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Rehan Pathan. Show More. Many methods have been proposed for quantitative predictions in drug metabolism; one example of a recent computational method is SPORCalc. 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. 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. As a result of the long time required to develop analogues and test a new medicine and the fact that of every potential new medicines typically only one will ever reach the open market, this is an expensive way of doing things, often costing over 1 billion dollars.
To recoup this outlay pharmaceutical companies may do a number of things: . The inverse benefit law describes the relationship between a drugs therapeutic benefits and its marketing. When designing drugs, the placebo effect must be considered to assess the drug's true therapeutic value. Drug development uses techniques from medicinal chemistry to chemically design drugs. This overlaps with the biological approach of finding targets and physiological effects. Theoretical pharmacology is a field of research uses techniques from computational chemistry, and molecular mechanics.
Furthermore, on the basis of the structure theoretical pharmacology aims to predict the biological activity of new drugs based on their properties and to predict new classes of drugs. Experimental pharmacology involves the study of pharmacology through bioassay , to test the efficacy and potency of a drug. Pharmacology can be studied in relation to wider contexts than the physiology of individuals. For example, pharmacoepidemiology is the study of the effects of drugs in large numbers of people and relates to the broader fields of epidemiology and public health.
Drugs may also have ethnocultural importance, so ethnopharmacology studies the ethnic and cultural aspects of pharmacology. Photopharmacology is an emerging approach in medicine in which drugs are activated and deactivated with light. The study of chemicals requires intimate knowledge of the biological system affected. With the knowledge of cell biology and biochemistry increasing, the field of pharmacology has also changed substantially. It has become possible, through molecular analysis of receptors , to design chemicals that act on specific cellular signaling or metabolic pathways by affecting sites directly on cell-surface receptors which modulate and mediate cellular signaling pathways controlling cellular function.
Introduction to Pharmacology
Chemicals can have pharmacologically relevant properties and effects. Pharmacokinetics describes the effect of the body on the chemical e.
Pharmacology is typically studied with respect to particular systems, for example endogenous neurotransmitter systems. The major systems studied in pharmacology can be categorised by their ligands and include acetylcholine , adrenaline , glutamate , GABA , dopamine , histamine , serotonin , cannabinoid and opioid. Molecular targets in pharmacology include receptors , enzymes and membrane transport proteins.
Enzymes can be targeted with enzyme inhibitors. Receptors are typically categorised based on structure and function.
Major receptor types studied in pharmacology include G protein coupled receptors , ligand gated ion channels and receptor tyrosine kinases. Pharmacological models include the Hill equation , Cheng-Prusoff equation and Schild regression. Pharmacological theory often investigates the binding affinity of ligands to their receptors. Medication is said to have a narrow or wide therapeutic index , certain safety factor 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. The effect of drugs can be described with Loewe additivity. Pharmacokinetics is the study of the bodily absorption, distribution, metabolism, and excretion of drugs. When describing the pharmacokinetic properties of the chemical that is the active ingredient or active pharmaceutical ingredient API , pharmacologists are often interested in L-ADME :.
Drug metabolism is assessed in pharmacokinetics and is important in drug research and prescribing. The FDA requires that all approved drugs fulfill two requirements:. Gaining FDA approval usually takes several years. Testing done on animals must be extensive and must include several species to help in the evaluation of both the effectiveness and toxicity of the drug. The dosage of any drug approved for use is intended to fall within a range in which the drug produces a therapeutic effect or desired outcome.
The safety and effectiveness of prescription drugs in the U. Medicare Part D is a prescription drug plan in the U. Prescription drugs are drugs regulated by legislation. The International Union of Basic and Clinical Pharmacology , Federation of European Pharmacological Societies and European Association for Clinical Pharmacology and Therapeutics are an organisations representing standardisation and regulation of clinical and scientific pharmacology.
Systems for medical classification of drugs with pharmaceutical codes have been developed. Ingredients of drugs have been categorised by Unique Ingredient Identifier. The study of pharmacology overlaps with biomedical sciences and is study of the effects of drugs on living organisms. Pharmacological research can lead to new drug discoveries, and promote a better understanding of human physiology. Students of pharmacology must have detailed working knowledge of aspects in physiology, pathology and chemistry. Modern pharmacology is interdisciplinary and relates to biophysical and computational sciences, and analytical chemistry.
Whereas a pharmacy student will eventually work in a pharmacy dispensing medications, a pharmacologist will typically work within a laboratory setting. Pharmacology is often taught to pharmacy and medicine students as part of a Medical School curriculum. From Wikipedia, the free encyclopedia. Branch of biology concerning drugs. This article is about the science. For the book type "a pharmacology" , see Materia medica. For the journal, see Pharmacology journal. Main articles: List of drugs by year of discovery and History of pharmacy.
Naturally derived opium from opium poppies has been used as a drug since before BCE. Opium's major active constituent, morphine , was first isolated in and is now known to act as an opioid agonist. When the ghosts are prepared in 14 C glucose, it will be possible to monitor the rate of release or uptake of the labeled 14 C glucose from the membranes into the aqueous environment.
When log 10 C was plotted vs time h a linear response was obtained with a slope of — 0. Calculate the following pharmacokinetic parameters;. Once the apparent volume of distribution is known for a particular drug the amount of drug that must be given to achieve a desired concentration can be determined from. For a practical loading schedule, the maintenance interval should be lowered to say 8.
The analytical method of assaying paracetamol relies on the introduction of a nitro group into the molecule after the removal of plasma proteins through precipitation. The resultant nitrophenol compound which is formed has a deep yellow colour in an alkaline medium and absorbs at nm Figure Describe how you would construct the standard curve for determination of paracetamol concentration.
These are the classical approaches to drug discovery that do not initially involve detailed scientific study they include the following;. This is the discovery of drugs based on traditional medical knowledge. The best example is the documented analgesic effects of extracts from opium poppy that led to the isolation of morphine from the plant and the subsequent synthesis of related analgesics.
This is the accidental discovery of novel drugs based on the ingenuity of a scientist investigating a problem initially unrelated to the observed phenomenon; examples of such discoveries include the observation by Alexander Flemmings that penicilliummould could inhibit the growth of bacteria. This finding led to the discovery of antibiotics. Discovery of therapeutic usefulness of a side effect e. An example of discovery arising from studies of endogenous agents in test animals is the anticoagulant action of the venom from the Malayan viper that led to the identification of the anticoagulant ancrod.
These are those approaches that form a basis for the rational design of drugs and include the following;. This is the screening of a large number of natural products, chemical entities, large libraries of peptides, nucleic acids and other organic molecules for biological activity.
This approach may lead to identification and development of new drug molecules. This is the profiling of natural products of related plant species screening using either liquid or gas chromatography mass spectrometry to determine active metabolites that may be present in novel crude herbal medical preparations. This is the most advanced technique for drug discovery. It entails virtual screening or docking of compounds on the 3-D- structure of a known receptor based on homologies of the test drug molecules with a known test parent drug. In silico screening can form a basis for the modification of a known drug molecule to determine possible therapeutic applications and may lead to the development of putative drugs against new targets.
Selection of molecules for further study is usually conducted in animal models of human disease and the pharmacological tests include both the in vitro and in vivo studies after the initial screening for biological activity. For instance, antibacterial activity of drugs is assessed by their ability to inhibit growth of a variety of micro-organisms, while hypoglycemic drugs are tested for their ability to lower blood pressure. The in vitro methods include incubation of a parent compound with various subcellular fractions such as microsomes, individual recombinant drug metabolizing enzymes from cells or tissue slices.
The in vivo studies involve working on typical animal models such as dogs or rats. Some of the invitro and invivo studies that may be performed are shown in tables 1 and 2 below;. If an agent possesses useful activity it would be further studied for possible adverse effects on other major organs. The data from animal studies form a basis for the calculation of the initial or starting doses to be used in the subsequent clinical studies. The human equivalent dose calculations for the maximum recommended dose are normally based on either the body surface area or body weight.
The candidate drugs that survive initial screening and profiling must be carefully evaluated for potential risks before and during clinical testing. The main types of evaluation needed from safety and toxicity studies include This involves looking at the effects of large single doses of therapeutic agent. Acute toxicity studies are usually performed in animal models such as mice and rats. These studies enable investigators to correlate any observed effects with the systemic level of the drug. This is similar to acute toxicity but measures the effects of multiple doses based on expected duration of clinical usage.
It entails haematological, histology and electron microscope studies to identify organs which might be affected by toxicity. It usually lasts between one to three months. This enables the selection of putative compounds for subsequent studies.
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These studies are required when the drug is intended to be used in humans for prolonged periods. The goals of this investigation are mostly similar to those of sub-acute toxicity. These are measurements intended to determine the effects of the drug agents on; mating behaviour, reproduction, parturition, progeny birth defects, and postnatal development. These studies are required to determine the effects of prolonged usage of the drug under investigation. They involve hematological and histological autopsy analysis. These studies look at the genetic stability and mutations of bacterial or mammalian cells in culture.
These studies are at the academic research level and are intended to provide data for future research. The main purpose of toxicology is to discover the pathways that are involved in toxic action. It includes studies on mechanisms of toxic action of drugs which may lead to the development of safer drugs. Toxicity testing is time consuming and expensive and may require two to five years to collect and analyze data before the drug can be considered ready for testing in humans.
The safety or efficacy of a drug must be thoroughly understood before the drug is administered to any group of individuals. Therefore regulations governing the development of new drugs have evolved to assure safety and efficacy of new medications. The clinical trials during drug development and post marketing experience form the scientific basis of patient response to a drug.
1: Introduction to Pharmacology
Once a drug is judged ready to be studied in humans, a notice of clinical investigational exemption for a new drug IND must be filled with the government body concerned with the regulation and registration of drugs. The IND includes manufacturing information, all data from animal studies, clinical plans and protocols and the names and credentials of physicians who will conduct the clinical trials. The main goal in phase I is to determine whether test animals and humans show significant different responses to the drug and to establish limits of the safe clinical dosage range.
The effects of the drug as a function of dosage are established in a small number 25 — 50 of healthy volunteers. When the drug is expected to have significant toxicity, as often the case with cancer and AIDS therapy, volunteer patients with the disease are used instead of the healthy volunteers. The requirements of clinical trials include the following:. Meaningful and sensitive indices for drug effects must be used i. The experimental observations must be converted to data and then into valid conclusions. The accuracy of diagnosis and severity of the disease must be comparable between the groups being contrasted.
The dosages of the drugs must be chosen and individualized in a manner that allows relative efficacy to be compared at equivalent toxicities. Compliance with experimental regimens should be assessed before subjects are assigned to experimental or control groups.
Introduction to Pharmacology
Non-compliance may cause false estimates of the true potential benefits or toxicity of a particular treatment. Ethical considerations. These may be the major determinants of the types of controls that can be used e. In such cases, new treatments must be compared with standard therapies.
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For clinical trials to have validity they must be based on a sound statistical basis. Some of the of the criteria that must be met include;. Randomization is a design which ensures that there is no bias in allocation of treatments among the different groups. The purpose of randomization is to minimize the possibility that an observed treatment effect is due to inherent differences between groups.
Randomization eliminates bias by avoiding recruiting patients who have a particular characteristic to one group and not the other e. Randomization should not be carried out until immediately before treatment. The delay allows a patient to have second thoughts about taking part or the investigator to have to re-consider about admitting patients to the study. Simple methods of randomization can be designed using published tables of random numbers, where treatments are in a form of a square in which each treatment is contained only once in each row and column and the order of treatment is different in each group Table 3.
The presence of other diseases or risk factors should be taken into consideration i. A random number table array for assignment of various treatment regimes to various groups of patients in clinical trials. This approach eliminates systematic variation between groups since the patients are allocated at random order to group 1, 2, 3, or 4.
A code list should be drawn up so that the main investigators may be kept blind to the treatment an individual is receiving but also so that it is possible to know the treatment by breaking the code. Coding should be such that when broken, it does not yield information about the treatments other patients are getting. The treatment information about all the patients should be left to one person preferably the pharmacist or trial co-ordinator.
Blinding is a design which does not allow the investigator to know what treatment the patient is receiving. The ideal trial should be double blind where neither the investigator nor the patient knows what treatment the patient is taking. Placebos or dummies are used in order to achieve blindness. The placebos should match the active treatment as closely as possible in terms of size, shape, color, texture, weight, taste and smell with the active formulation. Clinical trial should be carried out in a defined centre so as to minimize variations in the population and in the investigators techniques.
This also avoids problems of data collection, communication and follows up. Multi-centre trials may become necessary when studying a rare disease hence scarcity of patients or when the effect being investigated is small one e. Clinical trials designed to evaluate efficacy of new drugs should always be prospective i. For example, if one randomized all patients with heart failure to treatment with either digoxin or a new drug X and then studied the outcome over six months that would be a prospective trial.
In case of control study the outcome is first identified and then comparisons are made retrospectively between the characteristics of patients who did or did not have the outcome. Such a study for instance has shown that oral anticoagulants can reduce incidences of re-infarction in patients who have already had a myocardial infarction.
The case control studies may be carried out some time, after the introduction of a drug therapy in order to get some idea of its place in the overall management of the disease since the results of a case control study may prompt formal prospective trials in order to confirm original findings. In vitro predictive efficacy and toxico-genomics should be carried out after phase 1 clinical trials in order to validate the results of the phase 1 clinical trials. This is achieved by using animal cell lines in which gene expression profiling and patterns of protein production are used to identity candidate biomarkers for the disease.
The utilization of markers that are associated with the disease or those that indicate a known response to a therapeutic intervention or reflect a clinical outcome may yield information on efficacy or toxicity of a test drug. An example of a biological readout that has traditionally been used to determine efficacy during the treatment of diabetics is the determination of glucose in the urine of a diabetic patient. Reliable and specific biomarkers that act as predictors of efficacy or long-term toxicity are useful because they reduce the time, size and cost of clinical trials.
These are studies that recruit willing and informed patients and are designed to assess long term safety, refine pharmacokinetic data, determine optimal dose. The purpose of phase II studies is to determine efficacy. Typically, phase II trials require subjects and take months. An assessment of no effect or no worthwhile effect of a given drug demonstrates that it is futile to proceed with further clinical testing of the drug.
It is therefore important to minimize type I errors or false negatives in the study design in order to minimize the risk of discontinuing a potentially effective drug. The data from well designed phase I and phase II trials are therefore critical in planning the subsequent trials.
The phase III trials are large trials intended to determine whether a treatment is effective and to establish safety data. Phase II clinical trials include inert placebos as negative controls and older active drugs as positive controls alongside the investigative compound. These studies are done in special clinical centers such as University Hospitals. A broader range of toxicities may be detected at this phase. The drug is evaluated in a much larger number of patients thousands to further establish safety and efficacy.
Phase III trials are performed in settings similar to those anticipated for the ultimate use of the drug. After successful phase III trials, the next step is the application for review of the new drug to seek approval to use the drug for clinical management of the disease condition. This phase is concerned with post-marketing surveillance and the main goal is to assess adverse reactions, patterns of drug utilization, discovery of additional indications. The interrelationships between the various studies in drug development are illustrated in Fig 13 below;.
Illustration of the key steps in the development of a drug from a putative drug candidate extract. The personalized medication which takes into account the genetic make-up of individuals is known as pharmacogenomics. The pharmacogenomic differences that determine individualized therapy include genetic polymorphisms of drug transporters, drug receptors, and drug metabolizing enzymes.
For example, genetic variation in Cyt P enzymes that are largely responsible for drug metabolism shows that different individuals respond differently to drug efficacy or toxicity. Genetic variants in the drug target, the disease pathway, genes or drug metabolizing enzymes could all be used as predictors of drug efficacy or toxicity. For example, drug monitoring using perpherazine, a Cyt P substrate, shows that there are three main categories of individuals; the efficient metabolizers obtained from the heterozygotes, the poor metabolizers from the homozygotes and the ultra-rapid metabolizers which carry two or more active genes in the same chromosome, a phenomenon known as gene duplication.
The most common type of genetic variation are single nucleotide polymorphisms, therefore, a high resolution of single nucleotide map may expedite the identification of genes for various diseases. The molecular profiles of patients identified in phase I and II clinical trials as likely non-responders to the putative drug under investigation might present an opportunity to initiate new discovery programs for other pharmaceutical compounds. Clinical usage of drugs requires a basic understanding of the pharmacokinetic and pharmacodynamic drug processes and an appreciation that a relationship does exist between the pharmacological effect or toxic response to a drug and the concentration of the drug.
The interpatient and intrapatient variation in disposition of a drug must be taken into account in choosing a drug regimen. A drug dosage regimen therefore is a recipe for the administration of a drug so as to produce a desired therapeutic effect with minimum toxic effects. The factors that determine the relationship between the prescribed drug dosage and drug effect operate at three levels; prescription level, drug administration level and at the physiological level of patient Figure The operational levels that determine the relationship between prescribed drug dosage and the drug effect.
Drugs that are excreted primarily unchanged by the kidneys tend to have low variation among patients with similar renal function than do drugs which are inactivated by metabolism. For the extensively metabolized drugs, those with high metabolic clearance and large first pass elimination have marked difference in bioavailability, whereas those with low biotransformation tend to have largest variation in elimination rates among individuals. The simplest way of determining a drug dosage regimen is to base it on the published recommended dosage.
These are derived from the pharmacokinetics studies of the drug and the general procedure in using the published recommendations is to start at the lower end of the recommended dosage range and monitor the therapeutic effect. If the desired effect does not occur, the dosage can be increased gradually until one reaches the upper limit of the range. In certain conditions it may be necessary a sufficiently high dose for the drug to accumulate in the body to a satisfactory degree. This dose is known as the loading dose and is equal to the volume of distribution multiplied by the target concentration in the plasma.
The reason for giving a loading dose is to circumvent the sometimes unacceptable time lag preceding the steady state levels. Once the correct loading dose is given, a steady-state concentration can be achieved rapidly and then maintained by giving a smaller maintenance dose. Adjustment of dosage in individual patients is often as a result of the modification of pharmacokinetic parameters of which the three most important include; the bioavailability or the fraction of a drug that is absorbed into systemic circulation, its clearance and the volume of distribution. For drugs with a high toxicity to therapeutic ratio, the loading dose can be given as a single dose and for drugs with a low toxicity: therapeutic ratio and a long half-life, the loading dose can be divided into several portions and given at intervals long enough to allow detection of adverse effects, but short enough to ensure that the loading dose is a true loading dose i.
The extent of availability of a drug after oral administration is expressed as a percentage of the dose. The fractional availability F varies from 0 to 1. The extent of availability is more important parameter to measure rather than the rate of availability. Hepatic disease may in particular cause high availability because the metabolic capacity decreases or development of vascular shunts in the liver. Significantly high availability requires dosage adjustment by a factor of two, while significantly low in availability requires dosage adjustment by a factor of half.
In most clinical situations drugs are administered in such a way as to maintain a steady concentration i. Therefore, clearance is the most important pharmacokinetic term to be considered in defining a rational steady-state drug dosage regimen. The maintenance dose is usually altered when the clearance of the drug changes. For example, during renal impairment, the clearance of drugs which are predominantly cleared by the kidney is greatly reduced and therefore, the desired steady state concentration can only be achieved either through altering the dose or altering the dosing interval.
Therefore, when a drug is cleared almost completely via kidneys, the dosage interval should be changed in proportion to renal clearance as follows:. The normal steady-state theophylline concentration can be determined using the equation:. Drug absorption in the elderly is slightly different from the normal patients and therefore adjustment of the dosage should be taken into consideration during drug therapy.
The rate of transdermal drug absorption may be diminished in elderly because of reduced tissue blood perfusion. Compounds that permeate the intestinal epithelium by carrier mediated transport mechanisms may be absorbed at lower rates in the elderly. The volume of distribution of hydrophilic drugs will therefore decrease while plasma concentration will increase and the likelihood of toxic drug effects will also increase.
When geriatric patients use diuretics, the extracellular space reduces even further leading to a higher likelihood of drug toxicity. Therefore, for geriatrics a once or twice daily drug administration is optimal. This can be achieved though delayed release or fixed drug combinations. Drug treatment of any kind is often compromised by lack of full compliance by the patient. The common errors of compliance to a regimen by a patient include; omission in taking the drug, wrong timing of dosages, premature termination of therapy or using additional medications.
In order to improve patient compliance, the patient should be made to understand the nature and prognosis of the illness and what to expect from the medication by detailing both the acceptable and undesirable unwanted effects as well as signs of efficacy that may help enforce compliances.
Patients frequently discontinue taking a medication such as septrin because they have not been told the necessity of continuing with the drug after the acute symptoms have subsided. The effectiveness of physician-patient communication is inversely related to the error rate in the taking of drugs. A physician might prescribe a drug to be taken three times a day with meals for a patient who either eats only twice a day or sleeps all day and works at night. Therefore, an exploration of the patients eating, sleeping and working habits is necessary before a prescription is given.
The educational level of a patient may also require that the prescription is carefully worded and oral instructions given in the primary language of the patient since when such patients take three or more medications they are less likely to use them properly. It is therefore important to provide identifying symbols for each medication e. Pharmacological formulations are potentially harmful to the individuals taking the drugs. There is need to ascertain the safety of new drugs before allowing them to be marketed. Adverse drug reactions can be classified into two main categories: They may be dose related or non dose related with each being short-term or long-term.
Adverse drug reactions can occur because of the changes in the systemic availability of a formulation. For instance, the change of excipients in phenytoin capsules from CaSO 4 to lactose leads to high availability and hence adverse drug reactions. Sometimes, adverse drug reactions can occur due to the presence of contaminants like bacteria if quality control breaks down. Out-of-date formulations may also cause adverse drug reactions because of degradation products arising from the drug e. Dose related adverse reactions may also arise from pharmacokinetic variations in the individuals taking the drug.
Pharmacokinetic variations may also arise due to hepatic disease like advanced cirrhosis which lowers the clearance of drugs such as phenytoin and morphine. The pharmacological variations could be environmental such as diet or smoking, while others are genetic. The association of HLA antigens with foreign antigens stimulates T-lymphocytes. Some of these antigens expressed by major histocompatibility complex MHC genes have been associated with an increased risk of adverse drugs e.
This anaphylaxis or immediate hypersensitivity reactions; the body reacts within five to thirty minutes. The IgE molecules fixed to mast cells and basophil leucocytes release histamine and other pharmacological mediators such as kinins. Drugs likely to cause are anaphylactic shock include;-penicillins, streptomycin, local anaesthetics etc.
This leads to the activation of the complement leading to cell lysis of phagocytic attack of the cell with the complex. Drugs such as the cephalosporins, penicillins, quinine and transfusion of improperly matched blood can yield this type of reactions. In this type of allergy, the immune complex reactions initiate an inflammatory response due to the combination of the excess drug- protein complex with the IgG in circulation. The complex thus formed is deposited in the tissues and causes activation of the complement and damage of capillary endothelium.
Penicillins, sulphonamides and streptomycin may elicit type III allergic reactions.