Q: Make an exam oriented notes easy and crisp notes from the given source A: Here are crisp, exam-oriented notes from Shanbhag's Pharmacology General Pharmacology chapter: --- GENERAL PHARMACOLOGY - EXAM NOTES Shanbhag Pharmacology --- 1. PHARMACOKINETICS ADME = What the body does to the drug - Absorption A → Distribution D → Metabolism M → Excretion E --- 2. DRUG TRANSPORT ACROSS MEMBRANES Mechanism Key Features Examples --------- Passive diffusion High → Low conc; No energy; Most drugs Lipid-soluble drugs Active transport Low → High conc; Needs energy ATP Sympathomimetic amines, levodopa absorption Facilitated diffusion Carrier-mediated; No energy; High → Low Glucose via GLUT4 Filtration Depends on molecular size/weight Small molecules Endocytosis Cell takes up drug via vesicle formation Vit B12-intrinsic factor complex --- 3. DRUG ABSORPTION = Movement of drug from site of administration into blood Factors Influencing Absorption A. Physicochemical properties: - Liquid Solid forms - Lipid-soluble & unionized water-soluble & ionized - Smaller particle size = better absorption microfine aspirin, digoxin, griseofulvin - Shorter disintegration & dissolution time = better absorption - Formulations binding agents: calcium reduces tetracycline absorption B. Route of administration: - IV route bypasses absorption 100% bioavailability - Polar compounds not absorbed through GI e.g., gentamicin given parenterally C. pH and ionization: KEY CONCEPT - Weakly acidic drugs barbiturates → better absorbed from stomach acidic pH, unionized - Weakly basic drugs morphine, amphetamine → better absorbed from intestine alkaline pH, unionized - Strongly acidic heparin & strongly basic aminoglycosides → remain ionized at all pH → poorly absorbed D. Food: - Decreases absorption of: rifampicin, levodopa, etc. take on empty stomach - Milk/milk products decrease absorption of tetracyclines - Fatty meal increases absorption of griseofulvin E. Other factors: - Ascorbic acid increases oral iron absorption - Antacids reduce tetracycline absorption - Larger surface area small intestine = better absorption - GI diseases gastroenteritis, achlorhydria, congestive cardiac failure reduce absorption --- 4. BIOAVAILABILITY = Fraction of drug reaching systemic circulation from a given dose - IV route = 100% bioavailability - "Oral bioavailability" is used for drugs given orally - Bioequivalent = two formulations produce equal bioavailability - Bioinequivalent = formulations differ in bioavailability Factors Affecting Bioavailability 10 factors - memorize: 1. Physicochemical properties 2. Route of administration 3. pH and ionization 4. Food 5. Presence of other drugs 6. Area of absorbing surface 7. GI and other diseases 8. First-pass metabolism ← Most important 9. Hepatic diseases 10. Enterohepatic cycling First-Pass Metabolism First-pass effect / Presystemic elimination - Oral drug → gut wall → portal vein → liver → systemic circulation - Drug metabolized before reaching systemic circulation → decreased bioavailability - Examples: lignocaine, isoprenaline given IV for arrhythmias, propranolol, nitroglycerin - Consequences: - Drugs given parenterally lignocaine IV for ventricular arrhythmias - Oral dose parenteral dose e.g., nitroglycerin Hepatic Diseases: - Decrease first-pass metabolism → increase bioavailability of propranolol, lignocaine Enterohepatic Cycling: - Drug excreted via bile → reabsorbed from intestine → liver → bile cycle repeats - Increases bioavailability and duration of action - Examples: morphine, doxycycline --- 5. DRUG DISTRIBUTION = Reversible transfer of drugs between body-fluid compartments Body Fluid Compartments 70 kg person: TBW 42 L ├── ECF 14 L │ ├── Plasma 3 L │ ├── Interstitial fluid 10.5 L │ └── Transcellular fluid 0.5 L └── ICF 28 L Apparent Volume of Distribution aVd aVd = Total administered amount of drug ÷ Concentration of drug in plasma aVd Meaning Examples --------- Low 3-4 L Restricted to vascular compartment Heparin, warfarin high MW/protein bound 14-16 L Distributed in ECF Gentamicin, streptomycin 42 L Distributed in TBW Ethanol Very high 100 L Accumulates in tissues Chloroquine 13,000 L, digoxin 500 L Clinical significance of high aVd: Haemodialysis NOT useful for removal in overdose Redistribution: - Thiopentone highly lipid-soluble: quickly distributes to brain high blood flow → then redistributes to less-perfused adipose tissue - Results in short duration of action 5-10 min → used for induction of general anaesthesia Drug Reservoirs / Tissue Storage: - Tetracyclines → bones and teeth - Thiopentone, DDT → adipose tissue - Chloroquine → liver and retina - Digoxin → heart --- 6. PLASMA PROTEIN BINDING - Acidic drugs bind to albumin; Basic drugs bind to α1-acid glycoprotein - Only free unbound form is pharmacologically active Clinical Importance: 1. Highly protein-bound drugs → low Vd 2. Plasma protein binding delays metabolism 3. Bound form NOT available for glomerular filtration → excretion delayed 4. Highly protein-bound drugs → longer duration of action - Sulphadiazine less protein-bound: 6 hours - Sulphadoxine highly protein-bound: 1 week 5. In poisoning: hard to remove by haemodialysis 6. Hypoalbuminaemia anaemia, renal failure, liver disease → increased free drug → toxicity 7. Displacement interactions: Drug with higher affinity displaces drug with lower affinity → sudden increase in free concentration → toxicity --- 7. BIOTRANSFORMATION Drug Metabolism = Chemical alteration of drug in the body - Converts lipid-soluble/unionized → water-soluble/ionized → excreted via kidneys - Main site: Liver; Others: GI tract, kidney, lungs, blood, skin, placenta Types of Metabolic Transformation: Type Example ------ Active → Inactive metabolite most common Phenobarbitone → Hydroxyphenobarbitone Active → Active metabolite Codeine → Morphine; Diazepam → Oxazepam Inactive prodrug → Active metabolite Levodopa → Dopamine; Prednisone → Prednisolone Prodrug: Inactive form converted to active form after metabolism. Uses of Prodrugs: 1. Improve bioavailability: Levodopa crosses BBB → Dopamine 2. Prolong duration: Fluphenazine ester of phenothiazine 3. Improve taste: Clindamycin palmitate 4. Site-specific delivery: Methenamine → Formaldehyde urinary antiseptic, acidic urine --- 8. PHASES OF DRUG METABOLISM Phase I Reactions Non-synthetic: Reaction Process Examples --------- Oxidation most common Add O2/remove H2 Phenytoin, phenobarbitone, propranolol Reduction Remove O2/add H2 Chloramphenicol, methadone Hydrolysis Break down + water Esters procaine, amides lignocaine Cyclization Straight chain → ring Proguanil Decyclization Break ring structure Phenobarbitone, phenytoin - Catalyzed by cytochrome P450 mainly CYP3A4/5 - Other enzymes: CYP2D6, CYP2C9, CYP2E1, CYP2C19 Phase II Reactions Synthetic/Conjugation: Conjugation Enzyme Examples --------- Glucuronidation UDP-glucuronosyl transferase Aspirin, Morphine Acetylation N-acetyltransferase Isoniazid, Dapsone Sulphation Sulphotransferase Paracetamol, Methyldopa Methylation Transmethylase Adrenaline, Dopamine Glutathione conjugation Glutathione transferase Paracetamol Glycine conjugation Acyl CoA glycine transferase Salicylates Note: INH undergoes Phase II acetylation BEFORE Phase I exception! Microsomal vs Non-microsomal Enzymes: Feature Microsomal Non-microsomal --------- Location Smooth ER of liver, kidney, lungs CYP450, glucuronyl transferase Cytoplasm, mitochondria, plasma Reactions Phase I reactions, glucuronide conjugation Oxidation, reduction few, hydrolysis; all conjugations except glucuronide Inducible Yes Not inducible - may show genetic polymorphism Hofmann Elimination: - Drug inactivated without enzymes - Example: Atracurium skeletal muscle relaxant --- 9. FACTORS AFFECTING DRUG METABOLISM 1. Age: Neonates & elderly metabolize drugs less reduced microsomal enzyme activity - Neonates: grey baby syndrome with chloramphenicol - Elderly: increased toxicity with propranolol, lignocaine 2. Diet: Poor nutrition decreases enzyme function 3. Disease: Liver cirrhosis → decreased metabolism → prolonged diazepam action 4. Genetic factors Pharmacogenetics: - Slow & fast acetylators of INH: Slow acetylators → peripheral neuritis; fast acetylators need larger dose - Succinylcholine apnoea: Atypical pseudocholinesterase → prolonged apnoea dangerous - G6PD deficiency: Haemolysis with sulphonamides, primaquine, salicylates, dapsone 5. Simultaneous administration of drugs: Enzyme induction or inhibition --- 10. ENZYME INDUCTION & INHIBITION Enzyme Induction: - Repeated drug administration → increased synthesis of microsomal enzymes - Inducers: Rifampicin, phenytoin, barbiturates, carbamazepine, griseofulvin Clinical Importance: 1. Rifampicin → induces OCP metabolism → contraceptive failure 2. Autoinduction: carbamazepine 3. Increased hepatotoxicity with paracetamol toxic metabolite overproduction 4. Prolonged phenytoin → osteomalacia enhanced Vit D metabolism 5. Barbiturates → porphyria overproduction of porphyrins 6. Phenobarbitone in neonatal jaundice → induces glucuronyl transferase → bilirubin conjugated Enzyme Inhibition: - Drugs: Chloramphenicol, ciprofloxacin, erythromycin, metronidazole - Inhibition is rapid vs. induction which is slow Clinical Relevance: - Increased bleeding with warfarin when given with erythromycin/chloramphenicol → inhibit warfarin metabolism → increased plasma warfarin --- 11. DRUG EXCRETION Routes of Excretion: 1. Kidney main route 2. Lungs volatile anaesthetics: ether, halothane, isoflurane 3. Faeces purgatives, senna, cascara; tetracyclines via bile 4. Bile reabsorbed in gut → enterohepatic cycling 5. Skin arsenic, mercury 6. Saliva potassium iodide, phenytoin, metronidazole, lithium 7. Milk most drugs appear; avoid amiodarone during breastfeeding Renal Excretion: Rate of renal excretion = Rate of filtration + Rate of secretion - Rate of reabsorption 1. Glomerular filtration: - Small molecules freely filtered - Extent of filtration ∝ GFR and fraction of unbound drug 2. Passive tubular reabsorption: - Depends on pH of renal tubular fluid and ionization - Weakly acidic drugs salicylates, barbiturates: remain unionized in acidic urine → reabsorbed → making urine alkaline sodium bicarbonate increases their excretion - Weakly basic drugs morphine, amphetamine: remain unionized in alkaline urine → reabsorbed → making urine acidic Vit C increases their excretion 3. Active tubular secretion: - Carrier-mediated active transport - Most acidic drugs penicillin, diuretics, probenecid, etc. secreted by renal tubular cells - Probenecid inhibits tubular secretion of penicillins → prolongs penicillin's half-life → used in gonorrhoea treatment --- 12. PHARMACOKINETIC PARAMETERS Plasma Half-Life t½: = Time required for plasma concentration to decrease by 50% - Lignocaine t½ = 1 hour; Aspirin t½ = 4 hours - Drug almost completely eliminated in 4-5 half-lives - Steady state achieved in 4-5 half-lives Uses of t½: - Determine duration of drug action - Determine frequency of dosing - Estimate time to reach steady state Clearance Cl: = Volume of plasma from which drug is removed per unit time Clearance = Rate of elimination ÷ Plasma concentration of drug Kinetics of Elimination: Feature First-Order Zero-Order --------- Amount eliminated/time Constant fraction Constant amount Example Most drugs Ethanol 10 mL/h, phenytoin at high dose, aspirin t½ Constant Not constant increases as dose increases Rate proportional to Plasma concentration Independent of plasma concentration - Phenytoin & aspirin: First-order at low doses → Zero-order saturation kinetics at high doses - Once kinetics changes to zero-order → small increase in dose → large increase in plasma concentration → toxicity Steady-State Concentration: - Constant dosing at intervals → plasma concentration increases until amount eliminated = amount administered - Achieved after 4-5 half-lives - At steady state, plasma concentration fluctuates between peak and trough Loading Dose: - Large initial dose to rapidly attain target plasma concentration - Used when t½ is long e.g., lignocaine 1 hour Maintenance Dose: - Given at fixed intervals to maintain steady-state concentration - = Dose eliminated in one dosing interval --- 13. THERAPEUTIC DRUG MONITORING TDM Indications for TDM: 1. Narrow therapeutic index drugs: lithium, digoxin, phenytoin, aminoglycosides 2. Wide interindividual variation: tricyclic antidepressants 3. To ascertain patient compliance 4. Drugs with toxicity increased in renal failure: aminoglycosides 5. No response to therapy without known reason TDM NOT required when: 1. Clinical/biochemical parameters available: BP antihypertensives, blood sugar antidiabetics, PT/INR anticoagulants 2. Drugs producing tolerance: opioids 3. Drug effect persists longer than drug itself: omeprazole --- 14. FIXED-DOSE COMBINATIONS FDCs WHO-Approved Examples: - Levodopa + carbidopa Parkinsonism - Isoniazid + rifampicin + pyrazinamide + ethambutol TB - Ferrous sulphate + folic acid anaemia of pregnancy - Sulphamethoxazole + trimethoprim = cotrimoxazole - Amoxicillin + clavulanic acid Methods to Prolong Drug Action: 1. Sustained-release preparations e.g., diclofenac SR - 24h vs regular - 12h 2. Adding vasoconstrictor adrenaline with local anaesthetics 3. Combining with water-insoluble compound benzathine penicillin G - 3-4 weeks 4. Esterification testosterone propionate/enanthate - prolonged IM 5. Pellet implantation norplant for contraception 6. Transdermal patch 7. Increasing plasma protein binding sulphadoxine: 1 week 8. Inhibiting drug metabolism allopurinol inhibits 6-MP metabolism 9. Delaying renal excretion probenecid with penicillin/cephalosporins --- 15. PHARMACODYNAMICS = What the drug does to the body Types of Drug Effects: 1. Stimulation: Increase activity adrenaline → heart rate 2. Depression: Decrease activity alcohol, barbiturates, GA → CNS 3. Local action: Counterirritation eucalyptus oil, methyl salicylate 4. Cytotoxic: Toxic to cells antibiotics/anticancer drugs 5. Replacement: Replacing endogenous substances insulin, thyroxine --- 16. MECHANISM OF DRUG ACTION Mechanism of action ├── Receptor-mediated └── Non-receptor-mediated Non-Receptor Mechanisms: Physical: Osmosis mannitol in cerebral oedema/glaucoma, Adsorption charcoal in poisoning, Demulcent cough syrup, Radioactivity I¹³¹ in hyperthyroidism Chemical: - Antacids weak bases neutralize gastric acid - Chelating agents: dimercaprol BAL in arsenic/copper poisoning; desferrioxamine in iron poisoning; D-penicillamine in copper poisoning - ACE inhibitors inhibit enzyme ACE - Allopurinol: competitive inhibitor of xanthine oxidase → reduces uric acid synthesis gout Through ion channels: Local anaesthetics block Na+ channels Through antibody production: Vaccines BCG, oral polio Transporters: SSRIs block 5-HT transporter → antidepressant effect --- 17. RECEPTOR-MEDIATED MECHANISM Drug D + Receptor R ⇌ Drug-receptor complex → Response Key Definitions: - Affinity: Ability of drug to bind to receptor - Intrinsic activity: Ability of drug to produce pharmacological action after binding - Agonist: High affinity + high intrinsic activity morphine, adrenaline - Antagonist: High affinity + zero intrinsic activity; blocks effect naloxone, atropine - Partial agonist: Binds receptor but produces less effect than full agonist pindolol, buprenorphine - Inverse agonist: Binds receptor, produces effect opposite to agonist β-carbolines at BZD receptor → anxiety, convulsions Types of Antagonism: Type Features Example --------- Competitive equilibrium Same receptor; reversible; overcome by increasing agonist dose; rightward parallel shift of DRC Atropine vs ACh; Naloxone vs Morphine Non-competitive Different receptor site; irreversible or allosteric; flattening of DRC; cannot be overcome Diazepam vs bicuculline Physical Opposite physical property Activated charcoal adsorbs alkaloids Chemical Chemical neutralization Antacids + gastric acid; chelating agents Physiological functional Different receptors, opposite effects Insulin vs glucagon; Adrenaline vs histamine --- 18. RECEPTOR FAMILIES Feature Ligand-gated ion channels G-protein-coupled GPCRs Enzyme-linked Nuclear receptors --------------- Location Membrane Membrane Membrane Intracellular Effector Ion channel Channel or enzyme Enzyme Gene transcription Examples Nicotinic, GABA, glutamate Muscarinic, adrenergic, opioid Insulin, EGF, growth hormone receptors Steroids, thyroid hormones Response time Milliseconds Seconds Minutes to hours Hours GPCR Mechanism: - G proteins have 3 subunits α, β, γ; GDP bound to α subunit at rest - Agonist → receptor activation → GDP exchanges with GTP → α subunit dissociates → activates effectors - Gs β-adrenergic: ↑Adenylyl cyclase → ↑cAMP - Gi α2-adrenergic: ↓Adenylyl cyclase → ↓cAMP - Gq muscarinic M1: activates Phospholipase C → ↑IP3 + DAG Nuclear Receptors: - Steroids, thyroid hormones, Vitamins A and D, glucocorticoids - Steroid → binds cytoplasm → steroid-receptor complex → nucleus → binds DNA → regulates protein synthesis --- 19. REGULATION OF RECEPTORS Downregulation Upregulation ------ Prolonged use of agonists Prolonged use of antagonists ↓ Receptor number and sensitivity ↑↑ Receptor number and sensitivity Example: chronic salbutamol → decreased β-adrenoceptor response in asthma Example: propranolol stopped suddenly → rebound tachycardia, angina, hypertension, MI Therefore: propranolol should NOT be discontinued abruptly --- 20. DOSE-RESPONSE RELATIONSHIP Types of DRC: 1. Graded DRC: Rectangular hyperbola; log DRC is sigmoid shaped 2. Quantal DRC: All-or-none response e.g., drug causing ovulation - bell-shaped curve Therapeutic Index TI = LD50 ÷ ED50 - LD50 = dose lethal to 50% of population - ED50 = dose producing desired effect in 50% of population - Higher TI = safer drug - High TI drugs: penicillin, digitalis - Narrow TI drugs: lithium, digoxin, phenytoin need TDM Drug Potency vs Efficacy: - Potency: Dose required to produce a given response lower dose = more potent - Morphine more potent than pethidine morphine 10 mg vs pethidine 100 mg - Efficacy: Maximum effect a drug can produce Emax - Morphine more efficacious than aspirin as analgesic Therapeutic Range: - Concentration range producing desired response with minimal toxicity --- 21. COMBINED EFFECTS OF DRUGS Increased Response: 1. Additive: A + B = A + B e.g., aspirin + paracetamol 2. Potentiation supra-additive: A + B A + B; one drug inactive alone carbidopa + levodopa 3. Synergism: Combined effect either drug alone sulphamethoxazole + trimethoprim Decreased Response Drug Antagonism: 1. Physical: Activated charcoal adsorbs alkaloids 2. Chemical: Antacids neutralize gastric acid; chelating agents 3. Physiological: Adrenaline vs histamine different receptors, opposite effects 4. Receptor: Competitive or non-competitive --- 22. FACTORS MODIFYING DRUG ACTION Drug Factors: - Route of administration - Presence of other drugs - Cumulation Patient Factors: 1. Age: - Young's formula: Child dose = Age/Age+12 × adult dose - Dilling's formula: Child dose = Age/20 × adult dose - Neonates: grey baby syndrome chloramphenicol; immature enzymes - Elderly: reduced renal + hepatic function → reduced dosing 2. Body weight: Dose = Body weight/70 × Average adult dose 3. Sex: β-blockers, diuretics, clonidine → decreased libido in males 4. Diet and environmental factors: Milk reduces tetracycline absorption; fatty meal increases griseofulvin absorption; smoking increases theophylline metabolism 5. Genetic factors: Fast/slow acetylators; succinylcholine apnoea; G6PD deficiency; porphyria barbiturates; malignant hyperthermia halothane + succinylcholine 6. Psychological factor Placebo effect: - Placebo = pharmacologically inert substance - Used for subjective symptoms pain, anxiety, insomnia and in clinical trials to minimize bias 7. Pathological states: - GI disorders: achlorhydria reduces absorption of weakly acidic drugs - Liver disease: reduced metabolism → increased bioavailability propranolol - Renal failure: reduced clearance → aminoglycoside nephrotoxicity/ototoxicity - Iron deficiency anaemia: increased iron absorption from gut 8. Tolerance: Need for larger doses to produce same effect - Types: - Natural tolerance genetically determined: species tolerance, racial tolerance - Acquired tolerance: pharmacokinetic increased metabolism by OCP + rifampicin or pharmacodynamic receptor downregulation with opioids, barbiturates - Cross-tolerance: between chemically related drugs nitroglycerin, alcohol + ether - Tachyphylaxis acute tolerance: Rapid decrease in response on repeated rapid dosing; e.g., ephedrine, amphetamine, tyramine act by releasing noradrenaline → depletion 9. Drug dependence: See separate notes --- HIGH-YIELD EXAM POINTS ⭐ Topic Key Fact ------ Most common membrane transport Passive diffusion Most common metabolic transformation Active → Inactive metabolite Most important enzyme system Cytochrome P450 CYP3A4/5 Exception to Phase I before Phase II Isoniazid Phase II first Enzyme without enzyme inactivation Hofmann elimination Atracurium Narrowest TI drugs Lithium, digoxin, phenytoin, aminoglycosides Drug NOT to stop abruptly Propranolol rebound MI Zero-order kinetics drug Ethanol, phenytoin saturation, aspirin Tachyphylaxis drugs Ephedrine, amphetamine, tyramine Prodrug crossing BBB Levodopa → Dopamine Prolong penicillin action Probenecid blocks tubular secretion Succinylcholine apnoea cause Atypical pseudocholinesterase Tissue reservoir for chloroquine Liver and retina Redistribution example Thiopentone Q: This is the continued notes ..make an exam oriented notes from the given source A: Here are the crisp, exam-oriented notes for the continued topics: --- GENERAL PHARMACOLOGY - CONTINUED EXAM NOTES Shanbhag Pharmacology --- 23. DRUG INTERACTIONS = When effects of one drug are altered by another drug Occurs: In vitro outside body or In vivo inside body Drug Interactions ├── In vitro Pharmaceutical interactions └── In vivo ├── Pharmacokinetic interactions └── Pharmacodynamic interactions --- A. PHARMACEUTICAL INTERACTIONS - Physical/chemical incompatibility when drugs mixed in same syringe/IV infusion - Results in precipitation or inactivation Examples: - Phenytoin + dextrose → precipitates give in normal saline - Ampicillin + dextrose → unstable at acidic pH - Gentamicin + carbenicillin → loss of potency don't mix in same infusion --- B. PHARMACOKINETIC INTERACTIONS Stage Mechanism Example --------- Absorption Antacids Al, Mg, Ca form complexes with tetracyclines → reduced absorption Antacids + tetracycline Metoclopramide ↑ gastric emptying → ↑ aspirin absorption Distribution Plasma protein displacement: drug with higher affinity displaces one with lower affinity → ↑ free drug Salicylates displace warfarin → ↑ anticoagulant effect Metabolism Enzyme induction → ↑ metabolism of another drug Carbamazepine induces warfarin metabolism → ↓ anticoagulant effect Enzyme inhibition → ↓ metabolism of another drug Erythromycin inhibits carbamazepine metabolism → ↑ toxicity Excretion Interference with tubular secretion Salicylates interfere with methotrexate excretion → ↑ toxicity Probenecid blocks tubular secretion of penicillin → ↑ penicillin levels beneficial --- C. PHARMACODYNAMIC INTERACTIONS - Drug action on receptors or physiological systems - Can be additive, synergistic, or antagonistic Harmful example: Aminoglycosides + amphotericin B → enhanced nephrotoxicity Beneficial example: Levodopa + carbidopa → improved Parkinsonism treatment --- 24. RATIONAL USE OF MEDICINES WHO Definition: "Patients receive medications appropriate to their clinical needs in doses that meet their own individual requirements for an adequate period of time and at the lowest cost to them and their community" = Right drug, right dose, right duration, right cost to right patient Examples of IRRATIONAL Prescribing: - Antibiotics for viral infections - Not prescribing ORS in acute diarrhoea - Wrong drug selection, wrong route/dose - Medicines with doubtful efficacy appetite stimulants - Prescribing banned drugs cisapride - Irrational combinations ampicillin + cloxacillin for staphylococcal infections - Expensive drugs when cheaper alternatives available - Polypharmacy Hazards of Irrational Drug Use: - Therapeutic failure - Increased ADRs - Drug-resistant microorganisms - Increased cost of treatment - Financial burden to society - Loss of patient's faith in the doctor Rational Prescribing Steps WHO: 1. Make a diagnosis 2. Define the problem 3. Set therapeutic goals 4. Select right drug, route, dose, and duration 5. Write complete prescription 6. Give proper instructions to patient 7. Monitor therapy --- 25. ADVERSE DRUG REACTIONS ADR ADR WHO: "Any response which is noxious, unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis or therapy" Adverse Event AE: Any untoward medical occurrence during treatment, not necessarily causal. --- TYPES OF ADR Type A - Predictable Augmented Reactions: - Related to pharmacological action of drug - Include: side effects, secondary effects, toxic effects Type Definition Example --------- Side effects Unwanted pharmacological effects at therapeutic doses Atropine used for heart block → dry mouth, blurred vision, urinary retention Secondary effects Indirect result of primary action Corticosteroids → immunosuppression → opportunistic infections oral candidiasis Toxic effects Due to overdose or chronic use/overdose Warfarin → bleeding; aminoglycosides → nephrotoxicity in renal failure Type B - Unpredictable Bizarre Reactions: - NOT related to pharmacological action - Include: Drug allergy, idiosyncrasy --- 26. HYPERSENSITIVITY REACTIONS Drug Allergy Type I - Immediate/Anaphylactic: - IgE mediated; rapidly occurring Mechanism: Drug exposure penicillin, aspirin, lignocaine → Production of IgE antibodies → fix to mast cells → Re-exposure to same drug → Ag-Ab reaction on mast cell surface → Release of mediators histamine, 5-HT, PGs, LTs, PAF → Hypotension, bronchospasm, angioedema, urticaria, anaphylactic shock Manifestations: Itching, urticaria, hay fever, asthma, anaphylactic shock Treatment of Anaphylactic Shock Medical Emergency: 1. Inj. Adrenaline 1:1000 - 0.3-0.5 mL IM 2. Inj. Hydrocortisone 100-200 mg IV 3. Inj. Pheniramine 45 mg IM/IV 4. Maintain patent airway + IV fluids --- Type II - Cytotoxic Reactions: - IgG and IgM mediated - Antibodies react with cell-bound antigens → complement activation → cell destruction - Examples: Blood transfusion reactions, haemolytic anaemias quinine, quinidine, cephalosporins --- Type III - Arthus/Serum Sickness Reactions: - IgG mediated; immune complex deposition Mechanism: AG: AB complexes → Fix complement → Deposition on vascular endothelium → Destructive inflammatory response Examples: - Serum sickness fever, urticaria, joint pain, lymphadenopathy with penicillins, sulphonamides - Acute interstitial nephritis with NSAIDs - Stevens-Johnson syndrome with sulphonamides --- Type IV - Cell-Mediated/Delayed Hypersensitivity: - Mediated by sensitized T lymphocytes - Manifestations occur 1-2 days after exposure to sensitizing antigen - Examples: Contact dermatitis local anaesthetic creams, topical antibiotics, antifungal agents - Treatment: Glucocorticoids Types II, III, IV --- Summary Table of Hypersensitivity: Type Mediator Time Example ------------ I Anaphylactic IgE, mast cells Minutes Anaphylactic shock with penicillin II Cytotoxic IgG, IgM Hours Blood transfusion reaction, haemolytic anaemia III Immune complex IgG complexes Hours-days Serum sickness, Stevens-Johnson IV Delayed T lymphocytes 1-2 days Contact dermatitis --- 27. IDIOSYNCRASY - Genetically determined abnormal reaction to drug - Examples: - Aplastic anaemia with chloramphenicol - Prolonged succinylcholine apnoea atypical pseudocholinesterase - Haemolytic anaemia with primaquine + sulphonamides G6PD deficiency --- 28. DRUG DEPENDENCE WHO Definition: "A state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug characterized by behavioural and other responses that always include a compulsion to take the drug on a continuous or periodic basis" Examples: Opioids, alcohol, barbiturates, amphetamine Types: Type Features ------ Psychological dependence Intense desire to continue taking drug; patient feels well-being depends on drug Physical dependence Repeated use → physiological changes → body needs drug to maintain normal function; abrupt stoppage → withdrawal syndrome symptoms opposite to drug effects Principles of Treatment: 1. Hospitalization 2. Substitution therapy - methadone for morphine addiction 3. Aversion therapy - disulfiram for alcohol addiction 4. Psychotherapy 5. General measures - nutrition, family support, rehabilitation --- 29. IATROGENIC DISEASES - Physician-induced disease due to drug therapy - Iatros Greek = physician - Examples: Parkinsonism due to metoclopramide; acute gastritis/peptic ulcer due to NSAIDs --- 30. TERATOGENICITY = Ability of drug to cause fetal abnormalities during pregnancy Risk by Gestational Age: - Conception to 16 days: Abortion - 2-8 weeks organogenesis: Structural abnormalities most dangerous period - 2nd and 3rd trimester: Growth and development effects Teratogenic Drugs The T's - Mnemonic: Drug Teratogenic Effect ------ Thalidomide Phocomelia seal-like limbs Tetracyclines Yellowish discolouration of teeth Antithyroid drugs Fetal goitre Warfarin Warfarin embryopathy Methotrexate Abortion, organogenesis defects FDA Drug Categories old system, being replaced: - Category X = contraindicated in pregnancy risk proven, outweighs benefit - Examples: warfarin, methotrexate --- 31. OTHER ADVERSE DRUG EFFECTS Carcinogenicity & Mutagenicity: - Carcinogenicity: Ability to cause cancer - Mutagenicity: Abnormality in genetic material of a cell - Examples: Anticancer drugs, oestrogens Photosensitivity: - Photoallergy: Sulphonamides → cell-mediated immune response on UV exposure - Phototoxicity: Doxycycline, fluoroquinolones → local reaction erythema, blisters on UV exposure - Management: Sunscreen, avoid sunlight, calamine lotion, topical steroids Organ-Specific Toxicity: Organ Drugs ------ Hepatotoxic Isoniazid, rifampicin, pyrazinamide, halothane, paracetamol Nephrotoxic VACATION mnemonic Vancomycin, Aminoglycosides, Cisplatin, Amphotericin B, Tetracyclines Fanconi syndrome, Indinavir, Other gold salts, Nystatin, cyclosporine Ototoxic Aminoglycosides, loop diuretics, cisplatin Ocular toxicity Ethambutol, chloroquine, glucocorticoids --- 32. PHARMACOVIGILANCE = Science and activities relating to detection, assessment, understanding and prevention of adverse effects or any other drug-related problems WHO Aim: Improve patient safety, promote rational drug use, develop regulations, educate healthcare professionals Causality Assessment Tools: Naranjo's scale and WHO scale Pharmacovigilance Centers: - National: Ghaziabad India - International: Uppsala Monitoring Centre Sweden - Regional in India: Chennai and Cochin POISONDEX - At AIIMS: WHO has established poison information centres at AIIMS New Delhi and Ahmedabad INTOX --- 33. TREATMENT OF POISONING Toxicology = Study of poisons - actions, detection, prevention, treatment Note: All poisoning cases are medico-legal cases - police must be informed GENERAL MANAGEMENT Mnemonic: A to H 1. Hospitalization 2. Airway - clear secretions; left lateral position in coma; cuffed endotracheal tube 3. Breathing - O2 for hypoxaemia; mechanical ventilation if needed 4. Circulation - pulse rate and BP monitoring; IV line 5. Prevent further absorption: - Inhaled poisons gases: Move to fresh air - Contact poisons: Remove contaminated clothes; wash with soap and water - Ingested poisons: Gastric lavage within 2-3 hours if conscious; activated charcoal physical antagonism Contraindications to gastric lavage: - Corrosives carbolic acid, petroleum products/kerosene - Convulsants - Petroleum products Gastric lavage solutions: Normal saline, lukewarm water, KMnO4 solution, sodium bicarbonate - Activated charcoal - adsorbs many drugs and poisons; given after lavage - Laxatives magnesium sulphate/citrate - promote elimination of ingested poison - Whole bowel irrigation oral polyethylene glycol electrolyte solution - for iron, lithium, cocaine, heroin, foreign bodies 6. Promote elimination of absorbed drug: - Diuretics mannitol/furosemide - promote renal elimination - Alkalinization of urine sodium bicarbonate - in salicylate poisoning → ionizes salicylate → excreted - Acidification of urine Vit C - in amphetamine poisoning - Dialysis - severe poisoning lithium, aspirin, methanol 7. Symptomatic treatment: - IV diazepam 5-10 mg for convulsions - External cooling for hyperpyrexia 8. Fluid and electrolyte balance: - Hyponatraemia → IV normal saline - Severe hyponatraemia → IV furosemide - Hypokalaemia → potassium chloride oral or slow IV; dilute before IV; never give KCl rapid IV → cardiac arrest - Severe hyperkalaemia → 10% calcium gluconate IV; insulin + dextrose - Metabolic acidosis → IV sodium bicarbonate --- SPECIFIC MANAGEMENT - ANTIDOTES Poison Antidote ------ Alkalies Dilute acetic acid vinegar Organophosphorus compounds Atropine Morphine opioids Naloxone Atropine Physostigmine Benzodiazepines Flumazenil Carbamates Atropine Cyanide Sodium nitrite + sodium thiosulphate Methanol Fomepizole, ethyl alcohol Paracetamol N-acetylcysteine Heparin Protamine sulphate Warfarin Vitamin K1 phytonadione Iron compounds Desferrioxamine --- HIGH-YIELD EXAM POINTS ⭐ Topic Key Fact ------ First line drug for anaphylactic shock Adrenaline 1:1000, 0.3-0.5 mL IM Type IV hypersensitivity mediator T lymphocytes only type not antibody-mediated Stevens-Johnson syndrome Type III hypersensitivity; sulphonamides Thalidomide teratogenicity Phocomelia Most dangerous teratogenic period 2-8 weeks organogenesis Drug for alcohol aversion therapy Disulfiram Drug for opioid substitution therapy Methadone Antidote for paracetamol poisoning N-acetylcysteine Antidote for organophosphorus Atropine Antidote for benzodiazepines Flumazenil Antidote for heparin Protamine sulphate Antidote for warfarin Vitamin K1 Antidote for iron Desferrioxamine Antidote for opioids Naloxone Antidote for atropine Physostigmine KCl rapid IV danger Cardiac arrest Gastric lavage contraindicated in Corrosives, petroleum products, convulsants Nephotoxic drugs mnemonic VACATION Photosensitivity - tetracyclines type Phototoxicity local reaction Photosensitivity - sulphonamides type Photoallergy cell-mediated Phenytoin + dextrose Precipitates - give in normal saline Probenecid + penicillin Prolongs penicillin action beneficial interaction Salicylate poisoning urine modification Alkalinize urine sodium bicarbonate Amphetamine poisoning urine modification Acidify urine Vitamin C National Pharmacovigilance Centre Ghaziabad, India International Pharmacovigilance Centre Uppsala Monitoring Centre, Sweden Idiosyncrasy examples Aplastic anaemia chloramphenicol, prolonged apnoea succinylcholine, haemolysis primaquine in G6PD deficiency Withdrawal symptoms direction Opposite to drug effects --- QUICK REVISION - DRUG INTERACTION EXAMPLES Interacting Drugs Result Mechanism --------- Antacids + tetracycline ↓ tetracycline absorption Chelation in gut Salicylates + warfarin ↑ bleeding Plasma protein displacement Rifampicin + OCP Contraceptive failure Enzyme induction Erythromycin + carbamazepine ↑ carbamazepine toxicity Enzyme inhibition Probenecid + penicillin ↑ penicillin effect Block tubular secretion Aminoglycosides + amphotericin B ↑ nephrotoxicity Additive toxicity Levodopa + carbidopa ↑ levodopa bioavailability Enzyme inhibition peripheral decarboxylase Metoclopramide + aspirin ↑ aspirin absorption ↑ gastric emptying Q: Generate a quick revision PDF with exam mnemonics A: Your PDF is ready! Download it here: GeneralPharmacologyRevision.pdf/home/daytona/workspace/pharma-notes/GeneralPharmacologyRevision.pdf --- What's inside the PDF 15 sections + 3 bonus pages: Section Content ------ 1-9 Full ADME notes - membrane transport, absorption, bioavailability, distribution, plasma protein binding, biotransformation Phase I & II, excretion, PK parameters, TDM/FDCs 10-15 Pharmacodynamics - receptor families, dose-response, drug interactions, ADRs & hypersensitivity, drug dependence, teratogenicity, poisoning & antidotes Mnemonic Sheet All 17 key mnemonics consolidated PAFFE, VACATION, ACID, LGEN, BITS, RPBCG, CCEM, NARROW, LPAD, etc. High-Yield Tables Prodrugs, first-pass drugs, active metabolites, zero-order kinetics, dose adjustments in renal/hepatic failure, tolerance types Rapid Revision Card 40-point last-30-minutes cheat sheet with the most commonly asked exam facts
