• Pharmacology—It is a science of drugs; interaction of exogenously administered chemical molecules with specific molecules of living system which results in modulation of biologic function.
• Pharmacokinetics—What the body does to the drug.
• Pharmacodynamics—What the drug does to the body.
• Drug—Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient. (WHO 1966).
• Pharmacotherapeutics—Application of pharmacodynamic information together with knowledge of the disease for its prevention, mitigation and cure.
• Clinical pharmacology—Scientific study of drug in man; pharmacokinetic and pharmacodynamic investigation in healthy volunteers and in patients.
• Chemotherapy—Treatment of systemic infection and malignancy with specific drugs.
• Pharmacy—It is a science of compounding and dispensing drugs or preparing suitable forms for administration of drugs.
• Toxicology—Study of poisonous effects of drugs and other chemical with emphasis on detection, prevention and treatment.
• Drug nomenclature—3 names. These are:
  • Chemical name—It describes the substance chemically, e.g. para-aminophenol derivative.2
  • Nonproprietary name—This is accepted by competent scientific body; uniform; generic name, e.g. paracetamol.
  • Brand name—Name assigned by the manufacturing company; trade name, e.g. cetamol, paracet, cemol, cetanil.
• Pharmacogenetics—Drug responses that are governed by heredity.
  Idiosyncrasy—Inherited abnormal responses to drugs mediated by single gene; increased, deceased and bizarre responses to drugs.
• Pharmacovigilance—Observation of safety, efficacy and quality control of drug after it becomes available in the market.
• Pharmacopeia—An authorized book containing formulas and information that provide standard for preparation and dispension of drugs.

 

• Synthetic
• Plant source
  • Alkaloids
  • Glycosides
  • Oils (essential oils, fixed oils, mineral oils)
  • Gums
  • Tannins
  • Resins
• Animal source
• Microbiological source
• Mineral source
• Genetically engineered drugs.

 

• Synthesized in the laboratory.
• Quality can be better controlled.
• Process is easier and cheaper.
• Chemical structure of prototype drug can be modified in search of better, safer and more potent drug.
• For example aspirin, paracetamol, phenytoin, chlorpromazine, amphetamine, etc.3

 

• Alkaloids
  • Nitrogenous heterocylic bases derived from plants. For example atropine from Atropa belladonna, quinine from cinchona bark, morphine from papaver somniferum, reserpine from Rauwolfia serpentina, nicotine from tobacco leaves.
  • The names of all alkaloids usually end with ‘ne’.
• Glycosides
  • Sugar-O-Nonsugar (sugar portion → responsible for pharmacokinetic property, nonsugar → responsible for pharmacodynamic property).
  • Plant products in which sugar moiety is joined to nonsugar moiety with a ether linkage.
  • Sugar moiety → glucose = glucoside; sugar moiety → aminosugar = aminoglycoside.
  • For example digoxin (digitalis purpurea), ouabain (stroph-anthus gratus), aminoglycosides (source: micro-organisms).
• Oils
  • Essential oils (or volatile oils)—Obtained from leaves or flower petals by stem distillation; stem volatile. Used as carminatives, astringent in mouthwashes, as flavoring agent. For example eucalyptus oil, clove oil, peppermint oil, etc.
  • Fixed oils—Nonvolatile. For example ground nut-oil, coconut oil and olive oil.
  • Mineral oils—Mostly petroleum products; maily used as vehicles for preparation of ointments. For example hard and soft paraffin, as purgative-laxative, e.g. liquid paraffin.
• Gums
  • Colloidal exudates of plants. They either swell, or dissolve or form adhesive mucilage in water.
  • It is used as emulsifying or suspending agents, e.g. gum acacia and gum tragacanth.
• Tannins
  • Nonnitrogenous phenolic derivatives from plant source.
  • It is used as astringent, e.g. tinct.catachu.4
• Resins
  • Polymers of volatile oil and are insoluble in water. For example shellac (in enteric coating), tolu balsam (as expec-torant).

 

• Hormones, vitamins, vaccines, sera.
• For example insulin, vit B₁₂, thyroxin, etc.

 

• Fungi—Penicillin, griseofulvin, cephalosporin.
• Bacteria—Polymixin B, aztreonam, bacitracin, colistin.
• Actinomycetes—Aminoglycosides, macrolides, tetracycline, chloramphenicol.

 

• Ferrous sulfate (in anemia), magnesium sulfate (as purgative), aluminium hydroxide and sodium bicarbonate (as antacid), radioactive iodine I¹³¹ for the diagnosis treatment of thyrotoxicosis, etc.

 

• Molecular biology, recombinant DNA technology, DNA alteration, gene splicing, etc.
  

  Fig. 1.1: Formation of genetically engineered hepatitis B vaccine
• Hepatitis B vaccine, insulin.5

 

• Formulation
  • It is a recipe by which a drug is prepared. It contains the list of active ingredients and the other substances, like excipients, vehicles, flavoring agents and preservatives, with the amounts contained therein.
• Dosage form
  • It is the form in which the formulation can be administered to the patient. For example capsules, tablets, syrup, etc.
• Excipients
  • Pharmacologically inert substances which are added to the pharmaceutical preparation either to add bulk to the drug used in extremely small amount or to mask the unpleasant taste. For example lactose, calcium lactate, starch, etc.
• Vehicle
  • Substance which is used to dissolve or suspend the drugs, in a pharmaceutical preparation. For example gum acacia, petroleum jelly, etc.

• Solid dosage forms:
  • Powders
  • Granules
  • Tablets
    • Ordinary, sugar coated, film-coated, enteric coated, long (retard), pellets, lozenges.
  • Capsules
    • Spansules.6

   

• Weight in volume (W/V) solution—It means number of grams of the substance in 100 ml of the solution.
• Volume in volume (V/V) solutions—It means number of ml of the substance in 100 ml of the solution.
• Weight in weight (W/W) solution—It means number of grams of the substance in 100 gm of the solution.

 

• One molar solution is obtained by dissolving one gram molecular weight of a substance in one liter of the solution.
• The quantity of the solid present in one molar solution is dependent on the volume of the solution. 100 ml of the solution contains 100 mmol of the solid and 10 ml will contain 10 mmol.

 

• Solution may also be expressed as number of grams of solid in 1000 ml. A 1 in 1000 solution contains 1 gm of the solid in 1000 ml of the solution.

 

• Calculate the quantity of sodium chloride present in 200 ml of half normal saline. Ans: 0.9 gm.
  [Normal saline—0.9% NaCl; Half normal—0.45% → 100 ml contains 0.45 gm and 200 ml – 0.9 gm].
• Calculate the quantity of potassium permanganate present in 50 ml of potassium permanganate solution 1 in 1000 and give instruction for preparing 1 in 10,000 solutions to be used as a gargle. Ans: 50 mg and water to be added is 450 ml.
  [1000 ml contains 1 gm (1000 mg). So 50 ml contains 50 mg. Now, N₁V₁ = N₂V₂; 1/1000 × 50 = 1/10 000 × V₂; V₂ = 500 ml. 7So 450 ml should be added to the original solution. Hint— strength has beed reduced by 10 times, so 10 times dilution is required, i.e. 50 × 10 = 500 ml, so 450 ml water should be added].
• 0.5 ml of 1 in 1000 solution of adrenaline is given sub-cutaneously in the treatment of an acute of asthma. What is the exact quantity of the adrenaline present in 0.5 ml? Ans: 0.5 mg.
  [100 ml solution contains 1 gm (1000 mg) adrenaline. So 0.5 ml → 0.5 mg].
• Calculate the amount of pilocarpine required to prepare 10 ml of 1% eyedrops. Ans: 100 mg.
  [1% → 100 ml contains 1 gm (1000 mg). So in 10 ml, 100 mg is required].
• How many mmol of sodium bicarbonate are there in 100 ml of 8.4% solution? (The molecular weight of sodium bicarbonate is 84). Ans: 100 mmol.
  [8.4% → 100 ml contains 8.4 gm. Similarly, 1000 ml contains 84 gm. Note 84 is the mol wt of sodium bicarbonate. So this solution is in 1M concentration. 100 ml contains 100 mmol (as 1000 ml contains 1000 mmol)].
• If 1 ml of 1:200 solutions is diluted to 5 ml, what is the strength of resultant solution? Ans:1:1000.
  [Note five times dilution, i.e. five times reduction in the strength or alternatively N₁V₁ = N₂V₂ can be applied].

 

1. Physical and chemical properties
   solid/gas/liquid/pH/solubility.
2. Site of action.
3. Effects of digestive juices/first pass metabolism.
4. Rapidity of the response.
5. Accuracy of the dosage.
6. Condition of the patient.8

 

1. Topical (Fig. 1.2)

 

• 1. Mouth/pharynx—Lozenges, mouthwashes, gargles
  2. Eyes, ear, nose—Drops, ointments, nasal spray
  3. Bronchi and lungs—Aerosols
  4. Urethra—Jellys, bougies
  5. Vagina—Pessaries, vaginal tablets
  6. Anal canal—Suppositories.

2. Deeper tissues
   Intra-articular
   Intrathecal.
3. Arterial
   Contrast media in angiography.

 

1. Oral
   Advantages:
   • Commonest, safer
   • More convenient, noninvasive
   • Painless.
     Disadvantages:
   • Slow onset of action, first pass metabolism9
   • Unpalatable drugs, gasric irritation
   • Unco-operative, unconscious, vomiting patients, e.g. tablets, capsules, syrups.
2. Sublingual or buccal, e.g. nitroglycerine.
3. Rectal, e.g. diazepam.
4. Cutaneous
   • Transdermal therapeutic systems, e.g. insulin, testosterone.
5. Inhalational, e.g. volatile liquids and gases.
6. Nasal, e.g. desmopressin.
7. Parenteral
   Advantages:
   • Faster action, no gastric irritation
   • Unconscious patients
   • Liver is bypassed.
     Disadvantages:
   • Costlier, invasive and painful
   • Self-administration is difficult
   • Local tissue injury.

 

1. Subcutaneous (SC)
2. Intramuscular (IM)
3. Intravenous (IV)
4. Intradermal.

 

• Definition: A prescription is physician's written instructions to a pharmacist to supply drugs in a particular form to a patient. It includes directions to the pharmacist regarding the preparation and to the patient regarding the use of the medicament.10
• The actual writing of a prescription order, if possible, should be done in the presence of the patient.
  This tends to impress upon the patient that the order is being written for his particular illness and increases his confidence in the physician.
• One should write without hesitation and with a degree of determination, concentration and clarity indicative of the fact that the writer is perfectly acquainted with what he is doing.
• Erasing, crossing and tearing of a prescription order in the presence of the patient and the poor procedure psychologi-cally and should be avoided.
• The prescription order should be laid aside for a few minutes, and then read before affixing one's signature.
• This is important because errors do occur, especially if talkative patients or relatives have distracted the physician.

 

1. Superscription
2. Inscription
3. Subscription
4. Signature.

 

• R_X—Recipe, take thou
• The sign R_X is deemed to be an invocation to Jupiter—The God of healing.

 

• Ingredients and the quantity
• The quantities of ingredients → should be in metric system.

 

• Directions to the dispenser as to the quantity to be dispensed.

 

• (Signature—let it be labeled) consists the directions to the patient.
  This part of the prescription declares:
• The method of administration.11
• The dose (if the remedy is for internal use).
• The time of administration or application.
• The vehicle of administration or the means of application.
• The part of the body to which the remedy is to be applied (if the remedy is for external use).
• The patient's names, age, sex and address; the particulars may be written at the top. Date also should be written at the top.
• The prescriber's signature, name and date.

 

1. Physician and patient related
   1. Doctor's name
   2. Professional degree
   3. Medical counsil registration number
   4. Doctor's address and phone number
   5. Patient's name
   6. Patient's address
   7. Diagnosis
   8. The symbol R_X
   9. Refill information
   10. Prescriber's signature.
2. Drug related
   1. Dosage form
   2. Appropriate drug
   3. Strength of drug
   4. Quantity to be dispensed
   5. Direction for use.

• The importance of giving clear written instructions to the patient or attendant regarding administration of drugs cannot be overlooked.
• The more the attention given to this, the more will be the patient's compliance with the treatment.

Latin	Abbreviation	Meaning
Recipe Bis in die Ter in die Quarter in die Nocte Hora Somni Ante Cibos Post Cibos Postprandial sugar Statim Capsula Si opus sit Pro re nata Per oral	Rx bid tid qid noct hs ac pc pps Stat Caps Sos PRN PO D5W IM IV mg OTC PR SC Sup tab tbsp tsp Vag q	Take thou Twice a day Thrice a day Four times a day At night At night Before food After food Blood sugar after food Immediately A capsule If needed As required By mouth Dextrose 5% in water Intramuscular Intravenous Milligram Over the counter Per rectum Subcutaneous Suppository Tablet Tablespoon Teaspoon Vaginal Every

• The same language should be used throughout preferably English.
• Each ingredient's name shall have a separate line.13
• Each line begins with a capital.
• “Ditto” marks and “formulas” are not permissible.
• Be explicit in the directions given to the patient, as well as simple. No technical terms or abbreviations to be used here.
• Never sign a prescription or let it go out of your hands without carefully revising it.

   

1. Absorption
2. Distribution
3. Metabolism (Biotransformation)
4. Excretion.

   

• Aqueous solubility
• Concentration
• Area of absorbing surface
• Vascularity
• Route of administration:
  • Oral
  • SC/IM
  • Topical.

 

• 100% for IV route
• < 100% for other routes
  Incomplete absorption
  First pass metabolism
  Local binding of a drug.

 

• Lipid-solubility— ↑ solubility → more distribution.
• Ionization— ↑ ionization → less distribution.
• Plasma protein binding (PPB)—more PPB → less distri-bution.

 

• Penetration into brain—Lipid-soluble medicines.
• Passage across placenta—Lipid-soluble medicines; at high concentration any drug can cross.
• Plasma protein binding—More PPB, less volume of distribution.
• Tissue storage—Some drugs are deposited in tissues and have high volume of distribution.
• Skeletal muscle/heart/kidney—Digoxin
  • Liver—Chloroquine15
  • Retina—Chloroquine
  • Bone and teeth—Tetracycline
  • Adipose tissue—Thiopentone.

 

• Chemical alteration of the drug in the body.
• Lipid-soluble (nonpolar) drugs → lipid-insoluble (polar)—This is the main function or aim of drug biotransformation.
• Metabolism may result in:
  • Inactivation
  • Activation of inactive drug—Known as prodrug, e.g. L-dopa (inactive) → dopamine (active) used in parkinsonism.
• Two types of reactions:
  • Phase I/nonsynthetic reactions—Metabolites may be active or inactive.
  • Phase II/synthetic/conjugation reactions—Metabolite is inactive.
• Metabolizing enzymes:
  • Microsomal—Cytochrome p450 enzymes, glucuronyl transferase.
  • Nonmicrosomal—Esterases, amidases, acetyltransferase, pseudocholinesterase.
• Enzyme induction—More synthesis of microsomal enzymes → faster drug metabolism → decreased efficacy.
• Enzyme inhibition—Drug metabolism is inhibited → more chance of drug toxicity.
• First pass metabolism—Metabolism of drugs in the gastrointestinal mucosa and/or liver on the way to systemic circulation after absorption—Hence the name first pass as this is the first pass through hepatic tissues.
  Oral route— ↓ bioavailability (due to first pass metabolism)
  Liver disease— ↓ first pass metabolism.

 

• Urine, e.g. many drugs
• Feces, e.g. erythromycin, oral contraceptives
• Exhaled air, e.g. alcohol16
• Saliva and sweat, e.g. rifampin
• Milk, e.g. alcohol, amoxicillin.

• Renal excretion:
  • Glomerular filtration
  • Tubular reabsorption
  • Tubular secretion.
• Kinetics of elimination:
  • Fundamental pharmacokinetic parameters
  • Bioavailability
  • Volume of distribution
  • Clearance.
• Clearance—It is the theoretical volume of plasma from which the drug is completely removed in unit time.
• First order kinetics:
  Rate of elimination is directly proportional to the drug concentration. Constant fraction of the drug is eliminated.
• Zero order kinetics:
  Rate of elimination remains constant irrespective of drug concentration. A constant amount of the drug is eliminated.
• Plasma half-life (t½):
  It is time taken for the plasma concentration of a drug to be reduced to half of its original value.
  For first order kinetics, 4–5 plasma half lives are required for nearly complete elimination:
  1 t½—50% eliminated
  2 t½—75% (50 + 25) eliminated
  3 t½—87.5% (50 + 25 + 12.5) eliminated
  4 t½—93.75% (50 + 25 + 12.5 + 6.25) eliminated.
• Loading dose—To attain therapeutic concentration.
• Maintenance dose—To balance the rate of elimination.17

   

1. Physical action
   Mass of drug—Bulk laxatives
   Adsorptive property—Charcoal
   Osmotic activity—Mannitol
   Radiopacity—Contrast media (barium sulfate).
2. Chemical action
   Antacids [e.g. Al(OH)₃] neutralize gastric HCl.
3. Through enzymes
   Stimulation:
   Adrenaline →↑ adenyl cyclase
   Inhibition:
   1. Nonspecific—Ethyl alcohol, phenol
   2. Specific
      1. Competitive—Physostigmine and neostigmine compete with acetylcholine for cholinesterase.
      2. Noncompetitive—Aspirin, indomethacin → cyclo-oxygenase.
4. Through receptors
   • Receptor—It is a specific macromolecular component of the cell which binds and interacts with drug molecule.
   • Agonist—It activates receptor to produce an effect; brings about the conformational change.
   • Antagonist—It prevents the action of agonist on a receptor.
   • Inverse agonist—It activates a receptor to produce an effect opposite to that of agonist.
   • Partial agonist—It activates a receptor to produce submaximal effect.
   • Ligand—It is a drug molecule that binds to a receptor molecule.
   • Affinity—It is the ability of the drug to combine with a receptor.18

 

• It is ability of drug to activate, i.e. to induce conformational change in the receptor after its binding to the receptor.
• Agonist-affinity + IA (IA = 1).
• Competitive antagonist-affinity; no intrinsic activity, IA = 0.
• Partial agonist-affinity + submaximal IA (IA between 0 – 1).
• Inverse agonist-affinity + IA with minus sign {IA between 0 to (–1)}.

 

• Amplification, integration and transduction of drug receptor interaction as signal.
• Translation of receptor activation into functional response.

 

1. G-protein coupled receptors (metabotropic):
   • Adenylcyclase/cAMP pathway.
   • Phospholipase c/IP₃-DAG pathway.
   • Ion channel regulation (Na⁺, k⁺, Ca⁺⁺).
2. Receptors with intrinsic ion channels (ionotropic):
   Receptors enclose selective ion channels for Na⁺,K⁺, Ca⁺⁺ or Cl^– cholinergic nicotinic receptors, GABA_A receptor.
3. Enzymatic receptors—Receptor tyrosine kinase → insulin receptors.
4. Intracellular receptors:
   Receptors regulating gene expression—Steroid receptors.
   Receptor regulation:
   Up regulation, down regulation, desensitization.

 

1. To propagate regulatory signals
2. To amplify the signal
3. To integrate various extracellular and intracellular regulatory signal
4. To help maintain the homeostasis.

       

• Maximum response that can be produced by a drug, e.g. morphine is more efficacious than aspirin.

    20 21  

1. Synergism—Additive and supra-additive (potentiation).
2. Antagonism—Physical, chemical, physiological (functional), receptor.

 

1. Additive—Effect of drugs A + B = effect of drug A + effect of drug B, e.g. aspirin + paracetamol.
2. Supra-additive—Effect of drugs A + B > effect of drug A + effect of drugs B; effect of drugs A + B.

 

1. Physical—For example charcoal adsorbs alkaloids and prevents absorption (used in alkaloid poisoning).
2. Chemical—Two drugs react and form an inactive product, e.g. KMnO₄ oxidizes alkaloids (used for gastric lavage in alkaloid poisoning) thiopentone sodium + succinylcholine.
3. Physiological/functional
   • Different receptors/mechanisms → opposite effects on the same physiological effect, e.g. histamine and adrenaline on bronchial muscle and BP. Glucagon and insulin on blood sugar level.
4. Receptor
   • Antagonist interferes with binding of agonist
   • Antagonist inhibits the action of agonist.

 

• The maximum response can be obtained by increasing the dose of agonist → surmountable antagonism, e.g. morphine and naloxane.

 

• Maximum response can't be obtained → insurmountable antagonism, e.g. diazepam and bicuculline.22

 

1. Body size
   Individual dose= BW9(kg) / 70 × average adult dose
   Individual dose= BSA(m²) / 1.7 × average adult dose.
2. Age
   • Young's formula
   • Child dose = age/age+ 12 × adult dose
   • Dilling's formula
   • Child dose = age/12 × adult dose
   • Infant, adult, old.
3. Sex
   • Ketoconazole, metoclopramide → gynecomastia
   • Pregnancy, menstruation, lactation
   • Female sex hormones, male sex hormones.
4. Species and race
   • β-blockers are less effective in blacks.
5. Genetics
   • Rates of drug metabolism; target organ sensitivity (4–6 fold variation in doses).

6. Route of administration
   • MgSO₄, oral-purgative, local application-anti-inflamma-tory, IV—CNS depressant.
7. Environmental factors and time of administration
   • Presence of food; morning administration of cortico-steroids; exposure to insecticides, charcoal broiled meet, tobacco smoke.
8. Psychological factor
   • Placebo—Inert substance which may produce response through psychological effect.
9. Pathological states
   • Liver disease, kidney disease, heart disease.
10. Tolerance
    • Natural
    • Acquired
    • Cross tolerance
    • Pharmacokinetic
    • Pharmacodynamic
    • Antimicrobial drug resistance.23

   

• Side effects—Observed even with therapeutic dose
  • Mild and manageable.
• Secondary effects—Indirect consequences of main pharma-codynamic action
  • Superinfection by antibiotics
  • Weakening of host defense after glucocorticoids.
• Toxic effects—Exaggerated side effects and may occur due to
  • Overdose/prolong use
  • For example heparin (bleeding), barbiturate (coma), sulfonamide (crystalluria/glomerulonephritis), gentamicin (nephrotoxicity).

• Arise unexpectedly, even in therapeutic dose
  • Immunological/pharmacogenetically mediated/idiosyncratic reaction.
• Types
  • Drug allergy—Resultant of the interaction of drug/ metabolite/nondrug element24
  • Genetically determined
  • G6PD deficiency
  • Atypical pseudocholinesterase.
• Idiosyncratic reaction.

Idiosyncratic reaction	Offending drugs
Hemolytic anemia	Oxidizing agents, e.g. 8-aminoquinolines, sulfonamides
Acute porphyria	A large number of CNS-active drugs and some antimicrobial agents
Malignant hyperthermia	Halothane, suxamethonium

 

1. To prevent the serious consequences of over or under dosing.
2. To prevent the toxicity and to monitor the plasma concentration of the drugs having narrow therapeutic index.
3. To prevent drug interactions.
4. To check the patient compliance, especially in psychiatric patients.

     

1. Time of blood sample collection in relation to last dose
2. Duration of treatment with current dose
3. Dosing schedule
4. Age and gender of the patient
5. Other drug therapy, if any
6. Relevant disease states
7. Reasons for the request, e.g. lack of effect, routine monitoring, susceptible toxicity, etc.

 

1. Drugs with high therapeutic index, e.g. vitamins, penicillins, cephalosporins, etc.26
2. Medicines with irreversible action or long duration of action (hit and run medicines)—MAO inhibitors, omeprazole, organophosphates, corticosteroids.
3. Medicines with easily measurable clinical effects—Anti-hypertensives, diuretics, hypoglycemic, etc.
4. In case of prodrugs—L-dopa.

 

• It can be defined as those drugs or medicines that satisfy health care needs of the majority of population; these should therefore be available at all times, inadequate amounts and in appropriate dosage forms.
• It also known as essential medicines.
• Each country may have its own list depending upon the health care needs of the population.
• For example paracetamol, amoxicillin, oral rehydration solution, antitubercular drugs, oral iron preparations, folic acid, oral contraceptive pills, etc.
• Pharmaceutical companies → “me-too drugs”.
• Therapeutic “jungle”.
• Only a handful of drugs → enough for most ailments.
• WHO published 1st model list in 1977; latest at 2011—17th essential medicines list (EML), EML does not mean that the medicines outside it are not useful.

 

• Should meet the needs of majority.
• Medicine must meet the prescribed standard of quality, bioavailability and shelf life.
• In case of more than one drug, priority should be given to that drug which has been thoroughly investigated.
• Most favorable pharmacokinetic data.
• Cost: Benefit ratio.
• Preferably a single drug compound.
• Should be in generic name.

 

• Wider availability27
• Substantial savings without affecting health care needs
• Improvement in drug dispensing and patient compliance
• Help planners and policy makers.

   

• Step 1: Define the patient's problem
• Step 2: Specify the therapeutic objective
  • What do you want to achieve with the treatment?
• Step 3: Verify the suitability of your P-treatment (P-drug)
  • Check effectiveness and safety
• Step 4: Start the treatment
• Step 5: Give information, instructions and warnings
• Step 6: Monitor (and stop?) treatment.

 

• A 52-year-old taxidriver complains of a sore throat and cough which started two weeks earlier with a cold. He has stopped sneezing but still has a dry cough, especially at night. The patient is a heavy smoker who has often been advised to stop. Further history and examination reveal nothing special, apart from a throat inflammation. The doctor advises the patient to stop smoking, and writes a prescription for codeine tablets 15 mg, 1 tablet 3 times daily for 3 days.

1. Define the patient's problem
   • Sore throat and dry cough after a cold.
2. Specify therapeutic objective
   • Continuous irritation of the mucous membranes is the most likely cause of the cough.
   • The first therapeutic objective is therefore to stop this irritation by suppressing the cough, to enable the membranes to recover.
3. Verify the suitability of your P-treatment (P-drug)- SANE
   • Choose your P-treatment on the basis of efficacy, safety, suitability and cost.
   • Need—Smoking and traffic fumes.
   • Codeine, noscapine, pholcodine, dextromethorphan.28
   • Sedative antihistamines → diphenhydramine
   • Codeine → P-drug for dry cough
   • Adults → 30–60 mg 3–4 times daily.
4. Start the treatment
   R_X
   Tablet codeine 15 mg tid PO for 3 days, dispense 9 tablets.
5. Give information, instructions and warnings
   • It works within 2–3 hours.
   • It may cause constipation, and that it will make him sleepy if he takes too much of it or drinks any alcohol.
   • It should be advised to come back if the cough does not go within one week, or if unacceptable side effects occur.
   • Avoid alcohol, smoking, traffic fumes.
6. Monitor (and stop?) treatment
   • If the patient does not return, he is probably better.
   • If there is no improvement and he does come back, there are three possible reasons:
     1. The treatment was not effective.
     2. The treatment was not safe, e.g. because of unacceptable side effects.
     3. The treatment was not convenient.

• If the patient's symptoms continue, we will need to consider whether the diagnosis, treatment, adherence to treatment and the monitoring procedure were all correct.
• In fact the whole process starts again.
• Chronic diseases—Never ending process.

 

• Beneficial—Synergism is obtained. For example, paracetamol and ibuprofen combination in analgesia, aminoglycosides and penicillins in infective endocarditis, penicillins and probenecid in gram-positive bacterial infections.
• Adverse—Not wanted. Enzyme indicers may inhibt the efficacy of other medicines, when CNS depressants are used together → more CNS depression, when two nephro/ototoxic medicines are used → more toxicity, paracetamol+ chronic alcoholism → hepatotoxicity.29
• Pharmacokinetic—Interaction at the level of ADME.
  • Absorption—Milk, antacids + iron → complex formation → less absorption.
  • Distribution—Sulfonamides displace bilirubin in neonates → may cause kernicterus (unconjugated bilirubin easily crosses blood brain barrier → deposition of bilirubin in brain tissues).
  • Metabolism—Enzyme inducers (rifampin, phenytoin and carbamazepine inhibit the efficacy of oral contraceptive pills).
  • Excretion—Penicillin and probenecid (probenecid inhibits the tubular secretion of penicillins and cephalosporins and prolongs duration of action).
• Pharmacodynamic—Interaction at the level of receptors. Alcohol + diazepam (both these drugs are CNS depressants. So if taken together → greater degree of CNS depression, e.g. sedation).

   

• Chemotherapy for infections
• Cancer chemotherapy.

 

1. Type of cancer
2. Stage of cancer
3. Goal of the treatment
   • Curative
   • Palliative
   • Adjunctive.

 

• Chemotherapy
• Surgery
• Radiation therapy
• Hormonal therapy
• Combined modality approach/multimodality approach.30

 

1. Cytotoxic drugs
   1. Cell cycle specific
      Antimetabolites: Methotrexate (folate antagonist); azathioprine, fludarabine, mercaptopurine (purine antagonist); cytarabine, fluorouracil (pyrimidine antagonist).
      Antitumor antibiotics: Bleomycin, mitoxantrone.
      Taxanes: Paclitaxel.
      Vinca alkaloids: Vinblastine, vincristine.
      Epipodophyllotoxin: Etoposide.
      Camptothecin analogue: Topotecan, irinotecan.
   2. Cell cycle nonspecific
      Alkylating agents: Cyclophosphamide, busulfan, carmustine.
      Anthracyclines: Daunorubicin, doxorubicin.
   3. Miscellaneous—Hydroxyurea, L-asparginase, cisplatin, carboplatin.
2. Drugs altering hormonal environment
   Glucocorticoids—Prednisolone
   Estrogen—Diethylstilbestrol
   Antiestrogen—Tamoxifen
   Antiandrogen—Flutamide
   5-α reductase inhibitor—Finasteride.
3. Tyrosine protein kinase inhibitor—Imatinib.
4. Growth factor receptor inhibitor—Cetuximab.
5. Aromatase inhibitor—Letrozole, anastrozole.
6. Selective estrogen receptor down regulator—Fulvestrant.

   

• Transfer alkyl group to cellular macromolecules esp. DNA
• Cell cycle nonspecific (act on both dividing and resting cells).

 

• Competitively inhibit utilization of normal substrate and get incorporated themselves producing dysfunctional macro-molecules.31

 

• Mitotic inhibitors.
• Bind to microtubular protein—‘tubulin’ and prevent polymerization → failure of chromosomes to move apart during mitosis.

 

• Break DNA strands and interfere with DNA function.

 

• Enhances polymerization of tubulin → abnormal arrays/bundles of microtubules are produced.

 

• Inhibits DNA topoisomerase II.

 

• Inhibits DNA topoisomerase I.

 

• Not cytotoxic.
• Modify the growth of hormone dependant tumors.

 

1. Bone marrow
   • Neutropenia, lymphocytopenia— ↑ infections
   • Thrombocytopenia— ↑ bleeding tendency
   • Aplastic anemia—Fatigue, lethargy.
2. Epithelial linings
   • Oral—Stomatitis, oral ulcers.
   • GIT—Gastric ulcers, bleeding, nausea and vomiting.
   • Skin—Alopecia, dermatitis.
3. Reproductive function
   • Oligozoospermia—Male infertility.
   • ↓ ovulation, amenorrhea—Female infertility.
4. Pregnancy
   • Abortion/fetal death.
   • Teratogenesis.32
5. Carcinogenicity
   • Secondary cancers (leukemia, lymphomas).
6. Hyperuricemia
   • Gout (due to ↑ cell destruction →↑ purine metabolism →↑ uric acid).
7. Neurotoxicity
   • Peripheral neuropathies, e. g. cisplatin.
8. Nephrotoxicity
   • Cisplatin, ifosfamide and methotrexate.
9. Hemorrhagic cystitis
   • Cyclophosphamide and ifosfamide (acrolin–toxic metabolite causes bladder irritation and damage → bleeding episodes); mesna – for protection.
10. Hepatotoxicity
    • Asparginase, cytarabine, mercaptopurine, thioguanine and methotrexate.
    • Jaundice, hepatitis and elevation of liver transaminase enzymes.
11. Cardiotoxicity
    • Daunorubicin and doxorubicin.
    • Dexrazoxane—Cardioprotectant and is given with above drugs.
12. Hypersensitivity reactions
    • Asparaginase, carboplatin, cisplatin.
13. Tumorlysis syndrome (TLS)
    • In leukemias and lymphomas, due to spontaneous lysis and release of intracellular content such as K⁺, PO₄ and uric acid.
    • Preventive measures—Adequate hydration, alkalinization of urine and administration of allopurinol.

 

1. Toxicity blocking drugs
   • Methotrexate—Folinic acid
   • Antiemetic—Ondansetron.
2. Control of hyperuricemia
   • Allopurinol, alkalinization, plenty of fluids.33
3. Pulse therapy
   • Gap of 2–3 weeks interval → normal cells recover; malignant cells recover more slowly.
4. Topical administration
   • Skin, buccal mucosa, vagina.
5. Platelet/granulocyte transfusion.
6. Bone marrow transplantation.

         

• Sulfonamides and related drugs—Sulfadiazine, dapsone
• Diaminopyrimidine—Trimethoprim, pyrimethamine
• Quinolone—Nalidixic acid, ofloxacin, ciprofloxacin
• β-lactam antibiotics—Penicillins, cephalosporins
• Tetracycline—Oxytetracycline, doxicycline
• Nitrobenzene derivative—Chloramphenicol
• Aminoglycosides—Streptomycin, gentamicin
• Macrolides—Erythromycin
• Nitroimidazole—Metronidazole
• Polyene derivatives—Amphotericin B
• Imidazole derivatives—Ketoconazole, miconazole.

 

• Cell wall synthesis inhibitors—Penicillin, cephalosporins, cycloserin, vancomycine34
• Leakage from cell membrane—Polymyxin, amphotericin B
• Protein synthesis inhibitors—Tetracyclines, chloramphe-nicol, erythromycin
• Misreading of mRNA code and affecting permeability—Aminoglycosides
• DNA gyrase inhibitors—Fluoroquinolones
• Interfere with DNA function—Metronidazole
• DNA synthesis inhibitors—Acyclovir, zidovudine
• Interfere intermediary metabolism—Sulfonamides.

 

• Antibacterial—Penicillins, aminoglycoside
• Antifungal—Ketoconazole, itraconazole
• Antiviral—Zidovudine, acyclovir
• Antiprotozoal—Chloroquine, metronidazole
• Anthelmintic—Mebendazole, pyrentel, niclosamide.

 

• Narrow spectrum—Penicillin G, streptomycin
• Broad spectrum—Tetracycline, chloramphenicol.

 

• Bacteriostatic—Sulfonamides, tetracycline, chloramphenicol
• Bactericidal—Penicillin, aminoglycosides.

 

• Fungi—Penicillin, cephalosprin
• Bacteria—Polymixin B, colistin
• Actinomycetes—Aminoglycoside, macrolides, tetracyclines.

 

• Toxicity—Gastric irritation, diarrhea, ototoxicity, nephro-toxicity
• Hypersensitivity reactions
• Drug resistance
• Superinfections (suprainfections)—Broad spectrum antibio-tics; Candida, Clostridium difficile (clindamycin, tetracycline, etc.)35
• Nutritional deficiency
  • Vit B complex, vit K.
• Masking of an infection
  • Single dose of penicillin to cure gonorrhea (may mask syphilis).

   

• Age—Tetracycline (children)—Tooth discoloration, chloram-phenicol (in newborn)—Gray baby syndrome; sulfonamides kernicterus; aminoglycosides—Deafness.
• Renal and hepatic function
  • Renal failure—Aminoglycoside, cephalosporine, vanco-mycin, amphotericine B
  • Hepatic disease—Erythromycin estolate, pyrazinamide, tetracycline, etc.
• Local factors—Pus, anerobic environment
• Drug allergy
• Pregnancy
• Breastfeeding
• Genetic factors—G6PD deficient-hemolysis, primaquine, sulfonamides, etc.
• Impaired host defense.

 

• Clinical diagnosis.

 

• Spectrum of activity
• Type of activity
• Relative toxicity
• Route of administration
• Evidence of clinical efficacy
• Cost.36

   

• First antimicrobial agents
• Domagk—Prontosil.

 

• Derivatives of sulfanilamide (para-amino-benzene sulfona-mide)
• Sulfonamide N—Solubility, potency and pharmacokinetic property
• Free amino group in para (N₄) position → antibacterial activity.

 

• Short acting (4–8 hrs)
  • Sulfadiazine.
• Intermediate acting (8–12 hrs)
  • Sulfamethoxypyrazine, sulfamoxole.
• Long acting (approx 7 days)
  • Sulfadoxine, sulfamethoxypyrazine.
• Special purpose sulfonamide
  • Sulfacetamide sodium, sulfasalazine, mafenide, silver sulfa-diazine.

 

• Primarily bacteriostatic against gram-positive and gram- negative organisms.
• Streptococcus pyogenes, Haemophilus influenzae, H. ducreyi, Calymmatobacterium granulomatis, Vibrio cholerae.
• Chlamydia, actinomyces, nocardia, toxoplasma.

 

• Woods and Fildes (1940)—Sulfonamide being structural analogue of PABA inhibits bacterial folate synthetase → folic acid is not formed.37

 

• PABA—Antagonizes the effect
• Only those microbes synthesizing PABA are susceptible
• Pus—Purine, thymidine and PABA—Decrease the action.

   

• produce increased amounts of PABA
• decreased affinity for folate synthetase
• adopt an alternative pathways in folate metabolism.

 

• Rapid and complete absorption from GIT
• PPB (10–95%)
• Widely distributed, cross BBB and palcenta
• Metabolism → in liver, nonmicrosomal, acetylation at N₄
• Excretion—Glomerular filtration, less soluble in acidic urine → crystalluria.

 

• Nausea, vomiting, epigastric pain
• Crystalluria
• Hypersensitivity reactions
• Hepatitis
• Topical use is not permitted → contact dermatitis; ocular use is permitted
• Hemolysis in G6PD deficiency
• Kernicterus.

 

• It may displace phenytion, tolbutamide, warfarin, metho-trexate from protein binding → toxicity may occur.38

 

• Systemic therapy as monotherapy—Rare now.
• Suppressive therapy—Chronic UTI, streptococcal pharyngitis.
• Combined with trimethoprim, sulfamethoxazole—P. carinii and nocardiasis.
• Combined with pyrimethamine, sulfadoxine—Malaria.
• Sulfacetamide sodium—Ocular preparation.
• Topical silver sulfadiazine or mafenide—It is used to prevent infection on burn dressing.

   

• Diaminopyrimidine ralated to antimalarial drug—Selectively inhibits bacterial dihydrofolate reductase (DHFRase)
• > 50,000 times higher affinity for bacterial DHFRase
• Wide distribution, crosses BBB and placenta
• Partly metabolized in liver excreted in urine.

 

• Sequential block in folate metabolism—Bactericidal.
• Both have t½ ~10 hrs; optimal synergism in most bacteria; MIC of each agent may be reduced by 3–6 times.
• Dose ratio 1:5 (trimethoprim: sulfamethoxazole).
• Plasma concentration ratio 1:20.
• Resistance—Slow to develop compared to either drug; mostly through mutational or plasmid mediated acquisition of a DHFRase having low affinity.

 

• Nausea, vomiting, stomatitis.
• Folate deficiency—Megaloblastic anemia.
• Patient with renal disease—Uremia.
• In AIDS patients with pneumocystis carinii infection—Bone marrow depression.
• Elderly—Bone marrow depression.39

 

• UTI
• RTI (both upper and lower)
• Typhoid
• Bacterial diarrhea and dysentery
• Chancroid
• Granuloma inguinale
• Pneumocystis carinii.

 

• UTI
• Prostitis.

 

• Synthetic compounds.
• Primarily active against gram-negative bacteria.
• Newer fluorinated compounds—Also inhibits gram-positive bacteria.
• Nalidixic acid (1960).
• Fluorinated compounds—High potency, expanded spectrum, slow development of resistance, better tissue penetration and good tolerability.

 

• Active against E. coli, Proteus, Klebsiella, Enterobacter, Shigella but not pseudomonas
• Inhibits bacterial DNA gyrase—Bactericidal
• Resistance develop rapidly
• High concentration in urine (20–50 times higher than plasma) → lethal to common urinary pathogens.

 

• GI upset and rashes
• Neurological toxicity—Vertigo, visual disturbances, seizures
• Parkinsonism like symptoms
• Phototoxicity
• G6PD deficiency—Hemolysis.40

 

• As urinary antiseptic (nitrofurantoin should not be used with nalidixic acid concurrently—antagonism may occur).
• In diarrhea by Proteus, E. coli, Shigella, Salmonella (specially in ampicillin resistant Shigella enteritis).

 

• Quinolone antimicrobials having one or more fluorine subs-titutions.

 

• First generation (1 fluoro substitution in 1980s).
• Norfloxacin, ciprofloxacin, ofloxacin, pefloxacin.
• Second generation (2 fluoro substitutions in 1990s).
• Lomefloxacin, sparfloxacin, levofloxacin, gatifloxacin, moxi-floxacin.

 

• Inhibit DNA gyrase (two subunits A and B; A-nicking and resealing of DNA, B-introducing negative supercoiling); have higher affinity for A subunit.
• Recent studies → gram-positive bacteria → topoisomerase IV which nicks and separates daughter nuclei strands after DNA replication; greater affinity of fluoroquinolones for this enzyme → higher potency against gram-positive organism.

 

• Chromosomal mutation producing a DNA gyrase or topoisomerase IV with reduced affinity for FQs.
• Reduced permeability or increased efflux mechanism of these drugs across bacterial membranes.

 

• Most potent first generation agent.
• Most susceptible organisms → gram-negative bacilli including Enterobacteriaceae and Neisseria.41

 

• Rapidly absorbed from GIT, food delays the absorption.
• High tissue penetrability → high concentration in lung, sputum, muscle, bone, prostate and phagocytes.
• Excreted primarily in urine, both by glomerular filtration and tubular secretion; urinary and biliary concentration is 10–50 times higher than in plasma.

 

• Good safety; 10% patients; withdrawal in 1.5%.
• Gastrointestinal—Nausea, vomiting, anorexia, bad taste.
• CNS—Dizziness, headache, anxiety, impairment of concen-tration and dexterity.
• Skin/hypersensitivity.
• Tendonitis and tendon rupture.

 

• ↑ levels of theophylline, caffeine and warfarin by ciprofloxacin → toxicity may occur
• NSAID may enhance the CNS toxicity
• Antacids, sucralfate, iron salts reduce gastric absorption.

 

• UTI—Both uncomplicated and complicated (3 days regimen)
• Gonorrhea—Single 500 mg dose (~ 100% cure)
• Chancroid—500 mg BD for 3 days
• Bacterial gastroenteritis
• Typhoid—Ciprofloxacin is the drug of choice; 500–750 mg BD for 10 days; for typhoid carriers 750 mg for 2–4 weeks
• Bone, soft tissues, gynecological and wound infections
• Respiratory tract infections—Not the primary drug
• Tuberculosis in combination therapy
• Gram-negative septicemia
• Meningitis.
• Conjunctivitis by gram-negative bacteria.42

   

• β-lactam antibiotic.
• First discovered by Alexander Fleming in 1929.
• First used clinically in 1941.
• Other β-lactam compounds are:
  • Cephalosporins
  • Carbapenems
  • Monobactams.

 

• Interferes with bacterial cell wall synthesis
• Transpeptidase enzyme is inhibited
• Penicillin binding proteins
• Cell wall deficient structures that swell and burst → bacterial lysis.

 

1. Penicillins (PnG).
2. Acid resistant penicillin (PnV).
3. Penicillinase resistant penicillins:
   Nafcillin    Cloxacillin
   Methicillin   Dicloxacillin
4. Extended spectrum penicillins:
   • Aminopenicillins—Ampicillin, amoxicillin, bacampicillin.
   • Carboxypenicillins—Carbenicillin, ticarcillin.
   • Ureidopenicillins—Piperacillin, mezlocillin.
   • Mecillinam.
     Bacterial resistance:

• Due to one of the four general mechanisms:
  • Inactivation by penicillinase/β-lactamase.
  • Modification of target PBPs.
  • Impaired penetration of drug to target PBPs (located deeper under lipoprotein barrier).
  • The presence of an efflux pump.43

 

• Local irritancy and direct toxicity:
  • Pain at IM injection site
  • Nausea on oral ingestion
  • Thrombophlebitis of injected vein
  • Bleeding.
• Hypersensitivity (1–10%):
  • Anaphylaxis—Rare (1–4/10,000)
  • Prevention—History, scratch test or intradermal test.
• Superinfections
• Jarisch-Herxheimer reaction:
  • Penicillin injected in syphilitic patient may produce fever, chills, myalgia
  • Sudden release of spirochetal lytic products.

 

1. Streptococcal infections (SABE—Subacute bacterial endocarditis)
2. Pneumococcal infections
3. Meningococcal infections
4. Syphilis
5. Diphtheria
6. Tetanus and gas gangrene
7. Prophylactic uses:
   1. Rheumatic fever
   2. Gonorrhea or syphilis
   3. Bacterial endocarditis
   4. Surgical infections.

 

• UTI, RTI, meningitis, gonorrhea
• Typhoid
• Bacillary dysentery—Shigella
• Cholecystitis
• SABE
• Septicemia and mixed infections.

   

• Bind to cephalosporin binding proteins → inhibition of transpeptidation process → formation of imperfect cell wall → lysis of bacteria (bactericidal).

 

• Classified as:
  • First generation (1960s)
  • Second generation (1970s)
  • Third generation (1980s)
  • Fourth generation (1997–1998).

 

• Oral
  • Cephalexin, cephadroxil, cephadrine.
• Parenteral
  • Cefazolin, cephalothin, cefadroxil.

• UTI
• Staphylococcal infections (cellulitis or soft tissue abscess)
• Cefazolin—It is the drug of choice in surgical prophylaxis (because of better tissue penetration).

 

• Oral
  • Cefaclor, cefuroxime axetil.
• Parenteral
  • Cefuroxime, cefotetan, cefamandole, cefoxitin.
• Peritonitis (cefoxitin and cefotetan—more active against anaerobes).
• Respiratory tract infections (cefaclor—more active than first generation).
• Community acquired pneumonia.
• Gonorrhea (PPNG)—Single dose IM.
• Meningitis.

 

• Oral
  • Cefixime, cefpodoxime proxetil, cefdinir, ceftibuten.45
• Parenteral
  • Ceftriaxone, cefotaxime, ceftazidime, ceftizoxime, moxalactum.

• Ceftriaxone
  • Meningitis
  • Gonorrhea and chancroid
  • Community acquired pneumonia
  • Complicated UTIs, abdominal sepsis, septicemia
  • Multidrug resistant typhoid fever.

 

• Parenteral
  • Cefpirome and cefepime.

• Hypersensitivity reactions—Fever, skin rash, eosinophilia, angioedema.
• Cross sensitivity with penicillins.
• Superinfection—Pseudomembranous colitis and diarrhea (third generation).
• Bleeding—Cefamandole, cefoperazone, cefotetan (hypoprothrombinemia and destruction of vit K producing colonic bacteria).
• Local irritation after IM injection.

 

• Inhibits gram-positive bacterial cell wall synthesis by complexing with D-alanyl-D-alanine portion of the terminal end of peptidoglycan pentapeptide.

 

• MRSA infections.
• Orally in pseudomembranous colitis (if metronidazole is ineffective); IV route only.

 

• Red neck syndrome—Chills, fever, intense flushing (due to histamine release), ototoxicity, nephrotoxicity, eosinophilia.46

     

• Group I—Tetracycline, chlortetracycline
• Group II—Demeclocycline, methacycline
• Group III—Doxycycline, minocycline.

 

• Inhibit protein synthesis by binding to 30S ribosomes.

 

• Epigastric pain, nausea, vomiting, diarrhea
• Liver damage
• Kidney damage
• Phototoxicity
• Discoloration of teeth (if used during pregnancy or in child-hood)
• Hypersensitivity reactions
• Superinfection (pseudomembranous colitis).

 

• Pregnancy, during lactation and in children
• Renal disease, hepatitis.

 

• Veneral diseases—Lymphogranuloma venereum, granuloma inguinale
• Atypical pneumonia by Mycoplasma pneumoniae
• Cholera
• Brucellosis
• Plague
• Relapsing fever/rickettsial infections.47

   

• Binds with 50S ribosome → inhibit protein synthesis
• High dose → inhibit mammalian protein synthesis

 

• Bone marrow suppression
  • Aplastic anemia, agranulocytosis, thrombocytopenia, pancytopenia.
• Hypersensitivity reaction
  • Rashes, fever.
• Irritative effects
  • Nausea, vomiting, diarrhea.
• Superinfections.
• Gray baby syndrome
  • Baby stops feeding, becomes hypnotic and hypothermic; vomiting, distended abdomen, irregular respiration, grayish appearance.
  • Due to inability of newborn to metabolize and excrete chloramphenicol.

 

• Enteric fever
  • Ciprofloxacin, ceftriaxone, cotrimoxazole, ampicillin/amoxicillin
• H. influenzae meningitis
• Anaerobic infection—Bacteroides fragilis
• Intraocular infections
• Brucellosis, cholera, rickettsial and chlamydial infections.

   

• Streptomycin
• Gentamicin
• Kanamycin
• Tobramicin
• Amikacin.48

 

• Neomycin
• Framycetin.

 

• Highly water-soluble; highly ionized
• Not absorbed when given orally
• Bactericidal
• Active in alkaline medium; interfere with bacterial protein synthesis
• Narrow margin of safety
• Primarily active against aerobic gram-negative bacilli.

 

• Bactericidal
• Streptomycin bind to 30S ribosome, but other agents also bind to additional site on 50S ribosome and 30S–50S interface as well.

 

• Synthesis of drug inactivating enzymes
• Mutation of ribosomal proteins
• Reduced efficiency of transport mechanism.

 

• Ototoxicity
• Nephrotoxicity
• Neuromuscular blockade.

 

• Pregnancy—Contraindication (ototoxicity)
• Avoid concurrent use of other ototoxic and nephrotoxic drugs
• Old age; kidney diseases
• Use of muscle relaxants
• Do not mix with other drugs in the same syringe or infusion bottle.49

 

• Tuberculosis
• Subacute bacterial endocarditis
• Plague
• Tularemia.

 

• Respiratory infections
• Pseudomonas, Proteus or Klebsiella infections, burns, UTI, middle ear infections, septicemia
• Meningitis (by gram-negative bacteria)
• Subacute bacterial endocarditis.

 

• Infected wound, ulcers, burns.

• Preparation of bowel surgery
• Hepatic coma.

   

• Erythromycin
• Roxithromycin
• Clarithromycin
• Azithromycin.

 

• Inhibits bacterial protein synthesis by binding to 50S ribosome
• Mostly gram-positive and few gram-negative bacteria are inhibited
• Static at low concentration and cidal at higher concentration.

 

• Gastrointestinal—Epigastric pain, diarrhea50
• Reversible hearing impairment (at high dose)
• Hypersensitivity reactions—Rashes
• Hepatitis with cholestatic jaundice (resembling viral hepatitis—Erythromycin estolate)
• Uses.

• Atypical pneumonia by mycoplasma
• Whooping cough
• Chancroid.

• Streptococcal pharyngitis, tonsillits and most respiratory infections
• Diphtheria
• Syphilis and gonorrhea.

• Campylobacter enteritis
• Legionnaires’ pneumonia
• Chlamydia trachomatis
• Penicillin resistant staphylococcal infections.

• Similar to erythromycin except
  • Newer drugs are more potent, effective and safer
  • These have longer duration of action and less gastric irritation.

 

• Disinfectants are those chemical substances which are used to destroy or inhibit the growth of pathogenic vegetative bacteria (not their spores) on inanimate (nonliving) surfaces such as glass wares or surgical instruments.
• For example formaldehyde, phenols, ethyl alcohol, soaps, etc.
• Antiseptics are those chemical substances which are used to destroy pathogenic bacteria (not the spores) on animate surfaces such as skin and mucous membranes.51
• Chlorhexidine, listerine, povidone iodine, etc.
• Differences between disinfectants and antiseptics seems to be small and overlapping.
• Some antiseptics in higher concentration may work as disinfectants.
• Similarly, some disinfectants in lower concentration may serve as antiseptics.
• Sterilization—It is a process of killing all living organisms including spores, viruses and fungi.
• Germicide—Antiseptic and disinfectant.

 

• Chemically stable.
• Cheap.
• Nonstaining with acceptable color and odor.
• Cidal not only static.
• Active against all pathogens—Bacteria, fungi, viruses and protozoa.
• Able to spread through organic films.
• Active even in presence of blood, pus exudates and excreta.
• Classification.

• Aldehyde—Formaldehyde, glutaraldehyde
• Phenols—Phenol in 57% ethanol, cresol, triclosan
• Alcohol—Ethyl alcohol, isopropyl alcohol
• Heavy metal salts—Silver nitrate, zinc-calamine lotion.

• Mercurial antiseptics—Mercurochrome, nitromersol.

• Chlorophores—Chlorine dioxide, sodium hypochlorite
• Iodophores—Povidone iodine, tincture iodine
• Oxidizing agents—Hydrogen peroxide, potassium permanganate.52

• Chlorhexidine, cetylpuridinium chloride, benzalkonium chloride.

   

• Against lice (pediculus) and mite (sarcoptes/acarus scabiei)
• Permethrin—Drug of choice
• Lindane (gamma benzene hexachloride, BHC)
• Benzyl benzoate—Contraindicated in children
• Crotamiton—Second choice; may be preferred in child.

 

• Ivermectin—This is only drug which can be administered via oral route.

   

1. To prevent further exposure or absorption of the poison: Remove the victim from the poisoning source. Sometimes, contaminated clothing has to be removed (in case of organophosphorus poisoning), contaminated skin should be washed with soap and water thoroughly. Patient should be moved to the fresh air. Except in corrosive poisoning, patient is made to vomit to prevent further absorption. Some adsorbents like activated charcoal, tannic acid and magnesium oxide can be administered. In some heavy metal poisoning, chelating agents can be administered through nasogastric tube to help prevent the further absorption.
2. To increase the rate of elimination: Forced dieresis is carried out. Sometimes either alkalinization or acidification of urine 53may also help increase the excretion of poison depending upon the type of agent.

   

• Organophosphorus poisoning—Atropine
• Morphine poisoning—Naloxone
• Benzodiazepine—Flumazenil
• Atropine (belladonna poisoning)—Physostigmine

   

• Dimercaprol
• Dimercaptosuccinic acid (succimer)
• Disodium edetate
• Calcium disodium edetate
• Penicillamine
• Desferrioxamine
• Deferiprone.

• Oily, pungent smelling viscous liquid
• It is used in As, Hg, Bi, Ni, Cu poisonings
• SH group binds with the metals54
• Contraindication in Fe and Cd poisoning
• IM route.

• Similar to BAL
• Water-soluble, orally effective
• In As, Hg and Pb poisonings
• Disodium edetate (Na₂EDTA)
  • Potent chelator of calcium
  • Slow IV infusion
  • In hypercalcemia.

 

• In Pb, Zn, Cd, Mn, Cu, radioactive materials
• Ionized
• IV (IM is painful).

 

• Degradation product of penicillin
• Strong Cu chelation (Wilson's disease–1956)
• In Cu, Hg, Pb, Zn
• D-isomer
• Orally before (1hr) or after food (2hrs).

 

• Ferrioxamine → Iron containing, actinomycetes
• Fe removal → desferrioxamine → high affinity for Fe (1 gm → 85 mg elemental Fe)
• Acute iron poisoning
• Parenteral route.

 

• Orally active iron chelator.55

       

• Dryness of eye (xerosis)
• Bitot's spot—Triangular shiny gray spots in conjunctiva
• Keratomalacia—Softening of cornea
• Night blindness—Complete blindness (due to permanent damage to the rods)
• Phrynoderma—Dry rough skin with papules
• Hyperkeratinization
• Infertility
• Growth retardation.

• As prophylaxis
• Treatment of deficient state
• In skin diseases—Acne, psoriasis, ichthyosis.56

     

• Dry beriberi—Neurological symptoms (main features)— Polyneuritis, numbness, muscular weakness, ‘wrist drop’, ‘foot drop’, paralysis of limbs.
• Wet beriberi—Cardiovascular symptoms (main features)—Palpitation, breathlessness, CHF, anasarca (whole body edema).

• As prophylaxis
• In beriberi
• In acute alcoholic intoxication—It is given with glucose, also in chronic alcoholism to treat Wernicke's encephalopathy and Korsakoff's psychosis
• In neurological and cardiovascular disorders.57

 

• In prophylaxis.
• Treatment of pellagra.
• In Hartnup's disease (tryptophan transport is impaired) and carcinoid syndrome (tryptophan is used to produce 5-HT)-niacin supplement (inside the body tryptophan is converted into nicotinic acid, 60 mg tryptophan = 1 mg nicotinic acid).

 

• Active form—Pyridoxal phosphate—Coenzyme for transaminases and decarboxylases.
• Antitubercular drug isoniazid inhibits the generation of pyridoxal phosphate may produce pyridoxine deficiency → peripheral neuritis.
• Hydralazine, cycloserine and penicillamine interfere with pyridoxine utilization → deficiency state.

• Peripheral neuritis
• Seborrheic dermatitis
• Glossitis
• Confusion
• Growth retardation
• Decrease in seizure threshold.58

• Prophylaxis in alcoholics, with isoniazid therapy.
• In drug induced deficiency state (isoniazid, hydralazine, cycloserine and penicillamine).

 

• Antioxidant.
• Involved in hydroxylation of proline and lysine residues of protocollagen → required for formation and stabilization of collagen triple helix (so vit C deficiency there is inherent collagen defect →↑ capillary fragility → more prone to hemorrhage and decreased wound healing).
• Conversion of folic acid → folinic acid.
• Biosynthesis of adrenal steroids, catecholamines, oxytocin and vasopressin.

• Prophylaxis
• Treatment of scurvy
• Postoperatively to enhance wound healing
• In anemia increases iron absorption
• To acidify urine.

     

• Typhoid-paratyphoid
• Cholera
• Whooping cough (pertussis)
• Meningococcal
• Plague
• Haemophilus influenzae type b.

• Poliomyelitis inactivated (IPV, Salk)
• Rabies
• Influenza
• Hepatitis A and B.

 

• Bacillus Calmette-Guérin (BCG).

• Poliomyelitis oral alive (OPV, Sabin)
• Mumps
• Measles
• Rubella
• Varicella.

 

• Tetanus
• Diphtheria.

 

• DPT—Diphtheria-pertussis-tetanus
• MMR—Measles-mumps-rubella
• DPT + hepatitis B⁺ Haemophilus influenzae type b.60

 

Time of administration	Name of vaccine
At Birth	BCG + OPV (1st dose) + Hepatitis B (after 12–24 hrs)
At 6 weeks	DPT + OPV + Hepatitis B
At 10, 14 weeks	DPT + OPV
At 6 months	Hepatitis B
At 9 months	Measles
At 15–18 months	DPT + MMR + OPV (booster dose)
At 4–5 years	OPV (booster dose), Typhoid-paratyphoid
At 10 years	TT
At 16 years	TT
For pregnant females
At 16–24 weeks of pregnancy	TT (1st dose)
At 24–34 weeks of pregnancy	TT (2nd dose)

   

• Tetanus antitoxin—Prophylaxis when nonimmunized person gets highly contaminated and risky wounds with high risk of tetanus, human globulin is preferred.
• Gas gangrene antitoxin given for the prophylaxis and therapy of gas gangrene.
• Diphtheria antitoxin given in clinical diphtheria.
• Antirabies serum given in suspected exposure along with rabies vaccine.
• Antisnake venom polyvalent given to neutralize Cobra venom, Russell's viper venom, Sawscaled viper venom and Krait venom.61

 

• Normal human gammaglobulin prophylaxis for hepatitis A and B, measles, mumps, poliomyelitis.
• Anti-D immunoglobulin human IgG against Rh (D), used for prevention of postpartum/postabortion formation of antibodies in Rho (D) negative women → prevents Rh hemolytic disease in future offspring.
• Tetanus immunoglobulin is given for prophylaxis when nonimmunized person gets highly contaminated and risky wounds with high risk of tetanus.
• Rabies immunoglobulin given in suspected exposure along with rabies vaccine.
• Hepatitis B immunoglobulin given in persons exposed to hepatitis B positive blood or blood products.