Pharmacology Glossary

A
Anaphylaxis: serious and rapid allergic reaction usually involving more than one part of the body which, if severe enough, can be fatal. Usually associated with bee or wasp stings but is more common with food or drug allergies. Treatment: Epinephrine (im) is the drug of choice.
Autonomic nervous system: innervation of smooth muscle, glands and visceral organs, which are not normally under voluntary control. Subdivided principally into the sympathetic and parasympathetic efferent systems. Autonomic reflexes are reflexes that act through these efferent systems; their afferent pathways may be either the same as pathways that subserve conscious perceptions (as with salivation) or they may be different (as with baroreceptor reflexes). The afferent pathways are not distinctive in any anatomical way, and are not usually described as 'autonomic' except by association with particular reflex actions
Antagonism: The effect of two or more drugs such that the combined effect is less than the sum of the effects produced by each agent separately. The agonist is the agent producing the effect which is diminished by the administration of the antagonist. Antagonisms may be any of three general types:
1. Chemical: caused by combination of agonist with antagonist, with resulting inactivation of the agonist
2. Physiological: caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects
3. Pharmacological: caused by action of the agonist and antagonist at the same site ie. epinephrine and propranolol at beta-receptors
Aging: inhibition of acetycholinesterase (AchE) with organophosphates results in a increase in Ach levels. If allowed to associate with AchE for certain period of time a phenomenon called 'aging' occurs, involving the loss of a group attached to phosphorus and leading to the formation of a negatively charged irreversibly phosphorylated AchE enzyme. The aging process can be very short (ie. nerve gases, secs) or longer (ie. pesticides, hrs). Pralidoxime (2-PAM) can regenerate AchE from the organophosphate but only before the 'aging' process.
Area under the curve (AUC): The area under the plot of plasma concentration of drug (not logarithm of the concentration) against time after drug administration. The area is conveniently determined by the "trapezoidal rule": the data points are connected by straight line segments, perpendiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed. The AUC is of particular use in estimating bioavailability of drugs, and in estimating total clearance of drugs.
Affinity (drug): the equilibrium constant of the reversible reaction of a drug with a receptor to form a drug-receptor complex; the reciprocal of the dissociation constant of a drug-receptor complex. Under the most general conditions, where there is a 1:1 binding interaction, at equilibrium the number of receptors engaged by a drug at a given drug concentration is directly proportional to their affinity for each other and inversely related to the tendency of the drug-receptor complex to dissociate. Obviously, affinity depends on the chemical natures of both the drug and the receptor. "Affinity" is not the same as "duration of action".
Activity, intrinsic: the property of a drug which determines the amount of biological effect produced per unit of drug-receptor complex formed. Two agents combining with equivalent sets of receptors may not produce equal degrees of effect even if both agents are given in maximally effective doses; the agents differ in their intrinsic activities and the one producing the greater maximum effect has the greater intrinsic activity. Intrinsic activity is not the same as "potency" and may be completely independent of it. Meperidine and morphine presumably combine with the same receptors to produce analgesia, but regardless of dose, the maximum degree of analgesia produced by morphine is greater than that produced by meperidine; morphine has the greater intrinsic activity. Intrinsic activity - like affinity - depends on the chemical natures of both the drug and the receptor, but intrinsic activity and affinity apparently can vary independently with changes in the drug molecule
B
Benign prostrate hypertrophy (hyperplasia) is an enlargement of the prostrate gland. This can often compress the urethra and partially block urine flow. Prostate enlargement adversely affects about half the men in their 60s and close to 80 percent of men in their 80s. The presence or absence of prostate gland enlargement is not related to the development of prostate cancer. Treatment: Alpha1 blockers such as prazosin or terazosin (Hytrin).
Belladonna alkaloids: group of alkaloids, including atropine and scopolamine, found in plants such as belladonna and jimsonweed. They are used in medicine to dilate the pupils of the eyes, dry respiratory passages, prevent motion sickness, and relieve cramping of the intestines and bladder.
Bioavailability: the percent of dose entering the systemic circulation after administration of a given dosage form. More explicitly, the ratio of the amount of drug "absorbed" from a test formulation to the amount "absorbed" after administration of a standard formulation. Frequently, the "standard formulation" used in assessing bioavailability is the aqueous solution of the drug, given intravenously.



Baroreceptor reflex:: baroreceptors found in the aorta arch and carotid sinuses, sense changes in blood pressure. As blood pressure goes up, the baroreceptors are stimulated and they deliver a higher rate of impulses to the vasomotor center of the brain. This causes a reduction in sympathetic tone and a stimulation of vagal tone. As a result, there is a reduction in heart rate, cardiac contractility, and vasodilation of blood vessels throughout the body which all contribute to lower blood pressure. If blood pressure goes down, baroreceptors reduce their rate of firing, causing the opposite effect. The baroreceptor reflex is more sensitive to rapidly changing pressure (standing up, or sitting down) than to a constantly elevated or depressed pressure. Baroreceptors will adapt to long term increased or decreased blood pressure.
Bioassay (biological assay): the determination of the potency of a physical, chemical or biological agent, by means of a biological indicator .The biological indicators in bioassay are the reactions of living organisms or tissues.
C
Cycloplegia: paralysis or loss of function of the ciliary muscle; this results in loss of accommodation (ability to focus).
Ceiling (drug): The maximum biological effect that can be induced in a tissue by a given drug, regardless of how large a dose is administered. The maximum effect produced by a given drug may be less than the maximum response of which the reacting tissue is capable, and less than the maximum response which can be induced by another drug of greater intrinsic activity. "Ceiling" is analogous to the maximum reaction velocity of an enzymatic reaction when the enzyme is saturated with substrate.
Clearance of a chemical is the volume of body fluid from which the chemical is, apparently, completely removed by biotransformation and/or excretion, per unit time. In fact, the chemical is only partially removed from each unit volume of the total volume in which it is dissolved. Since the concentration of the chemical in its volume of distribution is most commonly sampled by analysis of blood or plasma, clearances are most commonly described as the "plasma clearance" or "blood clearance" of a substance.
Coombs Test is used to detect auto antibodies against your own red blood cells (RBCs). Many diseases and drugs (e.g., quinidine,  methyldopa, and procainamide) can lead to production of these antibodies. The test is only rarely used to diagnose a medical condition but is essential for use by laboratories such as blood banks. Blood banks use the Coombs' test is to determine whether there is likely to be an adverse reaction to blood that is going to be used for a blood transfusion.
Cross-over experiment: A form of experiment in which each subject receives the test preparation at least once, and every test preparation is administered to every subject. At successive experimental sessions each preparation is "crossed-over" from one subject to another. The purpose of the cross-over experiment is to permit the effects of every preparation to be studied in every subject, and to permit the data for each preparation to be similarly and equally affected by the peculiarities of each subject.
D
Drug selectivity: the propensity of a drug to affect one receptor population in preference to others. ie. propranolol is a non-selective beta-blocker (blocks all beta-receptors equally), whereas metoprolol is a beta1-selective blocker in that it has a greater preference (affinity) for beta1- over beta2-receptors. Selectivity is generally a desirable property in a drug as it can minimize potential side-effects ie. potential of propranolol causing bronchospasm. Selectivity is not to be confused with "potency"; a potent drug may be non-selective or a selective drug may not be very potent.
Drug abuse: misuse of a drug under conditions considered "more destructive than constructive for society and the individual. The abuse potential of a drug depends on its capacity to induce compulsive drug-seeking behavior in the user, its capacity to induce acute and chronic toxic effects (and to permit occurrence of associated diseases), and upon social attitudes toward the drug, its use, and its effects.
Drug dependence: a somatic state which develops after chronic administration of certain drugs; this state is characterized by the necessity to continue administration of the drug in order to avoid the appearance of uncomfortable or dangerous (withdrawal) symptoms. Withdrawal symptoms, when they occur, may be relieved by the administration of the drug upon which the body was "dependent". Recommended as a term to be substituted for such words as "addiction" and "habituation " since it is frequently difficult to classify specific agents as being only addictive, habituating, or non-addicting or non-habituating. e.g., drug dependence of the barbiturate type.
Drug: a chemical used in the diagnosis, treatment, or prevention of disease. More generally, a chemical, which, in a solution of sufficient concentration, will modify the behavior of cells exposed to the solution.
Dose-effect curve: characteristic, even the sine qua non, of a true drug effect is that a larger dose produces a greater effect than does a smaller dose, up to the limit to which the cells affected can respond. While characteristic of a drug effect, this relationship is not unique to active drugs, since increasing doses of placebos (q.v.) can, under certain conditions, result in increasing effects. Distinguishing between "true" and "inactive" drugs requires more than demonstration of a relationship between "dose" and effect. The curve relating effect (as the dependent variable) to dose (as the independent variable) for a drug-cell system is the "dose-effect curve" for the system. For a unique system, i.e., one involving a single drug and a single effect, such curves have three characteristics, regardless of whether effects are measured as continuous (measurement) or discontinuous (quantal, all-or-none) variates:

1. The curves are continuous, i.e. there are no gaps in the curve and effect is a continuous function of dose. Some effect corresponds to every dose above the threshold dose, and every dose has a corresponding effect; there is no inherent invalidity in interpolating doses or effects from a dose-effect curve.

2. The curves are "monotonic". The curve may have a positive slope, or a negative slope, but not both if the system under study is unique. The slope of the curve may show varying degrees of positivity (negativity), but the sign of the slope stays the same throughout the range of testable doses. When monotonicity of a dose-effect curve does not obtain, one may infer that the system under study is not unique or singular: either more than one active agent or more than one effect is under study.
3. The curves approach some maximum value as an asymptote, and the asymptote is a measure of the intrinsic activity of the drug in the system.

Dissolution time: the time required for a given amount (or fraction) of drug to be released into solution from a solid dosage form. Dissolution time is measured in vitro, under conditions which simulate those which occur in vivo, in experiments in which the amount of drug in solution is determined as a function of time. Needless to say, the availability of a drug in solution - rather than as part of insoluble particulate matter - is a necessary preliminary to the drug's absorption.
E
Epinephrine reversal describes the response seen to epinephrine (EPI) in the presence of an alpha-blocker. The normal response to EPI alone is an increase in BP and HR. However in the presence of an alpha-blocker, EPI can now only activate the beta-receptors to cause a fall in BP with an increase in HR.
ED50: see Mean effective dose
Exocytosis: vesicular release of transmitter ie. NE storage vesicle migrates to and fuses with the plasma membrane to release NE (and other compounds within the vesicle ie. DBH) into the synaptic cleft. Non-exocytotic release includes the displacement of NE by amphetamine or tyramine, which can then leak across the plasma membrane in the synaptic cleft.
F
First-pass effect: all drugs that are absorbed from the intestine enter the hepatic portal vein and pass through the liver before they are distributed systemically. Some drugs (ie. propranolol) have a high degree of removal from the circulation on their first passage through the liver.
First-order kinetics: according to the law of mass action, the velocity of a chemical reaction is proportional to the product of the active masses (concentrations) of the reactants. In a monomolecular reaction, i.e., one in which only a single molecular species reacts, the velocity of the reaction is proportional to the concentration of the unreacted substance (C). see also Zero-order kinetics.


G
Glaucoma is a group of eye diseases that are associated with a rise in intraocular pressure (IOP) that can cause blindness if untreated. Vision loss is caused by damage to the optic nerve. The two main types of glaucoma are open angle glaucoma (chronic, primary open angle glaucoma (POAG), and angle closure glaucoma (narrow angle).
Generic drugs: formulations of identical composition with respect to the active ingredient, i.e., drugs that meet current official standards of identity, purity, and quality of active ingredient. Drug dosage forms considered as "generically equivalent" are more properly considered as "chemically equivalent" in that they contain a designated quantity of drug chemical in specified stable condition and meet pharmacopoeial requirements for chemical and physical properties
H
Horner's syndrome is characterized by an interruption of the sympathetic nerve pathway somewhere between its origin in the hypothalamus and the eye. The damage can either to the pre- post-ganglionic sympathetic fibers. The classic clinical findings associated with Horner's syndrome are ptosis (eyelid sagging), pupillary miosis and facial anhidrosis. Treatment: depends upon the identifying and treating the cause, in many cases there is no treatment that improves or reverses the condition.
Half-life (drug): period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. The given concentration or amount need not be the maximum observed during the course of the experiment, or the concentration or amount present at the beginning of an experiment, since the half-life is completely independent of the concentration or amount chosen as the "starting point".
I
Intrinsic sympathomimetic activity: Beta-blocker that has partial agonist action. Has potential to prevent bradycardia or negative inotropy in resting heart (if b₁ partial agonist) and to prevent bronchoconstraction (if b₂ partial agonist). Pindolol is prototype agent.
Indirect amine (agent): compounds that can cause displacement of NA from storage vesicles (ie. amphetamine, tyramine). Note agents that inhibit neuronal uptake (uptake 1) can diminish the actions of indirect amines by preventing their uptake into the nerve terminal.
Indirect parasympathomimetic: agent that causes inhibition of acetyl cholinesterase (AchE) to elevate Ach levels (ie. organophosphates).


Idiosyncratic Response:  qualitatively abnormal or unusual response to a drug which is unique, or virtually so, to the individual who manifests the response. "Idiosyncratic Response" usually applies to a response which is not allergic in nature and cannot be produced with regularity in a substantial number of subjects in the population , and which is ordinarily not produced in a greater intensity in an individual, or in a greater fraction of the population, by the expedient of increase in the dose. In other words, were frequency or intensity of idiosyncratic response used as a measure of effect in constructing a dose-effect curve, a curve might indeed be constructed, but its slope would be found to be 0 (zero), indicating that effect was not significantly a function of dose.
L
Latency period: the period of time which must elapse between the time at which a dose of drug is applied to a biologic system and the time at which a specified pharmacologic effect is produced. In general, the latent period varies inversely with dose; the relationship between dose and latent period for a given agent is described by a time-dose or time-concentration curve.
Loading (priming) dose: a larger than normal dose (D*) administered as the first in a series of doses, the others of which are smaller than D* but equal to each other. The loading dose is administered in order to achieve a therapeutic amount in the body more rapidly than would occur only by accumulation of the repeated smaller doses. The smaller doses (D) which are given after D* are called "maintenance doses".
M
Membrane-stabilizing activity (Local anesthetic action): Beta-blocker that has the ability to decrease electrical conductance, particularly in heart (Quinidine-like effects).
Malignant hyperthermia (MH) is a pharmacogenetic disease of skeletal muscle.  When exposed to inhalation anesthetics (those which are gases ), muscle metabolism increases with a rapid rise in body temperature which if left untreated can lead to death. Triggering agents include succinylcholine (NMJ depolarizing blocker) and volatile anesthetic. Treatment: Drug of choice is Dantrolene (inhibits Ca++ release).
Mean effective dose (ED50): The dose of a drug predicted (by statistical techniques) to produce a characteristic effect in 50 percent of the subjects to whom the dose is given. The median effective dose (usually abbreviated ED50) is found by interpolation from a dose-effect curve. The ED50 is the most frequently used standardized dose by means of which the potencies of drugs are compared. Although one can determine the dose of drug predicted to be effective in one percent (ED1) or 99 percent (ED99) of a population, the ED50 can be determined more precisely than other similar values. An ED50 can be determined only from data involving all or none (quantal) response; for quantal response data, values for ED0 and ED100 cannot be determined. In analogy to the median effective dose, the pharmacologist speaks of a median lethal dose (LD50), a median anesthetic dose(AD50), a median convulsive dose (CD50), etc.
N
Neuromuscular Junction (NMJ): The junction between the terminal of a motor neuron and a skeletal muscle fiber is called the neuromuscular junction. It is simply one kind of synapse. Nerve impulses travel down the motor neurons and cause the skeletal muscle fibers at which they terminate to contract. This is part of the Somatic (Voluntary) Nervous System.
O
Orthostatic (postural) hypotension: The gravitational stress of sudden standing normally causes pooling of blood in the venous capacitance vessels of the legs and trunk. The subsequent transient decrease in venous return and cardiac output results in reduced BP and can cause the individual to faint. Baroreceptors in the aortic arch and carotid bodies sense the change in BP and activate autonomic reflexes that rapidly normalize BP by causing a transient tachycardia and vasoconstriction in the lower limbs. Agents that interfere with this reflex response can cause orthostatic (postural) hypotension ie. alpha-blockers, ganglionic blockers and guanethidine.
P
Pharmacokinetics the science and study of the factors which determine the amount of chemical agents at their sites of biological effect at various times after the application of an agent or drug to biological systems. Pharmacokinetics includes study of drug absorption and distribution ("biotranslocation"), study of the chemical alterations a drug may undergo in the body, ("biotransformation"), and study of the means by which drugs are stored in the body and eliminated from it. Simply put, pharmacokinetics considers how drugs move around the body and how quickly this movement occurs. This includes the processes which control the absorption, distribution, metabolism, and excretion of drugs (A.D.M.E.).

Pharmacodynamics the study of the relationship of drug concentration to drug effects

Pharmacogenetics the study of how people respond differently to medicines due to their genetic inheritance. The term has been pieced together from the words pharmacology (the study of how drugs work in the body) and genetics (the study of how traits are inherited). An ultimate goal of pharmacogenetics is to understand how someone's genetic make-up determines how well a medicine works in his or her body, as well as what side effects or toxicity are likely to occur.

Pheochromocytoma is a rare tumor that arises from tissue in the adrenal gland. The tumor increases production and release of epinephrine (adrenaline) and nor epinephrine (noradrenaline), which raises blood pressure and heart rate. Most pheochromocytomas are removed surgically, individuals are initially stabilized with alpha-blockers (ie. phenoxybenzamine) or alpha/beta-blockers (labetalol or carvedilol). Beta-blockers alone should never be given alone prior to administration of an alpha-blocker.
Prototype drug is the 'lead agent' in a drug class (family). ie propranolol is the prototype of the beta-blockers and metoprolol is the prototype of the beta1-blockers. These are common agents used in exam questions.
Prodrug: has no pharmacologic activity until converted into an active compound. ie. alpha-methyl dopa is converted to the biologically active agent, alpha-methyl-nor epinephrine (alpha2-agonist). The change may be a result of biotransformation, or may occur spontaneously, in the presence of, e.g., water, an appropriate pH, etc.
Placebo (effect): Latin: I will satisfy. A medicine or preparation with no inherent pertinent pharmacologic activity which is effective only by virtue of the factor of suggestion attendant upon its administration.
Potency: a measure of drug activity established by determining the dose of a drug required to produce a standard effect. Potency varies inversely with the magnitude of the dose required to produce a given effect. Thus, if twice the dose of drug "X" is required to produce analgesia equivalent to that produced by a dose of aspirin, it may be said that drug"X" is half as potent as aspirin.
Potentiation: a special case of synergy in which the simultaneous effects of two or more drugs is greater than the sum of the independent effects of these drugs. For example. although physostigmine has no acetylcholine-like activity of its own, it potentiates the actions of acetylcholine by inhibiting the enzymes responsible for the destruction of acetylcholine. Intensity of effect may be potentiated, duration of effect may be prolonged: potentiation and prolongation are independent phenomena, but frequently occur together.
Pharmacology: is the study of drugs in all their aspects. Pharmacy, although often confused with pharmacology, is, in fact, an independent discipline concerned with the art and science of the preparation, compounding, and dispensing of drugs. Pharmcodynamic, which in common usage is usually termed "pharmacology", is concerned with the study of drug effects and how they are produced. The  pharmacologist, identifies the effects produced by drugs, and determines the sites and mechanisms of their action in the body. The pharmacologist also studies the physiological or biochemical mechanisms by which drug actions are produced and investigates those factors which modify the effects of drugs, i.e. the routes of administration, influence of rates of absorption, differential distribution, and the body's mechanisms of excretion and detoxification, on the total effect of a drug. Pharmacotherapeutics is the study of the use of drugs in the diagnosis, prevention, and treatment of disease states.
Q
Quantitative Graded) dose-effect relationships: graph of the relationship between dose and response (effect) wherein all possible degrees of response between minimum detectable response and a maximum response are producible by varying the dose or drug concentration, i.e., the curve is continuous.
Quantal (All-or-none; binary) dose-effect relationships: relationship between dose and effect that describes the distribution of MINIMUM doses of drug required to produce a defined degree of a specific response in a population of subjects. Only two responses are allowed: Yes or No; 0 or 1. The purpose of the plot is to allow predictions about what proportion of a population of subjects will respond to given doses of the drug or toxin.
R
Raynaud's syndrome: condition in which small arteries, most commonly in the fingers and toes, spasm and cause the skin to turn pale or a patchy red to blue on exposure to cold or even the thought of cold. Although Raynaud's is usually a mild condition, it can have serious direct consequences, such as gangrene serious enough to warrant amputation.Treatment: Treatment: simple exercise may suffice (ie. swinging your arms around like a windmill), however if attacks are frequent or severe, dilating agents, such as nifedipine, calcium channel blocker may be prescribed.
Rate-limiting step: this is slowest point in a series of reactions (ie. uptake of choline into the nerve terminal in the synthesis of Ach) or where the enzyme involved is subject to regulatory control (ie. Tyrosine hydroxlase involved in NA systhesis)
Rebound effects: discontinuation of an agent my cause exacerbation of previous symptoms to a level which is greater than before, and than that which would have been expected. ie. sudden discontinuation of clonidine leads to rebound hypertension, tachycardia and angina (see also Super sensitivity)
S
Septic shock: serious condition that occurs when an overwhelming infection leads to low BP and low blood flow. Vital organs, such as the brain, heart, kidneys, and liver may not function properly or may fail. Treatment: Dopamine (iv) is the drug of choice.
Super sensitivity: when a some receptors are deprived of the actions of their agonists, they can become hypersensitive (increased affinity) to the agonist. ie. blockade of beta-receptors leads to super sensitivity such that if the beta-blocker was suddenly discontinued, an enhanced response to the agonist would be seen. Thus discontinuation from beta-blockers should be gradual. (see also Rebound effects).
Side effects: effects which are not desirable or are not part of a therapeutic effect; effects other than those intended. ie treatment of peptic ulcer with atropine, dryness of the mouth is a side effect and decreased gastric secretion is the desired drug effect. If the same drug were being used to inhibit salivation, dryness of the mouth would be the therapeutic effect and decreased gastric secretion would be a side effect.



Somatic nervous system: controls all voluntary systems within the body with the exception of reflex arcs. This system is comprised of the afferent nerve network, which include all sensory nerves leading to the brain, and the efferent nerve network, which includes all motor nerves leading from the brain to the muscles (NMJ). The somatic system is generally associated with all body movement and is not part of the Autonomic NS (involuntary).
Synergy: the summing of the simultaneous effects of two or more drugs such that the combined effect is greater than the effect of either of the drugs when they are given alone.
T
Tyramine - MAOIs interaction: certain foods (ie. aged cheese, red wine, figs, fermented and otherwise processed meats, fish and soy products) contain large amounts of the amino acid tyramine which can interact with MAOIs to dramatically raise HP and HR. The tyramine induces the release of large amounts of the stored neurotransmitter, NA from the nerve terminals. The reaction, which often does not appear for several hours after taking the medication, may also include headache, nausea, vomiting, possible confusion, psychotic symptoms, seizures, stroke and coma.
Tone (Autonomic): under resting conditions most organs of the body receive a low but steady release of NA or Ach (tonic release) to modulate tissue activity. In the heart the basal release of NA contributes about +5 bpm and the release of Ach about -10 bpm to the resting heart rate. This is why beta-blockers such as propranolol can cause a fall in HR as they prevent the action of the tonic release of NA. Likewise the muscarinic antagonists, such as atropine can cause an increase in HR as it prevents the action of Ach. Usually one division of the autonomic NS dominates under resting conditions, GI-tract, eye, heart (parasympathetic) and vasculature (sympathetic).
Tolerance - Tachyphylaxis: Continual use of an agent can result in diminished response. In some cases this can appear in mins-hrs or dose to dose and is termed tachyphylaxis (ie. amphetamines). In other cases it appears more gradual over days-months and is termed tolerance. (ie. opioids).
Therapeutics: the science and techniques of restoring patients to health. A single drug may have two or more therapeutic effects in the same patient at the same or different times, or in different patients. Drugs may be used prophylactic ally to prevent disease or to diminish the severity of a disease should it occur subsequent to or during treatment; such a use of drugs is commonly called "prophylactic therapy". Drugs are sometimes used to measure bodily function and contribute toward the diagnosis of disease.
Therapeutic index: a number, LD50/ED50, which is a measure of the approximate "safety factor" for a drug; a drug with a high index (ie. aspirin) can presumably be administered with greater safety than one with a low index (ie. digoxin).
Toxic effects: responses to a drug which are harmful to the health or life of the individual. Almost by definition, toxic effects are "side effects" when diagnosis, prevention, or treatment of disease is the goal of drug administration. Toxic effects are not side-effects in the case of pesticides and chemical warfare agents. Toxic effects may be idiosyncratic or allergic in nature, may be pharmacologic side effects, or may be an extension of therapeutic effect produced by over dosage.
Toxicology: the scientific discipline concerned with understanding the mechanisms by which chemicals produce noxious effects on living tissues or organisms; the study of the conditions (including dose) under which exposure of living systems to chemicals is hazardous.
V
Volume of distribution of a drug; the size of the "compartment" into which a drug apparently has been distributed following absorption.
Z
Zero-order kinetics: mechanism of chemical reaction in which the reaction velocity is apparently independent of the concentration of all the reactants. Typically, in biological systems, one reactant (X) is present in a concentration greatly exceeding that of the other (Y), but is capable of undergoing change, while the concentration of Y, in contrast, does not undergo substantial change during the course of the reaction (see First-order kinetics also).

Trease & Evans Pharmacognosy

 

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Bioinformatics: Its role in Drug Discovery and Development

INTRODUCTION:

Bioinformatics is the discipline of quantitative analysis of information relating to biological macromolecules with the aid of computers. The development of bioinformatics as a field is the result of advances in both molecular biology and computer science over the past 30–40 years.

The earliest bioinformatics efforts can be traced back to the 1960s, although the word bioinformatics did not exist then. Probably, the first major bioinformatics project was undertaken by Margaret Dayhoff in 1965, who developed a first protein sequence database called Atlas of Protein Sequence and Structure. Subsequently, in the early 1970s, the Brookhaven National Laboratory established the Protein Data Bank for archiving three-dimensional protein structures. At its onset, the database stored less than a dozen protein structures, compared to more than 30,000 structures today. The first sequence alignment algorithm was developed by Needleman and Wunsch in 1970. This was a fundamental step in the development of the field of bioinformatics, which paved the way for the routine sequence comparisons and database searching practiced by modern biologists.

  The fundamental reason that bioinformatics gained prominence as a discipline was the advancement of genome studies that produced unprecedented amounts of biological data. The explosion of genomic sequence information generated a sudden demand for efficient computational tools to manage and analyze the data. The development of these computational tools depended on knowledge generated from a wide range of disciplines including mathematics, statistics, computer science, information technology, and molecular biology. The merger of these disciplines created information oriented field in biology, which is now known as bioinformatics.

  As per the National Center for Biotechnology Information (NCBI), bioinformatics is the field of science in which biology, computer science, and information technology merge to form a single discipline.

  The science of Bioinformatics, which is the merging of molecular biology with computer science, is essential to the use of genomic information in understanding human diseases and in the identification of new molecular targets for drug discovery. In the area of drug discovery, bioinformatics is being increasingly used to support target validation by providing functionally predictive information mined from databases and experimental datasets using a variety of tools. The predictive power of these tools becomes strongest when information from several techniques is combined, including experimental confirmation of predictions.

IMPORTANT TOOLS OF BIOINFORMATICS USED IN DDD:

A number of tools of bioinformatics aid in the process of drug discovery. The important tools in relevance to the drug discovery process may be classified into the following classes:

A.    Methods for Sequence Alignment

B.     Methods for Structure Prediction

C.     Phylogenetic Analysis

Sequence Alignment Methods:

There are three different types of sequence alignment:

·         Global alignment

·         Local alignment

·         Multiple sequence alignment

GLOBAL ALIGNMENT:

This method gives the best alignment over the entire length of two sequences. The Needleman-Wunsch algorithm is the most simple and efficient way to carry out the global alignment.

This algorithm involves three steps:

1.      Initialization

2.      Matrix Fill

3.      Trace Back

This algorithm is mainly dependant on the DYNAMIC PROGRAMMING method. This algorithm is a very easy method to find out the similarity between the two sequences.

LOCAL ALIGNMENT:

The Needleman-Wunsch algorithm creates a global alignment. That is, it tries to take all of one sequence and align it with all of a second sequence. Short and highly similar subsequences may be missed in the alignment because they are outweighed by the rest of the sequence. Hence, one would like to create a locally optimal alignment. The Smith and Waterman algorithm finds an alignment that determines the longest/best subsequence pair that give the maximum degree of similarity between the two original sequences. This means that not all of the sequences might be aligned together.

Only minimal changes to the Needleman-Wunsch algorithm are required. These are

• A negative score/weight must be given to mismatches.
• Zero must be the minimum score recorded in the matrix.
• The beginning and end of an optimal path may be found anywhere in the matrix - not just the last row or column.

We also have a very powerful tool for the local alignment of sequences, the Basic Local Alignment Search Tool (BLAST) which is owned by the NCBI.

There are various types of BLAST programs:

S.No.	Type	Remarks
01.	blastn	Search a nucleotide database using a nucleotide query
02.	blastp	Search protein database using a protein query
03.	blastx	Search protein database using a translated nucleotide query
04.	tblastn	Search translated nucleotide database using a protein query
05.	tblastx	Search translated nucleotide database using a translated nucleotide query

MUTLIPLE SEQUENCE ALIGNMENT:

This involves the simultaneous alignment of more than two sequences. For this purpose a very important tool is the CLUTALW2 which is owned by the EBI.

This can accessed freely at www.ebi.ac.uk/clustalw

Protein Structure Prediction Methods:

Determining Protein Structure

Traditionally, a protein's structure was determined using one of two techniques: X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy.

The Advent of Computational Modeling

Researchers have been working for decades to develop procedures for predicting protein structure that are not so time consuming and that are not hindered by size and solubility constraints. To do this, researchers have turned to computers for help in predicting protein structure from gene sequences, a concept called homology modeling. The complete genomes of various organisms, including humans, have now been decoded and allow researchers to approach this goal in a logical and organized fashion.

Before going into more details of the process, it is very essential to understand the key terms used here:

• Folding motifs are independent folding units, or particular structures, that recur in many molecules.
• Domains are the building blocks of a protein and are considered elementary units of molecular function.
• Families are groups of proteins that demonstrate sequence homology or have similar sequences.
• Superfamilies consist of proteins that have similar folding motifs but do not exhibit sequence similarity.

It is theorized that proteins that share a similar sequence generally share the same basic structure. Therefore, by experimentally determining the structure for one member of a protein family, called a target, researchers have a model on which to base the structure of other proteins within that family. Moving a step further, by selecting a target from each superfamily, researchers can study the universe of protein folds in a systematic fashion and outline a set of sequences associated with each folding motif. Many of these sequences may not demonstrate a resemblance to one another, but their identification and assignment to a particular fold is essential for predicting future protein structures using homology modeling.

The scientific basis for these theories is that a strong conservation of protein three-dimensional shape across large evolutionary distances—both within single species, between species, and in spite of sequence variation—has been demonstrated again and again. Although most scientists choose high-priority structures as their targets, this theory provides the option to choose any one of the proteins within a family as the target, rather than trying to achieve experimental results using a protein that is particularly difficult to work with using crystallographic or NMR techniques.

Specific tasks must be carried out to maximize results when determining protein structure using homology modeling.

First, protein sequences must be organized in terms of families, preferably in a searchable database, and a target must be selected. Protein families can be identified and organized by comparing protein sequences derived from completely sequenced genomes. Targets may be selected for families that do not exhibit apparent sequence homology to proteins with a known three-dimensional structure.

Next, researchers must generate a purified protein for analysis of the chosen target and then experimentally determine the target's structure, either by X-ray crystallography and/or NMR. Target structures determined experimentally may then be further analyzed to evaluate their similarity to other known protein structures and to determine possible evolutionary relationships that are not identifiable from protein sequence alone. The target structure will also serve as a detailed model for determining the structure of other proteins within that family. In favorable cases, just knowing the structure of a particular protein may also provide considerable insight into its possible function.

PDB: The Protein Data Bank

The PDB was the first "bioinformatics" database ever built and is designed to store complex three-dimensional data. The PDB was originally developed and housed at the Brookhaven National Laboratories but is now managed and maintained by the Research Collaboratory for Structural Bioinformatics (RCSB). The PDB is a collection of all publicly available three-dimensional structures of proteins, nucleic acids, carbohydrates, and a variety of other complexes experimentally determined by X-ray crystallography and NMR.

Protein Modeling at NCBI

The Molecular Modeling Database

NCBI's Molecular Modeling Database (MMDB), an integral part of the Entrez information retrieval system, is a compilation of all of the PDB three-dimensional structures of biomolecules. The difference between the two databases is that the MMDB records reorganize and validate the information stored in the database in a way that enables cross-referencing between the chemistry and the three-dimensional structure of macromolecules. By integrating chemical, sequence, and structure information, MMDB is designed to serve as a resource for structure-based homology modeling and protein structure prediction.

NCBI has also developed a three-dimensional structure viewer, called Cn3D, for easy interactive visualization of molecular structures from Entrez. Cn3D serves as a visualization tool for sequences and sequence alignments. What sets Cn3D apart from other software is its ability to correlate structure and sequence information. For example, using Cn3D, a scientist can quickly locate the residues in a crystal structure that correspond to known disease mutations or conserved active site residues from a family of sequence homologues, or sequences that share a common ancestor. Cn3D displays structure-structure alignments along with the corresponding structure-based sequence alignments to emphasize those regions within a group of related proteins that are most conserved in structure and sequence. Cn3D also features custom labeling options, high-quality graphics, and a variety of file exports that together make Cn3D a powerful tool for literature annotation.

Phylogenetic Analysis:

The phylogenetic analysis can be efficiently done with the tool ClustalW2 which is owned and operated bye EMBL-EBI.

CLUSTALW

Multiple alignments of protein sequences are important tools in studying sequences. The basic information they provide is the identification of conserved sequence regions. This is very useful in designing experiments to test and modify the function of specific proteins, in predicting the function and structure of proteins and in identifying new members of protein families.

The program ClustalW2 can be used for two purposes:

1. It can be used to produce a multiple sequence alignment. Using the web form the user need only input or upload a file of the sequences that they want to align in an accepted format. The other options on the form are set to the default values for producing a multiple alignment. The user can use the defaults or they can make some changes on the form to customise their run. A multiple sequence alignment of the sequences submitted will be returned to the user (.aln file).

2. It can be used to produce a true phylogenetic tree. In order to use this option, the user must input or upload a multiple alignment of sequences in one of the standard multiple alignment formats (.aln file). Then, in the phylogentic tree section of the form, they must choose one of the tree type options; NJ, Pyhlip or Dist. These are programs for drawing phylogenetic trees. This time the user will retrieve a .ph (always), .dst and/or .nj files (depending on options chosen), which will contain the phylogenetic trees. By default, the form is set to produce a multiple alignment.

Phylogram and Cladogram:

A phylogram is a branching diagram (tree) that is assumed to be an estimate of a phylogeny. The branch lengths are proportional to the amount of inferred evolutionary change. A cladogram is a branching diagram (tree) assumed to be an estimate of a phylogeny where the branches are of equal length. Therefore, cladograms show common ancestry, but do not indicate the amount of evolutionary "time" separating taxa. It is possible to see the tree distances by clicking on the diagram to get a menu of options. The options available allow you to do things like changing the colours of lines and fonts and showing the distances.

BIOINFORMATICS IN DRUG DISCOVERY AND DEVELOPMENT:

Drug discovery and development through bioinformatics is one of the most actively pursued areas of research. The basic process of drug discovery can be divided into four steps:

§  Target Identification

§  Target Validation

§  Lead Identification

§  Lead Optimization

Bioinformatics has an important role in the Target Validation process and to a lesser extent in the other stages of the drug discovery process.

ROLE OF BIOINFORMATICS IN TARGET VALIDATION

  The importance of bioinformatics in target validation is justified because a rational and efficient mining of the information that integrates knowledge about genes and proteins is necessary for linking targets to biological information.

The validation of a drug target involves demonstrating the relevance of the target protein, which is a very essential step and this combines data from molecular biology, cell biology, bioinformatics, in-vitro and in-vivo experiments. Although experimental work is the key driver in target validation, bioinformatics plays a very important role in supporting this process as biological knowledge is to be mined from numerous databases containing data on DNA sequences, protein structures, pathways, organisms and disease that exist to uncover the disease links and provide clues to biological function.

Predicting function from sequence and structure:

The most commonly used approach to assign function to proteins is by sequence similarity, but this approach has its limitations, so attention has focused on complementing and extending this approach by the development of complementary methods to function prediction using sequence and structural information.

Sequence-based approaches

The identification of signatures of domains and functional sites in amino acid sequences has played an important and complementary role to similarity searching methods in the functional characterization of proteins. For this purpose the InterPro which is owned and maintained by the EBI plays a very important role. In an extension of this approach, the prediction of sequence motifs associated with post-translational modifications and sub cellular localization of proteins has the ability to transfer functional information between sequences that are unrelated at the primary sequence or evolutionary level. The key principle here is that functionally-related proteins will have similar posttranslational modifications and sorting signals even if they are unrelated at the sequence level. For this purpose, the ProtFun method may be used which integrates 14 individual attributes (e.g. glycosylation, phosphorylation, signal peptides etc.) to predict functional categories, also the Proteome Analyst may be used which enables one to predict sub cellular location using database text annotations from homologues in addition to sequence information. Another tool is the Eukaryotic Linear Motif (ELM) server which is a resource for investigating short peptide linear motifs which are used for cell compartment targeting, protein–protein interaction, regulation by phosphorylation, acetylation, glycosylation and a range of other post-translational modifications. Scansite is yet another important tool to identify short sequence motifs within query proteins that regulate protein–protein interactions in cell signaling and can be used to generate biochemical tools that enable the identification of interaction partners. The availability of the sequenced genomes of a wide range of organisms has facilitated the development of protein function prediction methods based on viewing this data in an evolutionary context. Phylogenomic profiling focuses on how proteins became similar in sequence through evolution rather than on the sequence similarity itself. In this approach, the evolutionary history of genes is used to predict the function of uncharacterized genes. The

Resampled Inference of Orthologues (RIO) web server has been developed to automate phylogenomic analysis.

Structure-based approaches

Protein structure plays a central role in the understanding and use of sequence data because of the tight relationship that exists between structure and function. As structures are more highly conserved than sequences during evolution they can also be used to detect more distant homologues.g Discovery Today: Technologies | Target validation Vol. 1, No. 2 2004

In addition, knowing the structure of a protein allows the in-silico design of targeted libraries of small molecule compounds which can be used as probes of cellular function and as possible drug leads in chemogenomics approaches. For this purpose, the Relibase and Chematica^TM database systems have been designed to facilitate the retrieval of protein–ligand related information. Despite of the efforts for high throughput production of protein structures, molecular modeling methods are increasingly being used to bridge the gap between the number of protein sequences in the databases and the number of experimentally-determined structures. Although homology modeling produces the most accurate models, it does require homologous proteins with a structure and a high percentage sequence identity with the target protein. Alternatively, fold recognition (threading) methods and are applied when homologous template structures are unavailable. And when no template structures are available, the ab initio prediction methods are applied. Such methods usually generate low resolution structures, which might be sufficient for functional annotation of the protein sequences. The detection of remote homologues having poor sequence homology, but having a good structural homology can be improved by the automatics extraction of SWISSPROT annotations in combination with PSI-BLAST.

Predicting function from protein–protein interactions:

Protein–protein interactions are fundamental to most cellular processes. As a result, such interactions are being increasingly used to assign functions to uncharacterized proteins on the principle that interactions with proteins of known function will be a strong indicator of the function of proteins of unknown function. In addition, protein interaction data also provides the basis for the reconstruction of cellular pathways.  A range of experimental techniques have been used to detect protein–protein interactions with computational methods playing an important role in this process by expanding the scope of experimental data and increasing the confidence of protein–protein interaction pairs. There are a number of publicly accessible protein interaction databases, many of which combine experimental data with curated literature information. In addition, tools to aid data integration and visualization of the protein networks generated have been developed. Clustering of protein interactions into networks provides information on the biological context of proteins, an important step towards identification of its functional role. The networks of relationships between proteins are visualized as interaction maps. Parallel with experiments to determine protein–protein interactions, the genomic-context approach uses conservation of gene order in different genomes to predict functional association of proteins. This approach exploits the fact that genes of functionally interacting proteins tend to be associated with each other on genomes. The STRING database and Predictome tool both make use of genomic context information. Interaction mining uses experimentally derived interactions in one organism to infer the structure of an interaction network in a related organism.

Predicting function from gene expression:

Microarray experiments allow the gene expression profiles of thousands of genes to be measured and compared with each other in cells and tissues under a range of experimental conditions, as well as between healthy and diseased states. Computational approaches are important in analyzing the large datasets produced and in prioritizing the resulting (long) lists of differentially expressed genes for target validation. The key challenges from a drug discovery perspective are: (1) Filtering the gene lists to create shortlists of targets that are most likely to be directly involved in the disease process;

(2) Deducing functional relationships from the datasets.

Clusters of genes that have similar expression profiles are often inferred to be functionally associated, although this is not always the case. However, the accuracy of such correlations can be improved by examining intraspecies and interspecies conservation of gene expression. To identify functionally related genes that do not have similar expression profiles, a method for the identification of ‘‘transitive’’ genes whose expression correlates with the expression of these genes has been described. An alternate approach to cluster analysis is to view the datasets at the level of biological processes or pathways, so that an overview of the main biological themes can be ascertained and this information can then be used as the basis for focusing in on particular groups of genes. Several tools have been developed to facilitate this process, which make use of the common vocabulary for biological function put together by the Gene Ontology (GO) Consortium. The ontology describes gene products in terms of their associated biological processes, cellular components and molecular functions in a species-independent manner, facilitating comparison of the functional features of proteins. Several tools like the MAPPfinder, GoMiner, FATIGO and EASE can be used to link gene expression data to the GO hierarchy.

As a complement to the tools developed for the analysis of microarray data, automatic pipelines for the analysis of open reading frames stemming from cDNA sequencing projects, like the LIFE database have also been developed.

Predicting function from linking proteins to pathways and signaling networks:

As most diseases result from the agitation of a signal transduction pathway, a full insight into the function of proteins, particularly their relevance to disease, requires information on the pathway in which a putative target participates. A number of databases that contain large amounts of curated pathway information and tools for pathway construction, modeling and analysis have been developed. The detailed biochemical knowledge about metabolic pathways is reflected in the extensive nature of metabolic pathway databases like the Kegg2 and has great potential for the validation of targets in pathogenic organisms.

Predicting function from text mining of the biological literature:

Much of the experimental information pertinent to a target’s biological function and potential links with a particular disease are hidden in the free text of the 11,000,000 journal articles in MEDLINE, the most widely used biomedical literature database. Literature evidence has always played a crucial part in target selection and validation and continues to be pivotal in accepting or rejecting associations derived from experimental or computational approaches. Careful curation of the literature is used as the basis for the manual annotation of entries in databases such as UniProt, DIP and BIND. Because of the large datasets obtained from transcriptomic and proteomic experiments, there is increasing interest in automating the identification of relevant MEDLINE articles (information retrieval) and finding facts and relationships in the unstructured text of these articles (information extraction). From a target validation perspective, the goals of text mining in bioinformatics are to identify and define the functional relationships between genes or proteins and to use this information to predict specific biological functions, links to disease pathology and/or pathway relationships. No single tool can currently perform all the required tasks and this is reflected in the range of text mining tools available. Starting from a nucleic acid or protein sequence, MedBlast is a tool for the identification of relevant literature references, which are either cited by the sequence annotation or cite the sequence (direct references), or contain gene symbols of the given sequence (indirect references). AbXtract is a web tool for the automatic extraction of biological information from collections of MEDLINE abstracts in which keywords, sentences and abstracts relevant to protein function are automatically extracted and displayed to the user. XplorMed summarizes MEDLINE search results and extracts the main associations between words so users can select abstracts of interest for further analysis as well as interactively examine the context of keywords in abstracts. PubMatrix uses two lists of keywords to generate an HTML matrix table of pair-wise comparisons so that users can quickly identify interesting combinations of terms and access the relevant MEDLINE abstracts. When used with lists of gene names and function, PubMatrix can be used to annotate and analyse the gene lists produced by proteomic and transcriptomic experiments. Using information retrieved from MEDLINE articles related to function, diseases and related genes, the Gene Information System predicts positive, cooperative or negative relationships between pairs of genes in a two-phase text mining process. The Medical Knowledge Explorer system uses GO and LocusLink  as the lexicons for constructing function name and gene/gene product name indices and extracts information from articles using a sentence alignment and classification algorithm. BITOLA is a tool for finding new relationships between genes and disease in which a discovery algorithm operates on a knowledge base of relations between biomedical concepts extracted from MEDLINE.

 CONCLUSION:

Bioinformatics has been found to play a key role in the drug discovery process. By providing prediction of biological function and potential disease related roles of targets in the experimental work, it serves as the hypotheses that can be tested in vivo and in vitro and then generated in silico. Although the experimental results will still remain to be the important factors that determine the progress of the drug discovery process, the information provided by bioinformatics will help facilitate the drug discovery process. With newer methods for the automated extraction of biological information from scientific literature, there will be an evolution of newer databases containing molecular interactions and pathways, thus aiding further in the drug discovery process. The emphasis on the future will be mainly on better methods for modeling function from the structure, thus enabling the researcher to rationally design or modify the protein and ligand alike and thereby producing significant numbers of specifically designed therapeutic proteins.