Textbook of Pharmacology, Pathology and Genetics for Nurses (2 Volumes) Suresh K Sharma
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1Pharmacology
CHAPTERS
  • Introduction to Pharmacology
  • Chemotherapy
  • Antiseptics, Disinfectants and Insecticides
  • Drugs Acting on Gastrointestinal System
  • Drugs used on Respiratory System
  • Drugs used on Urinary System
  • Miscellaneous Drugs
  • Drugs used on Skin and Mucous Membranes
  • Drugs Acting on Nervous System
  • Cardiovascular Drugs
  • Drugs Used for Hormonal Disorders and Supplementation, Contraception and Medical Termination of Pregnancy
  • Introduction to Drugs Used in Alternative System of Medicine
234

Introduction to Pharmacology1

Puneet Dhamija,
Suresh K Sharma
 
INTRODUCTION
The word Pharmacology is derived from Greek words Pharmacon means drug and logos means knowledge or study. Understanding how a drug or a substance is likely to modify the living system is the crux of pharmacol ogy. It is based on sound understanding of principles of physiology and pathology. By definition “Pharmacology is the science that deals with the study of drugs and their interaction with the living system”.
Many substances have been tried since time immemorial to minimize suffering of mankind. Every civilization had its own list of substances varying from plants and their extracts to different kinds of soils and minerals which were used in different diseases.
It is expected from nursing staff to be familiar with the various systems of medicine being practiced in contemporary world. The broad term Complementary and Alternative Medicine (CAM) covers all the systems of medicine other than allopathic medicine. The definitions given below describe briefly the common terms used in pharmacology of modern as well as alternative system of medicine.
 
TERMS AND DEFINITIONS
 
Drug
Drug has been defined as any substance or product used or intended to be used to modify or explore physiological systems or pathological states for the benefit of recipient.
 
Adverse Drug Reaction
World Health Organization defines adverse drug reaction as ‘A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function’.
 
Pharmacokinetics
It is the study of movement of drugs in the body including the processes of absorption, distribution, metabolism and elimination. It tells us about how body treats a drug molecule till it is removed.
 
Pharmacodynamics
The study of how a drug acts on a living organism, including the pharmacologic response and the duration and magnitude of response.6
 
Pharmacovigilance
It is the science relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. This branch of pharmacology deals exclusively with side effects of drugs.
 
Pharmacopeia
It is an authoritative book containing a list of medicinal drugs with their uses, preparation, dosages, formulas, storage and analysis, etc. These books are official publications and their contents are approved by regulatory bodies, e.g. British Pharmacopeia (BP), United States Pharmacopeia (USP), Indian Pharmacopeia (IP).
 
Clinical Pharmacology
Clinical pharmacology is a sub-discipline of pharmacology dealing exclusively with the effects of drugs in humans. It covers the dimensions of pharmacokinetics and pharmacodynamics in human beings.
 
Experimental Pharmacology
It is the sub-discipline of pharmacology dealing with effects of drugs in animals or cell-lines or tissues. It includes molecular level research dedicated to elucidating the mechanism of action.
 
SOURCES OF DRUGS
Drugs are obtained from various sources like microbes, plants, animals, minerals and synthetics. A synthetic source means the drug is synthesized in laboratory using chemical methods. Many natural products have been synthesized in laboratories for bulk production. Presently drugs like monoclonal antibodies obtained from natural sources are being developed in labs extensively.
  • Biological (natural) sources
    • Plants as source of drugs: Many drugs are obtained from plants. The active principal drugs are found in different parts of the plant. The drugs are extracted from the particular part of the plant. Some of the examples are given in Table 1.1.
      Table 1.1   Drugs obtained from plant parts
      S. No.
      Drugs
      Parts of plants
      1.
      Belladonna
      Root
      2.
      Cinchona
      Bark
      3.
      Digitalis
      Leaves
      4.
      Senna
      Fruit
      5.
      Stropunthus, castor oil
      Seed
      6.
      Opium
      Papaver somniferum (Seed pods)
      7.
      Physostigmine calabar
      Seed
    • 7Microbiological: Certain antibiotics are obtained from different types of microorganisms. Some of the examples are given in Table 1.2.
      Table 1.2   Drugs obtained from microorganisms
      S. No.
      Drugs
      Sources
      1.
      Penicillin
      Penicillium notaum
      2.
      Streptomycin
      Streptomyces griseus
      3.
      Bacitracin
      Mycobacterium bovis
      4
      BCG Vaccines
      Mycobacterium bovis
    • Animals as source of drugs: Many drugs are obtained from animal sources till today. Extensive research is going on to produce similar molecules in laboratories but it is not possible for all of the drugs. Drugs like adrenocorticotropic hormone (ACTH), liver extract, cod liver oil, heparin, anti-rabies vaccine, etc. are obtained from animal sources.
  • Minerals: Many minerals are used as drugs which are required in small amounts in the body. e.g. iron, zinc, calcium, etc.
  • Synthetic: Most drugs are now synthesized in laboratories using chemical methods and sophisticated instruments, e.g. sulphonamide, mepacrine, aspirin, neostigmine. This is the most important source of drugs presently.
  • Human: Some drugs are obtained from man, i.e. immunoglobulins from blood, growth hormone from anterior pituitary and human chorionic gonadotrophins from the urine of pregnant women. Human beings are sources for very few drugs only and other methods are used for drugs required for bulk use.
  • Other sources: Many biological agents which are proteins in nature are produced by using many techniques in cellular biology by manipulating genes in microbes or cell culture systems. The commonly used techniques include recombinant DNA technology and hybridoma techniques. The commonly used drugs include insulin analogues, urokinase, tissue plasminogen activator, etc.
    • Cell culture: Many drugs are obtained by cell cultures, i.e. urokinase from cultured human kidney cells.
    • Recombinant DNA technology: Some drugs are obtained/produced by recombinant DNA technology, i.e. human insulin, tissue plasminogen activator.
    • Hybridoma technique: Some drugs obtained by hybridoma technique, i.e. monoclonal antibodies.
 
SYSTEMS OF MEASUREMENT
The systems of measurement of drugs are as following:
  • Apothecary system
  • Metric system
  • Household system
Apothecary System: It is the older system of measurement based on arbitrary units of measure.8
This system was gradually replaced by metric system.
Common apothecary measures and symbols are:
Drop
gtt
Minim
m
Dram
3
Ounce (oz)
Pint
pt
Grain
gr
Equivalents:
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Metric system: It is a French invented system and basic units of measure are gram and litre. Other units include decimal, fractions and Arabic numerals.
Common metric measures and symbols are:
Gram
g, gm or G
Kilogram
kg
Milligram
mg
Milliliter
ml
Liter
L or l
Equivalents:
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Household system: This system is mainly based on the familiar measures used in home but most of the measures are not accurate for medicines.
Common household measures and symbols are:
Pint
pt
Teaspoon
tsp
Tablespoon
T
Quart
qt
Equivalents:
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9
 
CALCULATION OF DOSES
  1. Converting milligrams to grains:
    For example, convert 120 milligrams to grains
    zoom view
  2. Calculation of oral doses:
    zoom view
    For example, Calculate the capsules to be administered when dose is 500 mg of antibiotic and dose on hand is 250 mg.
    zoom view
  3. Calculation of drug doses of liquid drugs:
    zoom view
    For example, give 325 mg of ampicillin when it is supplied as 250 mg/5 mL.
    zoom view
 
FORMS of drugs
 
Solids
  • Extract: It is obtained through dissolving drug in alcohol or water and allowing the solution to evaporate; residue is called the extract.
  • Pills: It means a tablet and is made by rolling and binding the drug into a sphere.
  • Powder: These are finely ground drugs.
  • 10Suppository: It liquefies at body temperature when inserted into orifice and produces local and systemic effect.
  • Ointment: These are the drugs (semisolid) with fatty base.
  • Capsule: Drugs contained in the cylindrical gelatin containers which mask the taste of the drug.
  • Lozenge: A form of drug which is flavored and release drug slowly when held in mouth.
  • Tablet: Powdered form of drugs which is compressed into small disks and easily dissolve in water. The enteric coated tablets do not dissolve until reaching intestine where drug release takes place.
 
Liquids
  • Tincture: It is the diluted alcoholic extract of the drug.
  • Syrup: Concentrated sugar solution containing drug.
  • Elixir: Drug solution made with sugar, alcohol and pleasant smelling substance.
  • Suspension: Fine particles of a drug suspended in a liquid.
  • Emulsion: It is the solution made by suspension of unmixed fats or oils in water.
  • Lotion: Liquid suspension of medication which is applied to the skin.
 
ROUTES OF DRUG ADMINISTRATION
There are various routes through which a drug can be administered. Properties of the drugs and patient's requirements are two factors determining the choice of route in a patient. The routes of drug administration can be classified as following:
  • Enteral
  • Parenteral
  • Local
 
1. Entral Route
This route involves the oral ingestion of the drug and act as the safest route of drug administration.
 
Advantages
  • Safest and non-invasive route
  • Convenient and efficient route
  • Self-administration of drug
 
Disadvantages
  • Slower onset of action
  • Irritant and unpleasant drugs cannot be administered
  • Drugs with certain physical characteristics may not get absorbed, e.g. streptomycin
  • GI tract irritation can cause vomiting
  • 11Irregularities in absorption
  • Gastric juices may destroy some drugs, e.g. insulin
  • Not used in case of uncooperative and unconscious patients
  • Extensive first pass metabolism of some drugs in liver may leave only a small amount for therapeutic purpose.
Few drugs which are coated with substances (e.g. cellulose acetate, phthalate, gluten) are not digested by the gastric acid but break down in the alkaline juices of the intestine. It helps in preventing gastric irritation and destruction of drugs in stomach, also provides a high concentration of the drug in the small intestine. These drugs must be given with a full glass of water without crushing.
 
2. Parenteral Route
When the drug is administered through any route other than the enteral route is known as parenteral route. The drug can be administered to the muscle, mucosa, blood or skin. Some of different routes of drug administration are:
  1. Injection
  2. Transmucosal
  3. Transdermal
  4. Inhalation
 
Advantages
  • Rapid and predictable action
  • Can be used in unconscious or uncooperative patient
  • Gastric irritation can be avoided as irritants can be administered parenterally
  • Can be used in patients having difficulty in swallowing or vomiting
  • The first pass metabolism and digestion of the drugs by the gastric juices can be avoided
  • Highly beneficial in the emergency conditions.
 
Disadvantages
  • Needs asepsis to be maintained
  • Injections may be painful to the patient
  • Can be inconvenient and expensive
  • Involves risk of injury to nerves and other tissue.
 
A. Injections
Drugs through injections can be administrated by various routes:
  • Intramusclar: It involves the injection of drug (solution) into large muscles. The muscles used for intramuscular injections are deltoid muscle for small amount of drug administration, gluteus muscle for large amount in adults and vastus lateralis used in infants and small children.
  • 12Subcutaneous (hypodermic): Here drug is injected in the subcutaneous tissue, e.g. insulin and heparin is given through this route. Subcutaneous tissue is less vascular, so the absorption of the drug is slow as well as largely uniform which makes it long acting.
  • Intradermal: The drug is administered above dermis and below epidermis. This route is commonly used for BCG vaccination, drug hypersensitivity test and tuberculin test, etc. Here very small amount of drug is administered.
  • Intravenous: The drug is injected into one of the superficial veins of the body so that it reaches the circulation directly and is available for immediate action. Through this route drugs can be given in bolus, slowly, slow infusion mode as per requirement.
  • Intra-arterial: In this route the drug is injected directly into the arteries and used in the treatment of peripheral vascular disease, local malignancies and diagnostic studies like angiographies.
  • Intra-cardiac: Here the drug is directly given into heart. This route is rarely used, since it involves several complications without any additional benefit.
  • Intra-thecal or intra-spinal: It involves the administration of the drug into the subarachnoid space for action on the CNS, e.g. spinal anesthetics. Some antibiotics and corticosteroids can also be injected by this route to produce high local concentration.
  • Intraosseous/intra-articular: Here drugs are injected directly into a joint for the treatment of arthritis and other diseases of joint. Strict aseptic precautions are required, e.g. hydrocortisone is injected into the affected joint, in rheumatoid arthritis.
  • Intraperitoneal: A large surface area for absorption is being offered by peritoneum. In infants fluids are injected into peritoneum. This route can also be used for peritoneal dialysis.
  • Intramedullary: Here drug is injected into a bone marrow. It is rarely used nowadays.
 
B. Transmucosal
It involves the absorption of drugs across the mucous membranes. Transmucosal administration includes:
  1. Sublingual
  2. Rectal
  3. Nasal
  1. Sublingual
    Here, the drug contained by a tablet or pellet is placed under the tongue. The drug is dissolved and absorbed across the sublingual mucosa, e.g. nitroglycerine tablets, nifidipin, buprenorphine.
    Advantages
    • Rapid absorption; reaches circulation within minutes.
    • Helps in avoiding of first pass metabolism.
    • The drug can be spat out after obtaining the desired effects to avoid the unwanted effects.
    Disadvantages
    • Can cause buccal ulceration.
  2. 13Rectal route
    Rectum has a rich blood supply; drugs administered through this route cross the rectal mucosa, to get absorbed and produce the local or systemic effects. Drugs which can be given through this route are indomethacin, chlorpromazine, diazepam and paraldehyde. Some irritant drugs are given as rectal suppositories.
    Advantages
    • Gastric irritation can be avoided.
    • Beneficial in older patients and can also be used in patient with vomiting and difficulty swallowing.
    Disadvantages
    • Can cause buccal ulceration.
  3. Nasal route
    Nasal route of drug administration can be used either for systemic absorption or for local effects, e.g. oxytocin spray produces systemic effect, decongestant nasal drops like oxymetazoline used for local effect.
 
C. Transdermal
The drugs which are high lipid soluble can be applied to the skin for slow and prolonged absorption to achieve systemic effect, e.g. application of nitroglycerine ointment in angina pectoris. Inunction, adhesive units, iontophoresis and jet injection are some forms of transdermal drug delivery methods.
  • Inunction: Here the drug is rubbed into the skin and gets absorbed to produce systemic effects.
  • Adhesive units: The adhesive patches of different sizes and shapes are made to suite the area of application. The drug is held in a reservoir between an outer layer and a porous membrane. This membrane is smeared with an adhesive to hold on to the area of application. After application the drug is slowly diffused through the membrane and percutaneous absorption take place. The rate of absorption is constant and predictable. Usual site of application are chest, abdomen, upper arm, back or mastoid region, e.g. hyoscine, nitroglycerine, fentanyl, estrogen, testosterone trasdermal patches.
  • Iontophoresis: Here, the galvanic current brings about penetration of liquid insoluble drugs into the deeper tissues where the action of drug is required, e.g. salicylates fluoride iontophoresis in dental hypersensitivity.
  • Jet injection: Dermojet causes the absorption of drug occurs across the layers of the skin.
  • Implantation: It means planting or putting of solid drugs into the body tissue to achieve systematic effect.
 
D. Inhalation
Through inhalation, volatile liquids and gases are given in general anesthesia. Also, the solutions of drug particles and the fine droplets are inhaled as aerosol, e.g. salbutamol. Patient inhales the particles and fumes into the lung which produce local or systemic effect.14
 
Advantages
  • Rapid absorption.
  • More effective and less harmful in case of pulmonary disease.
  • Hepatic first pass metabolism is avoided.
  • Conveniently controlled blood level of volatile anesthesia, as their absorption and excretion is through the lungs are governed by the laws of gases.
 
Disadvantages
  • Irritant gases may enhance the production of pulmonary secretions.
 
3. Local Routes
Drugs may be applied on the skin or mucous membrane for local action:
  • Local Dermal Application: As ointment, cream, gel, powder, and paste applied on skin to achieve local action.
  • Instillation: Instillation is putting a drug in liquid form into a body cavity such as urinary bladder or into a body orifice as ears, eyes as ointment, drops, and spray.
  • Insertions: It means introducing solid form of drugs into the body orifices, i.e. suppositories for rectum, bougie for urethra and pessary and douche for vagina.
  • Insufflations: It is administration of drugs in the form of powder, vapour or air into a wound or body cavity.
 
4. Special Drug Delivery Systems
Special drug delivery systems are being tried in order to improve drug delivery, to prolong duration of action and thereby improve patient compliance. Drug targeting is also aimed at to deliver drugs at the site where action is required, especially in case of anticancer drugs. For example ocusert, progestasert, prodrugs, osmotic pumps, computerized pumps and methods using monoclonal antibodies and liposomes as carriers.
 
PHARMACOKINETICS
Pharmacokinetics is the study of the absorption, distribution, metabolism and excretion of drugs, i.e. the movement of the drugs into, within and out of the body. For a drug to produce its specific response, it should be present in adequate concentrations at the site of action. This depends on various factors apart from the dose. Once the drug is administered, it is absorbed, i.e. enters the blood, is distributed to different parts of the body, reaches the site of action, is metabolized and excreted (drug and/or metabolite (s) eliminated in urine, feces, sweat and bile); (may also be seen in flow chart 1.1 to understand pharmacokinetics at a glance).15
zoom view
Flow chart 1.1: Pharmacokinetics
 
I. Absorption
Absorption is the transfer of a drug from its site of administration to the blood stream. The rate and efficiency of absorption depend on the route of administration.
  • Transportation of drug from GI Tract
    Depending on their chemical properties, drugs may be absorbed from G.I. tract by either diffusion, or active transport.
    • Passive diffusion:
      • With the help of concentration gradient across a membrane separating two body compartments where the drug moves from region of high concentration to one of lower concentration.
      • It does not involve a carrier.
      • Liquid soluble drugs readily move across most biological membranes.
      • Water-soluble drugs penetrate the cell membrane through aqueous channels.
    • Active transport:
      • This mode of drug entry involves specific carrier protein that spans the membrane.
      • A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membrane using these specific carrier proteins.
      • Active transport is energy dependent and is driven by the hydrolysis of adenosine triphosphate (ATP).
  • Effect of pH on drug absorption
    • Most of drugs are either weak acids or weak bases.
    • Acidic drug (HA) release a H+ causing a charged anion (A) to form:
      zoom view
    • Weak bases (BH+) can also release a H+; however, the protonated form of basic drugs is usually charged and loss of a proton produces the uncharged base (B).
      zoom view
  • Physical factors influencing absorption
    • Blood flow to the absorption site
    • Total surface area for absorption
    • Contact time at the absorption surface
    • Particle size
    • 16Presence of other drugs
    • Route of administration.
  • Bioavailability
Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically uncharged form, e.g. if 100 mg of a drug is administered orally and 70 mg of this is absorbed uncharged, the bioavailability is 70%.
 
II. Drug distribution
  • In this process drug reversibly leaves the blood stream and enters the extracellular fluid and for the cell or the tissue.
  • The delivery of a drug from plasma to the interstitium primarily depends on blood flow, capillary permeability, the degree of binding of the drug to plasma and tissue protein and the relative hydrophobicity of the drug.
  • Blood-brain barrier (BBB): The endothelial cells of the brain capillaries have tight junctions. Moreover, glial cells envelope the capillaries and together these form the BBB. Only lipid soluble unionized drugs can cross BBB. During inflammation of the meninges, the barrier becomes more permeable to drugs, e.g. penicillin readily penetrates the BBB during meningitis. The barrier is week at some area like chemoreceptor trigger zone (CTZ) and allows some compounds to diffuse.
  • Placental barrier: Lipid soluble, unionized drugs readily cross the placenta while lipid insoluble drugs cross to a much lesser extent. Thus drugs taken by the mother can cause severe unwanted effects in the fetus.
 
III. Metabolism
  • Metabolism or biotrasformation is the process of biochemical alteration of the drugs in the body. Body treats most of the drugs as foreign substance and tries to inactivate and eliminate them by various biochemical reactions. These processes convert the drugs into more polar, water-soluble compounds so that they are easily excreted through the kidneys. Some drugs may be excreted largely unchanged in the urine, e.g. frusemide, atenolol.
  • The most important organ of biotransformation is the liver. However, kidneys, gut mucosa, lungs, blood and skin also metabolize drugs. Though biotrasformation generally inactivates the drugs, some times drugs may be converted to active (e.g. primidone converted into phenobarbitone) or more active metabolites (prednisone converted into prednisolone).
  • The biotransformation reactions are catalyzed by specific enzymes located either in the liver cells or in the plasma and other tissues. Certain enzymes which metabolize drugs like microsomal enzymes are present in the liver cells. The synthesis of these enzymes, can be enhanced by certain drugs and environmental pollutants. This is called enzyme induction and this process speeds up the metabolism of the induction drugs itself and other drugs metabolized by the microsomal enzymes, e.g. phenobarbitone, rifampicin, alcohol, cigarette smoke, DDT, griseofulvin, carbamazepine and phenttoin are some enzyme inductors.
17
 
IV. Excretion
Drugs are excreted from the body after being converted to water-soluble metabolites while some are directly eliminated without metabolism. The major organs of excretion are kidneys, the intestine, the biliary system and the lungs. Drugs are also excreted in small amount in saliva, sweat and milk.
 
PHARMACODYNAMICS
Pharmacodynamics is the study of the effects of the drugs on the body and their mechanism of action, i.e. what drugs do to the body, in other words we can say mechanism of drug action.
  • Body functions are mediated through control systems that involve receptors, enzymes, carrier molecules and other specialized macromolecules such as DNA.
  • Mechanism of drug action shows that, how drug acts on body by various means . There are different means by which drugs act on body, some of them are as following:
  1. On the cell membrane by:
    • Action on specific receptors, e.g. agonists and antagonists on adrenoceptors, histamine receptors, acetylcholine receptors, etc. Ca++ entry (or channel) blockers.
    • Interference with selective passage of ions across membranes.
    • Inhibition of membrane bound enzymes and pumps, e.g. membrane bound ATPase by cardiac glycoside’ tricyclic antidepressants block the pump by which amines are actively taken up from the exterior to the interior of nerve cells.
    • Physicochemical interaction, e.g. general and local anesthetics and alcohol appear to act on the lipid, protein or water constituents of nerve cell membranes.
  2. Through metabolic processes within the cells by:
    • Enzyme inhibition, e.g. monoamine oxidase by phenelzine, cholinesterase by pyridostigmine, xanthine oxidase by allopurinol.
    • Inhibition of transport process that carries substances across cells, e.g. blockage of anion transport in the renal tubule cell by probencid can be used to delay excretion of penicillin and to enhance elimination of urate.
    • Incorporation into large molecules, e.g. 5 fluoruracil is an anticancer drug is incorporated into messenger RNA in place of uracil.
    • In the case of successful antimicrobial agent, by altering metabolic process unique to microorganisms, e.g. penicillin interferes with formation of cell wall, or differences in affecting a process common to both human and microbes, e.g. inhibition of folic acid synthesis by trimethoprim.
  3. Outside the cell by:
    • Direct chemical interaction, e.g. chelating agents, antacids.
    • Osmosis as with purgatives, e.g. magnesium sulphate and diuretics (mannitol) which are active because neither they nor the water in which they are dissolved are absorbed by the cells lining the gut and kidney tubules respectively.
  4. Drug action through receptors: Most receptors are protein molecules
    • Agonists: Drugs that activate receptors. They do so because they resemble the natural transmitter or hormone.
      18When the agonists bind to the receptor the proteins undergo an alteration in confirmation which induces change in systems within the cell that in turn bring about the response to the drug, e.g. activation of B-adrenoceptors by a catecholamine increases the activity of adenylate cyclase which raise the rate of formation of cyclic AMP, a modulator of the activity of several enzyme systems that causes cell to act.
    • Antagonists (blockers): Blockers of receptors are sufficiently similar to the natural agonists to be recognized by the receptor and to occupy without activating it, thereby preventing (blocking) the natural agonist from exerting its effect.
 
Factors Affecting the Drug Action
The same dose of a drug can produce different degrees of response in different patients and even in the same patient under different situations. Various factors modify the response to a drug. They are:
  • Body weight: The recommended dose is calculated for medium built persons. For the obese and underweight persons, the dose has to be calculated individually. Though body surface area is a better parameter for more accurate calculation of the dose, it is inconvenient and hence not generally used.
    Formula:
    zoom view
  • Age: The pharmacokinetics of many drugs change with age resulting in altered response in extremes of age. In the newborn, the liver and kidneys are not fully mature to handle the drugs, e.g. chloramphenicol can produce gray baby syndrome. The blood-brain barrier is not well-formed and drugs can easily reach the brain. The gastric acidity is low, intestinal motility is slow, skin is delicate and permeable to drugs applied topically. Hence calculation of the appropriate dose, depending on body weight is important to avoid toxicity. Also pharmacodynamic differences could exist, e.g. barbiturates which produce sedation in adults may produce excitation in children.
    Formula for calculation of dose for children
    Young's formula
    zoom view
    In the elderly, the capacity of the liver and kidney to handle the drug is reduced and are more susceptible to adverse effects. Hence lower doses are recommended, e.g. elderly are at a higher risk of ototoxicity and nephrotoxicity by streptomycin.
  • Sex: The hormonal effects and smaller body size may influence drug response in women. Special care is necessary while prescribing for pregnant and lactating women during menstruation.
  • Species and race: Response to drugs may vary with species and race, e.g. rabbits are resistant to atropine. Then it becomes difficult to extrapolate the results of animal experiments. Blacks need higher doses of atropine to produce mydriasis.
  • 19Diet and environment: Food interferes with the absorption of many drugs, e.g. tetracyclines form complexes with calcium present in the food and are poorly absorbed. Polycyclic hydrocarbons present in cigarette smoke may induce microsomal enzymes resulting in enhanced metabolism of some drugs.
  • Route of administration: Occasionally route of administration may modify the pharmacodynamic response, e.g. magnesium sulfate given orally is a purgative. But given IV, it causes CNS depression and has anticonvulsant effects. Applied topically (poultice), it reduces the local edema. Hypertonic magnesium sulfate retention enema reduces intracranial tension.
  • Genetic factors: Variations in an individual's response to drugs could be genetically mediated. Pharmacogenetics is concerned with the genetically mediated variations in drug responses. The differences in response is most commonly due to variations in the amount of drug metabolizing enzymes since the production of these enzymes are genetically controlled. Examples:
    • Acetylation of drugs: The rate of drug acetylation differs among individuals. People may be fast or slow acetylators, e.g. INH, sulfonamides and hydralazine are acetylated. Slow acetylators treated with hydralazine are more likely to develop lupus erythematosus.
    • Atypical pseudocholinesterase: Succinylcholine is metabolized by pseudo cholinesterase. Some people inherit a typical pseudocholinesterase and they develop a prolonged apnea due to succinylcholine.
    • G6PD deficiency: Primaquine, sulphones and quinolones can cause hemolysis in people with this deficiency.
    • Malignant hyperthermia: Halothane and succinylcholine can trigger malignant hyperthermia in some genetically pre-disposed individuals.
  • Dose: It is interesting to know that the response to a drug may be modified by the dose administered. Generally as the dose is increased, the magnitude of the response also increases proportionately till the ‘maximum’ is reached. In case of some drugs, further increases in dose may produce effects opposite to their lower-dose effect, e.g. (i) in myasthenia gravis, neostigmine enhances muscle power in therapeutic doses, but in high doses it causes muscle paralysis, (ii) physiological doses of vitamin D promotes calcification while hypervitaminosis D leads to decalcification.
  • Diseases: Presence of certain diseases can influence drug responses, for example,
    • Malabsorption: Drugs are poorly absorbed.
    • Liver diseases: Rate of drug metabolism is reduced due to dysfunction of hepatocytes. Also protein binding is reduced due to low serum albumin.
    • Cardiac diseases: In heart failure, there is edema of the gut mucosa and decreased perfusion of liver and kidneys. These may result in cumulation and toxicity of drugs like propranolol and lignocaine.
    • Renal dysfunction: Drugs mainly excreted through kidneys are likely to accumulate and cause toxicity, e.g. streptomycin, amphotericin B—Dose of such drugs need to be reduced.
  • Repeated dosing can result in cumulation tolerance and tachyphylaxis.
  • 20Psychological factor: The doctor patient relationship as well as the nursing care influence the response to a drug often to a large extent by acting on the patient's psychology. The patient's confidence in the doctor may itself be sufficient to relieve a suffering, particularly the psychosomatic disorders. This can be substantiated by the fact that large number of patients respond to placebo.
  • Presence of other drugs: The concurrent use of two or more drugs can influence the response of each other.
 
Adverse Reaction of Drugs
Some of the terms related to adverse reactions of drugs are discussed below:
  • Side effects are actions of drugs that are not specifically desired in a treatment and are exerted at therapeutic dose levels.
  • Adverse effects are harmful or seriously unpleasant effects occurring at doses intended for therapeutic (prophylactic or diagnostic) effects and which call for reduction of dose or withdrawal of the drug and/or for cast hazard from future administration.
  • Toxicity implies a direct action of the drug often at high dose, damaging cells, e.g. liver damage from paracetamol overdose, eight cranial never damage from streptomycin. Some of the toxicity conditions are mutagenicity, carcinogenicity, teratogenicity.
  • Secondary effects are the indirect consequences of a primary drug action, e.g. hypokalamia due to diuretics, vitamin deficiency due to destructions of normal bowel flora by antibiotics.
  • Intolerance means a low threshold to the normal pharmacological action of a drug.
  • Idiosyncrasy implies an inherent qualitative abnormal reaction to a drug, usually due to genetic abnormality, e.g. porphyria.
Classification of adverse reactions: Adverse reactions are of two principal kinds:
  • Type a (Augmented) reactions will occur in everyone if enough of the drug is given because they are due to excess of normal, predictable, dose-related, pharmacodynamic effects. They are common and skilled management reduces their incidence, e.g. postural hypotension, hypoglycemia, hypokalemia, etc.
  • Type B (Bizarre) reactions will occur only in some people. They are due to unusual attributes of the patient interacting with the drug. The class includes unwanted effects due to inherited abnormalities and immunological process (drug allergy). These account for most drug fatalities.
Three subordinate types of adverse reactions:
  • Type C (Continuous): Reactions due to long-term use of drugs, e.g. analgesic nephropathy.
  • Type D (Delayed): For example, teratogenesis, carcinogenesis.
  • Type E (Ending of use): For example, rebound adrenocoritcal insufficiency.
Cause of adverse reaction:
  • Non-drug factors: Intrinsic to the patient; age, sex, genetics, tendency to allergy, disease, personality and extrinsic to the patient; the prescriber, environment.
  • Drug factors: Intrinsic to the drugs; use of drugs interactions between drugs.
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INDIAN PHARMACOPEIA (IP)
  • Manufacturing, sale, import and export of drugs are controlled by the Government.
  • The central drug authority, Indian Pharmacopeia (IP) is based in Nirman Bhawan, New Delhi.
  • The drug authorities of states are mostly based in their capitals.
  • Central drug authority formulates the policy and peripheral authorities implement these policies.
Implementation is under control of drug controller
There are three agencies to regulate drug administration.
  • Advisory agency: Includes Drug Technical Advisory Board (DTAB) and Drug Consultative Committee. DTAB frames and modifies rules regarding drugs.
  • Analytical agency: Includes Central Drug Laboratory (situated at Kolkata) and drug laboratories in respective states. These laboratories test and analyze the samples of drugs and cosmetics.
  • Executive agency: Authorities, which grant license to various organizations for manufacturing, storing, recapping, selling, importing and exporting drugs.
 
DRUG LAWS
Law is a system of rules to establish justice. Drugs are considered as vital service, as they are essential for the health of human beings. Dealing with drugs require specialized knowledge, skill and expertise; so it must be handled by the well qualified and expert staff.
There are certain drug laws for abiding to the rules and regulations. Drug laws in the order in which they were passed are given below in Table 1.3.
Table 1.3   Drug laws passed in India
Year
Name of the act
1878
The Opium Act
1919
The Poisons Act
1930
The Dangerous Drugs Act
1940
The Drugs and Cosmetics Act
1948
The Pharmacy Act
1954
The Drugs and Magic Remedies Act
1955
The Medical and Toilet Preparations Act
1985
The Narcotic Drugs and Psychotropic Substances Act
1995
The Drug Order
  • The Opium Act, 1878: This act deals with the cultivation of poppy and the manufacture, possession, transport, export, import and sale of opium.
  • The Poisons Act, 1919: This act controlled the possession, import and sale of poisons.
  • 22The Dangerous Drugs Act, 1930: This act prohibited the cultivation of opium plant, manufacturing and sale of its products. The central government controls the production and supply of opium and transport is under control of state government.
  • The Drugs and Cosmetics Act, 1940: This act was passed to control operations related to Allopathic drugs only. The act was amended several times and now it includes Ayurvedic, Unani, Siddha and Homeopathic drugs as well as Cosmetics.
  • The Pharmacy Act, 1948: The act is applicable all over India except Jammu and Kashmir. The act was passed for better regulation of the pharmacy profession.
  • The Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954: To prevent the misleading advertizements, the Drugs and Magic Remedies Act was passed in 1954.
  • The Medicinal and Toilet Preparations Act, 1955: Alcohol is a part of many medicinal preparations as a necessity. The people can misuse these alcohol preparations. This act was passed to prevent such misuse. The manufacture of spirit containing preparations needs a special license. If the State Government gets any information about the misuse of medicine as an ordinary alcoholic beverage, it can recommend to the Central Government to declare it as a ‘Spurious preparation’.
  • The Narcotic Drugs and Psychotropic Substances Act, 1985: The act totally prohibits the cultivation, manufacture, sale, purchase, use or transport of all narcotic and psychotropic drugs.
  • Drug (Price Control) Order, 1995: Under Essential Commodities Act, this order was passed so that the Government may control over the prices of bulk drugs and drug formulations.
 
SCHEDULES OF DRUGS
The schedules of drugs are discussed below:
  • Schedule C: It includes biological and special intravenous products, e.g. vaccines, sera, antigens, insulin, adrenaline.
  • Schedule C1: It includes cardiac glycosides, ergot, hormones, preparations not given parenterally.
  • Schedule E: It includes poisonous drugs and it applies to the storage and sale of such drugs.
  • Schedule F, F1: These include vaccines and sera.
  • Schedule G drugs: A warning for drugs under this schedule must be there—Caution: It is dangerous to take this preparation except under medical supervision.
    • For example, anticancer drugs, antidiabetic drugs, etc. Containers should be labelled in red bottles against white background.
  • Schedule H drugs: This includes drugs to be sold under physician prescription only.
    • Warning: “To be sold on the prescription of a Registered Medical Practitioner only” must be there.
    • Symbol Rx should be printed prominently on the left hand top corner of the label.
    • 23Symbol NRx should be printed instead of Rx if the drug is covered under The Narcotic Drugs and Psychotropic Substances Act.
    • The rules for sale are same as for schedule X drugs.
    • For example, acyclovir, alprazolam, amitriptyline, atenolol, azathioprine, barbiturates.
  • Schedule J: It includes list of discuss used for incurable diseases, e.g. AIDS, cancer, congenital malformations.
  • Schedule L: It includes antibiotics. These drugs should be sold on prescription only.
  • Schedule X: It includes psychotropic drugs.
    • The label should contain the warning—'Schedule X drug'.
    • Warning: To be sold on prescription of a registered medical practitioner only.
    • For example, amphetamine, barbiturates, methaqualone, glutethimide.
  • Schedule Y: It includes new drugs under investigation.
 
RATIONAL USE OF DRUGS
After identifying a person suffering with a specific disease, a therapeutic objective must be defined. For example, if a patient is having hypertension then objective will be to bring down the blood pressure to a level in order to prevent complications of prolonged hypertension. The choice of drugs should be made after the objective is clear. When there is the availability of many drugs for the treatment of many diseases then choice has to be made wisely. For example, in case of mild gastritis, antacids can be used. But when it is not controlled, then H2 receptor blocker like ranitidine can help. Only severe cases require to be treated with omeprazole. The other must be considered while administration of drugs like age, presence of other diseases, renal and liver function, other drugs being administered and cost of therapy. Newer drugs can be expensive than the old ones. So, older drugs must be preferred.
When there is the requirement of the long -term treatment, the regular review and monitoring of treatment should be planned. The therapeutic end point should be defined. On the other hand when combination of drugs is to be used for the treatment, the therapeutic benefit, avoiding drugs with overlapping adverse effects and cost of therapy must be kept in mind. It is equally important to avoid irrational combination of drugs. Few examples of such irrational combinations are given below:
  • Ibuprofen with Paracetamol: This combination serves no useful purpose. Any one medicine can be given based on requirement.
  • Diclofenac + Nimesulide: Any one of these drugs can be given on the basis of requirement but the combination serves no useful purpose. Nimesulide is now banned in most of the countries.
  • Ciprofloxacin + Tinidazole: This combination of drugs is used in the treatment of diarrhea. It is claimed that it helps in diarrhea caused by both gram negative bacteria and ameba. In fact the diarrhea is due to any one of the organisms and not both. Using this combination, there is increased risk of toxicity from the other antimicrobial agent and also adds to the cost of therapy.
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