Pharmacology for Physiotherapy Students Padmaja Udaykumar
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General PharmacologyCHAPTER 1

Pharmacology is the science that deals with the study of drugs and their interaction with the living systems.
Early man recognized the benefits and toxic effects of many plants and animal products. India's earliest pharmacological writings are from the ‘Vedas.’ An ancient Indian physician Charaka and then Sushruta and Vagbhata described many herbal preparations included in ‘Ayurveda’ (meaning the science of life). James Gregory recommended harsh and dangerous remedies like blood-letting, emetics and purgatives to be used until the symptoms of the disease subsided (such remedies often resulted in fatality). This was called ‘Allopathy’ meaning the other suffering. This word, still being used for the modern system of medicine, is a misnomer. Hannemann introduced the system of Homoeopathy meaning ‘similar suffering’ in the early 19th century. The principles of this include ‘like cures like’ and ‘dilution enhances’ the action of drugs. Thus, several systems of therapeutics were introduced, of which only few survived. The basic reason for failure of many systems is that man's concepts about diseases were incorrect and baseless in those days. By the end of the 17th century the importance of experimentation and observation became clear and many physicians applied these to the traditional drugs. Francois Magendie and Claude-Bernard popularized the use of animal experiments to understand the effects of drugs. The development of physiology also helped in the better understanding of pharmacology. The last century has seen a rapid growth of the subject with new concepts and techniques being introduced.
The word pharmacology is derived from the Greek word—Pharmacon meaning an active principle or drug and logos meaning a discourse or study.
Drug (Drogue—a dry herb in French) is a substance used in the diagnosis, prevention or treatment of a disease. WHO definition—‘A drug is any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.’
2Pharmacodynamics is the study of the effects of the drugs on the body and their mechanisms of action, i.e. what the drug does to the body.
Pharmacokinetics is the study of the absorption, distribution, metabolism and excretion of drugs, i.e. what the body does to the drug (in Greek Kinesis = movement).
Therapeutics deals with the use of drugs in the prevention and treatment of diseases.
Toxicology deals with the adverse effects of drugs and also the study of poisons, i.e. detection, prevention and treatment of poisonings (Toxicon = poison in Greek).
Chemotherapy is the use of chemicals for the treatment of infections. The term now also includes the use of chemical compounds to treat malignancies.
Pharmacopoeia (in Greek Pharmacon = drug; poeia = to make) is the official publication containing a list of drugs and medicinal preparations approved for use, their formula and other information needed to prepare a drug; their physical properties, tests for their identity, purity and potency. Each country may follow its own pharmacopoeia to guide its physicians and pharmacists. We thus have the Indian Pharmacopoeia (IP), the British Pharmacopoeia (BP) and the United States Pharmacopoeia (USP). The list is revised at regular periods to delete old useless drugs and to include newly introduced ones.
Pharmacy is the science of identification, compounding and dispensing of drugs. It also includes collection, isolation, purification, synthesis and standardization of medicinal substances.
Over-the-counter (OTC) drugs are the drugs that can be sold to a patient without a prescription. Examples paracetamol, ranitidine.
Prescription drugs: Many drugs can be sold only on producing a doctor's prescription. Such prescription drugs are classified as ‘Schedule H’ drugs as per the ‘Drugs and Cosmetics Act’ of India. Examples include diazepam, atenolol and antibiotics.
Sources of Drugs
The sources of drugs could be natural or synthetic.
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Flowchart 1.1:
Natural Sources
  • Plants, e.g. atropine, morphine, quinine, and digoxin.
  • Animals, e.g. insulin, heparin, gonadotrophins and antitoxic sera.
  • Minerals, e.g. magnesium sulfate, aluminium hydroxide, iron, sulfur and radioactive isotopes.
  • Microorganisms: Antibacterial agents like penicillin, cephalosporins, tetracyclines are obtained from some bacteria and fungi.
  • Human: Some drugs are obtained from human beings, e.g. immunoglobulins from blood; growth hormone from anterior pituitary and chorionic gonadotrophins from the urine of pregnant women.
Synthetic Drugs
Most drugs are now synthesized, e.g. quinolones, omeprazole.
Many drugs are obtained by cell cultures, e.g. urokinase from cultured human kidney cells. Some are now produced by recombinant DNA technology, e.g. human insulin, tissue plasminogen activator hematopoietic growth factors like erythropoietin and some others by hybridoma technique, e.g. monoclonal antibodies.3
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Flowchart 1.2: Routes of drug administration
Drugs may be administered by various routes. The choice of the route in a given patient depends on the properties of the drug and the patient's requirements. A knowledge of the advantages and disadvantages of the different routes of administration is essential.
The routes can be broadly divided into (Flowchart 1.2):
  • Enteral
  • Parenteral
  • Local.
Enteral Route (Oral Ingestion)
This is the most common, oldest and safest route of drug administration. The large surface area of the gastrointestinal tract, the mixing of its contents and the differences in pH at different parts of the gut facilitate effective absorption of the drugs given orally. However, the acid and enzymes secreted in the gut and the biochemical activity of the bacterial flora of the gut can destroy some drugs before they are absorbed.
  • Safest route
  • Most convenient
  • Most economical
  • Drugs can be self-administered
  • Non-invasive route.
  • Onset of action is slower as absorption needs time.
  • Irritant and unpalatable drugs cannot be administered.
  • Some drugs may not be absorbed due to certain physical characteristics, e.g. streptomycin.
  • Irritation to the gastrointestinal tract may lead to vomiting.
  • There may be irregularities in absorption.
  • Some drugs may be destroyed by gastric juices, e.g. insulin.
  • Cannot be given to unconscious and uncooperative patients.
  • Some drugs may undergo extensive first pass metabolism in the liver.
To overcome some of the disadvantages, irritants are given in capsules, while bitter drugs are given as sugar coated tablets. Sometimes drugs are coated with substances like synthetic resins, gums, sugar, coloring and flavoring agents making them more acceptable.
Enteric Coated Tablets
Some tablets are coated with substances like cellulose-acetate, phthalate, gluten, etc. which are not digested by the gastric acid 4but get disintegrated in the alkaline juices of the intestine. This will:
  • Prevent gastric irritation.
  • Avoid destruction of the drug by the stomach.
  • Provide higher concentration of the drug in the small intestine.
  • Retard the absorption, and thereby prolong the duration of action. However, if the coating is inappropriate, the tablet may be expelled without being absorbed at all. Similarly, controlled-release or sustained-release preparations are designed to prolong the rate of absorption and thereby the duration of action of drugs. This is useful for short-acting drugs.
  • Frequency of administration may be reduced.
  • Therapeutic concentration may be maintained specially when nocturnal symptoms are to be treated.
  • There may be ‘failure of the preparation’ resulting in release of the entire amount of the drug in a short-time leading to toxicity.
  • It is more expensive.
Certain precautions are to be taken during oral administration of drugs—capsules and tablets should be swallowed with a glass of water with the patient in upright posture either sitting or standing. This facilitates passage of the tablet into the stomach and its rapid dissolution. It also minimizes chances of the drug getting into larynx or behind the epiglottis. Recumbent patient should not be given drugs orally as some drugs may remain in the esophagus due to the absence of gravitational force which facilitates the passage of the drug into the stomach. Such drugs can damage the esophageal mucosa, e.g. iron salts, tetracyclines.
Parenteral Route
Routes of administration other than the enteral (intestinal) route are known as parenteral routes. Here the drugs are directly delivered into tissue fluids or blood.
  • Action is more rapid and predictable than oral administration.
  • These routes can be employed in an unconscious or uncooperative patient.
  • Gastric irritants can be given parenterally and therefore irritation to the gastrointestinal tract can be avoided.
  • It can be used in patients with vomiting or those unable to swallow.
  • Digestion by the gastric and intestinal juices and the first pass metabolism are avoided.
Therefore, in emergencies parenteral routes are very useful routes of drug administration as the action is rapid and predictable and are useful in unconscious patients.
  • Asepsis must be maintained.
  • Injections may be painful.
  • More expensive, less safe and inconvenient.
  • Injury to nerves and other tissues may occur.
Parenteral routes include:
  • Injections.
  • Inhalation.
  • Transdermal route.
  • Transmucosal route.
1. Injections
The drug is injected:
  • Into the layers of the skin raising a bleb, e.g. Bacillus Calmette-Guérin (BCG) vaccine, tests for allergy or
  • By multiple punctures of the epidermis through a drop of the drug, e.g. smallpox vaccine.
5Only a small quantity can be administered by this route and it may be painful.
Subcutaneous (SC) Injection
Here the drug is deposited in the SC tissue, e.g. insulin, heparin. As this tissue is less vascular, absorption is slow and largely uniform making the drug long-acting. It is reliable and patients can be trained for self-administration. Absorption can be enhanced by the addition of the enzyme hyaluronidase.
  • As SC tissue is richly supplied by nerves, irritant drugs can cause severe pain. Hence such drugs cannot be injected.
  • In shock, absorption is not dependable because of vasoconstriction.
  • Repeated injections at the same site can cause lipoatrophy resulting in erratic absorption.
Hypodermoclysis is the SC administration of large volumes of saline employed in pediatric practice.
Drugs can also be administered subcutaneously as:
  • Dermojet: In this method, a high velocity jet of drug solution is projected from a fine orifice using a gun. The solution gets deposited in the SC tissue from where it is absorbed. As needle is not required, this method is painless. It is suitable for vaccines.
  • Pellet implantation: Small pellets packed with drugs are implanted subcutaneously. The drug is slowly released for weeks or months to provide constant blood levels, e.g. testosterone.
  • Sialistic implants: The drug is packed in sialistic tubes and implanted subcutaneously. The drug gets absorbed over months to provide constant blood levels, e.g. hormones and contraceptives. The empty non-biodegradable implant has to be removed.
Intramuscular (IM)
Aqueous solution of the drug is injected into one of the large skeletal muscles—deltoid, triceps, gluteus or rectus femoris. As the muscles are vascular, absorption is rapid and quite uniform. Drugs are absorbed faster from the deltoid region than gluteal region especially in women. The volume of injection should not exceed 10 mL. For infants, rectus femoris is used instead of gluteus which is not well-developed till the child starts walking. If the drug is injected as an oily solution, absorption is slow and steady.
Soluble substances, mild irritants, depot preparations, suspensions and colloids can be injected by this route.
  • Intramuscular route is reliable.
  • Absorption is rapid.
  • Intramuscular injection may be painful and may even result in an abscess.
  • Nerve injury should be avoided near a nerve, irritant solutions can damage the nerve if injected.
  • Local infection and tissue necrosis are possible.
Intravenous (IV)
Here, the drug is injected into one of the superficial veins so that it directly reaches the circulation and is immediately available for action.
Drugs can be given IV as:
  • A bolus—where an initial large dose is given, e.g. heparin. The drug is dissolved in a suitable amount of the vehicle and injected slowly.
  • Slowly—over 15–20 minutes, e.g. aminophylline.
  • Slow infusion—when constant plasma concentrations are required, e.g. oxytocin in labor or when large volumes have to be given, e.g. dextrose, saline. 6Generally about one liter of solution is infused over 3 to 4 hours. However, the patients condition dictates the rate of infusion.
  • Most useful route in emergencies as the drug is immediately available for action.
  • Provides predictable blood concentrations with 100 percent bioavailability.
  • Large volumes of solutions can be given.
  • Irritants can be given by this route as they get quickly diluted in the blood.
  • Rapid dose adjustments are possible—if unwanted effects occur, infusion can be stopped; if higher levels are required, infusion rate can be increased—specially for short-acting drugs.
  • Once injected into the vein, the drug cannot be withdrawn.
  • Irritation of the veins may cause thrombophlebitis.
  • Extravazation of some drugs may cause severe irritation and sloughing.
  • Only aqueous solutions can be given IV but not suspensions, oily solutions and depot preparations.
  • Self medication is difficult.
Peritoneum offers a large surface area for absorption. Fluids are injected intraperitoneally in infants. This route is also used for peritoneal dialysis.
Drugs can be injected into the subarachnoid space for action on the central nervous system (CNS), e.g. spinal anesthetics. Some antibiotics and corticosteroids are also injected by this route to produce high local concentrations. Strict aseptic precautions are a must.
Drugs are also given extradurally. Morphine can be given epidurally to produce analgesia.
Drugs are injected directly into a joint for the treatment of arthritis and other diseases of the joints. Strict aseptic precautions are required, e.g. hydrocortisone in rheumatoid arthritis.
Here drug is injected directly into the arteries. It is used only in the treatment of:
  • Peripheral vascular diseases
  • Local malignancies and
  • Diagnostic studies like angiograms.
Injection into a bone marrow—now rarely used.
2. Inhalation
Volatile liquids and gases are given by inhalation, e.g. general anesthetics. In addition, drugs can be administered as solid particles, i.e. solutions of drugs can be atomized and the fine droplets are inhaled as aerosol, e.g. salbutamol. These inhaled drugs and vapors may act on the pulmonary epithelium and mucous membranes of the respiratory tract and are also absorbed through these membranes.
  • Almost instantaneous absorption of the drug is achieved because of the large suface area of the lungs.
  • In pulmonary diseases, it serves almost as a local route as the drug is delivered at the desired site making it more effective and less harmful.
  • First pass metabolism is avoided.
  • Blood levels of volatile anesthetics can be conveniently controlled as their absorption and excretion through the lungs are governed by the laws of gases.7
  • Irritant gases may enhance pulmonary secretions—should be avoided.
  • This is an important route of entry of certain drugs of abuse.
3. Transdermal
Highly lipid soluble drugs can be applied over the skin for slow and prolonged absorption, e.g. nitroglycerine ointment in angina pectoris. Adhesive units, inunction, iontophoresis and jet injection are some forms of transdermal drug delivery.
Adhesive units (transdermal therapeutic systems) are adhesive patches of different sizes and shapes made to suit 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. The drug slowly diffuses through the membrane and percutaneous absorption takes place. The rate of absorption is constant and predictable. Highly potent and short acting drugs are suitable for use in such systems.
Sites of application are chest, abdomen, upper arm, back or mastoid region, e.g. hyoscine, nitroglycerine, fentanyl transdermal patches.
  • Duration of action is prolonged
  • Provides constant plasma drug levels
  • Patient compliance is good.
Inunction: This route where a drug rubbed into the skin gets absorbed to produce systemic effects is called inunction.
Iontophoresis: In this procedure, galvanic current is used for bringing about penetration of lipid insoluble drugs into the deeper tissues where its action is required, e.g. salicylates.
Jet injection: As absorption of drug occurs across the layers of the skin, dermojet may also be considered as a form of transdermal drug administration.
4. Transmucosal
Drugs are absorbed across the mucous membranes. Transmucosal administration includes sublingual, nasal and rectal routes.
Here, the tablet or pellet containing the drug is placed under the tongue. It dissolves in the saliva and the drug is absorbed across the sublingual mucosa, e.g. nitroglycerine, nifedipine, buprenorphine.
  • Absorption is rapid—within minutes the drug reaches the circulation.
  • First pass metabolism is avoided.
  • After the desired effect is obtained, the drug can be spat out to avoid the unwanted effects.
Buccal ulceration can occur.
Drugs can be administered through nasal route either for systemic absorption or for local effects, e.g.
  • Oxytocin spray is used for systemic absorption.
  • For local effect
    • Decongestant nasal drops, e.g. oxymetazoline;
    • Budesonide nasal spray for allergic rhinitis.
Rectum has a rich blood supply and drugs can cross the rectal mucosa to be absorbed for systemic effects. Drugs absorbed from the upper part of the rectum are carried by the superior hemorrhoidal vein to the portal circulation (can undergo first pass metabolism), while that absorbed from the lower part of the rectum is carried by the 8middle and inferior hemorrhoidal veins to the systemic circulation.
Some irritant drugs are given per rectally as suppositories:
  • Gastric irritation is avoided.
  • Can be administered by unskilled persons.
  • Useful in geriatric patients and others with vomiting and those unable to swallow.
  • Irritation of the rectum can occur.
  • Absorption may be irregular and unpredictable.
  • Drugs like—indomethacin, chlorpromazine, diazepam and paraldehyde can be given rectally.
Drugs may also be given by this route as enema.
Enema is the administration of a drug in a liquid form into the rectum. Enema may be evacuant or retention enema.
Evacuant enema: In order to empty the bowel, about 600 mL of soap water is administered per rectally. Water distends and thus stimulates the rectum while soap lubricates. Enema is given prior to surgeries, obstetric procedures and radiological examination of the gut.
Retention enema: The drug is administered with about 100 mL of fluids and is retained in the rectum for local action, e.g. prednisolone enema in ulcerative colitis.
Drugs may be applied on the skin for local action as ointment, cream, gel, powder, paste, etc. Drugs may also be applied on the mucous membrane as in the eyes, ears and nose, as ointment, drops and sprays. Drugs may be administered as suppository for rectum, bougie for urethra and pessary and douche for vagina. Pessaries are oval shaped tablets to be placed in the vagina to provide high local concentrations of the drug at the site, e.g. antifungal pessaries in vaginal candidiasis.
In order to improve drug delivery, to prolong duration of action and thereby improve patient compliance, special drug delivery systems are being tried. Drug targeting, i.e. to deliver drugs at the site where it is required to act is also being aimed at, especially for anticancer drugs. Some such systems are ocusert, progestasert, transdermal adhesive units, prodrugs, osmotic pumps, computerized pumps and methods using monoclonal antibodies and liposomes as carriers.
  1. Ocusert systems are thin elliptical units that contain the drug in a reservoir which slowly releases the drug through a membrane by diffusion at a steady rate, e.g. pilocarpine ocusert used in glaucoma is placed under the lid and can deliver pilocarpine for 7 days.
  2. Progestasert is inserted into the uterus where it delivers progesterone constantly for over one year.
  3. Transdermal adhesive units: (See page 7).
  4. Prodrug is an inactive form of the drug which gets metabolized to the active derivative in the body. Using a prodrug may overcome some of the disadvantages of the conventional forms of drug administration; as follows:
    • Enhance availability at the site, e.g. dopamine does not cross the blood-brain barrier (BBB); levodopa, a prodrug crosses the BBB and is then converted to dopamine in the CNS
    • Prolong duration of action: Prodrug may be used to achieve longer duration of action, e.g. bacampicillin (a prodrug of ampicillin) is longer acting than ampicillin
    • 9Improve tolerability, e.g. cyclophosphamide, an anticancer drug gets converted to its active metabolite aldophosphamide in the liver. This allows oral administration of cyclophosphamide without causing much gastrointestinal toxicity
    • Drug targeting: Zidovudine is taken up by the virus infected cells and gets activated in these cells. This results in selective toxicity to infected cells
    • Improve stability: A prodrug may be more stable at gastric pH, e.g. aspirin is converted to salicylic acid which is the more stable active drug and aspirin also is better tolerated than salicylic acid.
  5. Osmotic pumps are small tablet shaped units consisting of the drug and an osmotic substance placed in two chambers. The osmotic layer swells and pushes the drug slowly out of a small hole. Iron and prazosin are available in this form.
  6. Computerized miniature pumps: These are programmed to release drugs at a definite rate either continuously as in case of insulin or intermittently in pulses as in case of gonadotropin-releasing hormone (GnRH).
    Various methods of drug targeting are tried especially for anticancer drugs to reduce toxicity.
  7. Monoclonal antibodies against the tumor specific antigens are used to deliver anticancer drugs to specific tumor cells.
  8. Liposomes are phospholipids suspended in aqueous vehicles to form minute vesicles. Drugs encapsulated in liposomes are taken up mainly by the reticuloendothelial cells of the liver and are also concentrated in malignant tumors. Thus, site-specific delivery of drugs may be possible with the help of liposomes.
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 (Fig. 1.1). All these processes involve passage of the drug molecules across various barriers—like the intestinal epithelium, cell membrane, renal filtering membrane, capillary barrier and so on. To cross these barriers the drug has to cross the cell membrane or pass in-between the epithelial or endothelial cells.
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Fig. 1.1: Schematic representation of movement of drug in the body
The cell membrane/biological membrane is made up of two layers of phospho-lipids with intermingled protein molecules (Fig. 1.2). All lipid soluble substances get dissolved in the cell membrane and readily permeate into the cells. The junctions between epithelial or endothelial cells have pores through which small water-soluble molecules can pass. Movement of some specific substances is regulated by special carrier proteins. The passage of drugs across biological membranes involves processes like passive (filtration, diffusion) and active transport.10
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Fig. 1.2: Cell/biological membrane (schematic)
Mechanisms of Transport of Drug Across Biological Membranes
Passive transfer
Carrier-mediated transport
• Simple diffusion
• Active transport
• Filtration
• Facilitated diffusion
Passive Transfer
The drug moves across the membrane without any need for energy either by simple diffusion in the direction of its concentration gradient, i.e. from higher concentration to a lower concentration or by filtration through aqueous pores in the membrane. Most drugs are absorbed by simple diffusion.
Carrier-mediated Transport
Active transport is the transfer of drugs against a concentration gradient and needs energy. It is carried by a specific carrier protein. Only drugs related to natural metabolites are transported by this process, e.g. levodopa, iron, amino acids.
Facilitated diffusion is a unique form of carrier transport which differs from active transport in that it is not energy dependent and the movement occurs in the direction of the concentration gradient. The carrier facilitates diffusion and is highly specific for the substance, e.g. uptake of glucose by cells, vitamin B12 from intestines.
Endocytosis is the process where small droplets are engulfed by the cell. Some proteins are taken up by this process (like pinocytosis in ameba).
Absorption is defined as the passage of the drug from the site of administration into the circulation. For a drug to reach its site of action, it must pass through various membranes depending on the route of administration. Absorption occurs by one of the processes described above, i.e. passive diffusion or carrier-mediated transport. Except for intravenous route, absorption is important for all other routes of administration. Rate and extent of absorption by all other routes is influenced by several factors (Fig. 1.3). They are:
  • Absorption from the gut: Drugs taken orally may be absorbed from any part of the gut. Acidic drugs are absorbed from the stomach while basic drugs from the intestines.
  • Disintegration and dissolution time: The drug taken orally should break up into individual particles (disintegrate) to be absorbed. It then has to dissolve in the gastrointestinal fluids. In case of drugs given subcutaneously or intramuscularly, the drug molecules have to dissolve in the tissue fluids.11
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    Fig. 1.3: Factors affecting absorption of drugs
    Liquids are absorbed faster than solids. Delay in disintegration and dissolution as with poorly water-soluble drugs like aspirin, result in delayed absorption.
  • Formulation: Pharmaceutical preparations are formulated to produce desired absorption. Inert substances used with drugs as diluents like starch and lactose may sometimes interfere with absorption.
  • Particle size: Small particle size is important for better absorption of drugs. Drugs like corticosteroids, griseofulvin, digoxin, aspirin and tolbutamide are better absorbed when given as small particles. On the other hand, when a drug has to act on the gut and its absorption is not desired, then particle size should be kept large, e.g. anthelmintics like bephenium hydroxynaphthoate.
  • Lipid solubility: Lipid soluble drugs are absorbed faster and better by dissolving in the phospholipids of the cell membrane.
  • pH and ionization: Ionized drugs are poorly absorbed while unionized drugs are lipid soluble and are well absorbed. Most drugs are weak electrolytes and ionize according to pH. Thus acidic drugs remain unionized in acidic medium of the stomach and are rapidly absorbed, e.g. aspirin, barbiturates. Basic drugs are unionized when they reach the alkaline medium of intestine from where they are rapidly absorbed, e.g. pethidine, ephedrine.
    12Strong acids and bases are highly ionized and therefore poorly absorbed, e.g. streptomycin.
  • Area and vascularity of the absorbing surface: The larger the area of absorbing surface and more the vascularity—better is the absorption. Thus most drugs are absorbed from small intestine.
  • Gastrointestinal motility:
    Gastric emptying time: if gastric emptying is faster, the passage of the drug to the intestines is quicker and hence absorption is faster.
    Intestinal motility: When highly increased as in diarrheas, drug absorption is reduced.
  • Presence of food: In the stomach delays gastric emptying, dilutes the drug and delays absorption. Drugs may form complexes with food constituents and such complexes are poorly absorbed, e.g. tetracyclines chelate calcium present in food. Moreover, certain drugs like ampicillin, roxithromycin and rifampicin are well-absorbed only on empty stomach.
  • Metabolism: Some drugs may be degraded in the gastrointestinal (GI) tract, e.g. nitroglycerine, insulin. Such drugs should be given by alternate routes.
  • Diseases of the gut like malabsorption and achlorhydria result in reduced absorption of drugs.
First pass metabolism is the metabolism of a drug during its passage from the site of absorption to the systemic circulation. It is also called presystemic metabolism or first pass effect and is an important feature of oral route of administration. Drugs given orally may be metabolized in the gut wall and in the liver before reaching the systemic circulation. The extent of first pass metabolism differs from drug to drug and among individuals, from partial to total inactivation. When it is partial, it can be compensated by giving higher dose of the particular drug, e.g. nitroglycerine, propranolol, salbutamol. But for drugs that undergo extensive first pass metabolism, the route of administration has to be changed, e.g. isoprenaline, hydrocortisone, insulin.
Absorption from parenteral routes: On intravenous administration, the drug directly reaches the circulation. On intramuscular injection, the drug molecules should dissolve in the tissue fluids and then be absorbed. Since muscles have a rich blood supply, absorption is fast. Drug molecules diffuse through the capillary membrane and reach the circulation. Lipid-soluble drugs are absorbed faster. Absorption from subcutaneous administration is slower but rate of absorption is somewhat steady.
Inhaled drugs particularly the lipid soluble ones are rapidly absorbed from the pulmonary epithelium.
On topical application, highly lipid soluble drugs are absorbed from the intact skin, e.g. nitroglycerine; but absorption is relatively slow because of the multiple layers of closely-packed cells in the epidermis. Most drugs are readily absorbed from the mucous membranes.
Bioavailability is the fraction of the drug that reaches the systemic circulation following administration by any route. 13Thus for a drug given intravenously, the bioavailability is 100 percent. On IM/SC injection, drugs are almost completely absorbed while by oral route, bioavailability may be low due to incomplete absorption and first pass metabolism. All the factors which influence the absorption of a drug also alter bioavailability.
For example, bioavailability of chlor-tetracycline is 30%, carbamazepine 70%, chloroquine 80%, minocycline and diazepam 100%. Transdermal preparations are absorbed systemically and may have 80–100% bioavailability.
Factors Affecting Bioavailability
In fact, all the ten factors including particle size, disintegration and dissolution time, lipid solubility, ionization, first pass metabolism, area and vascularity of the absorbing surface, presence of food and GI motility, which influence the absorption of a drug also alter the bioavailability. Large bioavailability variations of a drug, particularly when it is unpredictable can result in toxicity or therapeutic failure as in case of halofantrine.
Comparison of bioavailability of different formulations of the same drug is the study of bioequivalence (Fig. 1.4). Often oral formulations containing the same amount of a drug from different manufacturers may result in different plasma concentrations, i.e. there is no bioequivalence. Such differences occur with poorly soluble, slowly absorbed drugs mainly due to differences in the rate of disintegration and dissolution. Variation in bioavailability (nonequivalence) can result in toxicity or therapeutic failure in drugs that have low safety margin like digoxin and drugs that need precise dose adjustment like anticoagulants and corticosteroids. For such drugs, in a given patient, the preparations from a single manufacturer should be used.
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Fig. 1.4: Study of bioequivalence. Three different oral formulations—P, Q and R of the same drug yield different bioavailability values
After a drug reaches the systemic circulation, it gets distributed to other tissues. It should cross several barriers before reaching the site of action. Like absorption, distribution also involves the same processes, i.e. filtration, diffusion and specialized transport. Various factors determine the rate and extent of distribution, viz lipid solubility, ionization, blood flow and binding to plasma proteins and cellular proteins. Unionized lipid soluble drugs are widely distributed throughout the body.
Plasma Protein Binding
On reaching the circulation most drugs bind to plasma proteins; acidic drugs bind mainly albumin and basic drugs to alpha-acid glycoprotein. The free or unbound fraction of the drug is the only form available for action, metabolism and excretion while the protein bound form serves as a reservoir. The extent of protein binding varies with each drug, e.g. warfarin is 99% and morphine is 35% protein bound while binding of ethosuximide and lithium is 0 percent, i.e. they are totally free.
Clinical Significance of Plasma Protein Binding
  • Only free fraction is available for action, metabolism and excretion. When the free drug levels fall, bound drug is released.
  • 14Protein binding serves as a store (reservoir) of the drug and the drug is released when free drug levels fall.
  • Protein binding prolongs duration of action of the drug.
  • Many drugs may compete for the same binding sites. Thus one drug may displace another from the binding sites resulting in toxicity. For example, indomethacin displaces warfarin from protein binding sites leading to increased warfarin levels.
  • Chronic renal failure and chronic liver disease result in hypoalbuminemia with reduced protein binding of drugs.
Some Highly Protein Bound Drugs
Tissue binding: Some drugs get bound to certain tissue constituents because of special affinity for them. Tissue binding delays elimination and thus prolongs duration of action of the drug. For example, lipid soluble drugs are bound to adipose tissue. Tissue binding also serves as a reservoir of the drug.
Redistribution: When highly lipid soluble drugs are given intravenously or by inhalation, they get rapidly distributed into highly perfused tissues like brain, heart and kidney. But soon they get redistributed into less vascular tissues like the muscle and fat resulting in termination of the action of these drugs. The best example is the intravenous anesthetic thiopental sodium which induces anesthesia in 10–20 seconds but the effect stops in 5–15 minutes due to redistribution.
Blood-brain barrier (BBB): The endothelial cells of the brain capillaries lack intercellular pores and instead have tight junctions. Moreover, glial cells envelope the capillaries and together these form the BBB. Only lipid soluble, unionized drugs can cross this BBB. During inflammation of the meninges, the barrier becomes more permeable to drugs, e.g. penicillin readily penetrates during meningitis. The barrier is weak at some areas like chemoreceptor triggor zone (CTZ), posterior pituitary and parts of hypothalamus 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 several unwanted effects in the fetus.
Volume of Distribution (Vd)
Volume of distribution is defined as the volume necessary to accommodate the entire amount of the drug, if the concentration throughout the body were equal to that in plasma. It relates the amount of the drug in the body to the concentration of the drug in plasma. It is calculated as
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For example, if the dose of a drug given is 500 mg and attains a uniform concentration of 10 mg in the body, its Vd = 50 liters.
The knowledge of Vd of drugs is clinically important in the treatment of poisoning. Drugs with large Vd like pethidine are not easily removed by hemodialysis.
Biotransformation is the process of biochemical alteration of the drug in the body. Body treats most drugs as foreign substances 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.15
The most important organ of biotransformation is the liver. Many drugs are also metabolized to some extent by the kidney, gut mucosa, lungs, blood and skin.
Result of Biotransformation
Though biotransformation generally inactivates the drug, some drugs may be converted to active or more active metabolites (Table 1.1).
When the metabolite is active, the duration of action gets prolonged. Prodrug is an inactive drug which gets converted into an active form in the body (Table 1.1).
Enzymes in Biotransformation
The biotransformation reactions are catalyzed by specific enzymes located either in the liver microsomes (microsomal enzymes) or in the cytoplasm and mitochondria of the liver cells and also in the plasma and other tissues (non-microsomal enzymes).
The chemical reactions of biotransformation can take place in two phases (Fig. 1.5).
  1. Phase I (Non-synthetic reactions)
  2. Phase II (Synthetic reactions).
Phase I reactions convert the drug to a more polar metabolite by oxidation, reduction or hydrolysis. Oxidation reactions are the most important metabolizing reactions, mostly catalyzed by mono-oxygenases present in the liver. If the metabolite is not sufficiently polar to be excreted, they undergo phase II reactions.
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Fig. 1.5: Phases in metabolism of drugs. A drug may be excreted as phase I metabolite or as phase II metabolite. Some drugs may be excreted as such
Phase II reactions are conjugation reactions where water-soluble substances present in the body like glucuronic acid, sulfuric acid, glutathione or an amino acid, combine with the drug or its phase I metabolite to form a highly polar compound. This is inactive and gets readily excreted by the kidneys. Large molecules are excreted through the bile. Thus, phase II reactions invariably inactivate the drug.
Glucuronide conjugation is the most common type of metabolic reaction (Table 1.2).
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Table 1.1   Result of biotransformation
Active drug to inactive metabolite
Active drug to active metabolite
Inactive drug to active metabolite (prodrug)
e.g. Morphine
e.g. Primidone →
e.g. Levodopa →
Digitoxin → Digoxin
Prednisone → Prednisolone
Diazepam → Oxazepam
Enalapril → Enalaprilat
Table 1.2   Important drug biotransformation reactions
Examples of drugs
Phenytoin, diazepam, ibuprofen, amphetamine, chlorpromazine, dapsone
Chloramphenicol, halothane
Pethidine, procaine
Conjugation reactions
Glucuronide conjugation
Chloramphenicol, morphine
Sulfonamides, isoniazid
Adrenaline, histamine
Glutathione conjugation
Sulfate conjugation
Paracetamol, steroids
Enzyme Induction
Microsomal enzymes are present in the microsomes of 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 inducing drug itself and other drugs metabolized by the microsomal enzymes, e.g. phenobarbitone, rifampicin, alcohol, cigarette smoke, dichloro-diphenyl-trichloroethane (DDT), griseofulvin, carbamazepine and phenytoin are some enzyme inducers.
Enzyme induction can result in drug interactions when drugs are given together because one drug may enhance the metabolism of the other drug resulting in therapeutic failure.
Therapeutic application of enzyme induction: Neonates are deficient in both microsomal and nonmicrosomal enzymes. Hence their capacity to conjugate bilirubin is low which results in jaundice. Administration of phenobarbitone—an enzyme inducer, helps in rapid clearance of jaundice in them by enhancing bilirubin conjugation.
Enzyme Inhibition
Some drugs like cimetidine and ketoconazole inhibit cytochrome P450 enzyme activity. Hence, metabolism of other drugs get reduced and can result in toxicity. Therefore, enzyme inhibition by drugs is also the basis of several drug interactions. Chloramphenicol, cimetidine, erythromycin, ketoconazole, ciprofloxacin and verapamil are some enzyme inhibitors.
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 the kidneys, the intestines, the biliary system and the lungs. Drugs are also excreted in small amounts in the saliva, sweat and milk.
Renal Excretion
Kidney is the most important route of drug excretion. The three processes involved in the elimination of drugs through kidneys are glomerular filtration, active tubular secretion and passive tubular reabsorption.
Glomerular filtration: The rate of filtration through the glomerulus depends on glomerular filtration rate (GFR), concentration of free drug in the plasma and its molecular weight. Ionized drugs of low molecular weight (< 10,000) are easily filtered through the glomerular membrane.
Active tubular secretion: Cells of the proximal tubules actively secrete acids and bases by two transport systems. Thus, acids like penicillin, salicylic acid, probenecid, frusemide; bases like amphetamine and histamine are so excreted. Drugs may compete for the same transport system resulting in prolongation of action of each other, e.g. penicillin and probenecid.
Passive tubular reabsorption: Passive diffusion of drug molecules can occur 17in either direction in the renal tubules depending on the drug concentration, lipid solubility and pH. As highly lipid soluble drugs are largely reabsorbed, their excretion is slow. Acidic drugs get ionized in alkaline urine and are easily excreted while bases are excreted faster in acidic urine. This property is useful in the treatment of poisoning. In poisoning with acidic drugs like salicylates and barbiturates, forced alkaline diuresis (diuretic + sodium bicarbonate + IV fluids) is employed to hasten drug excretion. Similarly, elimination of basic drugs like quinine and amphetamine is enhanced by forced acid diuresis.
Fecal and Biliary Excretion
Unabsorbed portion of the orally administered drugs are eliminated through the feces. Liver transfers acids, bases and unionized molecules into bile by specific acid transport processes. Some drugs may get reabsorbed in the lower portion of the gut and are carried back to the liver. Such recycling is called enterohepatic circulation and it prolongs the duration of action of the drug; examples are chloramphenicol, tetracycline, oral contraceptives and erythromycin.
Pulmonary Excretion
The lungs are the main route of elimination for gases and volatile liquids viz general anesthetics and alcohol. This also has legal implications in medicolegal practice.
Other Routes of Excretion
Small amounts of some drugs are eliminated through the sweat and saliva. Excretion in saliva may result in a unique taste of some drugs, e.g. metronidazole and phenytoin. Drugs like iodide, rifampicin and heavy metals are excreted through sweat.
The excretion of drugs in the milk is in small amounts and is of no significance to the mother. But, for the suckling infant, it may be sometimes important especially because of the infant's immature metabolic and excretory mechanisms. Though most drugs can be taken by the mother without significant toxicity to the child, there are a few exceptions (Table 1.3).
Table 1.3   Example of drugs that could be toxic to the suckling infant when taken by the mother
Anticancer drugs
Nalidixic acid
Drugs are metabolized/eliminated from the body by:
  • First-order kinetics: In first order kinetics, a constant fraction of the drug is metabolized/eliminated per unit time. Most drugs follow first order kinetics and the rate of metabolism/excretion is dependant on their concentration (exponential) in the body. It also holds good for absorption of drugs.
  • Zero order kinetics (saturation kinetics): Here a constant amount of the drug present in the body is metabolized/eliminated per unit time. The metabolic enzymes get saturated and hence with increase in dose, the plasma drug level increases disproportionately resulting in toxicity.
Some drugs like phenytoin and warfarin are eliminated by both processes, i.e. by first order initially and by zero order at higher concentrations.
Plasma Half-life and Steady State Concentration
Plasma half-life (t½) is the time taken for the plasma concentration of a drug to be reduced to half its value (Fig. 1.6). Four to five half-lives are required for the complete elimination of a drug. Each drug has its own t½ and is an important pharmacokinetic parameter that guides 18the dosing regimen. It helps in calculating loading and maintenance doses of a drug. It also indicates the duration of action of a drug.
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Fig. 1.6: Plasma concentration-time curve following intravenous dose. Plasma t½ = 4 hours
Biological half-life is the time required for total amount of the drug in the body to be reduced to half.
Biological effect half-life is the time required for the biological effect of the drug to reduce to half. In some drugs like propranolol, the pharmacological effect of the drug may last much longer, i.e. even after its plasma levels fall. In such drugs, biological effect half life gives an idea of the duration of action of the drug.
If a drug is administered repeatedly at short intervals before complete elimination, the drug accumulates in the body and reaches a ‘state’ at which the rate of elimination equals the rate of administration. This is known as the ‘Steady-state’ or plateau level (Fig. 1.7). After attaining this level, the plasma concentration fluctuates around an average steady level. It takes 4–5 half-lives for the plasma concentration to reach the plateau level.
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Fig. 1.7: Drug accumulation and attainment of steady state concentration on oral administration
Drug Dosage
Depending on the patient's requirements and the characteristics of the drug, drug dosage can be of the following kinds:
Fixed dose: In case of reasonably safe drugs, a fixed dose of the drug is suitable for most patients, e.g. analgesics like paracetamol—500 mg to 1000 mg 6 hourly is the usual adult dose.
Individualized dose: For some drugs especially the ones with low safety margin, the dose has to be ‘tailored’ to the needs of each patient, e.g. anticonvulsants, antiarrhythmic drugs.
Loading dose: In situations when rapid action is needed, a loading/bolus dose of the drug is given at the beginning of the treatment. A loading dose is a single large dose or a series of quickly repeated doses given to rapidly attain target concentration, e.g. heparin given as 5000 IU bolus dose. Once the target level is reached, a maintenance dose is sufficient to maintain the drug level and to balance the elimination.
The disadvantage with the loading dose is that the patient is rapidly exposed to high concentrations of the drug which may result in toxicity.
Therapeutic Drug Monitoring
The response to a drug depends on the plasma concentration attained in the patient. In some situations it may be necessary to monitor treatment by measuring plasma drug concentrations. Such situations are:
  • While using drugs with low safety margin—to avoid therapeutic failure, e.g. digoxin, theophylline, lithium.
  • To reduce the risk of toxicity, e.g. aminoglycosides.
  • To treat poisoning.19
Methods of Prolonging Drug Action (Table 1.4)
In several situations it may be desirable to use long-acting drugs. But when such drugs are not available, the duration of action of the available drugs may be prolonged.
The duration of action of drugs can be prolonged by interfering with the pharmacokinetic processes, i.e. by
  • Slowing absorption.
  • Using a more plasma protein bound derivative.
  • Inhibiting metabolism.
  • Delaying excretion.
Pharmacodynamics is the study of actions of the drugs on the body and their mechanisms of action, i.e. to know what drugs do and how they do it.
Drugs produce their effects by interacting with the physiological systems of the organisms. By such interaction, drugs merely modify the rate of functions of the various systems. But they cannot bring about qualitative changes, i.e. they cannot change the basic functions of any physiological system. Thus drugs act by:
  • Stimulation
  • Depression
  • Irritation
  • Replacement
  • Anti-infective or cytotoxic action
  • Modification of the immune status.
Stimulation: Stimulation is the increase in activity of the specialized cells, e.g. adrenaline stimulates the heart.
Depression: Depression is the decrease in activity of the specialized cells, e.g. quinidine depresses the heart; barbiturates depress the central nervous system. Some drugs may stimulate one system and depress another, e.g. morphine depresses the CNS but stimulates the vagus.
Table 1.4   Methods of prolonging duration of action of drugs
Sustained release preparation, coating with resins, etc.
Iron, deriphylline
• Reducing solubility
  • Oily suspension
• Altering particle size
• Pellet implantation
  • Sialistic capsules
• Reduction in vascularity of the absorbing surface
• Combining with protein
• Chemical alteration
  • Esterification
Procaine + Penicillin
Depot progestins
Insulin zinc suspension as large crystals that are slowly absorbed
Deoxycorticosterone acetate (DOCA)
Adrenaline + lignocaine (vasoconstrictor)
Protamine + zinc + insulin
Transdermal adhesive patches,
Ocuserts (transmucosal)—used in eye
Choosing more protein bound member of the group
Sulfonamides-like sulfamethoxypyridazine
Inhibiting the metabolizing enzyme cholinesterase
By inhibiting enzyme peptidase in renal tubular cells
Physostigmine prolongs the action of acetylcholine
Cilastatin—prolongs action of imipenem
Competition for same transport system
—for renal tubular secretion
Probenecid prolongs the action of penicillin and ampicillin
20Irritation: This can occur on all types of tissues in the body and may result in inflammation, corrosion and necrosis of cells.
Replacement: Drugs may be used for replacement when there is deficiency of natural substances like hormones, metabolites or nutrients, e.g. insulin in diabetes mellitus, iron in anemia, vitamin C in scurvy.
Anti-infective and cytotoxic action: Drugs may act by specifically destroying infective organisms, e.g. penicillins, or by cytotoxic effect on cancer cells, e.g. anticancer drugs.
Modification of immune status: Vaccines and sera act by improving our immunity while immunosuppressants act by depressing immunity, e.g. glucocorticoids.
Mechanisms of Drug Action
Most drugs produce their effects by binding to specific target proteins like receptors, enzymes and ion channels. Drugs may act on the cell membrane, inside or outside the cell to produce their effect. Drugs may act by one or more complex mechanisms of action. Some of them are yet to be understood. But the fundamental mechanisms of drug action may be:
1. Through Receptors
Drugs may act by interacting with specific receptors in the body (see below).
2. Through Enzymes and Pumps
Drugs may act by inhibition of various enzymes, thus altering the enzyme-mediated reactions, e.g. allopurinol inhibits the enzyme xanthine oxidase; acetazolamide inhibits carbonic anhydrase.
Membrane pumps like H+ K+ ATPase, Na+ K+ ATPase may be inhibited by drugs, e.g. omeprazole, digoxin.
3. Through Ion Channels
Drugs may interfere with the movement of ions across specific channels, e.g. calcium channel blockers, potassium channel openers.
4. Physical Action
The action of a drug could result from its physical properties like:
– Activated charcoal in poisoning
Mass of the drug
– Bulk laxatives like psyllium, bran
Osmotic property
– Osmotic diuretics—mannitol
– Osmotic purgatives—magnesium sulfate
– 131I
– Barium sulfate contrast media.
5. Chemical Interaction
Drugs may act by chemical reaction.
– neutralise gastric acids
Oxidizing agents
–like potassium permanganate—germicidal
Chelating agents
– bind heavy metals making them nontoxic.
6. Altering Metabolic Processes
Drugs like antimicrobials alter the metabolic pathway in the microorganisms resulting in destruction of the microorganism, e.g. sulfonamides interfere with bacterial folic acid synthesis.
A receptor is a site on the cell with which an agonist binds to bring about a change, e.g. histamine receptor, α and β adrenergic receptors.
Affinity is the ability of a drug to bind to a receptor.
Intrinsic activity or efficacy is the ability of a drug to produce a response after binding to the receptor.
Agonist: An agonist is a substance that binds to the receptor and produces a response. It has affinity and intrinsic activity.
21Antagonist: An antagonist is a substance that binds to the receptor and prevents the action of agonist on the receptor. It has affinity but no intrinsic activity.
Partial agonist binds to the receptor but has low intrinsic activity.
Ligand is a molecule which binds selectively to a specific receptor.
Last three decades have seen an explosion in our knowledge of the receptors. Various receptors have been identified, isolated and extensively studied.
Site: The receptors may be present in the cell membrane, in the cytoplasm or on the nucleus.
Nature of receptors: Receptors are proteins.
Synthesis and life-span: Receptor proteins are synthesized by the cells. They have a definite life span after which the receptors are degraded by the cell and new receptors are synthesized.
Functions of Receptors
The two functions of receptors are:
  1. Recognition and binding of the ligand
  2. Propagation of the message.
For the above function, the receptor has two sites (domains):
  1. A ligand binding site: The site to bind the drug molecule.
  2. An effector site: Which undergoes a change to propagate the message.
Drug-receptor interaction has been considered to be similar to ‘lock and key’ relationship where the drug specifically fits into the particular receptor (lock) like a key. Interaction of the agonist with the receptor brings about changes in the receptor which in turn conveys the signal to the effector system. The final response is brought about by the effector system through second messengers. The agonist itself is the first messenger. The entire process involves a chain of events triggered by drug receptor interaction.
Receptor Families
Four families (types) of cell surface receptors are identified. The receptor families are:
  • Ion channels
  • G-protein coupled receptors
  • Enzymatic receptors
  • Nuclear receptors (receptors that regulate gene transcription).
Receptor Regulation
The number of receptors (density) and their sensitivity can be altered in many situations. Denervation or prolonged deprivation of the agonist or constant action of the antagonist all result in an increase in the number and sensitivity of the receptors. This phenomenon is called ‘up regulation.’
Prolonged use of a β adrenergic antagonist like propranolol results in up regulation of β adrenergic receptors.
On the other hand, continued stimulation of the receptors causes desensitization and a decrease in the number of receptors—known as ‘down regulation’ of the receptors.
Clinical importance of receptor regulation: After prolonged administration, a receptor antagonist should always be tapered. For example, if propranolol—a β adrenoceptor blocker is suddenly withdrawn after long-term use, it precipitates angina due to upregulation of β receptors.
Constant use of β adrenergic agonists in bronchial asthma results in reduced therapeutic response due to down regulation of β2 receptors.
Dose Response Relationship
The response to different doses of a drug can be plotted on a graph to obtain the dose response curve.
The clinical response to the increasing dose of the drug is defined by the shape of the dose response curve (DRC). Initially the extent of response increases with increase in dose till the maximum response is 22reached. After the maximum effect has been obtained, further increase in doses does not increase the response. If the dose is plotted on a logarithmic scale, the curve becomes sigmoid or ‘S’ shaped (Fig. 1.8).
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Fig. 1.8: Log dose response curve
Drug Potency and Maximal Efficacy
The amount of drug required to produce a response indicates the potency. For example, 1 mg of bumetanide produces the same diuresis as 50 mg of frusemide. Thus, bumetanide is more potent than frusemide. In Figure 1.9, drugs A and B are more potent than drugs C and D, drug A being the most potent and drug D—the least potent. Hence higher doses of drugs C and D are to be administered as compared to drugs A and B. Generally potency is of little clinical significance unless very large doses of the drug needs to be given due to low potency.
Maximal efficacy: Efficacy indicates the maximum response that can be produced by a drug, e.g. frusemide produces powerful diuresis, not produced by any dose of amiloride. In Figure 1.9, drugs B and C are more efficacious than drugs A and D. Drug A is more potent but less efficacious than drugs B and C. Such differences in efficacy are of great clinical importance.
Therapeutic index: The dose response curves for different actions of a drug could be different. Thus salbutamol may have one DRC for bronchodilation and another for tachycardia. The distance between beneficial effect DRC and unwanted effect DRC indicates the safety margin of the drug (Fig. 1.10).
Median lethal dose (LD50) is the dose which is lethal to 50 percent of animals of the test population.
Median effective dose (ED50) is the dose that produces a desired effect in 50 percent of the test population.
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Fig. 1.9: Dose response curves of four drugs showing different potencies and maximal efficacies. Drug A is more potent but less efficacious than B and C. Drug D is less potent and less efficacious than drugs B and C
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Fig. 1.10: The distance between curves A and B indicates safety margin of the drug. The greater the distance, more selective is the drug
Therapeutic index (TI) is the ratio of the median lethal dose to the median effective dose.23
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It gives an idea about the safety of the drug.
  • The higher the therapeutic index, the safer is the drug
  • TI varies from species to species
  • For a drug to be considered reasonably safe, it's TI must be > 1
  • Penicillin has a high TI while lithium and digoxin have low TI.
Drug Synergism and Antagonism
When two or more drugs are given concurrently the effect may be additive, synergistic or antagonistic.
Additive Effect
The effect of two or more drugs get added up and the total effect is equal to the sum of their individual actions.
Examples are ephedrine with theophylline in bronchial asthma; nitrous oxide and ether as general anesthetics.
When the action of one drug is enhanced by another drug, the combination is synergistic. In Greek, ergon = work; syn = with. Here, the total effect of the combination is greater than the sum of their independent effects. It is often called ‘potentiation’ or ‘supra-additive’ effect.
Examples of synergistic combination are:
  • Acetylcholine + physostigmine
  • Levodopa + carbidopa.
One drug opposing or inhibiting the action of another is antagonism. Based on the mechanisms, antagonism can be:
  • Chemical antagonism
  • Physiological antagonism
  • Antagonism at the receptor level
    • Reversible (competitive)
    • Irreversible
  • Non-competitive antagonism.
Chemical antagonism: Two substances interact chemically to result in inactivation of the effect, e.g. chelating agents inactivate heavy metals like lead and mercury to form inactive complexes; antacids like aluminium hydroxide neutralize gastric acid.
Physiological antagonism: Two drugs act at different sites to produce opposing effects. For example, histamine acts on H2 receptors to produce bronchospasm and hypotension while adrenaline reverses these effects by acting on adrenergic receptors.
Insulin and glucagon have opposite effects on the blood sugar level.
Antagonism at the receptor level: The antagonist inhibits the binding of the agonist to the receptor. Such antagonism may be reversible or irreversible.
Reversible or competitive antagonism: The agonist and antagonist compete for the same receptor. By increasing the concentration of the agonist, the antagonism can be overcome. It is thus reversible antagonism. Acetylcholine and atropine compete for the muscarinic receptors. The antagonism can be overcome by increasing the concentration of acetylcholine at the receptor. d-tubocurarine and acetylcholine compete for the nicotinic receptors at the neuromuscular junction (Fig. 1.11).
Irreversible antagonism: The antagonist binds firmly by covalent bonds to the receptor. Thus it blocks the action of the agonist and the blockade cannot be overcome by increasing the dose of the agonist and hence it is irreversible antagonism, e.g. adrenaline and phenoxybenzamine at alpha adrenergic receptors (Fig. 1.12).
Noncompetitive antagonism: The antagonist blocks at the level of receptor-effector linkage. For example, verapamil blocks the cardiac calcium channels and inhibits the entry of Ca ++ during depolarization. It thereby antagonizes the effect of cardiac stimulants like isoprenaline and adrenaline.24
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Fig. 1.11: Dose response curves of an agonist:
(A) in the absence of competitive antagonist;
(B) in the presence of increasing doses of a competitive antagonist
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Fig. 1.12: Dose response curves of an agonist:
(A) in the absence of antagonist. (B1), (B2) and (B3) in the presence of increasing doses of an irreversible antagonist
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:
  1. 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.
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  2. 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 grey 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
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    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.
  3. 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 and during menstruation.
  4. Species and race: Response to drugs may vary with species and race. For example, 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.
  5. 25Diet and environment: Food interferes with the absorption of many drugs. For example, 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.
  6. Route of administration: Occasionally route of administration may modify the pharmacodynamic response, e.g. magnesium sulfate given orally is a purgative, but given intravenously causes CNS depression and has anticonvulsant effects. Applied topically (poultice), it reduces local edema. Hypertonic magnesium sulfate retention enema reduces intracranial tension.
  7. 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.
    • Acetylation of drugs: The rate of drug acetylation differs among individuals who may be fast or slow acetylators, e.g. isoniazid (INH), sulfonamides and hydralazine are acetylated. Slow acetylators treated with hydralazine are more likely to develop lupus erythematosus.
    • Atypical pseudocholinesterase: Succi-nylcholine is metabolized by pseudocholinesterase. Some people inherit atypical pseudocholinesterase and they develop a prolonged apnea due to succinylcholine.
    • Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Primaquine, sulfones and quinolones can cause hemolysis in such people.
    • Malignant hyperthermia: Halothane and succinylcholine can trigger malignant hyperthermia in some genetically predisposed individuals.
  8. Dose: It is fascinating 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. Further increases in doses may with some drugs 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.
  9. Diseases: Presence of certain diseases can influence drug responses, e.g.
    • 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 congestive cardiac failure (CCF), 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.
  10. Repeated dosing can result in:
    • Cumulation
    • Tolerance
    • Tachyphylaxis.
    Cumulation: Drugs like digoxin which are slowly eliminated may cumulate resulting in toxicity.
    Tolerance: Tolerance is the requirement of higher doses of a drug to produce a given 26response. Tolerance may be natural or acquired.
    Natural tolerance: The species/race shows less sensitivity to the drug, e.g. rabbits show tolerance to atropine; Black race are tolerant to mydriatics.
    Acquired tolerance: Develops on repeated administration of a drug. The patient who was initially responsive becomes tolerant, e.g. barbiturates, opioids, nitrites produce tolerance.
    Tolerance may develop to some actions of the drug and not to others, e.g. morphine—tolerance develops to analgesic and euphoric effects of morphine but not to its constipating and miotic effects.
    Barbiturates—tolerance develops to sedative but not antiepileptic effects of barbiturates.
    Mechanisms: The mechanisms of development of tolerance could be:
    Pharmacokinetic: Changes in absorption, distribution, metabolism and excretion of drugs may result in reduced concentration of the drug at the site of action and is also known as dispositional tolerance, e.g. barbiturates induce microsomal enzymes and enhance their own metabolism.
    Pharmacodynamic: Changes in the target tissue, may make it less responsive to the drug. It is also called functional tolerance. It could be due to down regulation of receptors as in opioids or due to compensatory mechanisms of the body, e.g. blunting of response to some antihypertensives due to salt and water retention.
    Cross tolerance is the development of tolerance to pharmacologically related drugs, i.e. to drugs belonging to a particular group. Thus chronic alcoholics also show tolerance to barbiturates and general anesthetics.
    Tachyphylaxis: It is the rapid development of tolerance. When some drugs are administered repeatedly at short intervals, tolerance develops rapidly and is known as tachyphylaxis or acute tolerance, e.g. ephedrine, amphetamine, tyramine and 5-hydroxytryptamine. This is thought to be due to depletion of noradrenaline stores as the above drugs act by displacing noradrenaline from the sympathetic nerve endings. Other mechanisms involved may be slow dissociation of the drug from the receptor thereby blocking the receptor. Thus ephedrine given repeatedly in bronchial asthma may not give the desired response.
  11. Psychological factor: The doctor patient relationship influences the response to a drug often to a large extent by acting on the patient's psychology. The patients 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. Placebo is the inert dosage form with no specific biological activity but only resembles the actual preparation in appearance. Placebo = ‘I shall be pleasing’ (in Latin).
    Placebo medicines are used in:
    • Clinical trials as a control
    • To benefit or please a patient psychologically when he does not actually require an active drug as in mild psychosomatic disorders and in chronic incurable diseases.
      In fact all forms of treatment including physiotherapy and surgery have placebo effect. Substances used as placebo include lactose, some vitamins, minerals and distilled water injections.
  12. Presence of other drugs: When two or more drugs are used together, one of them can alter the response of the other resulting in drug interactions (See Drug Interactions page 30).
All drugs can produce unwanted effects. WHO has defined an adverse drug reaction as ‘any response to a drug that is noxious 27and unintended and that occurs at doses used in man for prophylaxis, diagnosis or therapy.’ Some patients are more likely to develop adverse effects to drugs.
Pharmacovigilance deals with the epidemiologic study of adverse drug effects.
Adverse drug reactions (ADRs) are classified as follows (Flowchart 1.3):
Type A (augmented) reactions are related to the known pharmacological effects of the drug and are predictable, dose-related and quantitative adverse effects. For example, hypotension following alpha blockers, insulin induced hypoglycemia, bleeding following anticoagulants. Most ADRs are of this category and are mostly reversible by dose reduction or stopping the drug. Type A reactions include side effects, secondary effects and toxic effects.
  • Side effects: Side effects are unwanted effects of a drug that are extension of pharmacological effects and are seen with the therapeutic dose of the drug. They are predictable, common and can occur in all people, e.g. hypoglycemia due to insulin; hypokalemia following frusemide.
  • Secondary effects: Secondary effects are the indirect results of a primary drug action. Example: superinfection on treatment of a primary infection by broad spectrum antibiotics.
  • Toxic effects: Toxic effects are seen with higher doses of the drug and can be serious, e.g. morphine causes respiratory depression in overdosage which can be fatal.
Type B (bizarre) reactions are unrelated to the primary pharmacological effects of the drug and are therefore not predictable. They are less common, not tolerated and are an abnormal reaction to the drug. They could be allergic reactions (immunologically mediated) or idiosyncratic (genetically mediated) reactions.
Idiosyncrasy is a genetically determined abnormal reaction to a drug, e.g. primaquine and sulfonamides induce hemolysis in patients with G6PD deficiency; some patients show excitement with barbiturates. In addition, some responses like chloramphenicol-induced agranulocytosis, where no definite genetic background is known, are also included under idiosyncrasy.
zoom view
Flowchart 1.3: Adverse drug reactions
Abbreviation: Ag-Ab, antigen-antibody; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis
28In some cases the person may be highly sensitive even two low doses of a drug (e.g. a single dose of quinine can produce cinchonism in some) or highly insensitive even to high doses of the drug.
Type C (Continuous or Chronic use) reactions occur on prolonged use of drugs and both dose and duration of drug use influence these ADRs, e.g. chloroquine retinopathy, Cushing's syndrome, analgesic nephropathy.
Type D (Delayed effects) occur long after stopping treatment, sometimes after years, e.g. leukemia following treatment of Hodgkin's lymphoma; teratogenic effects.
Type E (End of use): These effects are due to sudden discontinuation of a drug after prolonged use, e.g. acute adrenal insufficiency after sudden cessation of glucocorticoids: angina after sudden withdrawal of atenolol. Withdrawal syndrome to opioids and other drugs of abuse also are categorized as Type E ADRs.
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems. It deals with the epidemiologic study of adverse drug effects.
The aim of pharmacovigilance is to ensure safe and rational use of medicines.
Drugs can induce allergic reactions which could range from mild itching to anaphylaxis. They can induce both types of allergic reactions viz. humoral and cell-mediated immunity. Mechanisms involved in Type I, II and III are humoral while Type IV reactions are by cell-mediated immunity.
Allergic reactions to drugs are immunologically-mediated reactions which are not related to the therapeutic effects of the drug. The drug or its metabolite acts as an antigen to induce antibody formation. Subsequent exposure to the drug may result in allergic reactions. The manifestations of allergy are seen mainly on the target organs viz. skin, respiratory tract, gastrointestinal tract, blood and blood vessels.
Types of Allergic Reactions and their Mechanisms
Drugs can induce both types of allergic reactions viz humoral and cell-mediated immunity. Mechanism involved in type I, II and III are humoral while type IV is by cell-mediated immunity.
Type I (anaphylactic) reaction: Certain drugs induce the synthesis of IgE antibodies which are fixed to the mast cells. On subsequent exposure, the antigen-antibody complexes cause degranulation of mast cells releasing the mediators of inflammation like histamine, leukotrienes, prostaglandins and platelet-activating factor. These are responsible for the characteristic signs and symptoms of anaphylaxis like bronchospasm, laryngeal edema and hypotension which could be fatal. Allergy develops within minutes and is called immediate hypersensitivity reaction, e.g. penicillins. Skin tests may predict this type of reactions.
Type II (cytolytic) reactions: The drug binds to a protein and together they act as antigen and induce the formation of antibodies. The antigen antibody complexes activate the complement system resulting in cytolysis causing thrombocytopenia, agranulocytosis and aplastic anemia.
Type III (arthus) reactions: The antigen binds to circulating antibodies and the complexes are deposited on the vessel wall where it initiates the inflammatory response resulting in vasculitis. Rashes, fever, arthralgia, lymphadenopathy, serum sickness and Steven-Johnson's syndrome are some of the manifestations of arthus type reaction.
Type IV (delayed hypersensitivity) reactions are mediated by T-lymphocytes and 29macrophages. The antigen reacts with receptors on T-lymphocytes which produce lymphokines leading to a local allergic reaction, e.g. contact dermatitis.
Other Forms of Adverse Drug Reactions
  1. Drug intolerance: Drug intolerance is the inability of a person to tolerate a drug even in therapeutic doses and is unpredictable. It could be quantitative or qualitative. Patients show exaggerated response to even small doses of the drug—quantitative, e.g. vestibular dysfunction after a single dose of streptomycin may be seen in some patients. Intolerance could also be qualitative, e.g. idiosyncrasy and allergic reactions.
  2. Iatrogenic (Physician induced) diseases: These are drug induced diseases. Even after the drug is withdrawn toxic effects can persist, e.g. isoniazid induced hepatitis; chloroquine induced retinopathy.
  3. Drug dependence: Drugs that influence the behavior and mood are often misused to obtain their pleasurable effects. Repeated use of such drugs result in dependence. Several words like drug abuse, addiction and dependence are used confusingly. Drug dependence is a state of compulsive use of drugs in spite of the knowledge of risks associated with its use. It is also referred to as drug addiction. Dependence could be ‘psychologic’ or ‘physical’ dependence. Psychologic dependence is compulsive drug-seeking behavior to obtain its pleasurable effects, e.g. cigarette smoking.
    Physical dependence is said to be present when withdrawal of the drug produces adverse symptoms. The body undergoes physiological changes to adapt itself to the continued presence of the drug in the body. Stopping the drug results in ‘withdrawal syndrome.’ The symptoms of withdrawal syndrome are disturbing and the person then craves for the drug, e.g. alcohol, opioids and barbiturates.
    Mild degree of physical dependence is seen in people who drink too much of coffee.
  4. Teratogenicity: Teratogenicity is the ability of a drug to cause fetal abnormalities when administered to the pregnant lady. Teratos in Greek means monster. The sedative—thalidomide taken during early pregnancy for relief from morning sickness resulted in thousands of babies being born with phocomelia (seal limbs). This thalidomide disaster (1958–61) opened the eyes of various nations and made it mandatory to impose strict teratogenicity tests before a new drug is approved for use.
    Depending on the stage of pregnancy during which the teratogen is administered, it can produce various abnormalities.
    • Conception to 16 days
    – Usually resistant to teratogenic effects. If affected, abortion occurs.
    • Period of organogenesis (17–55 of gestation)
    — Most vulnerable period; major days physical abnormalities occur.
    • Fetal period —56 days onwards
    — Period of growth and development— hence developmen-tal and functional abnormalities result.
    Therefore, in general drugs should be avoided during pregnancy especially in the first trimester. The type of malformation also depends on the drug, e.g. thalidomide causes phocomelia; tetracyclines cause deformed teeth; sodium valproate causes spina bifida.
  5. Carcinogenicity and mutagenicity: Some drugs can cause cancers and genetic abnormalities. For example anticancer drugs can themselves be carcinogenic; other examples are radioactive isotopes and some hormones.30
Other Adverse Drug Reactions
Drugs can also damage various organ systems.
Organ system affected
• Hepatotoxicity
Isoniazid, pyrazinamide, paracetamol, chlorpromazine, 6-Mercaptopurine, halothane, ethanol, phenylbutazone
• Nephrotoxicity
Analgesics, aminoglycosides, cyclosporine, cisplatin, cephelexin, penicillamine, gold salts
• Ototoxicity
Aminoglycosides, frusemide
• Ocular toxicity
Chloroquine, ethambutol
• Gastrointestinal systems
Opioids, broad spectrum antibiotics
• Cardiovascular system
Digoxin, doxorubicin
• Respiratory system
Aspirin, bleomycin, busulfan, amiodarone, methotrexate
• Musculoskeletal system
Corticosteroids, heparin
• Behavioral toxicity
Corticosteroids, reserpine
• Neurological system
INH, haloperidol, ethambutol, quinine, doxorubicin vincristine
• Dermatological toxicity
Doxycycline, sulfonamides
• Electrolyte disturbances
Diuretics, mineralocorticoids
• Hematological toxicity
Chloramphenicol, sulfonamides
• Endocrine disorders
Methyldopa, oral contraceptives
Definition: Drug interaction is the alteration in the duration or magnitude of the pharmacological effects of one drug by another drug.
When two or more drugs are given concurrently, the response may be greater or lesser than the sum of their individual effects. Such responses may be beneficial or harmful. For example, a combination of drugs is used in hypertension—hydralazine + propranolol for their beneficial interaction. But unwanted drug interactions may result in severe toxicity. Such interactions can be avoided by adequate knowledge of their mechanisms and by judicious use of drugs.
Site: Drug interactions can occur:
  • In vitro in the syringe before administration—mixing of drugs in syringes can cause chemical or physical interactions—such drug combinations are incompatible in solution, e.g. penicillin and gentamicin should never be mixed in the same syringe.
  • In vivo, i.e. in the body after administration.
Pharmacological basis of drug interactions: The two major mechanisms of drug interactions include pharmacokinetic and pharmacodynamic mechanisms.
  1. Pharmacokinetic mechanisms: Alteration in the extent or duration of response may be produced by influencing absorption, distribution, metabolism or excretion of one drug by another.
    Absorption of drugs from the gut may be affected by:
    1. Binding: Tetracyclines chelate iron and antacids resulting in reduced absorption
    2. Altering gastric pH
    3. Altering GI motility.
    Distribution: Competition for plasma protein or tissue binding results in displacement interactions, e.g. warfarin is displaced by phenylbutazone from protein binding sites.
    Metabolism: Enzyme induction and inhibition of metabolism can both result in drug interactions (See page 16), e.g. phenytoin, phenobarbitone, carbamazepine and rifampicin are enzyme inducers while chloramphenicol and cimetidine are some enzyme inhibitors.
    31Excretion: When drugs compete for the same renal tubular transport system, they prolong each others duration of action, e.g. penicillin and probenecid.
  2. Pharmacodynamic mechanisms: Drugs acting on the same receptors or physiological systems result in additive, synergistic or antagonistic effects. Many clinically important drug interactions have this basis. Atropine opposes the effects of physostigmine; naloxone antagonises morphine; antihypertensive effects of β blockers are reduced by ephedrine or other vasoconstrictors in cold remedies.