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A variety of topics involved with pharmacology, including neuropharmacology, renal pharmacology, human metabolism, intracellular metabolism, and intracellular regulation.

Pharmacology (from Greek φάρμακον, pharmakon, "poison" in classic Greek; "drug" in modern Greek; and -λογία, -logia "study of", "knowledge of") is the branch of medicine and biology concerned 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/or physiological effect on the cell, tissue, organ, or organism. 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. The field encompasses drug composition and properties, interactions, toxicology, therapy, and medical applications and antipathogenic capabilities. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. The former studies the effects of the drugs on biological systems, and the latter the effects of biological systems on the drugs. In broad terms, pharmacodynamics discusses the chemicals with biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion 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 how drugs interact within biological systems to affect function. It is the study of drugs, of the reactions of the body and 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 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.

Dioscorides' De Materia Medica is often said to be the oldest and most valuable work in the history of pharmacology.[2] The origins of clinical pharmacology date back to the Middle Ages in 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.[3] Clinical pharmacology owes much of its foundation to the work of William Withering.[4] Pharmacology as a scientific discipline did not

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 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.[6] 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.[5]

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.[7]

Divisions

Clinical pharmacology

The basic science of pharmacology, with added focus on the application of pharmacological principles and methods in the real world

Neuropharmacology

Effects of medication on nervous system functioning.

Psychopharmacology

Effects of medication on the brain; observing changed behaviors of the body and read the effect of drugs on the human brain.

Pharmacogenetics

Clinical testing of genetic variation that gives rise to differing response to drugs.

Pharmacogenomics

Application of genomic technologies to new drug discovery and further characterization of older drugs.

Pharmacoepidemiology

Study of effects of drugs in large numbers of people.

Toxicology

Study of harmful or toxic effects of drugs.

Theoretical pharmacology

Study of metrics in pharmacology.

Posology

How medicines are dosed. It also depends upon various factors like age, climate, weight, sex, and so on.

Pharmacognosy

A branch of pharmacology dealing especially with the composition, use, and development of medicinal substances of biological origin and especially medicinal substances obtained from plants.

Behavioral pharmacology

Behavioral pharmacology, also referred to as 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. People in this field (called behavioral pharmacologists) typically use small animals (e.g. rodents) to study psychotherapeutic drugs such as antipsychotics, antidepressants and anxiolytics, and drugs of abuse such as nicotine, cocaine, methamphetamine, etc.

Environmental pharmacology

Environmental pharmacology is a new discipline.[8] 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 is 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.[9] More and more biodegradability of drugs are needed.

Scientific backgroundThe 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).

A chemical has, from the pharmacological point-of-view, various properties. 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).

When describing the pharmacokinetic properties of a chemical, pharmacologists are often interested 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. 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.

Medicine development and safety testingDevelopment 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 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 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.[10] 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.[11]

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.[11]

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, costing millions of dollars. To recoup this outlay pharmaceutical 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 differ from pharmacy programs. Students of pharmacology are trained as biomedical researchers, studying the effects of substances in order to better understand the mechanisms which might lead to 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 be directed (or new pathways for the sake of a more complete picture of its biochemistry). In addition, students of pharmacology must have detailed working knowledge of those areas in which 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 a pharmacy dispensing medications or some other position focused on the patient, a pharmacologist will typically work within a laboratory setting.

Pharmacological GlossaryDefinitions of commonly used pharmacological terms

Term Description

Agonist 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 activation 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.

Allosteric Modulator

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 affinity of the receptor for the endogenous ligand. Positive allosteric modulators increase the affinity, whilst negative allosteric modulators decrease the affinity.

Antagonist

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 antagonist 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.

Bmax

The maximum amount of drug or radioligand, usually expressed as picomoles (pM) per mg protein, which can bind specifically to the receptors in a membrane preparation. Can be used to measure the density of the receptor site in a particular preparation.

Cheng-Prusoff Equation

Used to determine the Ki value from an IC50 value measured in a competition radioligand binding assay:

Where [L] is the concentration of free radioligand, and Kd is the dissociation constant of the radioligand for the receptor.

Competitive Antagonist See Antagonist

Desensitization A reduction in response to an agonist while it is continuously present at the receptor, or progressive decrease in response upon repeated exposure to an agonist.

EC50 The molar concentration of an agonist that produces 50% of the maximum possible response for that agonist.

ED50 In vitro or in vivo dose of drug that produces 50% of its maximum response or effect.

Efficacy

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 low 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

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 the 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).

IC50

In a functional assay, the molar concentration of an agonist or antagonist which produces 50% of its maximum possible inhibition. In a radioligand 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).

i.c.v. Intracerebroventricular route of drug administration (see Useful Abbreviations).

ID50 In vitro or in vivo dose of a drug that causes 50% of the maximum possible inhibition for that drug.

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

In vitro Taking place in a test-tube, culture dish or elsewhere outside a living

organism.

In vivo Taking place in a living organism.

i.p. Intraperitoneal route of drug administration (see Useful Abbreviations).

Irreversible Antagonist See Antagonist

i.t. Intrathecal route of drug administration (see Useful Abbreviations).

i.v. Intravenous route of drug administration (see Useful Abbreviations).

KB The equilibrium dissociation constant for a competitive antagonist: the molar concentration that would occupy 50% of the receptors at equilibrium.

Kd The dissociation constant for a radiolabeled drug determined by saturation analysis. It is the molar concentration of radioligand which, at equilibrium, occupies 50% of the receptors.

Ki

The inhibition constant for a ligand, which denotes the affinity of the ligand for a receptor. Measured using a radioligand competition binding 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 Modulator

Neutral Antagonist See Silent Antagonist

Non-Specific Binding The proportion of radioligand that is not displaced by other competitive ligands specific for the receptor. It can be binding to other receptors or proteins, partitioning into lipids or other things.

pA2 Measure of the potency of an antagonist. It is the negative logarithm of 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 Modulator

Potency A measure of the concentrations of a drug at which it is effective.

s.c. Subcutaneous route of drug administration (see Useful Abbreviations).

Specific Binding The proportion of radioligand that can be displaced by competitive ligands specific for the receptor.

Silent Antagonist

A drug that attenuates the effects of agonists or inverse agonists, producing a functional reduction in signal transduction. Effects only ligand-dependent receptor activation and displays no intrinsic activity itself. Also known as a neutral antagonist.

Systemic In the periphery of the body (not in the central nervous system – see Useful Abbreviations).

t½ Biological half-life; (see Half-life).

Latin Abbreviations

Abbreviation Meaning Latin

ad.lib. freely as wanted ad libitum

aq. water Aqua

b.i.d. twice a day bis in die

cap. capsule capula

c with bar on top with Cum

div. divide divide

eq.pts. equal parts equalis partis

gtt. a drop Gutta

h. hour Hora

no. number numero

O. pint octarius

p.r.n. as occasion requires pro re nata

q.s. a sufficient quantity quantum sufficiat

q4h every 4 hours quaque 4 hora

q6h every 6 hours quaque 6 hora

q1d every day quaque 1 die

q1w every week

q.i.d. four times a day quater in die

s.i.d. once a day semel in die

Sig., S. write on the label Signa

stat. immediately statim

tab. a tablet tabella

t.i.d. three times a day ter in die

Weights and measures used in prescribing and toxicology

The Metric System

Weight

1 picogram (pg) 10-12 gram

1000 picograms 1 nanogram (ng) or 10-9 gram

1000 nanograms 1 microgram (ug) or 10-6 gram

1000 micrograms 1 milligram (mg) or 10-3 gram

1000 milligrams 1 gram (g)

1000 grams 1 kilogram (kg)

Volume

1000 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 drug residue 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 assumed that ppm is w/w unless otherwise specified.

The Apothecaries' System

Weight

20 grains (gr) 1 scruple ( )

3 scruples 1 dram( ) = 60 grains

8 drams 1 ounce ( ) = 480 grains

Volume

60 minims (m) 1 fluid dram ( )

8 fluid drams 1 fluid ounce ( )

16 fluid ounces 1 pint (O.)

Know eqivalents in bold faced typed

Conversion Equivalents

Approximate Exact

1 milligram 1/60 grain 1/65 grain

1 gram 15 grains 15.432 grains

1 kilogram 2.2 pounds* 2.2 pounds*

1 milliliter 15 minims 16.23 minims

1 liter 1 quart 1.06 quarts or 33.8 fluid ounces

1 grain 60 milligrams 65 milligrams

1 dram 4 grams 3.88 grams

1 ounce 30 grams 31.1 grams

1 pound* 450 grams 454 grams

1 minim 0.06 milliliter 0.062 milliliter

1 fluid dram 4 milliliters 3.7 milliliters

1 fluid ounce 30 milliliters 29.57 milliliters

1 pint 500 milliliters 473 milliliters

1 quart 1000 milliters 946 milliliters

1 drop 1 minim

1 teaspoonful 5 milliliters

1 dessertspoonful 8 milliliters

1 tablespoonful 15 milliliters

Know equivalents in bold faced type.Note: Where possible, use suitable units rather than decimal fractions, e.g., 10 mg not 0.010 g. When a decimal 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 equivalents

To convert To Multiply by

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 0.45

Know conversions in bold typeface

Pharmaceutical Abbreviations | Abbreviations in product information leaflets and literatureAcronyms | G

Sources 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 Drugs1. 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 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 natural extractions.

Drugs are obtained from six major sources:

1. Plant sources2. Animal sources3. Mineral/ Earth sources4. Microbiological sources5. Semi synthetic sources/ Synthetic sources6. Recombinant DNA technology

1. Plant Sources:

Plant source is the oldest source of drugs. Most of the drugs in ancient times were derived from plants. 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 cardiac glycosides.

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 vinblastine3. Rose gives rose water used as tonic.

Photo of Papaver somniferum by Evelyn Simak

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 in general 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.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, we call it synthetic.

Examples include Emetine Bismuth Iodide

ii. Semi Synthetic Source:

When the nucleus of drug obtained from natural source is retained but the chemical structure is altered, we call it semi-synthetic.

Examples include Apomorphine, Diacetyl morphine, Ethinyl Estradiol, Homatropine, Ampicillin and Methyl testosterone.

Most of the drugs used nowadays (such as antianxiety drugs, anti convulsants) are synthetic forms.

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 new genetic combination is inserted into the bacterial cultures which allow production of vast amount of genetic material.

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, Metabolism and 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.

ClassificationMedications can be classified in various ways,[3] such as by chemical properties, mode or route of administration, biological system affected, or therapeutic effects. An elaborate and widely used classification system is the Anatomical Therapeutic Chemical Classification System (ATC system). 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 malaria4. Antibiotics : inhibiting germ growth

5. Antiseptics : prevention of germ growth near burns, cuts and wounds

Types 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, opioid

For 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 system

See also: Psychiatric medication and Psychoactive drug

Drugs 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., Parkinson's 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)

See also: Analgesic

The main classes of painkillers are NSAIDs, opioids and various orphans such as paracetamol.

For musculo-skeletal disorders

The main categories of drugs for musculoskeletal disorders are: NSAIDs (including COX-2 selective 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. nitroglycerin

For the ear, nose and oropharynx

sympathomimetics, antihistamines, anticholinergics, NSAIDs, steroids, antiseptics, local anesthetics, antifungals, cerumenolyti

For the respiratory system

bronchodilators, NSAIDs, anti-allergics, antitussives, mucolytics, decongestantscorticosteroids, Beta2-adrenergic agonists, anticholinergics, steroids

For endocrine problems

androgens, antiandrogens, gonadotropin, corticosteroids, human growth hormone, insulin, antidiabetics (sulfonylureas, biguanides/metformin, thiazolidinediones, insulin), thyroid hormones, antithyroid drugs, calcitonin, diphosponate, vasopressin analogues

For the reproductive system or urinary system

antifungal, alkalising agents, quinolones, antibiotics, cholinergics, anticholinergics, anticholinesterases, antispasmodics, 5-alpha reductase inhibitor, selective alpha-1 blockers, sildenafils, fertility medications

For contraception

Hormonal contraception Ormeloxifene Spermicide

For obstetrics and gynecology

NSAIDs, anticholinergics, haemostatic drugs, antifibrinolytics, Hormone Replacement Therapy (HRT), bone regulators, beta-receptor agonists, follicle stimulating hormone, luteinising hormone, LHRH

gamolenic acid, gonadotropin release inhibitor, progestogen, dopamine agonists, oestrogen, prostaglandins, gonadorelin, clomiphene, tamoxifen, Diethylstilbestrol

For the skin

emollients, anti-pruritics, antifungals, disinfectants, scabicides, pediculicides, tar products, vitamin A derivatives, vitamin D analogues, keratolytics, abrasives, systemic antibiotics, topical antibiotics, hormones, desloughing agents, exudate absorbents, fibrinolytics, proteolytics, sunscreens, antiperspirants, corticosteroids

For infections and infestations

antibiotics, antifungals, antileprotics, antituberculous drugs, antimalarials, anthelmintics, amoebicides, antivirals, antiprotozoals

For the immune system

vaccines, immunoglobulins, immunosuppressants, interferons, monoclonal antibodies

For allergic disorders

anti-allergics, antihistamines, NSAIDs

For nutrition

tonics, electrolytes and mineral preparations (including iron preparations and magnesium preparations), Parental nutritional supplements, vitamins, anti-obesity drugs, anabolic drugs, haematopoietic drugs, food product drugs

For neoplastic disorders

cytotoxic drugs, therapeutic antibodies, sex hormones, aromatase inhibitors, somatostatin inhibitors, recombinant interleukins, G-CSF, erythropoietin

For diagnostics

contrast media

For euthanasia

See also: Barbiturate#Other non-therapeutical us

Drug action

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The action of drugs on the human body is called pharmacodynamics, and what the body does with the drug is called pharmacokinetics. The drugs that enter the human tend to stimulate certain receptors, ion channels, act on enzymes or transporter proteins. As a result, they cause the human 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 receptors

Once the receptors are activated, they either trigger a particular response directly on the body, or they trigger the release of hormones and/or other endogenous drugs in the body to stimulate a particular 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

Short Note on ReceptorsThe drugs interact at receptors by bonding at specific binding sites. Most receptors are made up of proteins, the drugs can therefore interact with the amino acids to change the conformation of the receptor proteins.

These interactions are very basic, just like that of other chemical bondings:

Ionic Bonds

Mainly occur through attractions between opposite charges. For example, between protonated amino (on salbutamol) or quaternary ammonium (e.g. acetylcholine), and the dissociated carboxylic acid group. Similarly, the dissociated carboxylic acid group on the drug can bind with amino 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 are weaker than ionic bonds.

Hydrogen bonds

Refer 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 between functional groups.

Of course, drugs not only just act on receptors. They also act on ion channels, enzymes and cell transporter proteins.

Receptors are located on all cells in the body. The same receptor can be located on different organ, and even on different types of tissues. There are also different subtypes of receptor which ellicit different effects in response to the same agonist, e.g.

There are two types of Histamine receptor; H1 and H2, activation of H1 subtype causes contraction 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 actionWhen talking about the shape of molecules, the scientists are mainly concerned with the 3D conformation of drug molecules. There are many isomers of a particular drug, and each one will have their own effects. This effect is not only what the drug activates, but also changes the potency of each drug.

Potency

Potency 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. The other terms used to measure the ability of a drug to trigger a response are:

Intrinsic Activity which defines: o Agonists as having Intrinsic Activity = 1o Antagonists as having Intrinsic Activity = 0o 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 drugs

Drug companies invest significant effort in designing drugs that interact specifically with particular 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 parasympathetic nervous system to activate muscarinic receptors and by the neuromuscular system to activate nicotinic receptors. However, the compounds muscarine and nicotine can each preferentially interact one of the two receptor types, allowing them to activate only one of the two systems where ACh itself would activate both.

Affinity

The specificity of drugs cannot be talked about without mentioning the affinity of the drugs. The affinity 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 be measured numerically by using the dissociation constant KD. The value of KD is the same as the concentration 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 the receptor. The higher the KD the lower the affinity of the drug.

References

External links

BASIC PHARMACOLOGY

How Do Drugs Work?

What Are Receptors?Basic Pharmacokinetics

Correlating Blood Levels with Effects of Impairment

How Do Drugs Work?

Did you ever wonder how aspirin knows to go to your head when you have a headache and to your elbow when you have "Tennis Elbow"? Or how one or two small aspirins containing only 325-650 mg of active drug can relieve a headache or ease the inflammation of a strained muscle or tendon in a 195 lb. athlete?

The answer to the first question is that drugs are distributed throughout the body by the blood and other fluids of distribution (see distribution below). Once they arrive at the proper site of action, they act by binding to receptors, usually located on the outer membrane of cells, or on enzymes located within the cell.

What Are Receptors?

Receptors are like biological "light switches" which turn on and off when stimulated by a drug which binds to the receptor and activates it. For example, narcotic pain relievers like morphine bind 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 an enzyme 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 known as prostaglandins, which cause pain and inflammation. These "peripherally-acting" (act outside of the central nervous system (CNS)) analgesics may also decrease the sensitivity of the local pain nerves causing fewer pain impulses to be sensed and transmitted to the brain for appreciation.

In some instances, a drug's site of action or "receptor" may actually be something which resides within the body, but is not anatomically a part of the body. For example, when you take an antacid like Tums or Rolaids, the site of action is the acid in the stomach which is chemically neutralized. However, if you take an over-the-counter (OTC) medication which inhibits stomach acid 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 for producing 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. Most antibiotics inhibit an enzyme inside the bacteria which causes the bacteria to either stop reproducing 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 the enzyme does not bind the inhibiting drug to the same extent that the bacterial enzyme does, thus providing what pharmacologists call a "Selective Toxicity". Selective toxicity means that the drug is far more toxic to the sensitive bacteria than it is to humans thus providing sick patients with a benefit that far outweighs any risks of direct toxicity. Of course, this does not mean that certain patients won't be allergic to certain drugs.

Penicillin is a good example to discuss. Although penicillin inhibits an enzyme found in sensitive bacteria which helps to "build" part of the cell wall around the outside of the bacteria, and this enzymatic 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 and demonstrates that certain people's immune system become "sensitized" to some foreign drug molecules (xenobiotics) which are not generally found in the body.

As medical science has learned more about how drugs act, pharmacologists have discovered that the 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 to several 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 many others.

Neurotransmitters* are chemicals released from the end of one neuron (nerve cell) which diffuse across the space between neurons called the synaptic cleft and stimulate an adjacent neuron to signal the transmission of information.

The rest of this section is designed to explain the complicated journey of a drug through the body, which pharmacologists call pharmacokinetics.

Basic Pharmacokinetics

Pharmacokinetics 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 the drug to a group of volunteer subjects or patients and obtaining blood and urine specimens for subsequent quantitative (how much) analysis. When the results of these analyses are plotted on graph paper with blood levels or urinary excretion on the verticle axis and time on the horizontal axis, 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 the bloodstream, the rates of formation of the compounds into which the drugs are transformed in the liver (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 the body:

1. ABSORPTION 2. DISTRIBUTION 3. METABOLISM 4. EXCRETION

These four processes occur contemporaneously until (1) all of the drug is absorbed from the GI tract, the muscle or subcutaneous tissue site into which it was injected, and there is no more absorption 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 the blood level-time profile of a single oral and intravenous (IV) dose of a drug. Figure 3, shows the accumulation pattern of a drug given orally once per half-life for six half-lives, at which time steady-state or equilibrium (the amount of drug entering the body equals the amount being excreted) is achieved.

Absorption

Absorption is the process by which a drug is made available to the fluids of distribution of the body (e.g., blood, plasma, serum, aqueous humor, lymph, etc.).

In the fasting state, most orally-administered drugs reach a maximum or "peak" blood concentration within 1-2 hours. Intravenous (IV) administration is the most rapid route of administration, with intra-nasal, smoking (inhalation), sublingual (under the tongue), intra-muscular (IM), subcutaneous (e.g., under the skin, SC or SQ), and percutaneous (through the skin) being the next most rapid.

The RATE of absorption of orally-administered drugs and the subsequent appearance of the drug 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 don't pass

through lipid (fat) soluble biologic membranes well), 4. Aqueous (water) solubility vs. lipid (fat) solubility. Water-soluble drugs are soluble but don't 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.

Distribution

Once a drug has been absorbed from the stomach and/or intestines (GI Tract) into the blood, it is circulated to some degree to all areas of the body to which there is blood flow. This is the process of distribution. Organs with high blood flow e.g., brain, heart, liver, etc. are the first to accumulate 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 bound are free to exert a pharmacologic effect, the ratio of "free" to "bound" drug is important in determining the onset and duration of action of drugs. Highly bound drugs are distributed less extensively throughout the body and are slower to act. By virtue of their high binding to plasma proteins, they also stay in the body for longer periods of time because the binding sites act as a sort of "reservoir" for the drug, releasing drug molecules slowly.

 

Metabolism

Drugs in the blood and tissues must be inactivated and excreted from the body. This process is initiated 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 easily excreted 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 alcohol dehydrogenase, to acetaldehyde which causes dilatation of the blood vessels and, after accumulation, is responsible for the subsequent hangover which ensues. The acetaldehyde is subsequently metabolized by the enzyme aldehyde dehydrogenase to acetate, a substance very similar 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 then excreted 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 or injected, a urine drug screen will most often detect the cocaine metabolite benzoylecgonine in the urine, not cocaine itself. The same analogy applies to other drugs of abuse like: heroin, morphine, amphetamines, PCP (Angel Dust), barbiturates, marijuana, etc.

Excretion

Excretion 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 many biological fluids like: bile, sweat, hair, breast milk, or tears. However, the most common fluid in which 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 that all the drug in the subject's GI tract has been absorbed. If not, calculation of a rate of excretion would be confounded be the ongoing absorption of more drug. Once all the drug has been absorbed, this is called the post-absorbtive, or distributive stage. At this time, serial (multiple) 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 drug's half-life, or rate of excretion. The half-life represents the amount of time required to eliminate half of the drug from the body.

Figure 4 shows a typical plot of the log of the drug's blood concentration on the verticle axis vs. time on the horizontal axis. The log of the blood concentration is used to convert the curved portions 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 completely eliminate the drug from the body. Using these mathematical relatonships allows pharmacologists to determine how often a therapeutic drug should be administered to a patient or toxicologists to determine a time interval within which one would test positive for drugs of abuse. Table I shows the approximate time intervals individuals will test positive in blood and urine for common drugs of abuse.

Correlating Drug or Ethanol Blood Levels and Positive Urine Tests With Effects of Impairment

A 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 individual's mental or physical capacity. In order for an individual to be presumed under the influence of an intoxicating or mind-altering drug, it is necessary to establish that there was a significant or pharmacologic concentration of the drug present in the individual's bloodstream, and that the individual was not sufficiently tolerant to the effects of the drug such as to mitigate any intoxicating effect(s). For example, an individual who had been taking a drug known to cause sedating or intoxicating effects to which the subject could become tolerant, could not be presumed to be too impaired to drive while taking the medication if the subject had been taking the drug long enough to permit the development of tolerance to the sedating or intoxicating properties of that drug.

Some examples would include benzodiazepines like Valium or Xanax, tricyclic antidepressant drugs like Elavil or Tofranil, anti-epileptic drugs like barbiturates and Dilantin which induce their own metabolism and are excreted more rapidly after they have been taken for several weeks, or narcotics like codeine, which are well-known to produce tolerance. In situations like these, it is important to obtain the testimony of other individuals such as co-worders or family members who can corroborate the lack of observable impairment in the subject following drug ingestion.

If an individual is accustomed to having 2-3 (or more) alcoholic drinks per day, with dinner or while watching TV after work, it is quite likely that they will have developed some tolerance to the intoxicating properties of alcohol and might not show signs of intoxication even at BACs over 0.10%. On the other hand, an individual who drinks infrequently would have developed no tolerance and might show signs of intoxication at BACs below the statutory level.

CONTACT INFORMATION

David M. Benjamin, Ph.D.

77 Florence StreetSuite 107Chestnut Hill, MA 02467

Telephone:   617-969-1393 Fax: 617-969-4285

send e-mail to Dr. Benjamin

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