General PharmacologyCHAPTER 1

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.

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.

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

The routes can be broadly divided into (Flowchart 1.2):

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.

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.

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.

5Only a small quantity can be administered by this route and it may be painful.

Hypodermoclysis is the SC administration of large volumes of saline employed in pediatric practice.

Drugs can also be administered subcutaneously as:

Soluble substances, mild irritants, depot preparations, suspensions and colloids can be injected by this route.

Drugs can be given IV as:

Drugs are also given extradurally. Morphine can be given epidurally to produce analgesia.

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.

Some irritant drugs are given per rectally as suppositories:

Drugs may also be given by this route as 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.

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

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.

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.

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.

For example, if the dose of a drug given is 500 mg and attains a uniform concentration of 10 mg in the body, its V_d = 50 liters.

The knowledge of V_d of drugs is clinically important in the treatment of poisoning. Drugs with large V_d like pethidine are not easily removed by hemodialysis.

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).

The chemical reactions of biotransformation can take place in two phases (Fig. 1.5).

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.

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).

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.

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).

Drugs are metabolized/eliminated from the body by:

Some drugs like phenytoin and warfarin are eliminated by both processes, i.e. by first order initially and by zero order at higher concentrations.

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.

The disadvantage with the loading dose is that the patient is rapidly exposed to high concentrations of the drug which may result in toxicity.

The duration of action of drugs can be prolonged by interfering with the pharmacokinetic processes, i.e. by

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:

Membrane pumps like H⁺ K⁺ ATPase, Na⁺ K⁺ ATPase may be inhibited by drugs, e.g. omeprazole, digoxin.

Last three decades have seen an explosion in our knowledge of the receptors. Various receptors have been identified, isolated and extensively studied.

For the above function, the receptor has two sites (domains):

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.

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.

Constant use of β adrenergic agonists in bronchial asthma results in reduced therapeutic response due to down regulation of β₂ receptors.

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).

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.

Therapeutic index (TI) is the ratio of the median lethal dose to the median effective dose.23

It gives an idea about the safety of the drug.

Examples are ephedrine with theophylline in bronchial asthma; nitrous oxide and ether as general anesthetics.

Insulin and glucagon have opposite effects on the blood sugar level.

Pharmacovigilance deals with the epidemiologic study of adverse drug effects.

Adverse drug reactions (ADRs) are classified as follows (Flowchart 1.3):

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.

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.

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.

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.