General Pharmacology Introduction Notes

Introduction (Definitions And Sources Of Drugs)

1. Pharmacology Drug It is the science that deals with the effects of drugs on the living system. World Health Organisation (WHO) defines drug as ‘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’.
2. Pharmacokinetics It means the movement of the drug within the body; it includes the processes of absorption (A), distribution (D), metabolism (M) and excretion (E). It means ‘what the body does to the drug’.
3. Pharmacodynamics It is the study of drugs— their mechanism of action, pharmacological actions and their adverse effects. It covers all the aspects relating to ‘what the drug does to the body’.
4. Pharmacy It is the branch of science that deals with the preparation, preservation, standardization, compounding and proper utilization of drugs.
5. Therapeutics Chemotherapy It is the aspect of medicine that is concerned with the treatment of diseases. It deals with the treatment of infectious diseases/cancer with chemical compounds that have relatively selective toxicity for the infecting organism/cancer cells.
6. Toxicology It is the study of poisons, their actions, detection, prevention and the treatment of poisoning.
7. Clinical pharmacology It is the systematic study of a drug in humans— both in healthy volunteers and patients. It includes the evaluation of pharmacokinetic and pharmacodynamic data, safety, efficacy and adverse effects of a drug by comparative clinical trials.
8. Essential medicine According to WHO, essential drugs are ‘those that satisfy the healthcare needs of the majority of the population’. They should be of assured quality, available at all times in adequate quantities and in appropriate dosage forms. They should be selected with regard to disease prevalence in a country, evidence on safety and efficacy, and comparative cost-effectiveness. Examples are iron and folic acid preparation for anaemia in pregnancy, and antitubercular drugs like isoniazid, rifampicin, pyrazinamide, ethambutol, etc.
9. Orphan drugs Drugs that are used for the diagnosis, treatment or prevention of rare diseases are called orphan drugs. The expenses incurred during the development, manufacture and marketing of the drugs cannot be recovered from selling the drugs by the pharmaceutical company, for example digoxin antibody (for digoxin toxicity) and fomepizole (for methyl alcohol poisoning).
10. Over-the-counter drugs (OTC drugs) OTC or nonprescription drugs are the drugs that can be sold to a patient without the need for a doctor’s prescription, for example vitamins and antacids.
11. Prescription drugs  These are the drugs that can be obtained only upon producing a prescription by a registered medical practitioner, example antibiotics and antipsychotics.

Read And Learn More: Pharmacology for Dentistry Notes

Sources Of Drug Information

1. Pharmacopoeia It is a book that contains a list of established and officially approved drugs having descriptions of their physical and chemical characteristics with tests for their identification, purity, methods of storage, etc.
   • Some of the pharmacopoeias are the Indian Pharmacopoeia (IP), the British Pharmacopoeia (BP), the European Pharmacopoeia and the United States Pharmacopoeia (USP).
   • Some other sources of drug information are National Formulary (NF), Martindale— the Extra Pharmacopoeia, Physician’s Desk Reference (PDR), American Medical Association Drug Evaluation, textbooks and journals of Pharmacology and therapeutics, drug bulletins and databases like drug Micromedex, Medline and Cochrane Library. Information can also be obtained from pharmaceutical companies through their medical representatives, meetings and drug advertisements in journals.
2. Formulary: It provides information about available drugs— their use, dosage, adverse effects, contraindications, precautions, warnings and guidance on selecting right drug for a range of conditions.

Drug Nomenclature

Drugs usually have three types of names. They are as follows:

1. Chemical name: It denotes the chemical structure of the drug, example acetylsalicylic acid is the chemical name of aspirin and N-acetyl-p-aminophenol for paracetamol. It is not suitable for use in a prescription.
2. Nonproprietary name: It is assigned by a competent scientific body/authority, example the United States Adopted Name (USAN) Council. WHO, along with its member countries, select and recommend the International Nonproprietary Name (INN) for a drug. So, it is uniform throughout the world and denotes the active pharmaceutical ingredient. INN is commonly used as generic name. Ideally, generic names should be used in prescriptions because it is generally uniform all over the world. Drugs sold under generic names are economical compared with their branded counterparts.
3. Proprietary name (brand name): It is given by the drug manufacturers. Brand names are short and easy to recall. Drugs sold under brand name are expensive compared with their generic version. A drug usually has many brand names— it may have different names within a country and in different countries. Brand names can also be used in prescriptions, example Disprin is a brand name of aspirin, and Crocin is a brand name of paracetamol.

Sources Of Drugs

They are natural, semi-synthetic and synthetic. Natural resources are plants, animals, minerals, microorganisms, etc. Semisynthetic drugs are obtained from natural sources and are later chemically modified. Synthetic drugs are produced artificially. The different sources of drugs are:

1. Plants:
   • Alkaloids, for example, morphine, atropine, quinine, reserpine, and ephedrine.
   • Glycosides, for example, digoxin, digitoxin.
   • Volatile oils have aroma. They are useful for relieving pain (clove oil), as carminative (eucalyptus oil), as a flavouring agent (peppermint oil), etc.
   • Resins are sticky organic compounds obtained from plants as exudate, for example, tincture benzoin (antiseptic).
2. Animals: Insulin, heparin.
3. Minerals: Ferrous sulfate, magnesium sulfate.
4. Microorganisms: Penicillin G, streptomycin, griseofulvin, streptokinase.
5. Semisynthetic: Hydromorphone, hydrocodone.
6. Synthetic: Most of the drugs used today are synthetic, example aspirin, and paracetamol.

Drugs are also produced by genetic engineering (recombinant DNA technology), example human insulin, human growth hormone, and hepatitis B vaccine.

Routes Of Drug Administration

Most of the drugs can be administered by different routes. Drug- and patient-related factors determine the selection of routes for drug administration. These factors are:

1. Characteristics of the drug.
2. Emergency/routine use.
3. Site of action of the drug— local or systemic.
4. Condition of the patient (unconscious, vomiting, diarrhoea).
5. Age of the patient.
6. Associated diseases.
7. Patient’s/doctor’s choice (sometimes).

Local Routes of Drug Administration

It is the simplest mode of administration of a drug at the site where the desired action is required. Systemic side effects are minimal.

1. Topical: The drug is applied to the skin or mucous membrane at various sites for local action.
   • Oral cavity: As a suspension, for example, nystatin; a troche, for example, clotrimazole (for oral candidiasis); a cream, for example, acyclovir (for herpes labialis); an ointment and a jelly, for example, 5% lignocaine hydrochloride (for topical anaesthesia); a spray, example 10% lignocaine hydrochloride (for topical anaesthesia); a mouthwash, example chlorhexidine mouthwash (antiseptic); an astringent; a paint, example tannic acid (for bleeding gums); and a styptic, example gelatin foam, fibrin (to check bleeding from tooth socket).
   • Intra-articular hydrocortisone injection for temporomandibular joint pain.
   • GI tract: As tablet that is not absorbed, for example, neomycin (for sterilization of gut before surgery).
   • Rectum and anal canal:
     • As an enema (administration of drug into the rectum in liquid form):
       1. Evacuant enema (for evacuation of the bowel): For example, soap water enema— soap acts as a lubricant and water stimulates the rectum.
       2. Retention enema: For example, methylprednisolone in ulcerative colitis.
     • As a suppository (administration of the drug in a solid form into the rectum), for example, bisacodyl— for evacuation of bowels.
   • Eye, ear and nose: As drops, ointment and spray (for infection, allergic conditions, etc.), for example, gentamicin eye/ear drops.
   • Bronchi: As an inhalation, for example, salbutamol and ipratropium bromide (for bronchial asthma and chronic obstructive pulmonary disease).
   • Skin: As ointment, cream, lotion or powder, for example, clotrimazole (antifungal) for cutaneous candidiasis.
2. Intra-arterial route: This route is rarely employed. It is mainly used during diagnostic studies such as coronary angiography and for the administration of some anticancer drugs, for example for treatment of malignancy involving limbs.
3. Administration of the drug into some deep tissues by injection, for example administration of triamcinolone directly into the joint space in rheumatoid arthritis.

Systemic Routes of Drug Administration

Drugs administered by this route enter the blood and produce systemic effects.

Enteral Routes of Drug Administration

It includes oral, sublingual and rectal routes.

1. Oral route It is the most common and acceptable route for drug administration. Dosage forms are tablet, capsule, syrup, mixture, etc., for example,., paracetamol tablet for fever, and omeprazole capsule for peptic ulcer are given orally. Tablets could be coated (covered with a thin film of another substance) or uncoated. They are also available in chewable (albendazole), dispersible (aspirin), mouth-dissolving (ondansetron) and sustained-release forms. Capsules have a soft or hard shell.
   • Oral route Advantages
     • Safer.
     • Cheaper.
     • Painless.
     • Convenient for repeated and prolonged use.
     • Can be self-administered.
   • Oral route Disadvantages It is not suitable for/in:
     • Unpalatable and highly irritant drugs.
     • Unabsorbable drugs (for example aminoglycosides).
     • Drugs that are destroyed by digestive juices (for example insulin).
     • Drugs with extensive first-pass metabolism (for example lignocaine).
     • Unconscious patients.
     • Uncooperative and unreliable patients.
     • Patients with severe vomiting and diarrhoea.
     • Emergency as onset of action of orally administered drugs is slow.
2. Sublingual route The preparation is kept under the tongue. The drug is absorbed through the buccal mucous membrane and enters the systemic circulation directly, for example nitroglycerin for acute attack of angina.
   • Sublingual route Advantages
     • Quick onset of action.
     • Action can be terminated by spitting out the tablet.
     • Bypasses first-pass metabolism.
     • Self-administration is possible.
   • Sublingual route Disadvantages It is not suitable for:
     • Irritant and lipid-insoluble drugs.
     • Drugs with bad taste.
3. Rectal route Drugs can be given in the form of solid or liquid.
   • Suppository: It can be used for local (topical) effects as well as systemic effects, for example, indomethacin for rheumatoid arthritis.
   • Enema: Retention enema can be used for local effects as well as systemic effects. The drug is absorbed through the rectal mucous membrane and produces systemic effects, for example, diazepam for status epilepticus in children.

Parenteral Routes

Routes of administration other than the enteral route are called parenteral routes. It generally refers to injections.

1. Parenteral Routes Advantages
   • The onset of the action of drugs is faster; hence it is suitable for emergencies.
   • It is useful in:
     • Unconscious patient.
     • Uncooperative and unreliable patients.
     • Patients with vomiting and diarrhoea.
   • It is suitable for:
     • Irritant drugs.
     • Drugs with high first-pass metabolism.
     • Drugs not absorbed orally.
     • Drugs are destroyed by digestive juices.
2. Parenteral Routes Disadvantages
   • Require aseptic conditions.
   • Preparations should be sterile and are expensive.
   • Require invasive techniques that are painful.
   • Cannot be usually self-administered.
   • Can cause local tissue injury to nerves, vessels, etc

Injections

1. Intradermal route: The drug is injected into the layers of the skin, for example, Bacillus Calmette–Guérin (BCG) vaccination and drug sensitivity tests. It is painful and only a small amount of the drug can be administered.
2. Subcutaneous (s.c.) route: The drug is injected into the subcutaneous tissues of the thigh, abdomen and arm, for example, adrenaline, insulin, etc.
   •  Subcutaneous (s.c.) routeAdvantages
     • Self-administration is possible (For example insulin).
     • Depot preparations can be inserted into the subcutaneous tissue, For example, Norplant for contraception.
   • Subcutaneous (s.c.) route Disadvantages
     • It is suitable only for nonirritant drugs.
     • Drug absorption is slow; hence it is not suitable for emergencies.
3. Intramuscular (i.m.) route: Drugs are injected into large muscles such as the deltoid, gluteus maximus and vastus lateralis, for example, paracetamol, diclofenac, etc. A volume of 5–10 mL can be given at a time.
   • Intramuscular Advantages
     • Absorption is more rapid as compared to the oral route.
     • Mild irritants, depot injections, soluble substances and suspensions can be given by this route.
   • Intramuscular Disadvantages
     • Aseptic conditions are needed.
     • Intramuscular injections are painful and may cause abscesses.
     • Self-administration is not possible.
     • There may be an injury to the nerves.
4. Intravenous (i.v.) route: Drugs are injected directly into the bloodstream through a vein. Drugs are administered as:
   • Bolus: Single, relatively large dose of a drug, injected rapidly or slowly into a vein. For example, i.v. ranitidine in bleeding peptic ulcer.
   • Slow intravenous injection: For example, i.v. morphine in myocardial infarction.
   • Intravenous infusion: For example, dopamine infusion in cardiogenic shock; mannitol infusion in cerebral oedema; and fluids infused intravenously in dehydration.
     • Intravenous infusion Advantages
       1. Bioavailability is 100%.
       2. The quick onset of action; therefore, it is the route of choice in emergency, for example, intravenous diazepam to control convulsions in status epilepticus.
       3. Large volumes of fluid can be administered, for  example, intravenous fluids in patients
          with severe dehydration.
       4. Highly irritant drugs, for example, anticancer drugs can be given because they get diluted in blood.
       5. The hypertonic solution can be infused by the intravenous route, for example, 20% mannitol in cerebral oedema.
       6. By i.v. infusion, a constant plasma level of the drug can be maintained, for example, dopamine infusion in cardiogenic shock.
     • Intravenous infusion Disadvantages
       1. Local irritation may cause phlebitis.
       2. Self-administration is usually not possible.
       3. Strict aseptic conditions are needed.
       4. Extravasation of some drugs can cause injury, necrosis and sloughing of tissues.
       5. Aqueous solutions can be administered. Depot preparations and suspensions cannot be given by i.v. route.
     • Intravenous infusion Precautions
       1. Drugs should usually be injected slowly.
       2. Before injecting, make sure that the tip of the needle is in the vein.

Inhalation

Volatile liquids and gases are given by inhalation for systemic effects, for example, general anaesthetics.

1. Inhalation Advantages
   • Quick onset of action.
   • The dose required is very low, so systemic toxicity is minimized.
   • The amount of drug administered can be regulated.
2. Inhalation Disadvantages
   • Local irritation may cause increased respiratory secretions and bronchospasm.

Transdermal route (transdermal therapeutic system)

The drug is administered in the form of a patch or ointment that delivers the drug into the circulation for systemic effect

For example, scopolamine patch for sialorrhoea and motion sickness, nitroglycerin patch/ointment for prophylaxis of angina, clonidine patch for hypertension, fentanyl patch for terminal stages of cancer pain and chronic pain and nicotine patch for tobacco deaddiction.

1. Transdermal route  Advantages
   • Self-administration is possible.
   • Patient compliance is better.
   • Duration of action is prolonged.
   • Systemic side effects are reduced.
   • Provides a constant plasma concentration of the drug.
2. Transdermal route  Disadvantages
   • Expensive.
   • Local irritation may cause dermatitis and itching.
   • The patch may fall off unnoticed.

Special Drug-delivery Systems

These have been developed to prolong the duration of drug action, for targeted delivery of drugs or to improve patient compliance.

1. Ocusert: For example, pilocarpine Ocusert is kept beneath the lower eyelid in glaucoma. It releases the drug slowly for a week following a single application.
2. Intraoral lignocaine patch: A patch containing lignocaine is used to anaesthetize the oral mucosa.
3. Jet injection: A small amount of local anaesthetic can be administered into the submucosa without the use of a needle to produce surface anaesthesia.
4. Liposomes: They are minute vesicles made of phospholipids into which the drug is incorporated. They help in targeted delivery of drugs, e.g. liposomal formulations of amphotericin B for fungal infections.
5. Monoclonal antibodies: They are immunoglobulins, produced by cell culture, selected to react with a specific antigen. They are useful for the targeted delivery of drugs, for example, the delivery of anticancer drugs using monoclonal antibodies.
6. Computerized, miniature pumps, for example, insulin pumps for continuous subcutaneous delivery of insulin.

Factors Modifying Drug Action

There are a number of factors that can influence drug response. Individuals may often
show quantitative variations in drug response but rarely show qualitative variations.

The important factors are described in Table.

Drug factors

1. Route of administration: When a drug is administered by different routes, it commonly exhibits quantitative variations; but sometimes it may also result in qualitative variations in response.
   • Quantitative variation: The oral dose of a drug is usually larger than the intravenous dose (since the i.v. route produces 100% bioavailability), example for analgesic effect, the intravenous dose of morphine is 5–10 mg, whereas the oral dose is 30–60 mg. The onset of drug action following intravenous administration is rapid compared to oral administration.
   • Qualitative variation: The drug may produce an entirely different response when administered by different routes. For example, magnesium sulfate produces a purgative effect when administered orally; parenterally, it causes CNS depression; and on local application, it reduces oedema in the inflamed area.
2. Presence of other drugs: See addition, potentiation, synergism and antagonism.
3. Cumulation: If the elimination of a drug is slow, then repeated administration of such drug will result in its accumulation in the body causing toxicity, for example, digoxin, emetine and chloroquine.

Patient factors

1. Age: In neonates, the metabolizing function of the liver and excretory function of the kidney is not fully developed, e.g. chloramphenicol can cause grey baby syndrome when given to neonates as the metabolizing enzymes are not fully developed. In adults, penicillin G is given sixth hourly; but in infants, it is administered 12 hourly as the excretory function is not completely developed. In the elderly, renal and hepatic functions progressively decline. The incidence of adverse effects of drugs is also relatively higher, and so drug doses have to be reduced accordingly, e.g. dose of aminoglycosides in the elderly is less than the normal adult dose. The dose of a drug for a child can be calculated as follows:
2. Body weight and body surface: An average dose of a drug is calculated in terms of body weight (mg/kg).In obese individuals and in patients with dehydration or oedema, dose calculation on the basis of body weight is not very appropriate. A more accurate method for calculating a dose is on the basis of the body surface area (BSA) of the patient. Nomograms are available to calculate BSA from the height and weight of the patient. Since it is inconvenient to calculate BSA, routinely dose is calculated on a body weight basis. The dose of anticancer drugs and a few other drugs are calculated on the basis of BSA.
3. Sex: Drugs like β-blockers, diuretics and clonidine can cause decreased libido in males.
4. Diet and environmental factors: Milk reduces the absorption of tetracyclines; fatty meal increases the absorption of griseofulvin (antifungal agent). Certain environmental pollutants such as DDT, cigarette smoke, insecticides, etc. induce hepatic microsomal enzymes and increase the metabolism of drugs such as oral contraceptives, theophylline, etc. So the dose of these drugs administered may be inadequate in smokers.
5. Genetic factor: Examples: fast and slow acetylation of isoniazid, prolonged succinylcholine apnoea, primaquine-induced haemolysis in G6PD-deficient individuals. Other examples are as follows:
   • Acute porphyria Barbiturates may precipitate attacks of acute intermittent porphyria in susceptible individuals by inducing the enzyme aminolevulinic acid (ALA) synthase that catalyses the production of porphyrins.
   • Malignant hyperthermia In some patients, a dangerous rise in body temperature (malignant hyperthermia) may occur, due to genetic abnormality, especially when the halothane–succinylcholine combination is used.
   • In a person with a shallow anterior chamber/and or narrow iridocorneal angle, mydriatics may precipitate acute congestive glaucoma.
   • There is an increased risk of bleeding with coumarin anticoagulants due to reduced activity of the metabolizing enzyme CYP2C9.
6. Psychological factor: The personality of the doctor as well as the patient can affect the response to a drug. Some patients respond to inert dosage forms (placebo) in conditions like pain, bronchial asthma, anxiety, etc.
   • Placebo effect: ‘Placebo’ is a Latin term that means ‘I will please’. It is a dummy medicine having no pharmacological activity. The effect produced by a placebo is called the placebo effect. Sugar tablets and distilled water injection are used as placebos.
   • Uses
     • Placebos are used for the relief of subjective symptoms like anxiety, headache, tremors, pain and insomnia.
     • Placebos are used in clinical trials in order to minimize bias.
   • Factors affecting the placebo effect are:
     • Patient factor: Patients with neurotic symptoms often respond to placebos.
     • Drug factor: The placebo response can be affected by the physical presentation or route of administration of the drug. For example, colourful tablets such as red, blue, green and injectable preparations give a better placebo effect.
     • Doctor factor: The personality of the doctor, motivation, way of instruction, doctor-patient relationship, etc. are important factors that also affect the response to a placebo.
7. Pathological states:
   • GI disorders: Achlorhydria reduces the absorption of weakly acidic drugs in the stomach by causing their ionization. In malabsorption syndrome, absorption of some drugs is reduced.
   • Liver disease: In chronic liver diseases, the metabolism of drugs is greatly reduced. This will increase the bioavailability of drugs having high first-pass metabolism, for example, propranolol.
   • Renal failure: Clearance of drugs that are excreted through the kidney is impaired. For example, the incidence of nephrotoxicity and ototoxicity with aminoglycosides is higher in the presence of renal failure.
8. Tolerance: It means ‘need for larger doses of a drug to produce a certain response’. Tolerance develops to the nasal decongestant effect of ephedrine on repeated use. Patients on organic nitrates for angina develop tolerance on long-term therapy. Tolerance is commonly seen with drugs like morphine, alcohol, amphetamines, etc.
   • Types of tolerance
   • Mechanism of development of tolerance: It could be pharmacokinetic or pharmacodynamic tolerance.
     • Pharmacokinetic tolerance (Dispositional tolerance): Reduced concentration of the drug at the site of action may be due to decreased absorption, increased metabolism and excretion, for example, barbiturates, and carbamazepine.
     • Pharmacodynamic tolerance (Functional tolerance): The drug effect is reduced, which may be due to a decrease in the number of receptors, a decrease in the activity of receptors and a decreased neurotransmitter. Repeated use of opioids, barbiturates, etc. results in the development of tolerance due to a decrease in the number of receptors (downregulation).
     • Cross-tolerance: The phenomenon of tolerance exhibited by closely related drugs is called cross-tolerance. For example, it occurs among nitrates, opioids, and between ether and alcohol.
     • Tachyphylaxis (tachy = rapid; phylaxis = protection; acute tolerance): When a drug is administered repeatedly at short intervals, the response diminishes rapidly. This is commonly seen with non-catecholamines, for example, tyramine, ephedrine, and amphetamine. These drugs act by releasing noradrenaline from the adrenergic nerve endings. Repeated administration of the drug causes gradual depletion of the neurotransmitter and hence a reduction in the response.
9. Drug dependence:

Drug Interactions

When two or more drugs are administered simultaneously, the effects of one drug may be altered by the other drug.

Drug interactions can occur either in vitro (outside the body) or in vivo (inside the body). Drug interactions can result in either beneficial or harmful effects.

Pharmaceutical Interactions

These can occur as a result of incompatibility (physical or chemical) of a drug with an intravenous solution or when two or more drugs are mixed in the same syringe/i.v. infusion. This may result in precipitation or inactivation of one or more drugs.

Phenytoin should not be administered in a dextrose solution as it gets precipitated. Dextrose solution is not suitable for i.v. infusion of ampicillin, as it is unstable at the acidic pH of dextrose.

Gentamicin and carbenicillin should not be given in the same infusion as it may result in loss of their potency.

1. Pharmacokinetic interactions These occur when one drug alters the absorption, distribution, metabolism or excretion of another drug.
   • Absorption: Antacids (containing aluminium, magnesium and calcium), iron, etc. interfere with the absorption of tetracyclines by forming unabsorbable complexes with them. Some drugs affect the absorption of other drugs by altering the gastrointestinal motility. Metoclopramide increases the rate of gastric emptying and promotes absorption of aspirin.
   • Distribution: Plasma protein binding can cause displacement interactions. More than one drug can bind to the same site on plasma protein. The drug with a higher affinity will displace the one with a lower affinity. This results in an increase in concentration of the unbound drug, for example, salicylates displace warfarin from binding sites resulting in increased free warfarin levels and an enhanced anticoagulant effect (bleeding).
   • Metabolism: This occurs when the metabolism of one drug is increased (enzyme induction) or decreased (enzyme inhibition) by another drug, for example, carbamazepine induces the metabolizing enzyme of warfarin; thus enhancing its metabolism and leading to a decreased anticoagulant effect. Erythromycin inhibits the metabolizing enzyme of carbamazepine and increases its toxicity.
   • Excretion: Most of them occur in the kidneys.
     • Salicylates interfere with the excretion of methotrexate and potentiate its toxicity.
     • Probenecid decreases renal tubular secretion of penicillins/cephalosporins and prolongs their duration of action (beneficial interaction).
2. Pharmacodynamic interactions The interaction is due to the action of drugs on receptors or physiological systems. This may result in either additive, synergistic or antagonistic effects. The interactions may also result in harmful effects, for example, enhanced nephrotoxicity seen with the concurrent use of aminoglycosides and amphotericin B; it may also result in beneficial effects, for example, levodopa and carbidopa in parkinsonism.

Adverse Drug Effects

Adverse Drug Effect

Adverse effect is defined as any undesirable or unwanted effect of a drug. The suggested definitions of adverse drug reactions (ADR) and adverse events (AE) are as follows:

1. Adverse drug reaction (ADR): ‘Any response that is noxious, unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of disease, or for modification of physiological function’.
2. Adverse event (AE): ‘Any untoward medical occurrence that may present during treatment with a pharmaceutical product but that does not necessarily have a causal relationship with the treatment’.

• Types of adverse drug reactions

1. Predictable reactions (Type A or Augmented reactions): These are predictable reactions to a drug which are related to its pharmacological actions. They include side effects, secondary effects and toxic effects.
2. Unpredictable reactions (Type B or Bizarre reactions): These are non-dose-related unpredictable reactions to a drug. They are not related to the pharmacological actions of the drug. Allergic reactions and idiosyncrasies are unpredictable reactions.

 

1. Predictable reactions
   • Side Effects: These are unwanted pharmacological effects of a drug that are seen with therapeutic doses, for example, atropine used in the treatment of heart block also produces dryness of mouth, blurring of vision, urinary retention, etc., which are the side effects.
   • Secondary Effects: The primary action of a drug may result in other effects, for example, immunosuppression by corticosteroids can lead to the development of opportunistic infections, and oral candidiasis.
   • Toxic Effects: These are the effects of a drug that is either due to overdosage or chronic use, for example, bleeding due to chronic use/overdosage of anticoagulants and nephrotoxicity with aminoglycosides, especially in patients with renal failure.
2. Unpredictable reactions
   • Drug Allergy: It is an abnormal response (local or systemic) to a drug/foreign antigen mediated by the immune system. Different types of hypersensitivity reactions are discussed below.
     • Those associated with humoral antibodies: Types 1, 2 and 3.
     • Those associated with cell-mediated immunity: Type 4 (delayed hypersensitivity).
       1. Type 1 hypersensitivity (immediate type, anaphylactic) reactions: It is a rapidly occurring reaction; hence they are called immediate hypersensitivity reaction. The manifestations are itching, urticaria, hay fever, asthma or even anaphylactic shock. Anaphylactic shock is a medical emergency and should be treated promptly with:
          • Inj. adrenaline (1:1000) 0.3–0.5 mL intramuscularly.
          • Inj. hydrocortisone 100–200 mg intravenously.
          • Inj. pheniramine 45 mg intramuscularly/intravenously.
          • Maintenance of patent airway, administration of intravenous fluids.
       2. Type 2 hypersensitivity (cytotoxic) reactions: The antibodies (IgG and IgM) react with cell-bound antigens and cause activation of complement, which destroys the cells Examples are blood transfusion reactions, haemolytic anaemias produced by quinine, quinidine, cephalosporins, etc.
       3. Type 3 hypersensitivity (Arthus, serum sickness) reactions: In this type of reaction, the antibodies involved are mainly IgG.
          • AG: AB complexes are formed → Fix complement → Deposition of complexes on vascular endothelium → Destructive inflammatory response. For example, serum sickness (fever, urticaria, joint pain, lymphadenopathy) with penicillins and sulfonamides; acute interstitial nephritis with nonsteroidal anti-inflammatory drugs (NSAIDs) and Stevens-Johnson syndrome with sulfonamides.
       4. Type 4 hypersensitivity (cell-mediated or delayed hypersensitivity) reactions: It is mediated by sensitized T lymphocytes. Re-exposure to the antigen leads to a local inflammatory response. The manifestations usually occur 1–2 days after exposure to the sensitizing antigen, for example, contact dermatitis due to local anaesthetic creams, topical antibiotics and antifungal agents. Type 2, type 3 and type 4 reactions are treated with glucocorticoids.

• Idiosyncrasy

It is usually a genetically determined abnormal reaction to drugs, e.g. succinylcholine apnoea, aplastic anaemia caused by chloramphenicol, and haemolytic anaemia seen with primaquine and sulfonamides.

• Drug Dependence

1. Psychological dependence: There is an intense desire to continue taking the drug as the patients feel that their well-being depends upon the drug.
2. Physical dependence: Repeated drug use produces physiological changes in the body that make the continuous presence of the drug in the body necessary to maintain normal function. Abrupt stoppage of the drug results in an imbalance wherein the body has to readjust to the absence of the drug resulting in the development of signs and symptoms known as withdrawal syndrome. The withdrawal signs and symptoms are generally opposite to the effects produced by the drug.

The principles of treatment of drug dependence are:

1. Hospitalization
2. Substitution therapy: for example Methadone/buprenorphine substitution for morphine addiction.
3. Aversion therapy: Disulfiram for alcohol addiction.
4. Psychotherapy
5. General measures: Maintain nutrition, family support and rehabilitation.

• Iatrogenic diseases

It is a physician-induced disease (‘Iatros’ is a Greek word, that means ‘physician’) due to drug therapy, for example parkinsonism due to metoclopramide; acute gastritis and peptic ulcer due to nonsteroidal anti-inflammatory drugs.

• TeratogenicityTeratogenic Effect Of Some Drugs

Certain drugs when given during pregnancy may cross the placenta and cause various dangerous effects in the foetus. This is called teratogenesis. carcinogen. The abnormalities of genetic material in a cell produced by a drug are known as mutagenicity, for example, anticancer drugs and oestrogens.

• Photosensitivity reactions

It is a drug-induced cutaneous reaction (photoallergy/phototoxicity) following exposure to ultraviolet radiation. Sulfonamides cause photoallergy on exposure to light; they produce dermatitis due to immune response (cell-mediated). Doxycycline and fluoroquinolones can cause phototoxicity— a local reaction (erythema, blisters) that occurs on exposure to UV light. Use of sunscreen and avoidance of exposure to sunlight is advised. Calamine lotion and topical steroids are used for treatment.

• Hepatotoxicity

Some of the hepatotoxic drugs are isoniazid, rifampicin, pyrazinamide, halothane, paracetamol, etc.

• Nephrotoxicity

Vancomycin, aminoglycosides, cisplatin, cyclosporine, amphotericin B, tetracyclines [Fanconi syndrome], indinavir, gold salts and nystatin are examples of nephrotoxic drugs. (Mnemonic for nephrotoxic drugs: VACATION.)

• Ototoxicity

It can occur with aminoglycosides, loop diuretics, cisplatin, etc.

• Ocular toxicity

Ethambutol, chloroquine, glucocorticoids, etc. can cause ocular toxicity.

Pharmacovigilance

It is defined as the ‘science and activities relating to detection, assessment, understanding and prevention adverse effects or any other possible drug-related problems’ (WHO).

The aim of pharmacovigilance is to improve patient care and safety related to the use of drugs, promote the rational use of medicines, develop regulations for the use of drugs and educate healthcare professionals about adverse drug reactions.

• Causality assessment: Some of the commonly used tools for causality assessment are Naranjo’s scale and the WHO scale.

The National Pharmacovigilance Centre is located in Ghaziabad. The International Centre is the Uppsala Monitoring Centre in Sweden. Any healthcare professional, for example, doctors, dentists, nurses and pharmacists can report a suspected adverse drug event. Patients can also report ADRs.

Treatment of Poisoning

Toxicology is the study of poisons— their actions, detection, prevention and treatment of poisoning. All poisoning cases require hospitalization and careful observation till recovery. Poisoning may be suicidal, homicidal or accidental. All cases of poisoning are medicolegal cases; hence the police should be informed.

General Management

1. Hospitalization.
2. Breathing should be assessed. If there is hypoxaemia, oxygen should be given. The patient may need mechanical ventilation, if there is respiratory insufficiency.
3. The airway should be cleared. In comatose patients, there is a danger of respiratory obstruction by tongue, secretions and aspiration of vomitus. Hence, the patient should be turned to his left lateral side. A cuffed endotracheal tube should be inserted and secretions should be aspirated regularly.
4. Circulation should be assessed (pulse rate and blood pressure) and an i.v. (intravenous) the line should be maintained.
5. To prevent further absorption of poison:
   • Inhaled poisons (gases): The patient should be moved to fresh air.
   • Contact poisons: Contaminated clothes should be removed and the body parts should be washed with soap and water.
   • Ingested poisons: Gastric lavage can limit the absorption if done within 2–3 hours of poisoning. If the patient is unconscious, endotracheal intubation should be done before gastric lavage. Gastric lavage is usually done with normal saline. Lukewarm water, potassium permanganate solution, and sodium bicarbonate are some other solutions used. Lavage should be repeated till the returning fluid is clear. After the lavage, activated charcoal is added to the stomach, which adsorbs many drugs and poisons (physical antagonism). Activated charcoal has a large surface area and is highly porous to bind with poisonous material. Gastric lavage should not be carried out in case of poisoning due to corrosives (except carbolic acid) due to fear of perforation, petroleum products (kerosene), convulsants, etc. Mustard, common salt, syrup ipecac, etc. can be used to induce vomiting and prevent further absorption of ingested poisons. However, this method is rarely practised now. Laxatives like magnesium sulfate or citrate can be used orally to promote the elimination of the ingested poison. Oral polyethene glycol electrolyte solution can be used for whole-bowel irrigation of the gastrointestinal tract in case of poisoning due to iron, lithium, cocaine, heroin, foreign bodies, etc.
6. To promote the elimination of the absorbed portion of the drugs:
   • Diuretics (i.v. mannitol or furosemide) are used to promote the elimination of the absorbed portion of the drug. Renal elimination of some of the drugs can be increased by altering the pH of urine, for example, alkalinization of urine in salicylate poisoning and acidification of urine in amphetamine poisoning.
   • Dialysis is used in cases of severe poisoning, for example, lithium, aspirin, methanol, etc.
7. Symptomatic treatment: Intravenous diazepam 5–10 mg if there are convulsions and external cooling for hyperpyrexia.
8. Maintenance of Fluid and Electrolyte balance: Hyponatraemia should be treated with i.v. normal saline and hypernatraemia with i.v. furosemide. Hypokalaemia is treated with potassium chloride, oral or slow i.v. infusion. Oral potassium chloride should be diluted in a tumbler of water to prevent intestinal ulceration. Potassium chloride should be given slowly intravenously as it has a cardiac depressant effect. Rapid injection can cause cardiac arrest and death. Thiazides or furosemide can be used to treat mild hyperkalaemia. Severe hyperkalaemia is treated with 10% calcium gluconate intravenously. Intravenous sodium bicarbonate is used to treat metabolic acidosis.

Note: Mnemonic for general management of poisoning: A–H.

• Specific management

Antidotes for some poisons are listed in Table.

Poison Information Centres

WHO has established poison information centres in AIIMS, New Delhi and Ahmedabad. Computer software on poisons (INTOX) is used in these centres. Regional centres are in Chennai and Cochin (POISONDEX). These centres provide information about toxicity assessment and treatment over the phone throughout the day.

Pharmacoeconomics

It is a scientific discipline that deals with the evaluation of the cost and consequences of drug therapy or other interventions to the health care system and society. The commonly used pharmacoeconomic analytical methods are cost-minimization analysis, cost-effectiveness analysis and cost-benefit analysis.