Introduction to Pharmacology

of 45 INTRODUCTION TO PHARMACOLOGY INTRODUCTION TO PHARMACOLOGY

of 45 Introduction: The word pharmacology comes from the Greek words pharmakos, meaning medicine or drug, and logos, meaning study. Pharmacology is the branch of biology & medicine concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. Pharmacology is the study of drugs including their origins, history, uses, and properties. It mainly focuses on the actions of drugs on the body. It also includes drug composition and properties, synthesis and drug design, molecular and cellular mechanisms, organ/systems mechanisms, signal transduction/cellular diagnostics, interactions, toxicology, chemical biology, therapy, and medical applications and antipathogenic capabilities. The two are pharmacodynamics and pharmacokinetics. If substances have medicinal properties, they are considered pharmaceuticals. Pharmacology, a biomedical science, deals with the research, discovery, and characterization of chemicals which show biological effects and the elucidation of cellular and organismal function in relation to these chemicals. Oswald Schmiedeberg (1838-1921) of Germany transformed the old fashioned materia medica into modern pharmacology as an independent science in the beginning of last century & considered father of pharmacology.Ram Nath Chopra Father of Indian Pharmacology. communication, molecular main areas of pharmacology Divisions of pharmacology The discipline of pharmacology can be divided into many sub disciplines each with a specific focus. Clinical pharmacology: It is the use of drugs in clinical routes. Clinical pharmacology is the scientific study of drugs in human. Clinical pharmacology is a branch of biomedical

of 45 science. It includes drug discovery, the study of the effects of drugs on their targets in living systems and their clinical use, as well as the study of biological function related to these chemicals. It includes pharmacokinetic and pharmacodynamic investigations in healthy or diseased individuals. It also includes the comparison with placebos, drugs in the market and surveillance programmes. The main objectives are: Maximize the effect of drug Minimize the adverse effects Promote safety of prescription Generate optimum data for use of drug Promote usage of evidence based medicine Neuropharmacology:It is the study of how drugs affect cellular function in the nervous system(CNS&PNS), and the neural mechanisms through which they influence behavior. There are two main branches of neuropharmacology: Behavioral neuropharmacology focuses on the study of how drugs affect human behavior including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves their neurochemical interactions. Psychopharmacology: Psychopharmacology, also known as behavioral pharmacology, is the study of the effects of medication on the psychology observing changed behaviors of the body and mind, and how molecular events are manifest in a measurable behavioral form. Psychopharmacology is an interdisciplinary field which studies behavioral effects of psychoactive drugs. Cardiovascular pharmacology:Cardiovascular pharmacology is the study of the effects of drugs on the entire cardiovascular system, including the heart and blood vessels. Pharmacogenetics: Pharmacogenetics is clinical testing of genetic variation that gives rise to differing response to drugs. It is the study of the genetic variation between individuals that affects their response to drugs/pharmaceuticals and other xenobiotics, both therapeutically and in terms of adverse effects. Personalized medicine is the use of pharmacogenetics to understand how an individual can benefit from specific drugs. Pharmacogenomics: Pharmacogenomics is the application of genomic technologies to drug discovery and further characterization of older drugs. It is the study of the role of the genome in drug response. Its name (Pharmaco+ genomics) reflects it’s combining of pharmacology and genomics. Pharmacogenomics analyzes how the genetic makeup of an individual affects his/her response to drugs. It deals with the influence of acquired and inherited genetic variation on drug response in patients by correlating gene expression with pharmacokinetics and pharmacodynamics. Pharmacoepidemiology: Pharmacoepidemiology is the study of the effects of drugs in large numbers of people. The effects may be good or harmful. It is conducted in three ways: Observational cohort studies Case control studies Phase trials the study of neurons and

of 45 Systems pharmacology: It is the application of systems biology principles to the field of pharmacology. It seeks to understand how drugs affect the human body as a single complex biological system. Instead of considering the effect of a drug to be the result of one specific drug-protein interaction, systems pharmacology considers the effect of a drug to be the outcome of the network of interactions a drug may have. Toxicology: It is a discipline, overlapping and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice to toxins and toxicants. The relationship between dose and its effects on the exposed organism is of high significance in toxicology. Theoretical pharmacology: Theoretical pharmacology is a relatively new and rapidly expanding field of research activity in which many of the techniques of computational chemistry & method of molecular mechanism are used. Theoretical pharmacologists aim at rationalizing the relation between the activity of a particular drug, as observed experimentally, and its structural features as derived from computer experiments.On the basis of the structure of a given organic molecule, the theoretical pharmacologist aims at predicting the biological activity of new drugs that are of the same general type as existing drugs. It also aims to predict entirely new classes of drugs, tailor-made for specific purposes. Posology:It is the branch of medicine concerned with the determination of appropriate doses of drugs or agents. This depends upon various factors including age, climate, weight, sex, elimination rate of drug, genetic polymorphism and time of administration. It is derived from the Greek words posos means "how much" & logia means "study of". Pharmacognosy:It is the study of plants or other natural sources as a possible source of drugs. It is the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources.Basically it deals with the drugs in crude or unprepared form and study of properties of drugs form natural sources or identification of new drugs obtained from natural sources.Pharmacognosy is the identification of drugs by just seeing or smelling them. Environmental pharmacology: It is a new discipline. Focus is being given to understand gene environment interaction, drug-environment interaction and toxin- environment interaction. There is a close collaboration between environmental science and medicine in addressing these issues, as healthcare itself can be a cause of environmental damage or remediation. This field is intimately linked with Public Health fields. Dental pharmacology: Dental pharmacology is the study of drugs used to treat conditions of the oral cavity. It is the study of drugs, or pharmaceuticals, typically used in the dental field. The most common types of drugs used by a dentist or dental professional are analgesics, antibiotics, anti-inflammatory drugs, and anesthetics. Each drug works in a different way to address whatever the dental issue may be. with biology, chemistry, pharmacology, of diagnosing and treating exposures

of 45 DRUG(API) A drug is any substance (other than food that provides nutritional support) that, when inhaled, injected, smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue causes a physiological change in the body. In pharmacology, a drug is a chemical substance of known structure, other than a nutrient of an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Natural or synthetic substance which (when taken into a living body) affects its functioning or structure, and is used in the diagnosis, mitigation, treatment, or prevention of a disease or relief of discomfort. According to WHO, drug is any substance that can affect the living process to alter the physiological and pathological processes. General definition of drug, a drug is a substance other than food intended to affect the structure or function of a physiological system such as the human body. MEDICINE (API+EXCIPIENTS) A medicine is a drug used to diagnose, cure, treat, or prevent disease which have definite dose and doses form. Medicine is the science and practice of establishing the diagnosis, prognosis, treatment, and prevention of disease. Medicine encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness. PRO-DRUG A pro-drug is a medication or compound that, after administration, is metabolized into a pharmacologically active drug. Inactive pro-drugs are pharmacologically inactive medications that are metabolized into an active form within the body. Instead of administering a drug directly, a corresponding pro-drug might be used instead to improve how a medicine is absorbed, distributed, metabolized, and excreted (ADME). Pro-drug is a precursor of a drug. A pro-drug must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent. A list of pro-drug and their active form: 6-Monoacetylmorphine (6-MAM) is heroine metabolite which converts into active morphine in vivo. ALD-52 & MLD-41 will both convert into active Psychedelic LSD-25. Codeine is converted into morphine by cytochrome P450 enzyme CYP2D6.

of 45 Mycophenolate mofetil is an ester of mycophenolic acid used in transplant medicine. Aspirin is a pro-drug which converts into salicylic acid. Carisoprodol is metabolized into meprobamate. Until 2012, carisoprodol was not a controlled substance in the United States, but meprobamate was classified as a potentially addictive controlled substance that can produce dangerous and painful withdrawal symptoms upon discontinuation of the drug. Enalapril is bioactivated by esterase to the active enalaprilat. Valaciclovir is bioactivated by esterase to the active aciclovir. Fosamprenavir is hydrolysed to the active amprenavir. Levodopa is bioactivated by DOPA decarboxylase to the active dopamine Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol, because pure chloramphenicol does not dissolve in water. Psilocybin is dephosphorylated to the active psilocin. Heroin is deacetylated by esterase to the active morphine. Molsidomine is metabolized into SIN-1 which decomposes into the active compound nitric oxide. Paliperidone is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone. Prednisone, a synthetic cortico-steroid drug, is bioactivated by the liver into the active drug prednisolone, which is also a steroid. Primidone is metabolized by cytochrome P450 enzymes into phenobarbital, which is major, and phenylethylmalonamide, which is minor. Dipivefrine, given topically as an anti-glaucoma drug, is bioactivated to epinephrine. Lisdexamfetamine is metabolized dextroamphetamine at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorder Diethylpropion is a diet pill that does not become active as a monoamine releaser or reuptake inhibitor until it has been Ndealkylated to ethylpropion. Fesoterodine is an antimuscarinic that is bioactivated to 5hydroxymethyl tolterodine, the principle active metabolite of tolterodine. Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA). in the small intestine to produce

of 45 Application of pro-drug: Prodrug to Improve Patient acceptability Prodrug to improve Stability Prodrug to improve absorption Prodrug for slow and prolonged release Prodrug to Improve Membrane Transport Prodrug for Prolonged duration of action PHARMACOKINETICS Safe and effective drug treatment is not only a function of the physical and chemical properties of drugs, but also a function of how the human body responds to the administration of medication. The study of the bodily processes that affect the movement of a drug in the body is referred to as pharmacokinetics. Pharmacokinetics is the movement of drug after administration in the body. It also determine the speed of onset of drug action, the intensity of the drugs effect and the duration of drug action. More specifically it refers what the body does to a drug. The study of the movement of drugs in the body,including the processes of absorption, distribution, localization in tissues, biotransformation and excretion. The actions of the body on the drug are called pharmacokinetic processes. Pharmacokinetic processes govern the absorption, distribution, metabolism and elimination of drugs. Pharmacokinetics is important because: The studies completed in laboratory animals may give useful indications for drug research and development. For example less powerful molecules in vitro can turn out more effective in vivo because of their favorable kinetics. Pharmacokinetics supports the studies of pre-clinical toxicology in animals because the drug levels in plasma or tissues are often more predictive than the dose to extrapolate the toxicity data to man. Knowledge of the kinetics and of the effects of drugs in man is necessary for a correct use of drugs in therapy.

of 45 Principles of pharmacokinetics: To understand the pharmacology of drugs, the pharmacy technician must also understand the four fundamental pathways of drug movement and modification in the body. Pharmacokinetics is a branch of pharmacology that examines how drug concentrations change with respect to time as a function of absorption, distribution, metabolism and elimination. These are disparate but interrelated processes that occur between drug administration and its irreversible elimination from the body. Another way to consider pharmacokinetic processes is to group them into two components: 1. intake, which describes the time course of drug movement from the site of administration, e.g. mouth, to the site of measurement, e.g. blood. 2. disposition, which describes the time course of drug distribution and elimination from the site of measurement e.g. blood. If we look at the basics of pharmacokinetic study we get to know it is about four distinct features and actions that drug performs in the body upon ingestion which ultimately comprises of the effect produced by the moiety. This is also called as ADME Process. ADME is an abbreviation in pharmacokinetics "absorption, distribution, metabolism, and excretion", and describes the disposition of a pharmaceutical compound within an organism. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug. The course of drug action is, therefore, directly correlated with the concentration of the drug in the blood stream, and is dependent upon the ADME processes. and pharmacology for Absorption: In pharmacokinetics, absorption is the movement of a drug from the site of administration to bloodstream. Most drugs are absorbed by passive absorption but some drugs need carrier mediated transport. Small molecules diffuse more rapidly than large molecules. Lipid soluble non-ionized drugs are absorbed faster. Absorption is affected by blood flow, pain, stomach PH, stress, body temperature, GI motility etc. The rate and extent of absorption depends on

of 45 the route of administration, the formulation and chemical properties of the drug, and physiologic factors that can impact the site of absorption. When a drug is administered intravenously, absorption is not required because the drug is transferred from the administration device directly into the bloodstream. For a compound to reach a tissue, it usually must be taken into the bloodstream often via mucous surfaces like the digestive tract before being taken up by the target cells. Absorption critically determines the compound's bioavailability Distribution: Once absorbed, the drug may then leave the blood stream and disperse into the tissues and intracellular fluids where it can reversibly bind to receptors. This dispersal is called distribution. Distribution is the movement of drugs throughout the body. Determined by the blood flow to the tissues, it is ability of the drug to enter the vasculature system and the ability of the drug to enter the cell if required. After absorption most drugs are distributed in the blood to the body tissue where they have their effect. Once a drug has gained access to the blood stream, it gets distributed to other tissues that initially had no drug, concentration gradient being in the direction of plasma to tissues. The extent of distribution of a drug depends on its lipid solubility, ionization at physiological pH, extent of binding to plasma and tissue proteins, presence of tissue-specific transporters and differences in regional blood flow. Movement of drug proceeds until an equilibrium is established between unbound drug in plasma and tissue fluids. Drug distribution Drug distribution refers to the movement of a drug to and from the blood and various tissues of the body (for example, fat, muscle, and brain tissue) and the relative proportions of drug in the tissues. Drug enters the body by absorption. Inside the body, drugs move in the blood to different parts of the body. Distribution of drugs can be defined as: “The process by which a drug reversibly leaves the blood stream and enters the interstitium and/or the cells or tissues.” The drugs are present in free or bound form and different processes or mechanisms affect their distribution. Compartments for Distribution: Plasma Interstitial fluid Intracellular fluid Transcellular fluid ****Factors Affecting Distribution: Factors affecting distribution of drugs include those related to the drug and those related to the body Factors Related to the Drug: 1. Lipid Solubility: Greater the lipid solubility, more is the distribution and vice versa.

of 45 2. Molecular size: Larger the size, less is the distribution. Smaller sized drugs are more extensively distributed. 3. Degree of Ionization: Drugs exist as weak acids or weak bases when being distributed. Drugs are trapped when present in the ionized form, depending upon the pH of the medium. This fact can be used to make the drugconcentrated in specific compartments. 4. Cellular binding Drugs may exist in free or bound form. Bound form of drugs exists as reservoirs. The free and bound forms co-exist in equilibrium. Cellular binding depends on the plasma binding proteins. 5.Tissue binding: Different drugs have different affinity for different cells. All cells do not bind the same drugs. 6. Duration of Action: The duration of action of drugs is prolonged by the presence of bound form while the free form is released. This leads to a longer half life and duration of action of drug. 7. Therapeutic Effects: Bisphosphonate compounds bind with the bone matrix cells and strengthen them. They are used in the treatment of osteoporosis. 8. Toxic Effects: Chloroquinine can be deposited in the retina. Tetracycline can bind the bone material. It may also get bound to the enamel of the teeth. Factors Related to the Body: 1. Vascularity: Most of the blood passes through the highly profused organs (75%) while the remaining (25%) passes through the less profused areas. Therefore, most of the drugs go first to the highly profused areas. They may get bound to these organs. They are then redistributed to the less profused areas like the skin and the skeletal muscles. This phenomenon is common among the lipid soluble drugs. Example includes thiopentone sodium which is used as general anesthetic. When given, it goes to the brain producing its effects. It is then redistributed to the less profused organs. Because of high lipid solubility, it is accumulated in the fatty tissue for longer duration. Thus the clearance of the drug is slow, producing prolonged period of drowsiness (up to 24 hours). 2. Transport Mechanism: Different drugs are taken up by different compartments of the body differently. Lipid soluble drug move by passive transport which is non specific. Active transport occurs only where carrier proteins are present.

of 45 3. Blood Barriers: Different blood barriers exist. Blood brain barrier is present because of the delicacy of nervous tissue to avoid chemical insult to the brain. Structure: Endothelial cells and pericytes and glial cells form the barrier through which drugs cannot pass easily. Only selective passage takes place. Transporters: Certain efflux pumps or transporters exist through which drug can be effluxed as well. Example includes p-glycoprotein. Disruption: Disruption of barrier may occur, e.g. by inflamed meningitis. Drugs may pass which might be toxic as well as beneficial i.e. during meningitis penicillin can pass which has beneficial effects. 4. Placental Barriers: Trophoblastic tissue separates maternal blood from fetal blood. Different transporters are present. Efflux transporters cause efflux back of the drugs from the fetus to the mother. 5. Plasma Binding Proteins: Many proteins exist in the plasma. Plasma binding proteins include: a. Albumin: Albumin is the most abundant plasma protein. It has higher affinity for acidic drugs but the capacity is low. Only two sites are present for binding drug molecules. However, albumin can bind a large number of basic drugs but has lower attractive forces. Its capacity for binding basic drugs is more but the affinity is less. b. Globulins: Globulins can bind hormones, vitamins, etc. c. Glycoproteins: Alpha glycoproteins mainly bind basic drugs. Their levels are increased during stress, trauma and surgery. It is during these times that their more amounts are required. d. Lipoproteins: Lipoproteins also bind some drugs. 6. Free and Bound Forms of Drugs: When drug enters the body, it exists in: Free form Bound form These two forms have certain effects on the pharmacokinetics and pharmacodynamics. Free forms are metabolized and excreted because they can cross the glomerular membrane. Free forms of drugs are therapeutically active. Bound forms of drugs act as a reservoir. They are not metabolized or excreted and do not have therapeutic or toxic effect. When the free form is used up, drug is released from the reservoirs. Thus both forms exist in equilibrium. 7. Drug Interactions: If a number of drugs are simultaneously given, or drugs interact with endogenous substances, one drugcan be displaced by another. Example includes interaction of sulphonamide with bilirubin, with the result that bilirubin is displaced which may cause kernicterus in babies. Drug interactions occur if both drugs bind to same protein and depend on: a.Affinity:Higher the affinity of the drug, more easily can it displace the other drug.

of 45 b.Concentration:Higher concentration drug can displace the lower concentration drugs. This phenomenon might be of consequence in the following situations: a. Volume of Distribution: The volume into which the drug is distributed is known as the volume of distribution. If drug can be distributed to different body compartments, it is diluted when goes to the different compartment. If the drug has a small volume of distribution, it stays in the same compartment producing toxic effects. (Explained separately) Toxic effects are produced when more drug is present in free form than usual. b. Therapeutic Index: Therapeutic index is the safety margin, the range in which the drug is safe. If drug has a large therapeutic index, then large concentrations of the drug are safe. If it has a small therapeutic index, it may move out of the safe range and cause toxic effects. Thus the drug displacement phenomenon is significant in low therapeutic index drugs. 8. Disease States: Different diseases affect the distribution of drugs. Renal diseases cause hypoalbuminemia. Due to less proteins, toxic levels of free drugs may be present. Uremic by-products are also produced which compete with drugs. Hepatic diseases cause decreased synthesis of proteins causing hypoalbuminemia. Free drugs may be present in toxic levels and bilirubin by products increase as well. Thus drug, whose doses have to be adjusted to produced desired effects (may be reduced even to half). 9. DrugReservoirs: Drugs are stored and are released slowly which affects their pharmacokinetics and pharmacodynamics. Drug reservoirs include: Plasma proteins Liver Adipose Bone Placenta Breast milk Transcellular fluid reserves Other body tissues- eye, kidneys, skeletal muscles, skin 10. Volume of Distribution: The apparent or hypothetical volume in the body into which a drug distributes. Redistribution of drugs: The movement of drug from more perfused organs to less perfused organs is known as redistribution of drugs. Initially the heart, liver, kidneys, brain and other highly perfused organs receive most of the drug, during the first few minutes after absorption.

of 45 Metabolism Drugs are eliminated from the body either unchanged through the kidneys and bile, or they may undergo chemical changes that allow them to be more easily excreted. The process of undergoing chemical changes is called biotransformation, or metabolism. As previously noted, anything absorbed through the GI tract goes directly into the portal circulation that feeds into the liver. The liver is adapted to clear toxins from the body and is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues. The kidneys cannot efficiently excrete highly fat-soluble drugs that readily cross cell membranes because they are reabsorbed in the last stages of filtration. These compounds must first be metabolized in the liver to more water-soluble compounds and then removed. There are two types of metabolic processes drugs undergo in the liver. Most undergo one or both types of reactions.Once drug effect is distributed it then undergo metabolism in the liver. Many drugs undergo first-pass metabolism where a significant amount of dose is inactivated by liver enzymes. This is kept in mind while the formulation of drugs. Fewer drugs are converted into their active form in the liver after which they produce their desired activity. Metabolism occurs in II phases. Phase I reactions alter drug molecules either for phase-II reactions or for direct elimination. Phase I Metabolism: Phase I reactions are that pharmacokinetics metabolism that convert lipophilic drugs into more polar molecules. This occurs by introducing or unmasking a polar functional group, such as –OH or –NH2. Phase I reactions usually involve reduction, oxidation, or hydrolysis. Phase 1 depends upon following: Phase I Reaction utilizing 450 system Inducer Inhibitors Phase II Metabolism: This phase consists of conjugation reactions. If the metabolite from phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many phase I metabolites are still too lipophilic to be excreted. Elimination Excretion is the elimination of the substance from the body. In rare cases, not all substances are eliminated; some drugs irreversibly accumulate in a tissue in the body. Drugs must be sufficiently polar to be eliminated from the body. Removal of drugs from the body occurs via a number of routes, the most important being elimination through the kidney into the urine.The rate of excretion depends upon the rate of distribution and metabolism as well as kidney functioning. Excretion is the passage out of systemically absorbed drug. Drugs and their metabolites are excreted in 1. Urine through the kidney. It is the most important channel of excretion for majority of drugs. 2.Faeces apart from the unabsorbed fraction, most of the drug present in faeces is derived from bile. 3. Exhaled air gases and volatile liquids are eliminated by lungs, irrespective of their lipid solubility. 4. Saliva and sweat are of minor importance for drug excretion.

of 45 PHARMACODYNAMICS Pharmacodynamics is defined as the response of the body to the drug. It refers to the relationship between drug concentration at the site of action and any resulting effects namely, the intensity and time course of the effect and adverse effects. Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs. The effects can include those manifested within animals, microorganisms, or combinations of organisms. Pharmacodynamics is affected by receptor binding and sensitivity, post receptor effects, and chemical interactions. Both pharmacodynamics and pharmacokinetics explain the drug's effects, which is the relationship between the dose and response. The pharmacologic response depends on the drug binding to its target. Duration of action The duration of action of a drug is the length of time that particular drug is effective. Duration of action is a function of several parameters including plasma half-life, the time to equilibrate between plasma and target compartments, and the off rate of the drug from its biological target. Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other methods of ingestion such as smoking or injection can take as little as seconds to minutes to take effect. The determination of the onset of action, however, is not completely dependent upon route of administration. There are several other factors that determine the onset of action for a specific drug, including drug formulation, dosage, and the patient receiving the drug. Dose of a drug Dose:The quantity to be admnistreted at one time as a specified amount of medicine. A dose of medicine or a drug is a measured amount of it which is intended to be taken at one time. Dose is the single unit of a drug that is given at fixed time in a specific form. Dose by definition is the amount of a substance administered at one time. However, other parameters are needed to characterize the exposure to xenobiotics. The most important are the number of doses, frequency, and total time period of the treatment. For example: 650 mg acetaminophen (Tylenol® products) as a single dose. 500 mg penicillin every 8 hours for 10 days. 10 mg DDT per day for 90 days

of 45 Different types of dose: An effective dose (ED) in pharmacology is the dose or amount of drug that produces a therapeutic response or desired effect in some fraction of the subjects taking it. The term effective dose is used when measurements are taken in vivo. Fractionateddose a fraction of the total dose prescribed, as of chemotherapy or radiation therapy, to be given atintervals, usually during a 24-hour period. Infectivedose(ID) that amount of a pathogenic agent that will cause infection in susceptible subjects. Lethaldose(LD) that quantity of an agent that will or may be sufficient to cause death. Loading dose a dose of medication, often larger than subsequent doses, administered for the purpose of establishing a therapeutic level of the medication. A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life. Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate therapeutic level, but this also means that, without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level. Maintenance dose the amount of a medication administered to maintain a desired level of the medication in the blood. Median curative dose (CD50) a dose that abolishes symptoms in 50 percent of test subjects. Median effective dose (ED50) a dose that produces the desired effect in 50 percent of a population. Median infective dose (ID50) that amount of pathogenic microorganisms that will produce demonstrable infection in 50 percent of the test subjects. Median lethal dose (LD50) the quantity of an agent that will kill 50 percent of the testsubject s; in radiology, the amountof radiation that will kill, within a specified period, 50 percent of individuals in a large group or population. Thresholddose the minimum dose of ionizing radiation, a chemical, or a drug that produce a detectable degree of any given effect. Tolerancedose the largest quantity of an agent that may be administered without harm. Called also maximum tolerated dose. will

of 45 DOSAGE FORM Dosage Form (DF) is defined as the physical form of a dose of a chemical compound used as a drug or medication intended for administration or consumption. Dosage forms are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration and apportioned into a particular dose. Types of dosage form: ORAL Pill, i.e. tablet or capsule syrups Specialty tablet like buccal, sub-lingual, or orally-disintegrating Liquid solution or suspension (e.g., drink o r syrup) Powder or liquid or solid crystals Pastes (e.g., Toothpaste) Buccal flim Inhalational Aerosol Inhaler Nebulizer Smoking Vaporizer Suppository Vaginal Rectal Urethral Suppositories Nasal suppositories Therapeutic window A usually short time interval (as after a precipitating event) during which a particular therapy can be given safely and effectively.The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects. Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include digoxin, lithium, and warfarin. Therapeutic window is a range of doses that produces therapeutic response without causing any significant adverse effect in patients. Topical Cream, gel, liniment or balm, l otion, or ointment Ear drops Eye drops Skin patch Vaginal rings Dermal patch Powder/Talc Parenteral Intradermal (ID) Subcutaneous (SC) Intramuscular (IM) Intraosseous (IO) Intraperitoneal (IP) Intravenous (IV) Ophthalmic Liquid solution Drops Cream

of 45 Generally therapeutic window is a ratio between minimum effective concentrations (MEC) to the minimum toxic concentration (MTC). The levels of drug should always be between MEC and MTC in order to provide risk free therapeutic effects. If any drug crosses MTC then it will surely elicit toxic effects and if drug is unable to surpass MEC then it will cause therapeutic failure. MEC is also called as minimum inhibitory concentration (MIC).Therapeutic window is also termed as safety window and can be quantified by therapeutic index. Therapeutic index The ratio between the toxic dose and the therapeutic dose of a drug, used as a measure of the relative safety of the drug for a particular treatment. Therapeutic index (TI) refers to any of the several indices that are used for measuring a drug's safety. The most common TI is the ratio of the median lethal dose(median toxic dose) to the median effective dose of a drug. The formula for TI is: Therapeutic Index: LD50/ED50 (animal studies) or Therapeutic Index: TD50/ED50 (human studies) Where LD50 is the minimum amount of drug that causes adverse effects in 50% of the population. LD50 could also be replaced with Toxic dose (TD50) ED50 is the quantity of a drug that can produce desired therapeutic effects in 50% of the population. Such types of studies are usually conducted in animal models Ideally any drug that requires more amount to produce toxic or adverse effects in 50% of population will have wider therapeutic index and vice versa. Drugs having wider therapeutic index are safer in comparison to those having low therapeutic index because minor modification in the dose of such drugs (aspirin, acetaminophen) will not produce toxic effects.

of 45 For examples NSAIDs have wider therapeutic index and warfarin has narrow therapeutic index as it has therapeutic index less than two. A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective. The larger the therapeutic index (TI), the safer the drug is. If the TI is small (the difference between the two concentrations is very small), the drug must be dosed carefully and the person receiving the drug should be monitored closely for any signs of drug toxicity. Significance: While prescribing drugs, healthcare providers rely on their clinical experience and the results of drug trials that determine the TI of a drug. The larger value of TI indicates that there is a wide margin between the toxic and effective dose, whereas a smaller value indicates that there is a narrow margin between the effective and toxic dose. In case of drugs that have a low TI, even a small increase in the dosage can produce toxic effects. Additional care must be taken while prescribing a drug with a narrow TI. Therefore, the pharmaceutical industry has been making efforts to replace NTI drugs with drugs with higher TIs. Healthcare providers mostly prescribe drugs that have a wide margin of safety. However, they might sometimes prescribe NTI drugs when the medical condition is of a serious nature, and other safer options are not available. In such cases, monitoring the effects of the drug becomes essential. Limitations: Initially, the ratio of the LD50 and ED50 was determined through animal studies. It must be noted that the ratio measured by animal studies might not be very accurate when it comes to humans. Also, human subjects cannot be used for determining a median lethal dose, for obvious reasons. To add to that, using animals for determining a lethal dose raises ethical issues. While this ratio might not give an accurate estimate of toxicity in humans, even defining an effective dose might not be a simple task. Also, median values for animals or healthy individuals might not be right for individuals of different age groups or those affected by diseases.

of 45 DRUG AGONIST An agonist is a chemical that binds or blocks to a receptor and activates the receptor to produce a biological response. A substance that acts like another substance and therefore stimulates an action.Agonist is the opposite of antagonist. An agonist is a compound that can bind to and cause activation of a receptor, thus mimicking an endogenous ligand or neurotransmitter. An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule.Example:heroin is an opioid agonist. It binds to opioid receptors that control pleasure and pain, the result being a feeling of euphoria and well being. An agonist is a molecule that can bind and activate a receptor to induce a biological reaction.The activity mediated by agonists are opposed by antagonists, which inhibit the biological response induced by an agonist. The level of agonist required to induce a desired biological response is referred to as potency Many drugs work by stimulating or blocking drug receptors. A drug attracted to a receptor displays an affinity for that receptor. When a drug displays an affinity for a receptor and stimulates it, the drug acts as an agonist. An agonist binds to the receptor and produces a response. This ability to initiate a response after binding with the receptor is referred to as intrinsic activity. Types of agonist: Direct binding agonist: The first act just like a neurotransmitter, binding directly to the receptor site, this direct bind allows the recipient to experience the effects of the drug as if they were released directly into brain. Example: Dopamine, Nicotine, apomorphine etc. Indirect-acting agonist :In pharmacology, an indirect agonist or indirect-acting agonist is a substance that enhances an endogenous neurotransmitter but has neurotransmitter receptor itself. Indirect agonists work through varying mechanisms to achieve their effects, including transporter blockade, induction of transmitter release, and inhibition of transmitter breakdown. Example: morphine ,cocaine etc. Further classification of agonist: Physiological Agonists: It creates same bodily response but does not bind to the same receptor.Physiological agonist describes the action of a substance which ultimately produces the same effects in the body as another substance as if they were both agonists at the same receptor without actually binding to the same receptor. the specific agonist activity release or action of the no at

of 45 *Example of this type of agonist is the activation of NF-kappa B by both cytokines (Interleukin [IL]-6, IL-1, and tumor necrosis factor) and environmental stimuli via signaling through the associated cytokine receptors and pathogen recognition receptors, respectively. *Epinephrine induces platelet aggregation, and so does hepatocyte growth factor (HGF). Thus, they are physiological agonists to each other. Endogenous agonist: In pharmacology, an endogenous agonist for a particular receptor is a compound naturally produced by the body which binds to and activates that receptor. Endogenous agonists constitute internal factors which induce a biological response. For example, the primary endogenous agonist for serotonin receptors is serotonin, and the primary endogenous agonist for dopamine receptors is dopamine. In general, receptors for small molecule neurotransmitters such as serotonin will have only one endogenous agonist,but often have many different receptor subtypes.On the other hand, neuropeptide receptors tend to have fewer subtypes, but may have several different endogenous agonists. This allows for a high degree of complexity in the bodies signalling system, with different tissues often showing quite distinct responses to a particular ligand. Superagonist: In the field of pharmacology, a superagonist is a type of agonist that is capable of producing a maximal response greater than the endogenous agonis for the target receptor, and thus has an efficacy of more than 100%.The most common form of superagonists are drugs. For example, TGN1412 is a superagonist of CD28, resulting in the polyclonal activation of T cells and is associated with the risk of pathogenic cytokine production if used at a high dose. For example, goserelin is a superagonist of the gonadotropin-releasing hormone receptor. Full agonists: It binds and active areceptor producing full efficacy at the receptor.Full agonists bind to and activate a receptor with the maximum response that an agonist can elicit at the receptor.Full agonists are able to fully bind to and activate their cognate receptor, thereby inducing the complete response capable of that receptor. One example of a drug that can act as a full agonist is isoproterenol, which mimics the action of adrenaline at β adrenoreceptors. Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the central nervous system. However, a drug can act as a full agonist in some tissues and as a partial agonist in other tissues, depending upon the relative numbers of receptors and differences in receptor coupling Partial agonist: In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic effects when both a full agonist and partial agonist are present, the partial agonist actually acts as a competitive

of 45 antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone.Clinically, partial agonists can be used to activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present. Some currently common drugs that have been classed as partial agonists at particular receptors include buspirone, aripiprazole, buprenorphine, nalmefene and norclozapine pindolol, nalorphine, acebutol. Inverse agonist: An inverse agonist binds to the same receptor as an agonist; however, it exerts the opposite biological response of an agonist. An inverse agonist differs from an antagonist in that rather than simply inhibiting the response of the agonist, the opposing response is induced. An inverse agonist is an agent that binds to the same receptor binding site as an agonist for that receptor and inhibits the constitutive activity of the receptor. Inverse agonists exert the opposite pharmacological effect of a receptor agonist, not merely an absence of the agonist effect as seen with an antagonist. An example is the cannabinoid inverse agonist rimonabant. Nearly all antihistamines acting at H1 receptors and H2 receptors have been shown to be inverse agonists. Co-agonist: A co-agonist works with other co-agonists to produce the desired effect together. A co- agonist requires the combination of two or more agonists to elicit a particular biological response. NMDA receptor activation requires the binding of both glutamate, glycine and D- serine co-agonists. For example, the activation of infected macrophages to produce nitric oxide is dependent on the binding of bacterial ligands, IFN-gamma, and TNF, to their respective receptors. Irreversible Agonists: Irreversible agonists are agonists that form a permanent association with a receptor via the formation of covalent bonds. An irreversible agonist is a type of agonist that binds permanently to a receptor in such a manner that the receptor is permanently activated. It is distinct from a reversible agonist in that the association of an agonist to a receptor is reversible, whereas the binding of an irreversible agonist to a receptor is, at least in theory, irreversible. Some of the most well-characterized irreversible agonists are μ-opioid receptor agonists, such as naloxazone and oxymorphazone. Oxymorphazone is an example of an irreversible agonist. In practice, the distinction may be more a matter of degree, in which the binding affinity of an irreversible agonist is some orders of magnitude greater than that of an agonist. ,

of 45 Selective Agonists: Selective agonists are specific to a particular receptor. For example, IFN-gamma is a selective agonist of the IFN-gamma receptor. Buspirone is selective for 5-HT1A(serotonin) DRUG ANTAGONIST A chemical that binds to a receptor but does not produce a physiological response,thereby blocking the action of agonist chemicals. An antagonist is a type of drug that blocks a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers; examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, and binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not normally involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding.The majority of drug antagonists achieve their potency by competing with endogenous substrates at structurally defined binding sites on receptors. Types of antagonist: In contrast to agonist drugs which bind to the neurotransmitters in the brain, antagonist drugs do the opposite: they block the brain’s neurotransmitters. There are two main types of antagonist drugs: direct-acting antagonists and indirect-acting antagonists. Direct-acting Antagonist:This set of antagonists work by taking up the space present on receptors otherwise occupied by neurotransmitters. The end result is that neurotransmitters themselves are blocked from binding to the receptors. The most common example of a drug belonging to this category is Atropine. Indirect-acting Antagonist:Drugs that work by inhibiting the release or production of neurotransmitters are known as indirect-acting antagonists. An example of this type of drug is Reserpine. Differences between Agonist vs. Antagonist Drugs: Agonists and antagonists are known to be key players in human body and in pharmacology. Agonist and antagonist act in opposite directions. When agonist produces an action, antagonist opposes the action. First of all when talking of muscles, agonist is that works with muscles and antagonist is that works against the muscles. Agonist works when the muscles relax and antagonist works when

of 45 muscles contract. Agonists can be called as ‘prime movers’ as these very much responsible for producing specific movements. Agonist is a substance, which combines with the cell receptor to produce some reaction that is typical for that substance. On the other hand, antagonist is a chemical, which opposes or reduces the action. In medicines, an agonist ties to a receptor site and causes a response whereas an antagonist works against the drug and blocks the response. While agonists stimulate an action, antagonists sit idle, doing nothing. Agonists are also chemicals or reactions, which help in binding and also altering the function of the activity of receptors. On the other hand, antagonists though help in binding receptors, they do not alter its activity. When agonist is a compound that impersonate the action of neurotransmitter, antagonist blocks the action of neurotransmitter. Agonists combine with other chemical substances and promote some action. On the contrary, antagonists after combining with certain chemical substances only interfere with its action. Agonist has been derived from late Latin word agnista, which means contender. Antagonist has been derived from Latin antagonista and from Greek antagonistes, which means “competitor, rival or opponent.” Agonist Drugs Antagonist Drugs Taken from a Latin word, “agnista” meaning contender. signify being ‘rival, competitor or opponent.’ Derived from both Greek and Latin words that Aids in the production or enhancement of an action. Stimulates an action Opposes the action of agonist and blocks reception. Sit idle and do nothing while agonists are working. The response is blocked by working against the drug. Works during the contraction. They tend to manage the status-quo of the receptors by staying away from altering its activity although they might help in getting receptors bound. A response is caused when the agonists bind to the receptor site. Works at the time of relaxation of muscles. Can be described as reactions or chemicals that function by changing the activity or function of receptors and helps getting bound to the receptors Imitates the action of neurotransmitter. The action of neurotransmitter is obstructed phase of muscle Drug Synergism Synergism comes from the Greek word "synergos" meaning working together. It refers to the interaction between two or more "things" when the combined effect is greater than if one added the "things" on their own (a type of "when is one plus one is greater than two" effect).In toxicology, synergism refers to the effect caused when exposure to two or more chemicals at one time results in health effects that are greater than the sum of the effects of

of 45 the individual chemicals. When chemicals are synergistic, the potential hazards of the chemicals should be re-evaluated, taking their synergistic properties into consideration. Synergism is a coordinated or correlated action of two or more agents so that the combined action is greater than the effect of each acting separately. Interaction between two or more agents, entities, factors, or substances that produces an effect greater than the sum of their individual effects.Also called synergetic effect or synergistic effect that is opposite of antagonism. Combinations of drugs are widely used because they often provide therapeutic benefits over individual drugs. While the mechanisms of synergism can change from situation to situation, most of the time there appears to be an effect on the enzymes that regulate or influence the way our bodies work. There are various examples including: (a) Carbon tetrachloride and ethanol (ethyl alcohol) are individually toxic to the liver, but together they produce much more liver injury than the sum of their individual effects on the liver. (b) The much higher incidence of lung cancer resulting from occupational exposure to asbestos in smokers (compared to exposed non-smokers). (c) The toxicity of some insecticides notably pyrethrin (from chrysanthemums) and synthetic pyrethrins (pyrethroids) can be increased many times by the addition of compounds which themselves are not insecticides. These synergists are sesamin, sesamolin, piperonyl butoxide, MGK-264 (bicycloheptenedicarboximide) and sesamex. Piperonyl butoxide is perhaps the most widely used synthetic pyrethrin synergist. The insecticide activity of pyrethrins increases tenfold when 1 part piperonyl butoxide is mixed with 9 parts pyrethrin. There are no reports available on toxic effects on humans resulting from the exposure to piperonyl butoxide. (d) Barbiturate drugs have a greater effect on the central nervous system (CNS) by causing CNS depression when taken with general anesthetics, alcohol (acute consumption) narcotic analgesic (pain reliever) and other sedative hypnotic drugs. Side Effects of Drug These are unwanted but often unavoidable pharmacodynamic effects that occur at therapeutic doses. Generally, they are not serious, can be predicted from the pharmacological profile of a drug and are known to occur in a given percentage of drug recipients. Reduction in dose, usually ameliorates the symptoms. A side effect may be based on the same action as the therapeutic effect, e.g. atropine is used in pre-anaesthetic medication for its anti-secretory action. The same action produces dryness of mouth as a side effect. Glyceryl trinitrate relieves angina pectoris by dilating peripheral vasculature which is also responsible for postural hypotension and throbbing headache. The side effect may also be based on a different facet of action, e.g. promethazine produces

of 45 sedation which is unrelated to its antiallergic action; estrogens cause nausea which is unrelated to their antiovulatory action. An effect may be therapeutic in one context but side effect in another context, e.g. codeine used for cough produces constipation as a side effect, but the latter is its therapeutic effect in traveller’s diarrhoea; depression of A-V conduction is the desired effect of digoxin in atrial fibrillation, but the same may be undesirable when it is used for CHF. Many drugs have been developed from observation of side effects, e.g. early sulfonamides used as antibacterial were found to produce hypoglycaemia and acidosis as side effects which directed research resulting in the development of hypoglycaemic sulfonylureas and carbonic anhydrase inhibitor—acetazolamide The secondary response that produce by a drug that may be adverse or undesirablewith primary or intended therapeutic dose is called side effect of a drug.In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug. Developing drugs is a complicated process, because no two people are exactly the same, so even drugs that have virtually no side effects, might be difficult for some people. Also, it is difficult to make a drug that targets one part of the body but that doesn’t affect other parts, the fact that increases the risk of side effects in the untargeted parts. Occasionally, drugs are prescribed or procedures performed specifically for their side effects; in that case, said side effect ceases to be a side effect, and is now an intended effect. For instance, X-rays were historically used as an imaging technique; the discovery of their oncolytic capability led to their employ in radiotherapy. Example of therapeutic side effects: Bevacizumab (Avastin), used to slow the growth of blood vessels, has been used against dry age-related macular degeneration, as well as macular edema from diseases such as diabetic retinopathy and central retinal vein occlusion. Buprenorphine has been shown experimentally to be effective against severe, refractory depression. Bupropion (Wellbutrin), an anti-depressant, is also used as a smoking cessation aid. Carbamazepine is an approved treatment for bipolar disorder and epileptic seizures. Dexamethasone and betamethasone in premature labor, to enhance pulmonary maturation of the fetus. Doxepin has been used to treat angiodema and severe allergic reactions due to its strong antihistamine properties. Hydroxyzine, an antihistamine, is also used as an anxiolytic. Magnesium sulfate in obstetrics for premature labor and preeclampsia. Methotrexate (MTX), approved for the treatment of choriocarcinoma, is frequently used for the medical treatment of an unruptured ectopic pregnancy. 

of 45 Adverse effect Adverse effect is ‘any undesirable or unintended consequence of drug administration’. It is a broad term, includes all kinds of noxious effect—trivial, serious or even fatal. All drugs are capable of producing adverse effects, and whenever a drug is given a risk is taken. The magnitude of risk has to be considered along with the magnitude of expected therapeutic benefit in deciding whether to use or not to use a particular drug in a given patient, e.g. even risk of bone marrow depression may be justified in treating cancer, while mild drowsiness caused by an antihistaminic in treating common cold may be unacceptable. Adverse effects may develop promptly or only after prolonged medication or even after stoppage of the drug. Adverse effects are not rare; an incidence of 10–25% has been documented in different clinical settings. They are more common with multiple drug therapy and in the elderly. Difference between side effect and adverse effect: Adverse effect harmful & undesirable hinder the treatment & leads to more complications more severe & life threatening Drug toxicity The critical or fatal reaction to an erroneous dosage of medication is called drug toxicity. Toxicity refers to how poisonous or harmful a substance can be. In the context of pharmacology, drug toxicity occurs when a person has accumulated too much of a drug in his bloodstream, leading to adverse effects on the body. Drug toxicity may occur when the dose given is too high or the liver or kidneys are unable to remove the drug from the bloodstream, allowing it to accumulate in the body. Drug toxicity refers to the level of damage that a compound can cause to an organism. The toxic effects of a drug are dose-dependent and can affect an entire system as in the CNS or a specific organ such as the liver. Drug toxicity usually occurs at doses that exceed the therapeutic efficacy of a drug; however, toxic and therapeutic effects can occur simultaneously. It can be assessed at the behavioral or physiological level. Behaviorally, drug toxicity can be exhibited in a variety of ways, for example, decreases in locomotor activity, loss of motor coordination, cognitive impairment. Examples of physiological effects include lesions to tissue, neuronal death, and disrupted hormonal cycles. These are the result of excessive pharmacological action of the drug due to over dosage or prolonged use. Over dosage may be absolute (accidental, homicidal, suicidal) or relative (i.e. usual dose of gentamicin in presence of renal failure). The manifestations are predictable and dose related. They result from functional alteration (high dose of atropine causing delirium) or drug induced tissue damage (hepatic necrosis from paracetamol over dosage). The CNS, Side effect therapeutic & harmful do not hinder the main effect of the drug mild & self resolving

of 45 CVS, kidney, liver, lung, skin and blood forming organs are most commonly involved in drug toxicity. Types of toxicity: Acute toxicity describes the adverse effects of a substance that result either from a single exposureor from multiple exposures in a short period of time.To be described as acute toxicity, the adverse effects should occur within 14 days of the administration of the substance. Acute toxicity is distinguished from chronic toxicity, which describes the adverse health effects from repeated exposures, often at lower levels, to a substance over a longer time period Chronic toxicity, the development of adverse effects as a result of long term exposure to a contaminant or other stressor, is an important aspect of aquatic toxicology. Adverse effects associated with chronic toxicity can be directly lethal but are more commonly sublethal, including changes in growth, reproduction, or behavior. Chronic toxicity is in contrast to acute toxicity, which occurs over a shorter period of time to higher concentrations. Various toxicity tests can be performed to assess the chronic toxicity of different contaminants, and usually last at least 10% of an organism’s lifespan. Occurrence: Drug toxicity can occur as a result of over-ingestion of a medication having too much of a drug in a person's system at once. This can happen if the dose taken exceeds the prescribed dose, either intentionally or accidentally. However, with certain medications, drug toxicity can also occur as an adverse drug reaction (ADR). In this case, the normally given therapeutic dose of the drug can cause unintentional, harmful and unwanted side effects. In some cases, such as with the drug lithium, the threshold between what is an effective dose and what is a toxic dose is very narrow. What is a therapeutic dose for one person might be toxic to another person. Drugs with a longer half-life can build up in a person's bloodstream and increase over time. Additionally, factors such as age, kidney function, and hydration can affect how quickly your body is able to clear a medication from your system. This is why medications such as lithium require frequent blood testing to keep track of the levels of the drug in your bloodstream. Signs and Symptoms: The signs and symptoms of toxicity differ depending on the medication. In the case of lithium, different symptoms can occur depending on whether the toxicity is acute or chronic. Problems with vital signs (temperature, pulse rate, respiratory rate, blood pressure) are possible and can be life-threatening. Vital sign values can be increased, decreased, or completely absent. Sleepiness, confusion, and coma are common and can be dangerous if the person breathes vomit into the lungs (aspiration). Skin can be cool and sweaty, or hot and dry. Seizures (convulsions) may occur.

of 45 Chest pain is possible and can be caused by heart or lung damage. Shortness of breath may occur. Breathing may get rapid, slow, deep, or shallow. Abdominal pain, nausea, vomiting, and diarrhea are possible. Vomiting blood, or blood in bowel movements, can be life-threatening. Specific drugs can damage specific organs, depending on the drug Diagnosis: Acute toxicity is more easily diagnosed, as the symptoms will follow the one-time administration of a medication. Blood tests can also screen for levels of the medication in the person's bloodstream. Chronic toxicity is harder to diagnose. Stopping the medication and then "re- challenging" it, later on, is one method of testing whether the symptoms are caused by the medication. This method can be problematic, however, if the medication is essential and doesn't have an equivalent substitute. Treatment: There are several ways in which drug toxicity may be treated. If the toxicity is the result of an acute overdose, then a person may undergo stomach pumping to remove drugs that have not yet been absorbed. Activated charcoal may be given to bind the drugs and prevent them from being absorbed into the blood. For certain overdoses, other medicine may need to be given either to serve as an antidote to reverse the effects of what was taken or to prevent even more harm from the drug that was initially taken. The doctor will decide if treatment needs to include additional medicines. DRUG INTERACTIONS A drug interaction is an unintentional effect of using two (or more) drugs, or an interaction between a drug and food, beverage, or supplement. It is defined as the change in efficacy or toxicity of one drug by prior or concomitant administration of a second drug or other active substance. A drug interaction can be defined as an interaction between a drug and another substance that prevents the drug from performing as expected. This definition applies to interactions of drugs with other drugs (drug-drug interactions), as well as drugs with food (drug-food interactions) and other substances. HOW DO DRUG INTERACTIONS OCCUR? There are several mechanisms by which drugs interact with other drugs, food, and other substances. An interaction can result when there is an increase or decrease in: the absorption of a drug into the body; distribution of the drug within the body; alterations made to the drug by the body (metabolism); and

of 45 elimination of the drug from the body. Most of the important drug interactions result from a change in the absorption, metabolism, or elimination of a drug. Drug interactions also may occur when two drugs that have similar (additive) effects or opposite (canceling) effects on the body are administered together. For example, there may be major sedation when two drugs that have sedation as side effects are given, for example, narcotics and antihistamines. Another source of drug interactions occurs when one drug alters the concentration of a substance that is normally present in the body. The alteration of this substance reduces or enhances the effect of another drug that is being taken. The drug interaction between warfarin (Coumadin) and vitamin K-containing products is a good example of this type of interaction. Warfarin acts by reducing the concentration of the active form of vitamin K in the body. Therefore, when vitamin K is taken, it reduces the effect of warfarin. Examples of drug interactions Sometimes when two drugs interact, the overall effect of one or both of the drugs may be greater than desired. For example, both aspirin and blood-thinners like warfarin or Coumadin—used to protect against heart attack—help to prevent blood clots from forming. Using these medications together, however, may cause excessive bleeding. Other times, the overall effect of one or both of the drugs may be less than desired. For example, certain antacids can prevent certain medicines (such as antibiotics, blood- thinners and heart medications) from being absorbed into the blood stream. If this happens, the medicine may not work as well—or may not work at all. Vitamins and minerals also have the potential to interact with medications you're taking. For example, ferrous sulfate (iron supplements) can hinder the effects of some commonly used antibiotics. Certain foods, like grapefruit juice, can prevent the body from breaking down some medicines, which means the medicine may stay in your system longer. Alcoholic beverages can interact with many types of medicine and can be particularly dangerous to use with stimulants, sedatives, sleeping pills and prescription painkillers. For example, both prescription pain relievers and alcohol slow breathing. Taking too much of these together at the same time can cause someone to literally stop breathing Types: Drug-Drug Interaction:A change in a drug’s effect on the body when the drug is taken together with a second drug. A drug-drug interaction can delay, decrease, or enhance absorption of either drug. This can decrease or increase the action of either or both drugs or cause adverse effects.Examples: Fluoxetine and Phenelzine:The interaction can result in a central serotonin syndrome. Digoxin and Quinidine:The interaction can lead to a marked increase in plasma concentration levels of digoxin in more than 90% of patients.

of 45 Sildenafil and Isosorbide Mononitrate :Sildenafil may markedly increase the hypotensive effects of isosorbide mononitrate. Potassium Chloride and Spironolactone:The combination may result in hyperkalemia Clonidine and Propranolol:The combination may produce a mysterious hypertension. Warfarin and Diflunisal :shown to increase the risk for gastrointestinal (GI) bleeding and the anticoagulant response of warfarin. Theophylline and Ciprofloxacin:Concurrent administration may lead to toxic increases in theophylline. H2 blockers+PPI: Increase PH of stomach.  Drug-Food Interaction:A change in a drug’s effect on the body when the drug is taken together with certain foods (or beverages). Not all drugs are affected by food, and some drugs are affected by only certain foods. A drug-food interaction can delay, decrease, or enhance absorption of a drug. This can decrease or increase the action of the drug or cause adverse effects.Examples: Calcium-Rich Foods + Antibiotics:Dairy products such as milk, yogurt, and cheese can interfere with certain medications, including antibiotics such as tetracycline, doxycycline, and ciprofloxacin. Pickled, Cured, and Fermented Foods + MAIOs:This food category contains tyramine, which has been associated with a dangerous increase in blood pressure among patients taking monoamine oxidase inhibitors (MAIOs) and certain medications for Parkinson’s disease. Vitamin K-Rich Foods + Warfarin:Pharmacists should counsel patients taking warfarin to maintain a consistent intake of vitamin K and avoid introducing kale, spinach, and other leafy greens to their diets.Vitamin K is vital for the production of clotting factors that help prevent bleeding, but anticoagulants like warfarin exert their effect by inhibiting vitamin K. Therefore, an increased intake of the nutrient can antagonize the anticoagulant effect and prevent the drug from working. Alcohol + Prescription Stimulants:Patients should always be wary of mixing any medication with alcohol, but some interactions are more serious than others. For instance, ingesting alcohol while taking a prescription stimulant could cause the patient to not fully realize how intoxicated they are. This is especially true when the stimulant is being abused, but it can also happen when the patient takes the drug as prescribed Grapefruit and Grapefruit Juice + Statins:Patients should avoid eating grapefruit or drinking grapefruit juice particular statins.Compounds in grapefruit called furanocoumarin chemicals cause an increase in medication potency by interacting with enzymes in the small intestine and liver. This interaction partially inactivates a number of medications under normal circumstances Aspirin+Milk: Upset stomach Caffeine+Food: Rapid heart beat Drug-Disease Interaction:A drug-disease interaction is an event in which a drug that is intended for therapeutic use causes some harmful effects in a patient because of a disease or condition that the patient has. There are some diseases that alter the body's ability to metabolize, or break down, a drug so that it can have the intended effect. This can be true while taking some medications, in

of 45 of both prescription and over-the-counter drugs. When it is known that a patient has such a disease, care must be taken to choose therapeutic drugs accordingly and to adjust the doses when necessary.Example: Non-steroidal anti-inflammatory drugs, or NSAIDS, may be dangerous in the context of high blood pressure because they cause fluid retention. Antacids also cause fluid retention and often contain magnesium, which can affect the heart rhythm Patients with peptic ulcer disease should not take NSAIDS. Beta blockers are drugs commonly given for heart failure and hypertension, but these must be given with caution to those with asthma because their blocking action on beta receptors, which is therapeutic for hypertension, also causes constriction of the airways. Nicotine+High blood pressure: Increased heart rate. Drug tolerance Tolerance is a person's diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug. People can develop tolerance to both illicit drugs and prescription medications. As stated, tolerance is a physical effect of repeated use of a drug, not necessarily a sign of addiction. For example, patients with chronic pain frequently develop tolerance to some effects of prescription pain medications without developing an addiction to them. Drug tolerance is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects, however this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction.The process of tolerance development is reversible and can involve both physiological factors and psychological factors. The National Institute on Drug Abuse (NIDA)briefly defines drug tolerance as, “a state in which an organism no longer responds to a drug.” It is defined by progressively diminished response to drug at a certain dose following repeated exposure, and requiring increasing dosages to achieve the desired effect on subsequent administrations. Drug tolerance refers to changes in the potency (higher effective dose required), the effectiveness (decreased maximal effect), or both aspects of the drug. There are four key characteristics of drug tolerance: Reversible, once exposure to the drug is discontinued. Dependent on the dose and frequency of drug exposure. Variable time course and extent of tolerance development between different drugs. Not all drug effects develop the same amount of tolerance. If we were to take a look inside the body, we could see this happening on a cellular level. For example, when a person uses a drug like morphine, the morphine will bind to opioid receptors in the brain, spinal cord, and other parts of the body and activate it. Over time, as

of 45 the person continues to use morphine, their body will adjust to the presence of the drug and the effects of the morphine will be severely diminished. At this point, the drug user will have to take a larger dose of the morphine to feel the same desirable effects they are used to. There are 7 types of tolerance to chemical substances, all of which have at least some impact on the processes of drug abuse and addiction. Tolerance invariably leads many addiction-prone people to use more and more of a substance in order to achieve the same results, but there’s more to it than this alone. In fact, most people are unaware that there is more than one type of tolerance. The following are the 7 types and their descriptions. Acute:Acute tolerance also known as tachyphylaxis.Acute tolerance refers to a process whereby the brain and central nervous system enact processes to immediately mitigate the effects of a given substance. The most common substances used as examples of this are nicotine – which not only creates acute tolerance but in some cases may increase tolerance throughout the day for some smokers – and hallucinogens like psilocybin mushrooms, LSD, Ecstasy, Philosopher’s Stones, Peyote and others.Acute tolerance means that in most cases the effects of these drugs will be minimized by the reduction of receptor sites in the brain for each particular substance, and in some cases for certain classes of substances. Behavioral:Experienced drug users demonstrate behavioral tolerance when they adjust their appearance, mannerisms and behavior in order to mask their drug use. Some chronic users are able to suddenly appear sober when presented with a stress such as authority, and then return to being “high” when the threat passes. This can also occur when a person who is high is subjected to a sudden and dramatic experience, where the brain will quickly refocus on the new threat and the high will diminish or be eliminated.The human brain is a remarkable organ and is able to quickly adapt to many different chemicals. Acute tolerance allows the brain in part to use areas of the brain not affected by the substance in question, then revert to its normal state when the drug is not present, barring of course long-term changes related to chronic drug abuse and addiction. Dispositional:Part of the problem with many drugs – including cocaine, meth and heroin, is that the brain cannot dispose of the drugs on its own. In most cases the brain relies on the interactions between neurotransmitters and receptors, but drugs interrupt this process, leaving the brain helpless to respond. Dispositional tolerance refers to the body essentially taking this task over by speeding up the metabolism so that the blood can circulate the foreign substances quickly for removal by the liver. This reduces the effect of the drug and in general means that in order to achieve the same effects, addicts will need to increase their doses. Inverse:Inverse tolerance is not entirely understood, and in fact this type of tolerance has a dual-characteristic that makes it more challenging to analyze and comprehend. Inverse tolerance is effectively the same as the Kindling Effect, which refers to changes in the brain and central nervous system concerning the way chemicals are processed. The Kindling Effect refers to either a sensitization – such as chronic alcohol use and breakdown of the liver and thus the body’s ability to “handle” alcohol – or desensitization, where the effects of a chemical become more pronounced.Inverse tolerance can have a significant impact on subsequent relapses from recovery attempts, resulting in an increase in the severity and duration of symptoms related to withdrawal and post acute withdrawal.

of 45 Pharmacologic:This type of tolerance is the brain actively working to mitigate the effect of a foreign substance. Nerve cells, transmission processes, reuptake and receptor sites can be adjusted by the brain to become desensitized to the drugs, effectively producing an antidote to the substance or increasing the amount of receptor sites in order to diffuse the chemical across a wider spread of sites and thereby lessen its effects. Reverse:Often grouped together with Inverse Tolerance and Kindling, reverse tolerance refers exclusively to the increased sensitivity one experiences toward a particular drug as a result of the breakdown of the body’s ability to process the substance. Reverse tolerance usually occurs in chronic alcoholics whose livers have stopped functioning normally and thus permit alcohol to remain in the blood longer and in higher concentrations, resulting in a severe increased sensitivity to the substance. Select:This type of tolerance is not well-understood, but refers to the fact that in some cases the brain will selectively mitigate some effects of a substance, but not others. For instance, some people may smoke marijuana for a long period of time without obtaining the “euphoric” effect, despite the fact that other parts of the body – especially the lungs, throat, and cannabinol receptors, are clearly being affected.This could be dangerous in some cases where higher doses of a substance are taken in order to attempt to offset the select tolerance to a particular drug. For example, a person may not get the “high” they are seeking from heroin, despite the fact that the drug is having severe effects on other parts of the body. In order to get this high, the user may consume more than normal and in doing so poison their body without realizing it because they relate the potency, toxicity and effect of the drug to the high alone. This is a dangerous situation that could result in a fatal overdose. Drug dependence Drug dependence as a state of psychic and sometimes also physical, resulting from the interaction between a living organism and drug, characterized by behavioral and other responses that always include a compulsion to take the drugs on a continuous or periodic basis in order to experience its psychic effect and sometimes to avoid the discomfort of its absence. In medical terms, dependence specifically refers to a physical condition in which the body has adapted to the presence of a drug. If an individual with drug dependence stops taking that drug suddenly, that person will experience predictable and measurable symptoms, known as a withdrawal syndrome.A withdrawal syndrome is in discontinuation or dosage reduction of some types of medications and recreational drugs. The risk of a discontinuation syndrome occurring increases with dosage and length of use. Although dependence is often a part of addiction, non-addictive drugs can also produce dependence in patients. Drug dependence, is an adaptive state that develops from repeated drug administration, and which results in withdrawal upon cessation of drug use. Dependence is caused by changes in the body as a result of constant exposure to a drug. In the case of prednisone, the body adapts to repeated doses of the drug by decreasing its own cortisol production, which can leave the body without a baseline level of cortisol “support” a set of symptoms occurring

of 45 when prednisone use is stopped resulting in steroid withdrawal symptoms until the normal balance is re-established. Drug dependence is a medically treatable condition. The goal is to separate the patient from the drug slowly, instead of suddenly, to allow the body to readjust to normal functioning. For patients who have developed dependence as a side effect of taking a needed medication, a doctor can use the tapering method to minimize withdrawal. Types: Psychological dependence: It is said to have developed when the individual believes that optimal state of wellbeing is achieved only through the actions of the drug. The subject feels emotionally distressed if the drug is not taken. It may start as liking for the drug effects and may progress to compulsive drug use in some individuals who then lose control over the use of the drug. The intensity of psychological dependence may vary from desire to craving. Obviously, certain degree of psychological dependence accompanies all patterns of self medication. Physical dependence: It is an altered physiological state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium. Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome. Since the essence of the process is adaptation of the nervous system to function normally in the presence of the drug, it has been called ‘neuroadaptation’. Drugs producing physical dependence are-opioids, barbiturates and other depressants including alcohol and benzodiazepines. Stimulant drugs, e.g. amphetamines, cocaine produce little or no physical dependence. Symptoms of drug dependence: One can often determine if an addiction has turned into dependence by looking at behavior. When a person addicted to drugs hasn’t had them for a period of time, this can cause a physical reaction. Physical symptoms of withdrawal occur when the body becomes stressed without the drug. These symptoms include: anxiety depression muscle weakness nightmares body aches sweating nausea vomiting Signs of drug dependence: Sudden change in behavior Withdrawl from family members Careless about personal grooming Lose of interest in hobbies, sports & other favorite activities Changed sleeping pattern

of 45 Red or glassy eyes Sniffly or runny nose Treatment of drug dependence: At first need to stop using the drug immediately & then the following treatment can apply: Psychotherapy: It is a type of therapy used to treat emotional problems and mental health conditions. Psychotherapy can help eliminate or control troubling symptoms so a person can function better and can increase well-being and healing. It involves talking but sometimes other method may be used for e.g: art, music, drama, movement etc.Psychotherapy may be used in combination with medication or other therapies. Self-help groups: It also known as mutual help. These may help the recovering individual meet others with the same disorder which often boosts motivation and reduces feelings of isolation. They can also serve as a useful source of education, community, and information. Medications: It is a medical care provide by pharmacist whose aim is to optimize drug therapy & improve therapeutic outcomes for patients. A person might take medication on a continuous basis when recovering from a substance-related disorder and its related complications. However, people most commonly use medications during detoxification to manage withdrawal symptoms. The medication will vary depending on the substance that the person is dependent to. Longer-term use of medications helps to reduce cravings and prevent relapse, or a return to using the substance after having recovered from dependence. Detoxification: The goal of detoxification, also called "detox" or withdrawal therapy, is to enable one to stop taking the dependent drug as quickly and safely as possible. Detoxification is normally the first step in treatment. This involves clearing a substance from the body and limiting withdrawal reactions. Toxic substance may be natural or synthetic. Rehabilitation programs: Longer-term treatment programs for substance-related and addictive disorders can be highly effective and typically focus on remaining drug-free and resuming function within social, professional, and family responsibilities. Fully licensed residential facilities are available to structure a 24-hour care program, provide a safe housing environment, and supply any necessary medical interventions or assistance. Prevention: It is the best treatment to decrease the drug dependence.

of 45 Drug Addiction It is a pattern of compulsive drug use characterized by overwhelming involvement with the use of a drug. Procuring the drug and using it takes precedence over other activities. Even after withdrawal most addicts tend to relapse. Physical dependence, though a strong impetus for continued drug use, is not an essential feature of addiction. Amphetamines, cocaine, cannabis, LSD are drugs which produce addiction but little/no physical dependence. On the other hand, drugs like nalorphine produce physical dependence without imparting addiction in the sense that there is little drug seeking behaviour. Drug addiction is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). ACCORDING TO THE NATIONAL INSTITUTE ON DRUG ABUSE (NIDA),ADDICTION IS A“CHRONIC, RELAPSING BRAIN DISEASE THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND USE, DESPITE HARMFUL CONSEQUENCES”.IN OTHER WORDS, ADDICTION IS AN UNCONTROLLABLE OR OVERWHELMING NEED TO USE A DRUG, AND THIS COMPULSION IS LONG- LASTING AND CAN RETURN UNEXPECTEDLY AFTER A PERIOD OF IMPROVEMENT. Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations. This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. Addiction is characterized by inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of significant problems with one’s behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death Its characteristics include: (1) An overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means; (2) A tendency to increase the dose; (3) A psychic (psychological) and generally a physical dependence on the effects of the drug; (4) Detrimental effect on the individual and on society. (5) Withdrawl syndrome Cross-dependence It is the substitution of addiction to one drug to that of another-that second being less harmful to the addict's health, in theory. This is the ability of one drug to suppress the manifestations of physical dependence produced by another & to maintain the physically dependent state. It may be partial or complete & gives similar pharmacological action. When one drug is able to suppress the withdrawal signs and symptoms resulting from discontinued repeated administration of another drug, cross-dependence is said to occur.

of 45 A well-known example of cross-dependence is heroin and methadone: methadone has been prescribed by doctors to replace heroin, since it was originally thought to be a more benign and non-addictive option, which would eventually lead to opiate withdrawal altogether. Current thinking on that has changed, however, and there are those who contend that methadone is addictive itself. Difference between drug addiction & drug abuse: Drug dependence is typically defined as what causes tolerance and withdrawal (physical effects), while addiction is characterized by having more of a mental component. Dependence is physical; addiction is neurological. In traditional diagnoses, ‘addiction’ generally referred to a person’s physical reliance on alcohol, drugs, and others substances and behaviors, while ‘dependence’ was viewed more as the psychological reliance on the addictive behavior. It's possible to be dependent on a drug without being addicted . Drug abuse Refers to use of a drug by self medication in a manner and amount that deviates from the approved medical and social patterns in a given culture at a given time.The term conveys social disapproval of the manner and purpose of drug use. For regulatory agencies, drug abuse refers to any use of an ilicit drug. The two major patterns of drug abuse are: Continuous use: The drug is taken regularly, the subject wishes to continuously remain under the influence of the drug, e.g. opioids, alcohol, sedatives Occasional use: The drug is taken off and on to obtain pleasure or high, recreation (as in rave parties) or enhancement of sexual experience, e.g. cocaine, amphetamines, psychedelics, binge drinking (alcohol), cannabis, solvents (inhalation), etc. Effects: Some general consequences associated with drug abuse include interferences with work, school, or home life, such as job loss, poor work or school performance, suspension or expulsion from school, legal problems, loss of close friends, divorce, and child neglect. Of course, not every user is going to experience these long-term effects, but chronic use increases the likelihood of adverse consequences. Problems with the laws ,may cause organ damage, can leads to addiction.

of 45 Difference between drug abuse and drug dependence: Drug abuse The use of drug for non medicinal purpose is called drug abuse Drug dependence On repeated administration of certain drugs the individual may be both psychological & physiological dependent on them called drug dependence Drug abusers will continue to use even though their social life is falling apart and their financial stability is collapsing. Drug abuse refers to an individual who continues to use drugs even though they know it is having an adverse affect on their health and well being Psychological & physiological state does not present Withdrawl symptom will be less Short term effect Easy treatment Psychological & physiological state present Withdrawl symptom will be severe Long term effect Treatment difficult Drug idiosyncrasy An abnormal individual response to a drug causing an effect quite different from thatexpecte. Idiosyncracy is inherent in the person concerned and is usually due to a genetic anomaly. It may take the form ofhypersensitivity so that the normal effect is produced by a does which is a small fraction of the standard dose. Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. It is genetically determined abnormal reactivity to a chemical. The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction. As such, the type of reaction is restricted to individuals with a particular genotype.In addition, certain bizarre drug effects due to peculiarities of an individual (for which no definite genotype has been described) are included among idiosyncratic reactions, e.g.: • Barbiturates cause excitement and mental confusion in some individuals. • Quinine/quinidine cause cramps, diarrhoea, purpura, asthma and vascular collapse in some patients. • Chloramphenicol produces nondose-related serious aplastic anaemia in rare individuals. Idiopathic The term idiopathic is often used to describe a disease with no identifiable cause. It may be a diagnosis of exclusion; however, what specific minimum investigations need to be performed to define idiopathic is not always clear. This commentary describes the problems inherent in reaching a definition for the term idiopathic. An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin.

of 45 From Greek “idios” "one's own" and “pathos” "suffering", “idiopathy” means approximately "a disease of its own kind".For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause may not be readily apparent or characterized. In these cases, the origin of the condition is said to be idiopathic. With some other medical conditions, the root cause for a large percentage of all cases have not been established—for example, focal segmental glomerulosclerosis or ankylosing spondylitis; the majority of these cases are deemed idiopathic. Biological half life The time required for the body to eliminate half of an administered dose of any substance by regular physiological processes. The biological half life is approximately the same for stable and radioactive isotopes of a specific element.Also called metabolic half-life. No drug stays in your system forever. In pharmacology, the time it takes for a drug to decrease by half its plasma (blood) concentration is called its half-life (t1⁄2). Why Half-Life Matters: Drugs with a longer half-life take longer to work, but on the positive side, they take less time to leave your bloodstream. On the flip side, those with a short half-life become effective more quickly but are harder to come off of. In fact, drugs with very short half-lives can lead to dependency if taken over a long period of time. A drug's half-life is an important factor when it's time to stop taking it. Both the strength and duration of the medication will be considered, as will its half-life. This is important because you risk unpleasant withdrawal symptoms if you quit cold turkey. Withdrawal symptoms are caused by quickly getting off of some types of medication. When you are being weaned from this type of medication, the drug's half-life will be considered so that those with a longer half-life will take longer to come off of. Medication side effects occur usually when the blood level of the drug is not in its steady state. That's why it's important to follow the dosage and duration recommendations to the letter. Otherwise, the body will react and the effect of the drug will be either toxic, as in more than intended, or not therapeutic, as in ineffective for treatment. One impact of half-life is found in the SSRI antidepressants. People taking SSRIs with short half-lives are much more likely to experience SSRI discontinuation syndrome. People taking an SSRI with a long half-life such as Prozac need to wait far longer between stopping Prozac and starting a new antidepressant, such as an MAOI. Depending on biological half life drugs are classified as: Drugs with short half life:Shorter half-life drugs tend to take action quickly, and their effects may wear off rapidly as well. This may encourage a person who is abusing a short half-life drug to take more of it in a binge pattern, following doses on top of each other to prolong the effects.Examples of drugs with a short half-life

of 45 Cocaine: Cocaine has a very short half-life of less than an hour. The illegal drug cocaine takes effect quickly and wears off quickly, the National Highway Traffic Safety Association (NHTSA) reports. Heroin: The Drug Enforcement Administration (DEA) publishes that heroin is the most rapidly acting of all the opioid drugs, taking effect almost immediately. It has a short half-life of around 30 minutes. Drugs with long half lives: A long half-life drug, on the other hand, may stay in the body for longer than a person wants it to as the effects can be prolonged. Drugs with longer half-lives can be beneficial in the case of medicinal necessity; for instance, if a person only has to take a medication once daily and it remains active for 12-24 hours, this can be helpful instead of having to take more doses more often.Example: Methadone: One of the longest-acting opioid drugs, the prescription drug methadone has an elimination half-life of 8-59 hours and a vastly different analgesic duration of action of about 4-8 hours, the FDA Plasma half life "Time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%." By definition, the plasma concentration of a drug is halved after one elimination half-life. Therefore, in each succeeding half-life, less drug is eliminated. After one half-life the amount of drug remaining in the body is 50% after two half-lives 25%, etc. After 4 half- lives the amount of drug (6.25%) is considered to be negligible regarding its therapeutic effects.The half-life of a drug depends on its clearance and volume of distribution. The elimination half-life is considered to be independent of the amount of drug in the body. Half-life determines the length of the drug effect. It also indicates whether accumulation of the drug will occur under a multiple dosage regimen and it is essential to decide on the appropriate dosing interval. Bioavailabity Bioavailability refers to the rate and extent of absorption of a drug from a dosage form as determined by its concentration-time curve in blood or by its excretion in urine. It is a measure of the fraction (F) of administered dose of a drug that reaches the systemic circulation in the unchanged form. Bioavailability of drug injected i.v. is 100%, but is frequently lower after oral ingestion because- (a) the drug may be incompletely absorbed. (b) the absorbed drug may undergo first pass metabolism in the intestinal wall/liver or be excreted in bile. Incomplete bioavailability after s.c. or i.m. injection is less common, but may occur due to local binding of the drug.

of 45 In pharmacology, bioavailability (BA or F) is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%.However, when a medication is administered via other routes (such as orally), its bioavailability generally or may vary from patient to patient. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. The absolute bioavailability of a drug, when administered by an extra-vascular route, is usually less than one (i.e., F< 100%). Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora.Disease states affecting liver metabolism or gastrointestinal function will also have an effect.

of 45 Other factors may include, but are not limited to: Physical properties of the drug hydrophobicity, pKa, solubility The drug formulation immediate release, excipients used, manufacturing methods, modified release – delayed release, extended release, sustained release Whether the formulation is administered in a fed or fasted state Gastric emptying rate Circadian differences Interactions with other drugs/foods: oInteractions with other drugs (e.g., antacids, alcohol, nicotine) oInteractions with other juice, brassica vegetables Transporters: Substrate of efflux transporters foods (e.g., grapefruit juice, pomello, cranberry P-glycoprotein Health of the gastrointestinal tract Enzyme induction/inhibition by other drugs/foods: oEnzyme induction increased rate of metabolism e.g., Phenytoin induces CYP1A2, CYP2C9, CYP2C19, and CYP3A4 oEnzyme inhibition decreased rate of metabolism e.g., grapefruit juice inhibits CYP3A → higher nifedipine concentrations Individual variation in metabolic differences: oAge: In general, drugs are metabolized more slowly in fetal, neonatal, and geriatric populations oPhenotypic differences, enterohepatic circulation, diet, gender Disease state: oE.g., hepatic insufficiency, poor renal function Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation). In clinical trials, inter-individual variation is a critical measurement used to assess the bioavailability differences from patient to patient in order to ensure predictable dosing.

of 45 Drug accumulation Accumulation represents the relationship between the dosing interval and the rate of elimination for the drug. When the dosing interval is long relative to the time needed to eliminate the drug, accumulation is low. When the dosing interval is short relative to the time needed to eliminate the drug, accumulation is high. Thus, changing the dosing interval can change accumulation. The most common approach to the maintenance of drug therapy is the repeated administration regimen. In repeated administration, accumulation occurs when the drug is administered before the previous dose is completely eliminated. The amount of drug in the body will then progressively rise. When the drug is administered at a fixed dose and a fixed dosing interval, “accumulation occur because drug from previous dose has not been remove.” Accumulation of drug depend upon the dosing interval and elimination half life and is independent of the dose size. The progressive increase in the concentration of a chemical, drug, or other agent in an organis m or tissue, due to higherdoses than can be metabolised, or due to poor metabolism of the age nt; the amount of a drug or therapeutic agent in thebody, which after the drug has reached a st ate of equilibrium, is a function of the dose interval and the drug’sT1⁄2. Equilibrium usually requires a time interval of 4- to 6-times the drug’s half- life, and depends on the rates of absorption andelimination; the drug continues to accumulate until the amount of drug administered in a time period equals that eliminated in the same period. Factors in accumulation: Selective binding of the drug in tissues, concentration of fat soluble drugs in fat, absent or slow metabolism of the drug, slowexcretion of the drug, intercurrent illness; accumulation continues until the amount eliminated per dosage interval isequal to the amount administered during that time. First pass metabolism It is a process in which a drug administered by mouth is absorbed from the gastrointestinal tract and transported via the portal vein to the liver, where it is metabolized. As a result, in some cases only a small proportion of the active drug reaches the systemic circulation and its intended target tissue. First-pass metabolism can be bypassed by giving the drug via sublingual or buccal routes. The first-pass effect (also known as first-pass metabolism or pre systemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall. Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, demerol, cimetidine, and lidocaine.

of 45 After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver thus greatly reduces the bioavailability of the drug. In drug design, drug candidates may have good drug likeness but fail on first-pass metabolism, because it is biochemically selective. • The four primary systems that affect the first pass effect of a drug are the enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and hepatic enzymes. • In drug design, drug candidates may have good drug likeness but fail on first-pass metabolism, because it is biochemically selective. • Alternative routes of administration like suppository, intravenous, intramuscular, inhalational aerosol, transdermal and sublingual avoid the first-pass effect because they allow drugs to be absorbed directly into the systemic circulation. Note that the intravenous route also avoids the absorption phase. • Drugs with high first pass effect have a considerably higher oral dose than sublingual or parenteral dose. There is marked individual variation in the oral dose due to differences in the extent of first pass metabolism. Oral bioavailability is apparently increased in patients with severe liver diseases like Cirrhosis. It is increased if another drug competing with it in first pass metabolism given concurrently. Eg. propranolol and chlorpromazine. Plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, and α, β‚ and γ globulins. A drug in blood exists in two forms: bound and unbound. Depending on a specific drug's affinity for plasma protein, a proportion of the drug may become bound to plasma proteins, with the remainder being unbound. If the protein binding is reversible, then a chemical equilibrium will exist between the bound and unbound states, such that: Protein + drug ⇌ ⇌ Protein-drug complex Most drugs possess physicochemical affinity for plasma proteins and get reversibly bound to these. Acidic drugs generally bind to plasma albumin and basic drugs to α1 acid glycoprotein. Binding to albumin is quantitatively more important. Extent of binding depends on the individual compound; no generalization for a pharmacological or chemical class can be made (even small chemical change can markedly alter protein binding), for example the binding percentage of some benzodiazepines is: Flurazepam 10% , Alprazolam 70% , Lorazepam 90%, Diazepam 99% Increasing concentrations of the drug can progressively saturate the binding sites: fractional binding may be lower when large amounts of the drug are given. The generally expressed percentage binding refers to the usual therapeutic plasma concentrations of a drug.

of 45 The clinically significant implications of plasma protein binding are: Highly plasma protein bound drugs are largely restricted to the vascular compartment because protein bound drug does not cross membranes (except through large paracellular spaces, such as in capillaries). They tend to have smaller volumes of distribution. The bound fraction is not available for action. However, it is in equilibrium with the free drug in plasma and dissociates when the concentration of the latter is reduced due to elimination. Plasma protein binding thus tantamounts to temporary storage of the drug. High degree of protein binding generally makes the drug long acting, because bound fraction is not available for metabolism or excretion, unless it is actively extracted by liver or by kidney tubules. Glomerular filtration does not reduce the concentration of the free form in the efferent vessels, because water is also filtered. Active tubular secretion, however, removes the drug without the attendant solvent → concentration of free drug falls → bound drug dissociates and is eliminated resulting in a higher renal clearance value of the drug than the total renal blood flow.The same is true of active transport of highly extracted drugs in liver. Plasma protein binding in this situation acts as a carrier mechanism and hastens drug elimination, e.g. excretion of penicillin (elimination t½ is 30 min); metabolism of lidocaine. Highly protein bound drugs are not removed by haemodialysis and need special techniques for treatment of poisoning. The generally expressed plasma concentrations of the drug refer to bound as well as free drug. Degree of protein binding should be taken into account while relating these to concentrations of the drug that are active in vitro, e.g. MIC of an antimicrobial. One drug can bind to many sites on the albumin molecule. Conversely, more than one drug can bind to the same site. This can give rise to displacement interactions among drugs bound to the same site(s). The drug bound with higher affinity will displace that bound with lower affinity. ****Why is Plasma Protein Binding Important? If the majority of the drug is bound to plasma protein then only the unbound fraction can have a biological effect or be metabolised/excreted. Therefore, the degree of binding to plasma proteins significantly influences the pharmacokinetic and pharmacodynamic properties of a drug. The efficacy of the drug will be related to the exposure to the amount of unbound drug in plasma, i.e. the proportion free to penetrate into surrounding tissues. The bound drug in plasma can also serve as a reservoir for free drug removed by various elimination processes thus prolonging the duration of action. The proportion of binding can also be affected if two drugs are used at the same time because each drug may displace a proportion of the other from being bound to the plasma protein, resulting in a greater proportion of unbound drug. The bulk of experimental data available relates to percent or fraction of drug bound to all plasma proteins (mainly serum albumin and a1-acid glycoprotein).

Introduction to Pharmacology