugs which bind to a receptor that is not part of your body are antibiotics.Antibiotics bind to portions of a bacterium that is living in your body and making you sick. Mostantibiotics inhibit an enzyme inside the bacteria which causes the bacteria to either stopreproducing or to die from inhibition of a vital biochemical process.In many instances, the enzyme in the bacteria does not exist in humans, or the human form of theenzyme does not bind the inhibiting drug to the same extent that the bacterial enzyme does, thusproviding what pharmacologists call a "Selective Toxicity". Selective toxicity means that thedrug is far more toxic to the sensitive bacteria than it is to humans thus providing sick patientswith a benefit that far outweighs any risks of direct toxicity. Of course, this does not mean thatcertain patients wont be allergic to certain drugs.Penicillin is a good example to discuss. Although penicillin inhibits an enzyme found in sensitivebacteria which helps to "build" part of the cell wall around the outside of the bacteria, and thisenzymatic process does not occur in human cells, some patients develop an allergy to penicillin(and related cepahlosporin) antibiotics. This allergy is different from a direct toxicity anddemonstrates that certain peoples immune system become "sensitized" to some foreign drugmolecules (xenobiotics) which are not generally found in the body.As medical science has learned more about how drugs act, pharmacologists have discovered thatthe body is full of different types of receptors which respond to many different types of drugs.Some receptors are very selective and specific, while others lack such specificity and respond toseveral different types of drug molecules.To date, receptors have been identified for the following common drugs, or neurotransmitters*found in the body: narcotics (morphine), benzodiazepines (Valium, Xanax), acetylcholine*(nicotinic and muscarinic cholinergic receptors), dopamine*, serotonin* (5-hydroxytryptamine;5-HT), epinephrine (adrenalin) and norepinephrine* (a and b adrenergic receptors), and manyothers.Neurotransmitters* are chemicals released from the end of one neuron (nerve cell) which diffuseacross the space between neurons called the synaptic cleft and stimulate an adjacent neuron tosignal the transmission of information.
  27. 27. The rest of this section is designed to explain the complicated journey of a drug through thebody, which pharmacologists call pharmacokinetics.Basic PharmacokineticsPharmacokinetics is the branch of pharmacology which deals with determining the movement(kinetics) of drugs into and out of the body. Experimentally, this is done by administering thedrug to a group of volunteer subjects or patients and obtaining blood and urine specimens forsubsequent quantitative (how much) analysis. When the results of these analyses are plotted ongraph paper with blood levels or urinary excretion on the verticle axis and time on the horizontalaxis, a blood level-time or urinary excretion pattern is obtained.These graphs can be used to calculate the rates of appearance and elimination of the drug in thebloodstream, the rates of formation of the compounds into which the drugs are transformed in theliver (metabolized), and finally the rates of elimination or excretion of the metabolites.There are four scientific or pharmacokinetic processes to which every drug is subject in thebody: 1. ABSORPTION 2. DISTRIBUTION 3. METABOLISM 4. EXCRETIONThese four processes occur contemporaneously until (1) all of the drug is absorbed from the GItract, the muscle or subcutaneous tissue site into which it was injected, and there is no moreabsorption phase, and (2) all of the drug has been metabolized, and there is no more "parent"drug and it is no longer detectable in the blood.Figure 1 depicts the four contemporaneous pharmacokinetic processes. Figure 2 depicts theblood level-time profile of a single oral and intravenous (IV) dose of a drug. Figure 3, shows theaccumulation pattern of a drug given orally once per half-life for six half-lives, at which timesteady-state or equilibrium (the amount of drug entering the body equals the amount beingexcreted) is achieved.Absorption
  28. 28. Absorption is the process by which a drug is made available to the fluids of distribution of thebody (e.g., blood, plasma, serum, aqueous humor, lymph, etc.).In the fasting state, most orally-administered drugs reach a maximum or "peak" bloodconcentration within 1-2 hours. Intravenous (IV) administration is the most rapid route ofadministration, with intra-nasal, smoking (inhalation), sublingual (under the tongue), intra-muscular (IM), subcutaneous (e.g., under the skin, SC or SQ), and percutaneous (through theskin) being the next most rapid.The RATE of absorption of orally-administered drugs and the subsequent appearance of thedrug in the blood is dependent on the following factors: 1. The rates of disintegration and dissolution of the pill or capsule in the stomach or gastrointestinal (GI) tract, 2. The solubility of the drug in stomach or intestinal fluids (the more soluble, the faster), 3. The molecular charge on the drug molecule (charged substances are soluble, but dont pass through lipid (fat) soluble biologic membranes well), 4. Aqueous (water) solubility vs. lipid (fat) solubility. Water-soluble drugs are soluble but dont pass through lipid-soluble biologic membranes well, 5. The presence or absence of food in the stomach (food delays the absorption of some drugs and enhances the absorption of others), 6. The presence of any concomitant medication(s) that can interfere with gastrointestinal (GI) motility, e.g., Reglan increases GI motility, Aluminum antacids slow, drugs like atropine or scopolamine used for ulcers or "queasy stomachs" slow GI motility keeping some drugs in the stomach slowing absorption, while drugs like Tagamet, Zantac and Prilosec (Pepcid-AC) decrease gastric acid production increasing the rate of gastric emptying and increasing the rate of absorption of some drugs.DistributionOnce a drug has been absorbed from the stomach and/or intestines (GI Tract) into the blood, itis circulated to some degree to all areas of the body to which there is blood flow. This is theprocess of distribution. Organs with high blood flow e.g., brain, heart, liver, etc. are the first toaccumulate drugs, while connective tissue and lesser perfused organs are the last.Many drugs are bound to plasma proteins such as albumin. Since only drugs which are not boundare free to exert a pharmacologic effect, the ratio of "free" to "bound" drug is important indetermining the onset and duration of action of drugs. Highly bound drugs are distributed lessextensively throughout the body and are slower to act. By virtue of their high binding to plasmaproteins, they also stay in the body for longer periods of time because the binding sites act as asort of "reservoir" for the drug, releasing drug molecules slowly.
  29. 29. MetabolismDrugs in the blood and tissues must be inactivated and excreted from the body. This process isinitiated by altering the chemical structure of the drug in such a way as to promote its excretion.The transformation of the drug molecule into a chemically related substance that is more easilyexcreted from the body is called metabolism, biotransformation or detoxification.In the case of ethanol, the alcohol molecule is metabolized in the liver by the enzyme alcoholdehydrogenase, to acetaldehyde which causes dilatation of the blood vessels and, afteraccumulation, is responsible for the subsequent hangover which ensues. The acetaldehyde issubsequently metabolized by the enzyme aldehyde dehydrogenase to acetate, a substance verysimilar to acetic acid or vinegar.Therapeutic agents like antibiotics and drugs used for the treatment of high blood pressure,epilepsy (e.g., phenobarbital, Dilantin), pain (e.g., morphine, codeine), anxiety (e.g., Valium,Xanax) are also metabolized to chemically-related compounds called metabolites, which are thenexcreted in the urine.REMEMBER: Urine drug screens usually determine metabolites in urine, not the original"parent" drug which was ingested or taken. For example, if cocaine is snorted, smoked orinjected, a urine drug screen will most often detect the cocaine metabolite benzoylecgonine inthe urine, not cocaine itself. The same analogy applies to other drugs of abuse like: heroin,morphine, amphetamines, PCP (Angel Dust), barbiturates, marijuana, etc.ExcretionExcretion is the process by which a drug is eliminated from the body.Drugs can be excreted by various organs including the kidney and lungs, and found in manybiological fluids like: bile, sweat, hair, breast milk, or tears. However, the most common fluid inwhich to look for drugs is the urine.In order to determine the rate of excretion of any drug from blood, one must first be certain thatall the drug in the subjects GI tract has been absorbed. If not, calculation of a rate of excretionwould be confounded be the ongoing absorption of more drug. Once all the drug has beenabsorbed, this is called the post-absorbtive, or distributive stage. At this time, serial (multiple)
  30. 30. blood level determinations should show a decline with time. The slope of the log concentration-time graph is called the half-life (T1/2) and is indicative of the drugs half-life, or rate ofexcretion. The half-life represents the amount of time required to eliminate half of the drug fromthe body.Figure 4 shows a typical plot of the log of the drugs blood concentration on the verticle axis vs.time on the horizontal axis. The log of the blood concentration is used to convert the curvedportions of the graph shown in Figure 2 to a straight line.Generally, it takes six half-lives to rid the body of 98% of a drug and 10 half-lives to completelyeliminate the drug from the body. Using these mathematical relatonships allows pharmacologiststo determine how often a therapeutic drug should be administered to a patient or toxicologists todetermine a time interval within which one would test positive for drugs of abuse. Table I showsthe approximate time intervals individuals will test positive in blood and urine for common drugsof abuse.Correlating Drug or Ethanol Blood Levels and Positive Urine TestsWith Effects of ImpairmentA statutory level for the presumption of DWI is just that, an arbitrary standard. Any BAC level,whether 0.10% or 0.08%, speaks only to a legal standard, and not a scientific (physiological)standard.The same analogy applies for intoxicating drugs or drugs with an ability to impair an individualsmental or physical capacity. In order for an individual to be presumed under the influence of anintoxicating or mind-altering drug, it is necessary to establish that there was a significant orpharmacologic concentration of the drug present in the individuals bloodstream, and that theindividual was not sufficiently tolerant to the effects of the drug such as to mitigate anyintoxicating effect(s). For example, an individual who had been taking a drug known to causesedating or intoxicating effects to which the subject could become tolerant, could not bepresumed to be too impaired to drive while taking the medication if the subject had been takingthe drug long enough to permit the development of tolerance to the sedating or intoxicatingproperties of that drug.Some examples would include benzodiazepines like Valium or Xanax, tricyclic antidepressantdrugs like Elavil or Tofranil, anti-epileptic drugs like barbiturates and Dilantin which inducetheir own metabolism and are excreted more rapidly after they have been taken for severalweeks, or narcotics like codeine, which are well-known to produce tolerance. In situations like
  31. 31. these, it is important to obtain the testimony of other individuals such as co-worders or familymembers who can corroborate the lack of observable impairment in the subject following drugingestion.If an individual is accustomed to having 2-3 (or more) alcoholic drinks per day, with dinner orwhile watching TV after work, it is quite likely that they will have developed some tolerance tothe intoxicating properties of alcohol and might not show signs of intoxication even at BACsover 0.10%. On the other hand, an individual who drinks infrequently would have developed notolerance and might show signs of intoxication at BACs below the statutory level.CONTACT INFORMATIONDavid M. Benjamin, Ph.D.77 Florence StreetSuite 107Chestnut Hill, MA 02467Telephone: 617-969-1393Fax: 617-969-4285send e-mail to Dr. Benjamin×Top of Form×

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