Introduction to Pharmacology
Definition and historical landmarks of pharmacology
Scope of Pharmacology
Nature and source of drugs,
Essential drugs concept
Routes of drug administration,
Agonists, antagonists (competitive and non competitive),
Enzyme induction, enzyme inhibition, kinetics of elimination
?Pharmacology : The science which deals with the drugs and their action on human body and animals.
Pharmacokinetics : The study of absorption, distribution, metabolism and excretion of drug.
Pharmacodynamics : The study of mechanism of action of drug and pharmacological effect produced on the human body.
Toxicology : The science dealing with poison’s.
Agonist: Any drug/chemical molecule that binds a receptor and produces an effectThe magnitude of the drug effect is proportional to the amount of drug receptor complexes formed.
Antagonist : Any drug/chemical molecule that blocks the effect of an agonist
Absorption : is a process of movement of unchanged drug from the site of administration to systemic circulation
Distribution : Distribution involves reversible transfer of a drug between compartments.
Metabolism : Metabolism of drugs is defined as the conversion from one chemical to another.
Excretion: Drug or their Metabolite is removed from the body by excretion.
Historical landmarks of pharmacology
Since the beginning of the species, people have treated pain and disease with substances derived from plants, animals, and minerals. However, the science of pharmacology is less than 150 years old, ushered in by the ability to isolate pure compounds and the establishment of the scientific method. Historically, the selection and use of drugs were based on superstition or on experience (empiricism).
First Phase: In the first or earliest phase of drug usage, noxious plant and animal preparations were administered to a diseased patient to rid the body of the evil spirits believed to cause illness. The Greek word pharmakon, from which the term pharmacology is derived, originally meant a magic charm for treating disease. Later, pharmakon came to mean a remedy or drug.
Second Phase: In the second phase of drug usage, experience enabled people to understand which substances were actually beneficial in relieving particular disease symptoms. The first effective drugs were probably simple external preparations, such as cool mud or a soothing leaf; the earliest known prescriptions, from 2100 BCE, included salves containing thyme. Over many centuries, people learned the therapeutic value of natural products through trial and error. By 1500 BCE, Egyptian prescriptions called for castor oil, opium, and other drugs that are still used today. In China, ancient scrolls from that time listed prescriptions for herbal medicines for more than 50 diseases. Dioscorides, a Greek army surgeon who lived in the 1st century, described more than 600 medicinal plants that he collected and studied as he traveled with the Roman army. Susruta, a Hindu physician, described the principles of Ayurvedic medicine in the 5th century. During the Middle Ages, Islamic physicians (most famously Avicenna) and Christian monks cultivated and studied the use of herbal medicines.
Third Phase: The third phase of drug usage, the rational or scientific phase, gradually evolved with important advances in chemistry and physiology that gave rise to the new science of pharmacology. At the same time, a more rational understanding of disease mechanisms provided a scientific basis for using drugs whose physiologic actions and effects were understood. The advent of pharmacology was particularly dependent on the isolation of pure drug compounds from natural sources and on the development of experimental physiology methods to study these compounds. The isolation of morphine from opium in 1804 was rapidly followed by the extraction of many other drugs from plant sources, providing a diverse array of pure drugs for pharmacologic experimentation.
The first medical school pharmacology laboratory was started by Rudolf Buchheim in Estonia. Buchheim and one of his students, Oswald Schmiedeberg, trained many other pharmacologists, including John Jacob Abel, who established the first pharmacology department at the University of Michigan in 1891 and is considered the father of American pharmacology.
Current Phase: The goal of pharmacology is to understand the mechanisms by which drugs interact with biologic systems to enable the rational use of effective agents in the diagnosis and treatment of disease. The success of pharmacology in this task has led to an explosion of new drug development, particularly in the past 50 years. Twentieth-century developments include the isolation and use of insulin for diabetes, the discovery of antimicrobial and antineoplastic drugs, and the advent of modern psychopharmacology. Recent advances in molecular biology, genetics, and drug design suggest that new drug development and pharmacologic innovations will provide even greater advances in the treatment of medical disorders in this century.
THE NOBEL PRIZE PHARMACOLOGY
Nobel Persons Year Award Significant discovery in pharmacology
Ilya Metchnikoff, Paul Ehrlich 1908 First antimicrobial drugs (magic bullet)
Frederick Banting, John Macleod 1923 Isolation and discovery of insulin and its application in the treatment of diabetes
Sir Henry Dale, Otto Loewi 1936 Chemical transmission of nerve impulses
Sir Alexander Fleming, Ernst Chain, Sir
Howard Florey 1945 Discovery of penicillin and its curative effect in various infectious diseases
Edward Kendall, Tadeus Reichstein, Philip Hench 1950
Hormones of the adrenal cortex, their structure and biologic effects
Daniel Bovet 1957 Antagonists that block biologically active amines, including the first antihistamine
Sir Bernard Katz, Ulf von Euler, Julius Axelrod 1970 Transmitters in the nerve terminals and the mechanism for storage, release, and inactivation
Earl Sutherland, Jr. 1971 Mechanisms of the action of hormones with regard to inhibition and stimulation of cyclic AMP
Sune Bergström, Bengt Samuelsson, John Vane 1982
Discovery of prostaglandins and the mechanism of action of aspirin that inhibits prostaglandin synthesis
Sir James Black, Gertrude Elion, George Hitchings 1988 Development of the first ?-blocker, propranolol, and anticancer agents that block nucleic acid synthesis
Alfred Gilman, Martin Rodbell 1994 Discovery of G proteins and the role of these proteins in signal transduction in cells
Robert Furchgott, Louis Ignarro, Ferid Murad 1998 Recognition of nitric oxide as a signaling molecule in the cardiovascular system
Arvid Carlsson, Paul Greengard, Eric Kandel 2000 Role of dopamine in schizophrenia and signal transduction in the nervous system leading to long-term potentiationDefinition Pharmacology is the science, which deals with the drugs and their action on human body or animals. The word Pharmacology has been derived from the Greek word ‘Pharmakon’ which means ‘drugs’ and Logos means treatise or treat i.e., to give medical treatment especially. The word drug means a chemical substance used in prevention, for diagnosis, treatment or cure of the disease in human beings or animals. The word Pharmacology has its origin only about hundred years ago, earlier it was known as Materia medica. Pharmacology is the science, which deals with response of living organisms to chemical stimuli. The pharmacology from medical point of view can be further divided into Pharmacokinetics and Pharmacodynamics actions therapeutically.
Fig. 1.1 Process of pharmacokinetics and pharmacodynamicsPharmacokinetics: It includes the study of absorption, distribution, metabolism and excretion of drug. It deals with the drug from its entry in the body, its excretion, and what happens to drug in the body is known as pharmacokinetics.
Pharmacodynamics: Pharmacodynamics is concerned with the study of mechanism of action of drugs and Pharmacological effect produced on the human body. The drugs administered are not having effectiveness only but they have also adverse effects, side effects and toxicity. The drug used for treatment should be of maximum effectiveness and with minimum toxicity and side effects.
The drug is administered for one of its particular and therapeutically useful effect on the body, where as a drug does not have single effect. It has a number of effects on our body. Drug entered in the body produces effect/action on blood, blood vessels, lungs, heart, liver, kidneys, brain and eyes differently. The drugs which have useful effects on our body, have also side effects, adverse effects, untowards effects even have their toxic effects.
The drug used in clinical purpose should have maximum medicinal effectiveness and minimum toxicity. The term therapeutic index is used to express safety of drug in clinical practice.
1.2 SCOPE OF PHARMACOLOGY
The pharmacology is an experimental science and one of the youngest discipline (branch) of the basic medical sciences. The scope of pharmacology is constantly enlarging. Its contribution to medicinal therapy has made its position in the medical field and in medicines, of greater importance. Its relationship to the other medical sciences is interesting that enables medical students to understand the better position of this science.
When there is imbalance in normal bodily process, a pathological condition (illness) is present. Then a drug or pharmaceutical agent (chemical product) is administered to the sufferer to cure the diseased condition. The action of the drug introduced in the body to cure pathogenic state is studied by the pharmacology. Pharmacology use chemical substances to produce change in function and morphology in living system (men ; animals).
It is known by going through the past history of research and inventions. The first alkaloid morphine was isolated from plant opium by the German Apothecary serturner in the year 1807. In 1828, Woher synthesized urea from ammonium cyanate,
He made urea without a kidney.
In the year 1900, Abel and his associates isolated adrenalin (epinephrine) from medulla of adrenal glands.
In the year 1905, Reid Hunt isolated acetylcholine from the adrenal glands. Since then large number of new drugs have been synthesized and prepared every year in the scientific field.
A science was needed for the purpose of regular screening and testing these new drugs to determine their therapeutic uses, harmful effects and safety and efficacy on use in human being and animals. This science was destined to be as pharmacology by clinical testing.
The discoveries of new chemical substances, drugs in the field of science created the medical need for pharmacology. It became necessary to bridge the gap in between the drug manufacturer and the prescriber of drugs. The pharmacology study and evaluating the efficacy of drugs are through clinical trials by testing drug on animals and human volunteers in the laboratory.
Clinical Testing Drug: The main objectives of the clinical testing (trial) of a new drug are (1 ) To determine the efficacy and safety of the new products. (2) The optimal conditions of use of the drug. (3) To assess dosage and necessary precautions to be taken for use of drugs.(4) Method (route) of administration of drug i.e. to be administered orally, by parenteral rout or both. (5) What precautions to be adopted to assure maximum efficacy and usefulness of drug. While conducting any clinical trial it must be ensured that nothing to be done that may harm the concerned individual.
The new product synthesized or invented requires rigorous pharmacologic study and evaluation to determine its mechanism of action, therapeutic uses, toxicity etc. The study of metabolism and excretion of drug is must to be conducted. The clinical trials are made in laboratory on animals and on human volunteers.
Fig.1.2 Representation the scope of Pharmacology
The pharmacology has two types : (1) Clinical pharmacology : The clinical pharmacology deals with the study of actions/effects of drugs in human beings. (2) Experimental pharmacology : The experimental pharmacology deals with the action and effect of drug on experimental animals such as action on rodents, non rodents. The experiments and clinical trials are performed in the laboratory.
Pharmacology:- Pharmacology is defined as the science of drugs. The term is derived from Greek words pharmakon ,meaning a drug ,and logos ,meaning a study. It includes knowledge about the sources of drugs ,their absorption ,distribution ,metabolism ,and excretion,their mode of action or mechanism of action and their toxicity . Pharmacology has major subdivisions,Pharmacokinetics,,Pharmacodynamics,Pharmacotherapeutics,Therapeutics,Chemotherapy ,Toxicology etc.
Pharmaceutical sciences Pharmacy is the study of the preparation, compounding and dispensing of medicines . It is the science and art of preparing a drug or drug combination ,in a suitable dosage form,fit for administration to the patient.The pharmacist concerned primarily with preparing, compounding and dispensing medicines upon the written order of a licensed medical practitioner.
Pharmacokinetics: (Greek kinesis,means movement)is the study of the fate of drugs in the body,right from the time they enter the body until they,or their by-products,are eliminated from the body,or movement of drugs in the body. In other words this includes absorption, distribution ,metabolism and excretion of drugs. These studies are done both in animals and man ,and the data are essential for the safe use of drugs.
Pharmacodynamics: (Greek dynamics means force) is the experimental study of actions of drugs on the living organism,including their mode of action or mechanism of action.
Pharmacotherapeutics: (Greek therapeia means medical treatment)- Pharmacotherapeutics is the treatment of disease by means of drugs.It utilizes information on drugs obtained by pharmacodynamic studies.
Therapeutics: (Greek therapeutike,means medical practice)Therapeutics is the practical branch of medicine dealing with the science and art of the treatment of disease . Empirical therapeutics is therapy bases on clinical evidence that the drug is effective ,although the mechanism by which it act is unknown.
Chemotherapy: according to the definition proposed by Paul Ehrlich ,deals with the use of drugs capable of inhibiting or destroying invading microbes ,parasites,or cancer cells,while having minimal effect on healthy living tissues.
Toxicology: ( Greek toxikon means poison )Toxicology is the science of poisons,their sources,chemical composition ,action, tests for detection and antidotes. It forms a major part of forensic and environmental medicine. All drugs are potential poisons when given in high doses. Clinical toxicology deals with the detection, diagnosis and treatment of poisoning. Toxicodynamics describes the harmful effects that the poison produces on the body.Toxicokinetics encompasses the absorption, distribution, biotransformation and elimination pf the poison.
Pharmacognetics: Pharmacognetics:is a relatively new field, and deals with the study of genetically determined variationin drug response.
Clinical Pharmacology: Clinical pharmacology is the division which which deals with the pharmacological effects of drugs in man. It provides information about the usefulness ,potency,and toxicity of new drugs in humans .It is of great importance for the effective and safe use of drugs in man
1.3 NATURE AND SOURCE OF DRUGS
The drug are represented by three names, which is commonly know as
Non proprietary name-Generic name
Propitiatory name-Brand name
The use of natural products with therapeutic properties is as ancient as human civilisation and, for a long time, mineral, plant and animal products were the main sources of drugs
Fig. 1.3 Origin of drug from different sources
Plant Source: The drugs are obtained from plant origin. Plants can be used as therapeutic resources in several ways. It can be used as herbal teas or other home made remedies, when they are considered as medicinal plants. They can be used as crude extracts or “standard enriched fractions” in pharmaceutical preparations, such as tinctures, fluid extracts, powder, pills and capsules, when they are considered as phytopharmaceutical preparations or herbal medicines. Finally, plants can be subjected to successive extraction and purification procedures to isolate the compounds of interest, which can themselves be active and used directly as a drug, examples being quinine, digoxin and ergotamine.
Animal Source: Drugs obtained from animal source. Some animal sources continue to be used to procure some modern drugs because of cumbersome and expensive procedures for the synthesis of such chemicals. For example: Insulin, extracted from pork and beef pancreas, is used for the treatment of diabetes mellitus. Thyroid powder is used for treating the hypothyroidism. Heparin is used as an anticoagulant. Hormones and vitamins are used as replacement therapy. Vaccines (cholera, T.B., smallpox, polio and antirabic) and sera (antidiptheria andantitetanus) are used for prophylaxis/treatment
Mineral Sources: Drugs obtained from mineral origin Minerals or their salts are useful pharmacotherapeutic agents. For example: Ferrous sulfate is used in iron deficiency anaemia. Magnesium sulfate is employed as purgative. Magnesium trisilicate, aluminium hydroxide and sodium bicarbonate are used as antacids for hyperacidity and peptic ulcer. Kaolin (aluminium silicate) is used as adsorbent in antidiarrheal mixtures. Radioactive isotopes of iodine, phosphorus, gold are employed for the diagnosis/ treatment of diseases particularly malignant conditions.
Microbiological Sources: Many life-saving drugs are obtained from fungi, moulds and bacteria e.g. penicillin from Penicillium notatum, chloramphenicol from Streptomyces venezuelae, grisofulvin (an anti-fungal drug) from Penicillium griseofulvum, neomycin from Streptomyces fradiae and streptomycin from Streptomyces griseus.
Semisynthetic Sources: Sometimes semi-synthetic processes are used to prepare drugs when the synthesis of drugs (complex molecules) may be difficult, expensive and uneconomical or when the natural sources may yield impure compounds. In these situation this methods plays an important role. For examples are semi synthetic human insulin and 6-aminopenicillanic acid derivatives. Prepared by chemically modifying substances that are available from natural source improve to improve its potency, efficacy and also reduce side effects.
Synthetic Sources: The drugs used in clinical practice are prepared synthetically, such as aspirin, oral antidiabetics, antihistamines, amphetamine, chloroquine, chlorpromazine, general and localanaesthetics, paracetamol, phenytoin, synthetic corticosteroids, sulphonamides and thiazidediuretics. Most of the synthetic drugs are prepared synthetically i.e. by chemical process ( reaction) with the help of the knowledge of phytochemical investigation.
Biosynthetic Sources: DNA Recombinant Technology This is relatively a new field which is being developed by mixing discoveries from molecularbiology, recombinant DNA technology, DNA alteration, gene splicing, immunology andimmunopharmacology.Some of the recent developments are genetically engineered novel vaccines (Recombinex HB – ahepatitis-B vaccine), recombinant DNA engineered insulins (Humulin- human insulin) fordiabetes and interferon-alpha-2a and interferon-alpha-2b for hairy cell leukaemia.
1.4 ESSENTIAL DRUGS CONCEPT
The essential drugs concept combined two emergent critical discourses regarding the role of biomedicine in public health.
Definition: Essential medicines as defined by the World Health Organization (WHO), are the medicines that “satisfy the priority health care needs of the population”. These are the medications to which people should have access at all times in sufficient amounts.
World Health Organization (WHO) introduced the concept of essential medicines in 1977. These drugs are selected in the list with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. Essential medicines are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford.
Developed list of essential drug and Revised every two year
First list 167 Essential drugs Mention. (1977)
Priority to health care needs of the population. withEfficacy and Safety,
Appropriate dosage forms
Essential Drug Concept
Fig.1.4 Basic concept of Essential drug
The implementation of the concept of essential medicines is intended to be flexible and adaptable to many different situations; exactly which medicines are regarded as essential remains a national responsibility. It has shown that careful selection of a limited range of essential medicines results in a higher quality of care, better management of medicines (including improved quality of prescribed medicines), and a more cost-effective use of available health resources.
WHO has developed the first list 167 essential medicines in 1977 and since then the list has been revised every 2 years. The current one is the 15th model list released in 2007. The essential medicine list contains limited cost-effective and safe medicines, while the open pharmaceutical market is flooded with large number of medicines many of which are of doubtful value.. The concept of essential medicines has been worldwide accepted as a powerful tool to promote health equity and its impact is remarkable as the essential medicines are proved to be one of the most cost-effective elements in health care.
1.5 ROUTES OF DRUG ADMINISTRATION
Route of administration are two main routes of administration of drugs. (1) Enteral Route (2) Parenteral Route
1. Enteral Route
The enteral route includes oral route (By mouth) , nasal route, sublingual route, vaginal route and rectal route.
Oral Route (By Mouth)
This is a natural route of administration of drugs. The drugs in the form of tablets, capsules powders mixtures etc. are administered through this route.
1.This route is the most convenient route of drug administration.
2.Patient can take the prescribed medicines himself.
3.There is no pain to the patient; this route is very convenient and economical.
1.The effect of drug taken by oral route is delayed.
2.It is not an emergency route.
3.The irritant drugs can not be given through this route.
4.This route can not be used in case of unconscious and non-cooperative patients.
5.Certain drugs cannot be given through this route as they are destroyed by gastric enzymes.
Care should be taken that sufficient quantity of water should be given to patient with drug to prevent sticking of drug in oesophagus, and to decrease irritant effect of medicines taken.
The patient has difficulty in swallowing should be given medicines in liquid form as suspensions, mixtures etc.
Certain drugs can produce local effect and are given in the form of nasal guttae (nasal drops) or in the form of inhalation. The drugs of imidazoline compounds like naphazoline, xylometazoline, oxymetazoline, ephedrine are administered in the form of nasal drops.
Sub Lingual Route
The tablets are placed under the tongue sucked. This route is used for administration of nitroglycerin tablets in the disease Angina pectoris. Methyl testosterone in the form of sub lingual tablets is given as male hormone. Isoprinaline is given in the treatment of Bronchial asthma.
(1) On set action is quick.
(2) The overdose of drug is avoided.
(3) The drug is not destroyed by stomach enzymes, metabolic destruction in the liver is avoided (prevented).
The medicines are not allowed to swallow or chew, the tablet is kept below tongue.
This route is also used to produce local or systemic effect. Clotrimazole vaginal suppositories, are used in case of vulvo vaginal Candidiasis. Other medicines like Miconazole ketoconazole etc are also administered by this route.
The drugs through this route in the form of suppository or enema are given to produce local or systemic effect. Glucose, Paraldihyde can be administered through this route. Chlorpromazine suppositories are given for vomiting control. Suppositories are medicines incorporated in waxy base which melts at body temperature. The medicated suppositories are stored in refrigerator.
Indomethacin suppositories are administered for rheumatoid arthritis, aminophyllin suppository for bronchial asthma. Enema is liquid preparation introduced in the colon. Evacuation enema is used for purgation effect. Retention enema is meant for administration of drugs for systemic as well as for local use. Example cortisone is given through this route in ulcerative colitis.
Advantages of rectal route
(1)Irritation of gastric mucosa is avoided by this route.
(2)The drugs, which are destroyed by gastric enzymes gastric acidity can be administered by this route.
(3)The medicines which are destroyed during first pass through liver can be administered through this route.
(4)This route is useful in terminal sick patients.
2. Parenteral Route
The drug is introduced in the body with the help of a syringe and needle to produce certain physiological effect.
The types of injections are as under : –
Subcutaneous- An injection is made by inserting a hypodermic needle through the layers of the skin into areolar tissue.
Intradermal- The drug in small quantity is introduced in the upper layer of skin with the help of needle and syringe. By this route test, dose of penicillin is administered. BCG and small pox vaccines are administered by this route.
Intramuscular- The needle is introduced deeply in the deltoid muscles or gluteal muscle. The injected medicine reaches in the blood circulation and produces effect. The action of medicine administered is quicker than in oral route. if proper care is not used, there is danger of nerve injury. Total or maximum 10 ml volume of drug can be administered by this route.
Intravenous- The drug is administered with the help of syringe and needle directly into the venous blood. Care must be taken that if excess dose is administered, the toxic effect may occur. The drug introduced through this route can not be taken back. There is a danger of infection being introduced into the blood if the syringe needle and hands of person are not sterile properly.
Intrathecal- An injection is made by inserting the needle through the interspinous spaces into the spinal fluid Bone Marrow-The drug (medicine) is administered by inserting needle into the marrow of the sternum or other bones. This route is useful in case of spinal anesthesia and infections of the central nervous system.
Intraperitoneal- The drug is introduced with the help of syringe and needle in the peritoneal cavity. This route is not commonly used in clinical practice.
Intramedullary – The drug is introduced with the help of syringe and needle in the bone marrow. This route has rapid onset action. This route is used when there is difficulty in administering the drug, like blocking of veins in case of Thrombosis or circulation collapse. This route should be avoided in patients suffering from Osteomylitis or BacteraemiaAdvantages or Merits of Injections
1. There is very rapid response of drug
2. The drugs go directly into the blood, so no absorption is required.
3. This route can be used in case of a unconscious patient.
4. Less dose of drug is required by this route as compared to oral route.
Disadvantages or Demerits of Injections1. There is a pain when needle is inserted/introduced in the body.
2. This route can be used by the trained persons only like Doctors, Pharmacists, and Nurses, which require the presence of a skilled or trained person for administration of drugs so it is an expensive route for the patient.
3. The needles and syringe are required to be properly sterilized.
4. Irritant drugs administered through this route irritate muscles and an abscess may occur. This route is not liked by patient.
5. The excess of dose if administered, cannot be taken back, the side effects of drugs are quicker.
Local use medicines
Drugs or medicines are used to produce local effect or systemic effect. For local effects, ointmens, lotions, pastes, sprays, tinctures, dusting powders are used. The topical applications may be used for various body cavities or for the mucous membrnaes, such as irrigation and instillations of medicines in eyes, ears, nose, throat, mouth, bladder vagina etc. The preparation for local effects be used at normal atmospheric or body temperature. Droppers should be kept covered with stoppers to avoid contamination of medicines. The preparations for local application, their apearance, expiry date, name and contents of medicine must be checked carefuly before use. Nasal drops, sprays, nasal decongestants when used, avoid excess dose of drug, the drug may get aspirated.
Skin preparations : The skin should be cleaned before application of ointments, powders, tinctures, lotion and spray etc. The eye drops should be instilled carefully into the lower eyelid pouch. Similarly, while instillation ear drops use aseptic techniques. Vaginal medications be given at bed time.
1.6 AGONISTS, ANTAGONISTS (COMPETITIVE AND NON COMPETITIVE)
Agonist An agonist is a molecule that can bind and activate a receptor to induce a biological reaction. The activity mediated by agonists is opposed by antagonists, which inhibit the biological response induced by an agonist. The level of agonist required to induce a desired biological response is referred to as potency.
Potency: the amount of drug required to produce an effect of given intensity. Differences in drug potency are evaluated by comparing EC50 (or ED50) values. (Example: the drugs in Figure 2 vary only by their potency or receptor affinity, and not in terms of their maximal response.)
Efficacy: the ability of a drug to produce a maximum response. Differences in drug efficacy are evaluated by comparing differences in maximal response at high drug doses or concentrations. (Example: the drugs in Figure 3 vary only by their efficacy or maximal response, and have the same potency or EC50 values.)
Partial agonists: agonists that produce less than a full response when they fully occupy their receptors. In contrast, full agonists produce a full or maximal response. In figure 3, Drug A is a full agonist, and Drugs B, C ; D are partial agonists.
Two fundamental properties of agonists are affinity and efficacy. The affinity can be defined as the tenacity with which a drug binds to its receptor. In statistical terms, it can be defined as the probability that a drug molecule will bind to an available receptor at any given instant in time. The Efficacy is an inherent property of an agonist that determines its ability to produce its biological effect. By definition, it is a property of the drug, not the receptor or tissue. Affinity gets the drug bound to the receptor, and efficacy determines what happens once the drug is bound.
Different drugs that bind to the same receptor and produce the same type of response will typically differ from each other in terms of their affinity (potency) and/or efficacy. The term potency is used as a comparative term for distinguishing which agonist has a higher affinity for a given receptor. The drug which can produce an effect at lower drug concentrations is “more potent” (in Figure-1.5 Drug A is the most potent, and Drug D is the least potent).
Fig. 1.5. Schematic illustration of the dose-response curves for a series of agonists (A, B, C and D) that have the same efficacy, but differ in terms of their potency. The most potent drug (Drug A) has the lowest EC50 value, and is approximately 20-30 fold more potent than Drug D.
Agonists can also differ in terms of their efficacy, or maximum response. Figure 1.5 shows a plot of four agonists that differ in terms of their relative efficacy. Drug A is the most efficacious, and Drug D the least. Drugs that bind to a receptor, but produce less than maximal activation (e.g. Drugs B, C ; D) are referred to as partial agonists.
Antagonist: When agonist produces an action, antagonist opposes the actionAntagonists are drugs that bind to receptors (have affinity), but do not produce a substantial degree of receptor stimulation (they have very low efficacy). Antagonists are typically classified as competitive or noncompetitive.
Competitive antagonists bind reversibly to the same receptor site as the agonist. Because they bind reversibly and compete for the same binding site, their inhibitory effects can be “surmounted” by addition of a higher concentration of agonist (Figure 9A). This effect produces a rightward parallel shift of the dose-response for the agonist (towards higher concentrations). In the presence of a competitive antagonist, agonists can still produce the same (e.g. 100%) maximal effect as in the absence of an antagonist, the only difference being that higher agonist concentrations are needed to produce the same level of effect. The vast majority of clinically used drugs that act as receptor antagonists are competitive antagonists.
Noncompetitive antagonists either bind irreversibly (e.g. by covalent bonds) to the same site as the agonist, or bind to a different site which reduces the binding of the agonist by an allosteric mechanism. The primary effect of a noncompetitive antagonist is a reduction in the maximal effect produced by the agonist (see Figure 9 B). (In some cases the slope may also be reduced.) In contrast to a competitive antagonist, the effect of a noncompetitive antagonist cannot be reversed by simply increasing the concentration of the agonist, since the law of mass action does not apply.
Fig.1.6. Competitive and noncompetitive Antagonism
For example, competitive antagonism is where both the agonist (Isoproterenol) and antagonist (Propranolol) bind reversibly to the same receptor subtype (?-adrenoceptor). In the presence of the competitive antagonist, the dose-response curve is shifted to the right in a parallel manner. However, in non-competitive antagonism the Phenoxybenzamine is binds irreversibly (with covalent bonds) to ?-adrenergic receptors. This reduces the fraction of available receptors, and reduces the maximal effect that can be produced by the agonist
Reverse Agonists: Some drugs, in some biological systems, have been shown to act as “reverse agonists” in that they produce a response that is opposite of that typically produced by a receptor when it is stimulated by a conventional agonist. One mechanism that has been proposed to explain such an effect is by a drug-induced decrease in the basal activity of the receptor. For example, some G-protein coupled receptors appear to have a basal or “tonic” level of intrinsic activity in the absence of a hormone or neurotransmitter. This results in a tonic level of stimulation of downstream events, such as stimulation of adenylate cyclase. When a “reverse agonist” binds to this receptor, it acts similar to a conventional antagonist by binding to the receptor without “stimulating it”. However, in addition, the binding of the reverse agonist to the receptor alters the receptor conformation in such a way as to decrease its interaction with G-proteins, resulting in a decrease in basal stimulation of G-proteins and a reduction in the activity of adenylate cyclase.
1.6.1 SPARE RECEPTORS
Maximal efficacy means a state at which receptor mediated signaling is maximal and that, further increase in the drg dose does not produce any additional response. theoretically, it should happen when all the receptors get occupied by the drug. But normally when drugs act on receptors to produce the response all the receptors are not occupied to produce the maximal response by a full agonist i.e each cell or tissue has some receptors unoccupied which may be called spare receptors.
Maximum response is elicited by agonist at a concentration that does not require full occupancy of the receptor. They are not hidden or unavailable. When they are occupied, they can be coupled to response. They are not differ from non-spare receptor.
Fig. 1.7 Effect of Spare receptors
Spare receptor may be demonstrated by using irreversible antagonist, to prevent binding of an agonist to available receptors. Experimentally, the spare receptor concept can be shown when the agonist can still produce an undiminished maximal response in presence of an irreversible antagonist. For example the amplitude of muscle twitch in response to Ach. Acetylcholine blocked by addition of toxin (curare) .This toxin occupies at least 50% of receptors. But still max response can be demonstrated. That means, at least 50% of receptor were spare in sense that they were not required for completely normal twitch of Ach.
Drug addiction is a chronic disease characterized by drug seeking and use that is compulsive, or difficult to control, despite harmful consequences.
Brain changes that occur over time with drug use challenge an addicted person’s self-control and interfere with their ability to resist intense urges to take drugs. This is why drug addiction is also a relapsing disease. Relapse is the return to drug use after an attempt to stop. Relapse indicates the need for more or different treatment.
Most drugs affect the brain’s reward circuit by flooding it with the chemical messenger dopamine. This overstimulation of the reward circuit causes the intensely pleasurable “high” that leads people to take a drug again and again.
Over time, the brain adjusts to the excess dopamine, which reduces the high that the person feels compared to the high they felt when first taking the drug—an effect known as tolerance.
Fig. 1.8. A major factor involves in the drug addition
Drug addiction information indicates any type of drug can be abused or cause drug addiction. Drug addiction involves easily accessible drugs like tobacco and alcohol, as well as illegal drugs like cocaine and heroin. Some drug addictions, like alcoholism, appear to be declining, while others, like methamphetamine addiction, is on the rise. Drug addiction info indicates the following drugs and drug types are commonly associated with drug addiction:
Alcohol – most widely abused drug with 20% of users becoming dependent on it at some point
Opiates – substances derived from the opium poppy, the most common drug addiction is that of heroin
Cocaine, crack – up to 10% of users go on to heavy drug use
Amphetamines – like crystal meth, use on the rise in rural communities
Hallucinogens – like PCP, LSD and marijuana, often combined with other drugs
Prescription medication – such as oxycodone and morphine
Other chemicals – like tobacco, steroids and others
The tolerance may be defined as unusual resistance to the ordinary dose of a drug. The continuous and regular use of drugs may cause tolerance. Tolerance may be acquired by constant use of drug or it may be congenital. Repeated administration of drug produces less effect. If the same effect is required, the higher dose of drug will be required to produce the required effect. The regular intake of alcohols, opium, morphine barbiturates leads to tolerance. The tissue cells of the body may become acclimatized to the drug presence and failed to respond to drug concentrations which are ordinarily effective. The cellular acclimatization to the presence of a drug is true tolerance.
Fig.1.9. Fundamental concept of Tolerance
When the drug is discontinued, the tolerance usually disappears after a time. The chemical Glyceryl trinitrate is used in dynamite factories. The new workers in dynamite factories when inhale, vapours of Glyceryl trinitrate cause headache. The workers of dynamite factories soon acquire a tolerance to the compound and do not suffer from headache. When they are away from the factory for long period of time, the acquired tolerance is lost and if they return to work, they again experience headach.
1.9 DRUG DEPENDENCE
Drug dependence is the body’s physical need, or addiction, to a specific agent. There is therefore virtually no difference between dependency and addiction. Over the long term, this dependence results in physical harm, behavior problems, and association with people who also abuse drugs. Stopping the use of the drug can result in a specific withdrawal syndrome.
Fig. 1.10 A diagram representation the effect of drug dependence
With repeated use of heroin, dependence also occurs. Dependence develops when the neurons adapt to the repeated drug exposure and only function normally in the presence of the drug. When the drug is withdrawn, several physiologic reactions occur. These can be mild (e.g., for caffeine) or even life threatening (e.g., for alcohol). This is known as the withdrawal syndrome. In the case of heroin, withdrawal can be very serious and the abuser will use the drug again to avoid the withdrawal syndrome.
The signs and symptoms displayed. Most agents cause a change in level of consciousness usually a decrease in responsiveness. Suppression of brain activity can be so severe that the person may stop breathing, which can cause death.
Alternatively, the user may be agitated, angry, anxious, and unable to sleep. Hallucinations are possible. Abnormal vital signs (temperature, pulse rate, respiratory rate, blood pressure) are possible and can be life threatening.
Chest pain is possible and can be caused by heart or lung damage from drug abuse. Abdominal pain, nausea, vomiting, and diarrhea are possible. Vomiting blood, or blood in bowel movements, can be life threatening. Withdrawal syndromes are variable depending on the agent but can be life threatening.
The repeated administration of drugs at short intervals produces less effect. The Ephedrine 50 milligram shows curve reducing curve and the same effect can not be achieved by administration of the same dose.
On graph paper, the curve for the action of 50 mg and 30 mg of ephedrine administered to a patient shows like this. The same effect by administering same dose of 50 mg or 30 mg of ephedrine can not be obtained. To obtain same effect, higher dose of ephedrine is required to be administered. The usual adult dose of ephedrine by mouth is 15 mg to 60 mg. Children upto 1 year may be given 7.5 mg, 1 to 5 years 15 milligram, 6 to 12 years 30 mg. These doses can be given three times daily.
The methods of administration drugs and factors which modify their dose, our attention would be directed to mechanism of drugs action by keeping in mind the contraindications and side effects of drugs.
Drug idiosyncrasy” refers to untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy. The liver is a frequent target for toxicity
Fig 1.11 Induction of idiosyncrasy
The body system of defense is against foreign invaders, particularly pathogens (the agents of infection). The allergic reaction is misguided in that these foreign substances are usually harmless. The substances that trigger allergy are called allergen. Examples include pollens, dust mite, molds, HYPERLINK “https://www.medicinenet.com/script/main/art.asp?articlekey=2911″danders, drug and certain foods.
The most common allergic conditions include hay fever (allergic rhinitis), asthma, allergic eyes (allergic conjunctivitis), allergic eczema, hives (urticaria), and allergic shock (also called anaphylaxis and anaphylactic shock).
Hay fever (allergic rhinitis) is the most common of the allergic diseases and refers to seasonal nasal symptoms that are due to pollens. Year round or perennial allergic rhinitis is usually due to indoor allergens, such as dust mites or molds. Symptoms result from the inflammation of the tissues that line the inside of the nose (mucus lining or membranes) after allergens are inhaled. Adjacent areas, such as the ears, sinuses, and throat can also be involved. The most common symptoms include: Such as Runny nose, Stuffy nose, Sneezing, Nasal itching (rubbing), Itchy ears and throat, Post nasal drip (throat clearing).
Fig.1.12 a diagram shows the type of allergy
Hives (urticaria) are skin reactions that appear as itchy swellings and can occur on any part of the body. Hives can be caused by an allergic reaction, such as to a food or medication, but they also may occur in non-allergic people. Typical hive symptoms are: Raised red welts and Intense itching
Allergic eczema is an allergic rash that is usually not caused by skin contact with an allergen and features the following symptoms: Itching, redness, and or dryness of the skin, Rash on the face, especially children, Rash around the eyes, in the elbow creases, and behind the knees, especially in adults.
Allergic shock (anaphylaxis or anaphylactic shock) is a life-threatening reaction that can affect a number of organs at the same time. It typically occurs when the allergen is eaten (for example, foods) or injected (for example, a bee sting). Allergic shock is caused by dilated and “leaky” blood vessels, which result in a drop in blood pressure. Some or all of the following symptoms may occur: Hives or reddish discoloration of the skin, Nasal congestion, Swelling of the throat, Stomach pain, nausea, vomiting, Shortness of breath, wheezing and low blood pressure or shock
Allergic eyes (allergic conjunctivitis) is inflammation of the tissue layers (membranes) that cover the surface of the eyeball and the undersurface of the eyelid. The inflammation occurs a result of an allergic reaction and features: Redness under the lids and of the eye overall, Watery, itchy eyes and swelling of the membranes.
Mechanism of drug allergy: Drug hypersensitivity results from interactions between a pharmacologic agent and the human immune system. These types of reactions constitute only a small subset of all adverse drug reactions. Allergic reactions to medications represent a specific class of drug hypersensitivity reactions mediated by IgE. Immune-mediated drug reactions divided into humoral mediated adverse reaction and cell mediated immunity.
The most important drug-related risk factors for drug hypersensitivity concern the chemical properties and molecular weight of the drug. Larger drugs with greater structural complexity (e.g., nonhuman proteins) are more likely to be immunogenic. Heterologous antisera, streptokinase, and insulin are examples of complex antigens capable of eliciting hypersensitivity reactions. Most drugs have a smaller molecular weight (less than 1,000 daltons), but may still become immunogenic by coupling with carrier proteins, such as albumin, to form simple chemical-carrier complexes (hapten).
Another factor affecting the frequency of hypersensitivity drug reactions is the route of drug administration; topical, intramuscular, and intravenous administrations are more likely to cause hypersensitivity reactions. These effects are caused by the efficiency of antigen presentation in the skin, the adjuvant effects of repository drug preparations, and the high concentrations of circulating drug antigen rapidly achieved with intravenous therapy. Oral medications are less likely to result in drug hypersensitivity
Pharmacokinetics – The study of the absorption, distribution, metabolism and excretion of drugs from the body. In operational terms “what the body does to drugs”. To produce its characteristic effects, a drug must be present in an appropriate concentration at its sites of action. Thus, it is important to know the interrelationship of the absorption, distribution, binding, biotransformation, and excretion of a drug and its concentration at its locus of action.
Fig. 1.13 A systematic diagram of Pharmacokinetic? Absorption?, distribution?, metabolism? excretion1.13.1 MEMBRANE TRANSPORT
The membrane barriers play a major role during any drug action or adverse reacton. Membrane barriers can either consist of a layer of closely packed cells or a cell membrane also known as the plasma membrane.The cell membrane is what surrounds and protects the living cells of our body. It must regulate what can enter from the extrinsic environment into the intrinsic envionment of the cell to cause an action or adverse reaction. The Drug are transported by various mechanism. Based on the function it can be classified as
Fig.1.14 Mode of transporter
Passive membrane transport: In passive transport, the drug molecule usually penetrates by diffusion along a concentration gradient by virtue of its solubility in the lipid bilayer. Such transfer is directly proportional to the magnitude of the concentration gradient across the membrane.
Passive diffusion: Drugs diffuse across a cell membrane from a region of high concentration (eg, GI fluids) to one of low concentration (eg, blood). Diffusion rate is directly proportional to the gradient but also depends on the molecule’s lipid solubility, size, degree of ionization, and the area of absorptive surface. Also, some degree of water solubility is needed for the passive diffusion. No matter how lipid soluble the drug is it will never cross the cell membrane unless it can dissolve in the extracellular fluid. Because the cell membrane is lipoid, lipid-soluble drugs diffuse most rapidly. Small molecules tend to penetrate membranes more rapidly than larger one.
Fig.1.15 Transport of drug molecules by various process
Simple Diffusion: Simple diffusion is the process by which solutes are moved along a concentration gradient in a solution or across a HYPERLINK “https://biologydictionary.net/semipermeable-membrane/” o “semipermeable membrane” “_blank” semipermeable membrane. Simple diffusion is carried out by the actions of hydrogen bonds forming between water molecules and solutes. Water molecules move in to surround individual solute molecules, which maximizes hydrogen bonding. Hydrogen bonds are extremely temporary, however, and the solution is constantly stirred as a result. This helps distribute the solute evenly throughout the solution. If the molecules are small enough, this simple diffusion can happen across cell membranes, between the individual phospholipids that make up the membrane. Water can move along its concentration gradient through a cell membrane in this manner, a form of simple diffusion known as osmosis.
Facilitated diffusion: The distribution of a substance across a cell membrane using specialized embedded transport proteins. The cell membranes often incorporate specialized membrane proteins which help transport substances across the membrane. This is known as facilitated diffusion. Facilitated diffusion includes both the active and passive transport of solutes across the membrane. Active transport uses ATP to provide energy to the proteins providing the transport.
Carrier mediated transport: The passage of lipid insoluble substances through the cell membrane is mediated by carrier proteins in the cell membrane. The Carrier-mediated transport exhibits the properties of specificity, competition, and saturation. The transport rate of molecules reaches a maximum when the carriers are saturated. This maximum rate is called the transport maximum. The transport of molecules such as glucose from the side of higher to the side of lower concentration by means of membrane carriers is called facilitated diffusion.
A. Like simple diffusion, this is passive transport, cellular energy is not required.B. Unlike simple diffusion, facilitated diffusion displays the properties of specificity, competition, and saturation.
Active transport: The active transport of molecules and ions across a membrane requires the expenditure of cellular energy (ATP).
In active transport, carriers move molecules or ions from the side of lower to the side of higher concentration. for example of active transport is the action of the Na+/K+ pump. The Sodium is more concentrated on the outside of the cell, whereas potassium is more concentrated on the inside of the cell. The Na+/K+ pump helps to maintain these concentration differences by transporting Na+ out of the cell and K+ into the cell.
Filtration: Passage of drug molecules through the endothelial lining of the capillaries as a bulk flow. Lipid insoluble substance (often the only mechanism for lipid insoluble) . Filtration is involved in the distribution and elimination of almost ALL drugs.Endocytosis and exocytosis: Endocytosis is a series of events in which substance is engulfed and internalized by the cell. Exocytosis is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane. These membrane-bound vesicles contain soluble proteins to be secreted to the extracellular environment, as well as membrane proteins and lipids that are sent to become components of the cell membrane.
Absorption is defined as the process of movement of unchanged drug from the site of administration to systemic circulation. The passage of drug from its site of administration to its entry into blood stream is called drug absorption. The absorption of a drug refers to its entry from route of administration site to absorption in blood stream and passage of drug across cell membranes. This passage is restricted by the lipids barrier present at the permeable membrane.
The process of absorption may be simple diffusion. The drugs like urea, alcohol easily absorbed by simple diffusion.
The cell membrane is a lipid bilayer so the lipid soluble drugs diffuse quickly than water soluble drugs. The cell membrane is more permeable to nonionised drugs in comparison to ionised water soluble drugs.
The drug may be absorbed by active transport process, the ions which are transported by this active transport process are K+, Na+, I–, amino acids, organic acids and bases, weak electrolytes in ionised form. The drugs like pyrimidines, glucose are transported by this process. This process is more rapid than simple diffusion.
Pinocytosis is the process of absorption in unicellular organisms like amoeba. The cell in this process takes up fluid from its surroundings.
The major routes of drug administration include: a) oral (enteral – or via the intestine); b) parenteral (other than the intestine) such as intramuscular (i.m.) or subcutaneous (s.c.): and c) direct injections into the cardiovascular system (intravenously or i.v.). If a drug is applied to a body surface (e.g., G.I. tract, skin, lungs, etc.), its rate of absorption will be determined the time for its maximal concentration in plasma and at the receptor to produce its peak effect.
Fig.1.16. A systematic diagram of Absorption of drug
The factors effecting absorption of drugs are as under :1.The liquid medicinal preparations are better absorbed than solid medicines. Crystalloids are readily absorbed than colloids. Soluble insulin suspension are more quickly absorbed than insoluble protamine zinc insulin suspensions.
2.Higher concentration of drug helps in better absorption of the drug.
3.The small particle size of drug is necessary for better absorption of drugs in the gut. Small particle size is useful in absorption of antibiotics, corticosteroids and oral coagulants.
4.The absorption of drug through sublingual route which is floor of mouth cavity is faster as compared to gastro intestinal mucosa. The drug is better absorbed from the small intestine than the stomach. The larger the surface area of absorbing more will be absorption and vice versa.
5.The acidic drugs are rapidly absorbed from the stomach. The salicylates and barbiturates are rapidly absorbed after oral administration whereas Ephedrine, pethidine are not absorbed untill, they reach in small intestines, this causes delay in absorption of drug and action is delayed. So pH of drug plays an important role in absorption.
6.The absorption of drug from gastro intestinal tract may be decreased with increased peristaltic movement (reduce gut motility) so there is more absorption of drug. The functioning of gastro intestinal tract effects absorption.
Low degree of ionisation, high lipid non ionised form, small molecular size of water soluble drugs (substances) favour rapid absorption. Insoluble precipitate formed in gastro intestinal tract is not absorbed.
Definition : “Fraction of a dose of drug that is absorbed from its site of administration and reaches, in an unchanged form, the systemic circulation is called bioavailability.
“The percentage of the drug absorbed is a measurement of the drug formulation’s ability to deliver the drug to the target site.
“Amount absorbed” is conventionally measured by one of two criteria, either the area under the time-plasma concentration curve (AUC) or the total (cumulative) amount of drug excreted in the urine following drug administration,” according to the Boston University School of Medicine. “A linear relationship exists between “area under the curve” and dose when the fraction of drug absorbed is independent of dose, and elimination rate (half-life) and volume of distribution are independent of dose and dosage form.
Fig. 1.17. Process of Bioavailability
Alinearity of the relationship between area under the curve and dose may occur if, for example, the absorption process is a saturable one, or if drug fails to reach the systemic circulation because of, e.g., binding of drug in the intestine or biotransformation in the liver during the drug’s first transit through the portal system.
Distribution involves reversible transfer of a drug between compartments. It is defined as the reversible transfer of drug between one compartment to another. The blood, total body water, extracellular, lymphatic and cerebrospinal fluids are involved in movement of drug through the body. Depending upon its chemical and physical properties, the drug may be bound to plasma proteins or dissolved in body fat, delaying its progress to its site of action, metabolism or excretion.
It is a process when drug is absorbed in the body, it is distributed to various body tissues and fluids. The drugs which pass easily through cell membranes, achieve wide distribution and drugs which do not pass through cell membrane has limited distribution. The drug bound with blood components is called bound drug and some drug are free drug is called free drug.
Effect on foetal circulation: In case of pregnant women, drug entry into foetal blood circulation is controlled or restricted by blood placental barrier. This barrier exists between maternal and foetal circulation. Digitalis crosses placental barrier, may cause toxicity to foetus and lead to premature delivery. The blood placental barrier allows lipid soluble, non ionised drugs to pass through this barrier
Effect on central nervous system: Effect of central nervous system After absorption of drug, entry into central nervous system is restricted by ‘blood brain barrier’. It is a hypothetical barrier which exists between plasma and extra cellular surface of brain. Only non ionised drugs, lipid soluble enters the central nervous system through blood brain barrier.
Metabolism of drugs is defined as the conversion from one chemical to another. Drugs are handled biochemically by the body it includes hydrolysis, conjugation, and oxidation-reduction. A drug when absorbed in the body, after absorption it may be inactivated or activated and converted into a more active compound. This biotransformation is called as drug metabolism or detoxication.
Sites of metabolism or biotransformation: Metabolism of drugs occurs mainly in liver, other minor sites are kidneys, placenta, testis and plasma. In the liver drug, metabolizing enzymes are present which are called as hepatic microsomal drug metabolising enzymes. Metabolism of drugs is poor (slow) in children, it is because of improper development of drug metabolising enzymes. Women have also less ability to metabolize drugs. Increase in body temperature causes increase in metabolism rate whereas decrease in body temperature decreases metabolism
Phase-I Reaction: Phase I reactions involve formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis); these reactions are nonsynthetic. The drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization; whatever the process, the goal is to make the drug easier to excrete.
Phase-II Reaction: Many drugs, metabolism occurs in 2 phases. It involves conjugation with an endogenous substance (eg, glucuronic acid, sulfate, glycine); these reactions are synthetic. Metabolites formed in synthetic reactions are more polar and thus more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions
Fig.1.18 A systematic diagram of metabolism of drug
The genetic deficiency in drug metabolism, drug metabolising enzymes can be inherited. Drug metabolism is different in species. In rabit atropine is metabolised due to presence of enzyme atropinase. Humans are lack of this enzyme, so atropine is toxic to humans and non toxic to rabbits.
1.13.6 EXCRETION OF DRUGS
Drug or their metabolite is removed from the body by excretion. Excretion is defined as the process whereby drugs or metabolites are irreversible transferred from internal to external environment. When a drug is taken i.e., ingested it is absorbed and is distributed to various tissues, fluids and organs of the body. It is then excreted after its therapeutic action. Excretion of a drug decreases its duration of action. The excretion of drug, in turn, decreases toxicity. The drug may be excreted in an active or inactive form. The drugs are eliminated or excreted from body in the following ways/methods:
Excretion through kidneys :
The drugs are excreted through kidneys by :(i)Active tubular secretions as penicillin.
(ii)Passive glomerular filtration : Most of drugs are excreted by this mechanism.
(iii)Passive tubular infusion : Mepacrine and salicylates are excreted by this method.
In case of renal impairment, renal damage excretion of drug is decreased and the toxicity is increased.
Excretion through lungs : Volatile drugs like alcohol, general anaesthetics, paraldehyde are excreted through lungs.
Excretion through saliva : The drugs excreted through saliva may impart metallic taste to tongue. The drugs like iodides, metallic salts are excreted through saliva. Lead is eliminated through saliva and its deposition produces black lining of teeth.
Excretion through milk : Breast milk is more acidic than plasma. The basic drug as pethidine is eliminated/excreted through milk. Many other drugs are excreted in breast milk.
Excretion through skin : The mercurial salts, arsenic which are heavy metals are excreted through skin.
Excretion through intestines : Purgatives, Senna, cascara has been absorbed in small intestine which are further excreted in large intestine and passed through faeces.
Excretion through bile : Medicines like phenolphathalein, diphenyl hydantoin are excreted through bile to small intestine. These drugs are reabsorbed and carried to the liver, which are further excreted through bile to small intestines. By this process, duration of action of drug is prolonged and this process is called as ‘Entero-hepatic circulation’ of drug.
1.14 ENZYME INDUCTION, ENZYME INHIBITION, KINETICS OF ELIMINATION
Enzyme Induction: The enzyme induction is a process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme is called enzyme induction. Enzyme induction is one of the most important mechanisms underlying chemical interactions. The enzyme Cytochromes P450, glutathione S-transferases, epoxide hydrolase, glucuronosyl transferase, and other enzymes involved in xenobiotic metabolism are readily inducible by a variety of substances.
The exposure to many common environmental chemicals can induce xenobiotic metabolism, including pollutants, cigarette smoke, and dietary constituents. Additionally, many chemicals induce their own metabolism upon repeated exposure. In general, enzyme induction increases the apparent Vmax for a biotransformation reaction because the total enzyme involved in the reaction increases. This can lead to increases or decreases in the biological effects of chemicals, depending upon whether the parent chemical or the metabolite is the active entity.
Mechanism of enzyme induction: A drug’s metabolic clearance can increase & efficacy decreases if a 2nd drug induces the enzyme responsible for the victim’s drug metabolism. Since this may compromise effectiveness or safety of the drug, the FDA ; others recognize drug interactions. The phenomenon of increased drug metabolism ability of the enzymes by several drugs and chemicals is called an enzyme induction. A number of drug can cause in increase in liver enzyme activity over time. This in turn an increase the metabolic rate of the same or other drugs. Phenobarbitone induced the metabolism itself.
Fig. 1.19 Basic mechanism of enzyme induction
Enzyme Inhibition : Enzyme inhibition refers to a decrease in enzyme-related processes, enzyme production, or enzyme activity. A number of clinically important interactions between drugs result from CYP450 inhibition. CYP450 inhibitors are different in their selectivity toward enzymes and are classified by their mechanisms of action. Some drugs are potent competitive inhibitors and compete for the active site, but they are not a substrate for the enzyme (e.g., quinidine and CYP2D6), while other drugs are noncompetitive inhibitors (e.g., ketoconazole and CYP3A4). Enzyme inhibition can cause many adverse drug interactions that tend to happen more rapidly (within a couple of days) than those seen with enzyme induction, as they occur once the concentration of the inhibiting drug becomes high enough to compete with the affected drug. Examples of enzyme-inhibiting agents are cimetidine, erythromycin, ciprofloxacin, and isoniazid.
Enzymes can be inhibited by two way competitive and non completive. Competitively, If the substrate and inhibitor compete for binding to the same active site. Noncompetitively: If the inhibitor binds somewhere else on the enzyme molecule reducing its efficiency. The distinction can be determined by plotting enzyme activity with and without the inhibitor present.
Competitive InhibitionIn the presence of a competitive inhibitor, it takes a higher substrate concentration to achieve the same velocities that were reached in its absence. So while Vmax can still be reached if sufficient substrate is available, one-half Vmax requires a higher S than before and thus Km is larger.
right276860Competitive Inhibition Non competitive Inhibition
Fig.1.20 Graph shows the competitive and non competitive
Non Competitive Inhibition: With noncompetitive inhibition, enzyme molecules that have been bound by the inhibitor are taken out of the game so Enzyme rate (velocity) is reduced for all values of S, including Vmax and one-half Vmax but Km remains unchanged because the active site of those enzyme molecules that have not been inhibited is unchanged.
Uncompetitive Inhibitor: An uncompetitive inhibitor binds is to the enzyme and enhance the binding of substrate (so reducing Km) but the resultant enzyme inhibitor substrate complex only undergoes reaction to from the product slowly so that V.max is also reduced. Shown in fig.
Fig. 1.21 A representation of uncompetitive Inhibitor
VERY SHORT ANSWER QUESTION
Q.1. Define Pharmacology?
Ans. Pharmacology is the science, which deals with Pharmacokinetic and pharmacodynamic of drugs on human body or on animals.
Q.2. What are the allied fields of Pharmacology?
Ans. Pharmacology science also includes fields such as (1) Pharmacy, (2) Pharmacognosy (3) toxicology (4) Posology. Each of these sub divisions has a highly specialized field and makes its contribution to composite knowledge of drugs to the world especially to the persons of Medical, Paramedical and Nursing field category. The knowledge of Pharmacologic principles is essential for maintenance of optimal health of the humanity and animals.
Q. 3.What is the nature and sources of drugs ?
Ans. The drugs may be derived from Plants (vegetable) kingdom, animals, minerals, synthesis and from microorganisms.
The drugs mostly were derived from roots leaves, bark of plants. The alkaloids, glycosides, oils (Fixed and volatile oils) resins, gums, Tannins and Antibiotics are derived from the Plants kingdom.
Q.4. Explain the factors effecting dose of drugs?.Ans. The age of patient, Sex, Time of administration, Pathological state, Route, Tolerance, Presence of other drugs, Hypersensitivity and Taccyphylaxis are to be explained in details.
Q.5. Explain the advantages?
Ans. The advantages or Merits of Injections are 1. There is very rapid response of drug. 2. The drugs go directly into the blood so no absorption is required. 3. This route can be used in case of a unconscious patient. 4. Less dose of drug is required by this route.
Q.6. Define AntibioticsAns. Antibiotics are the substances produced by or derived from living organisms. They are used either to kill bacteria or prevent multiplication of disease causing organisms. The example is Penicillin which is a complex organic acid obtained from Penicillium notatum, or Penicillium chrysogenum. Penicillins, like Benzyl Penicillin, Benzathine Penicillin, and Phenoxymethyl Penicillin and other group of drugs like Tetracycline, Oxytetracyline, Erythromycin, Bacitracin, Gentamycin etc are used as antibiotics.
Q.7.Name the two main routes of administration of drugs ?Ans.Two main routes for administrations of drugs are (i) Enteral route –By mouth or oral administration (ii) Parenteral route , the drug is administered through injections by intramuscular /intravenous injections.
Q.9.Name the organs from where the drugs are excreted from human body.
Ans.The drugs are excreted from the body (i) Through kidneys (ii)Through lungs (iii) Through Saliva (iv) Through breast milk. (v)Through skin (vi) Through intestines (vii) Through bile.
Q.10.What are chelating agents?.Ans.Some organic compounds combine with metallic ions and form non toxic water soluble complexes which are easily excreted through kidneys.
Q.11.Name the drugs obtained from plants?
Ans.The drugs like morphine, digoxin, reserpine, vinblastin (anticancer drug) are obtained from plants. The details of other drugs obtained from plants are given below.
Resins :- Pine rosin, Alkaloids: Morphine, emetine, atropine, nicotine, strychnine. Glycosides: Digitalis,digitoxin. Fixed oils: Castor oil, olive oil. Volatile oil: Clove oil, eucalyptus oil, turpentine oil. Gums: Gum acacia, agar, tragacanth: Tannins? Tannic acid, catechu.
Q.12.Name the drugs obtained from microorganisms?
Ans.The drugs used as an antibiotics are obtained from microorganisms by the process of fermentation for example:- Penicillin, Rifampicin.
Q.13.What are the drugs obtained from minerals?
Ans.The minerals are used for medicinal purpose.The drugs are Kaolin,magnesium sulphate, liquid paraffin.
Q.14.Name the drugs obtained from animals?
Ans.The drugs like Insulin,thyroid extract, heparin,sex-harmones are the secretions obtained from animal body.
Q.15.Name the commonly used synthetic drugs?
Ans.The drugs like Aspirin (Acetyl salicylic acid) Sulphunamides, corticosteroids antima-larials, general anaesthetics used are of synthetic origin.
Q.16.Name the sources of drugs?
Ans.The drugs (medicines) used for the treatment and prevention of diseases are obtained from various sources i:e from plants, animals, minerals, microorganisms and are also synthesized. In majority, the drugs used in clinical practice for treatment of various diseases are of synthetic origin.
Q.17.What should be the characteristics of a drug?
Ans.The drug (medicine) to be used for clinical purpose should have maximum medicinal effectiveness and minimum toxicity.
Q.18.What is therapeutic effect of the drug on the body?
Ans.When a drug is admninistered for one of its particular and therapeutical useful effect on the body does not have single effect. It has number of effects on the body. It effects blood, blood vessels, lungs, heart, liver, kidneys, brain ,eyes/ears,and skin differently. The drug which has useful effect on our body also has side effects,adverse effects,untoward effects,and has its toxic effects.
Q.19.What is tacchyphylaxis ?Ans.The repeated administration / use of drug at a short intervals for prolong duration produces less effect . The effect of drug goes on decreasing. The same effect can be attained with higher doses.
Q.20.What is the role of a place and environment in drugs administration?
Ans.The place and environment play important role in drug administration. In hot climates with humidity the metabolic rate is depressed and resistance of the body is lowered and the drug produce more action. On high altitudes barometric pressure is low due to which capacity of body for oxidation is decreased and there are more chances of increase in drug toxicity.
Q.21.Explain excretion through breast milk.?Ans.The breast milk is more acidic than blood plasma. The basic drugs like Pethidine and other drugs are excreted through breast milk. The care should be taken while admini-stering drugs to lactating mother because drug passed through breast milk will also affect adversely to the babies fed on mother’s milk.
Q. 22.What are allied branches of Pharmacology.
Ans. Pharmacology is an experimental science, it deals with the effects of drugs on a man and animals. Pharmacology science includes allied fields like, (1) Pharmacy (2) Pharmacognosy (3) toxicology (4) Posology (5) Chemotherapy (6) Teratology (7) Therapeutics.
Q. 23. Explain agonist and antagonist
Ans. Any drug/chemical molecule that binds a receptor and produces an effectThe magnitude of the drug effect is proportional to the amount of drug receptor complexes formed. Antagonist is defined as a drug/chemical molecule that blocks the effect of an agonist
Q. 25. Explain Bioavailability
Q. 26. Define Absorption
Ans. is a process of movement of unchanged drug from the site of administration to systemic circulation.
Q. 27. Define Distribution
Ans. It is defined the distribution involves reversible transfer of a drug between compartments.
Q. 28. Define metabolism
Ans. It is defined as the metabolism of drugs is defined as the conversion from one chemical to another.
Q. 29. What is excretion?
Ans. It is a process in which drug or their Metabolite is removed from the body by excretion.
Q. 30. Discuss on spare receptor
Ans. When drugs act on receptors to produce the response all the receptors are not occupied to produce the maximal response by a full agonist i.e each cell or tissue has some receptors unoccupied which may be called spare receptors.
Q. 31. Describe Competitive antagonist
Ans. It binds reversibly to the same receptor site as the agonist. Because they bind reversibly and compete for the same binding site, their inhibitory effects can be “surmounted” by addition of a higher concentration of agonist
Q. 32. What is Non proprietary drug?
Ans. A short name (often called a generic name) of a chemical, drug, or other substance that is not subject to trademark (proprietary) rights but is, in contrast to a trivial name, recognized or recommended by government agencies
Q.33. What is Propitiatory drug?
Ans. A drug that has a trade name and is protected by a patent (can be produced and sold only by the company holding the patent.
Q.34. What is meant by antagonism?
Ans.Antagonism refers to the opposing action of two drugs when given in combination. Example is of caffeine which is a cerebral stimulant (CNS stimulant), if given in combination antagonise the effects of chloral hydrate which is a CNS depressant. The effect of chloral hydrate is decreased when given in combination with caffeine. The term antagonism refers to decreased effectiveness of two or more drugs when administered in combination.
Q. 35. What is Tolerance ? Ans. The regular, continuous use of drug cause tolerance. The regular use of (intake) alcohol, opium, morophine, barbiturates leads to tolerance.
Q. 36. Explain Tacchyphylaxis
Ans. The repeated use of drugs causes less effect. To produce same effects more dose is needed. This effect is called tacchyphylaxisQ.37. What is the importance of time in drug administration ?Ans.In the administration of medicines, the time of administration plays important role in drugs treatment.
1)The drugs when given in empty stomach, medicines are quickly absorbed and enters the blood criculation to produce effect. The oral medicines administered before meal will act more quickly. If medicines are taken after meals, food cause delay in absorption of drug means cause delay in action.
2)The diuretic drugs should be administered in the morning and not in the evening because patient will be disturbed during night to pass the urine several time, after drug is given.
3)At bed time after giving hipnotic drug, the patient should not be disturbed, to avoid disruption of sleep.
Time plays an important role and effects dose of drug for example sedatives if given during day time require more dose in comparison to night as there is natural tendency to sleep. Similarly, stimulants at night time require more dose as compared to day time as there is natural tendency to awake. Seasonal variations also play role in the dose of drug.
Q.37. Describe the Route of administration
Ans. Route also effects the dose, the dose for oral route is required more as compared to intramuscular or intravenous route. The drugs given also effect differently, example magnesium sulphate when given orally causes purgative effect, when given intravenously produces CNS depression and cause sleep.
SHORT ANSWER QUESTIONS
Q.1. Explain the scope of Pharmacology Refer-1.2.
Q.2. Describe the Pharmacokinetic and Pharmacokinetic Refer.1.2
Q.3. What is Bioavailability explain with example? Refer1.11.3
Q.4. Write a note on allergy. Refer 1.10
Q.5. Discuss the Idiosyncrasy Refer.1.9
Q.6. Describe the Phase-III history of Pharmacology Refer.1.1
Q.7. Explain essential drugs concept Refer.1.4
Q.8. Describe the advantage and disadvantage of oral route Refer.1.5
Q.9. What is spare receptor? Refer.1.6.1
Q.10. Write a note on drug addiction Refer.1.7
Q.11. Discuss the drug tolerance Refer.1.8
Q.12. Describe the drug dependence Refer.1.9
Q.13. What is taccphylaxis? Refer.1.10
Q.14. What do you understand by drug idiosyncrasy? Refer.1.11
Q.15. Describe the Hives (urticaria) Refer.1.11
LONG ANSWER QUESTIONS
Q.1. Describe the mechanism of cell membrane transport Refer.1.13.1
Q.2. Explain the Pharmacokinetic with suitable example Refer 1.13.
Q.3. Write a detail note on Sources of drugs Refer 1.3.
Q.4. Define essential drug concept and role of WHO Refer 1.13.1
Q.5. Discuss the Mechanism of enzyme induction and Inhibition Refer1.14
Q.6. What is Phase-I and Phase-II Reaction? Explain the role in metabolism of drug Refer1.13.5
Q.7. Define drug dependence, explain the effect on human body. Refer 1.9
Q.8. Explain the mechanism of drug addition Refer 1.7
Q. 9. Write a detail note on agonists, antagonists and spear receptor Refer 1.6
Q.10. Explain the Route of drug Administration Refer 1.5
MULTIPLE CHOICE QUESTIONS
Q.1. Driving force in drug movement in aqueous diffusion model:
a) active transport– energy requiring
b) facilitated transport
c) drug concentration gradient
Q. 2. (Multiple Choice) Drug(s) which exhibit(s) a high hepatic” first-pass” effect:
a) lidocaine b) propranolol c) both d) neitherAns. C
Q. 3. Permanently charged amine form:
a) primary amine
b) secondary amine
c) tertiary amine
d) quaternary amine
Q. 4. (Multiple Choice) Concerning parenteral drug administration:
a) less predictable compared to oral administration route
b) not acceptable for unconscious patients
c) rate of drug systemic absorption insensitive to drug solubility in interstitial fluid
d) rate of systemic drug absorption following parenteral administration depends on absorbing
capillary membrane surface area
Q. 5. Drugs for which “first-pass” pulmonary uptake may exceed 65% of injected dose
a) fentanyl b) alfentanil c) sufentanil d) meperidine e) all of the above
Q. 6. Drugs least likely to penetrate across membranes
a) protein-bound drugs
b) charged drugs
c) neutral drugs
Q. 7. Two most important sites for drug elimination
a) pulmonary and liver
b) liver and gastrointestinal tract
c) kidney and liver
d) skin and liver
e) pulmonary and kidney
Q. 8. Concerning transfer of basic drugs such as nonionized local anesthetics from mother to fetus:
a) fetal pH is higher than maternal pH
b) in fetal distress alkalosis contributes to local anesthetic accumulation
c) concerning maternal blood: fetal blood — gradient is maintained for continual local anesthetic transfer from maternal circulation to fetal circulation
Q.9. Comparison of the rate and extent of the absorption of drug from the formulation under study to the data of a reference standard that is given intravenously, is known as
b. Absolute bioavailability
c. Relative bioavailability
d. BiopharmaceuticsAns. B.
Q.10.First pass effect is seen with which route of administration.
a) Oral route
b) Sub lingual
c) Intra muscular
d) Intra venous.
Q.11. Which of the following statements best describes pharmacodynamics?
a) The study of how drugs reach their target in the body and how the levels of a drug in the blood are affected by absorption, distribution, metabolism and excretion.
b) The study of how drugs can be designed using molecular modelling based on a drug’s pharmacophore.
c) The study of how a drug interacts with its target binding site at the molecular level.
d) The study of which functional groups are important in binding a drug to its target binding site and the identification of a pharmacophore.
Ans.CQ. 12. Which of the following statements best describes pharmacokinetics?
a) The study of how drugs reach their target in the body and how the levels of a drug in the blood are affected by various factors.
b) The study of how drugs can be designed using molecular modelling based on a drug’s pharmacophore.
c) The study of how a drug interacts with its target binding site at the molecular level.
d) The study of which functional groups are important in binding a drug to its target binding site and the identification of a pharmacophore.
Q. 13. Which of the following characteristics is detrimental to oral activity?
a) stability to digestive enzymes
b) susceptibility to metabolic enzymes
c) stability to stomach acids
d) solubility in both aqueous and fatty environments
Q.14. Which of the following is one of the rules in Lipinski’s rule of five?
a) a molecular weight equal to 500
b) no more than five hydrogen bond acceptor groups
c) no more than 10 hydrogen bond donor groups
d) a calculated logP value less than +5
Q. 15. Some orally active drugs do not obey the rule of five. For example, some drugs with molecular weights greater than 500 are found to be orally active. Which of the following mechanisms is the most likely reason for this?
a) transport by transport proteins
b) passage through pores between the cells of the gut wall
c) pinocytosisd) ion channels
Q.16. Some orally active drugs do not obey the rule of five. For example, some highly polar drugs with a molecular weight less than 200 are found to be orally active. Which of the following mechanisms is the most likely reason for this?
a) transport by transport proteins
b) passage through pores between the cells of the gut wall
c) pinocytosisd) ion channels
Q.17. Which type of infection could be orally treated with a highly polar antibacterial agent?
a) brain infection
b) kidney infection
c) gut infection
d) lung infection
Q.18. Which of the following statements is false regarding the blood-brain barrier?
a) The walls of the capillaries supplying the brain have tight fitting cells making it difficult for polar drugs to leave the capillaries.
b) The capillaries in the brain have a fatty coating making it more difficult for drugs to enter the brain.
c) The walls of the capillaries supplying the brain are made up of several layers of cells, which act as a barrier to the release of drugs.
d) Hydrophobic drugs pass through the blood brain barrier more easily than hydrophilic drugs.
Q.19. Which of the following statements is the closest description of Phase I metabolism?
a) Reactions which add a polar molecule to a functional group already present on a drug or one of its metabolites.
b) Reactions which occur in the blood supply.
c) Reactions which add a polar functional group to a drug.
d) Reactions which occur in the gut wall.
Q.20. Which of the following statements is the closest description of Phase II metabolism?
a) Reactions which add a polar molecule to a functional group already present on a drug or one of its metabolites.
b) Reactions which occur in the blood supply.
c) Reactions which add a polar functional group to a drug.
d) Reactions which occur in the gut wall.
Q.21. Which of the following statements is not true about cytochrome P450 enzymes?
a) They contain haem and magnesium.
b) They belong to a general class of enzymes called monooxygenases.
c) There are over 30 different cytochrome P450 enzymes.
d) Variation in cytochrome P450 enzyme profile between individuals can explain individual variation in drug susceptibility.
Q. 22. Which of the following groups is least susceptible to cytochrome P450 enzymes?
a) terminal methyl groups
b) allylic carbons
c) benzylic carbon atoms
d) quaternary carbon atoms
Ans.D.Q.23. Alkenes and aromatic groups can be metabolised to diols. Which enzymes are involved?
a) cytochrome P450 enzymes
b) epoxide hydrolasec) both of the above
d) neither of the above
Q. 24. Which of the following enzymes is not involved in catalysing a Phase I metabolic reaction?
a) flavin-containing monooxygenasesb) monoamine oxidases
c) glucuronyltransferased) esterasesAns. C
Q. 25. Which of the following reactions is not a Phase I metabolic transformation?
a) reduction of ketonesb) conjugation to alcohols
c) oxidation of alkyl groups
d) ester hydrolysis
Q.26. The effect of drug given through sublingual route is ?a) On set action is quick
b) Overdose can be avoided by spitting tablet
c) Drug is not destroyed by stomach enzymes
d) All the above.
Q.27.Advantages of injections are?
a) Rapid response of drug
b) Route can be used in unconscious patients
c) Less dose is required as compared to oral route
d) All the above
e) None of the above.
Q.28.Eye drops should be instilled?
a) Into the lower eye lid pouch
b) Below upper eye lid
c) Instill drops by closing eye lids
d) On outer side of eye lids.
Q.29.While administrating of drugs to a female patient which factor is to be kept in mind?a) Lactation
d) All the above.
Q.30.Pathological state effects dose of drug. In sever pain, the dose required is?
a) Large dose
b) Less doseC)No medicine required
d) Normal dose.