Anitmicrobial agents General Considerations (1) MBBS June-July 2015

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Antimicrobial Agents (General Considerations):

Antimicrobial Agents (General Considerations) Prof. R. K. Dixit Pharmacology and Therapeutics K.G.M.U. Lucknow [email protected]


Objectives After this lecture you will be able to answer What are antimicrobials, antibiotics, chemotherapeutic agents (Terminologies used in antimicrobial treatment) Classification of antimicrobials (chemicals, mechanism, spectrum) Mechanisms of action of antimicrobials Resistance development in antimicrobials General adverse effects of antimicrobials General drug interactions related to antimicrobials Uses of antimicrobials (Therapeutic and Prophylaxis) Selection of appropriate antimicrobials Precautions while prescribing antimicrobials and failure

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A naturopath tells “ One should never take antibiotics Except in Pneumonia, a kidney infection, boils, meningitis, encephalitis, osteomyelitis, occular infections, or other serious illness………………………………………………….”

Allopath is Lucky to have the help of Antimicrobials :

Allopath is Lucky to have the help of Antimicrobials But This Luck may not last long due to reasons…… Inappropriate use,… Overuse….. Antimicrobial resistance Reduced immunity and worsening of environment patients having co morbid illnesses like diabetes, malnutrition……………….. Less interest of pharmaceuticals in this field Costly new antimicrobials

Antimicrobials , Antimicrobials , Antimicrobials , Antimicrobials, Antimicrobials , Antimicrobials Antimicrobials!!!:

Antimicrobials , Antimicrobials , Antimicrobials , Antimicrobials, Antimicrobials , Antimicrobials Antimicrobials !!! Penicillin, ampicillin , amoxycillin , ticarcillin , piperacillin , flucloxacillin , dicloxacillin , oxacillin , methicillin , nafcillin , carbenicillin , eryhtromycin , clindamycin , roxythromycin clarithromycin , tetracycline, doxycycline , minocycline , vancomycin , teicoplanin , augmentin , gentamicin , tobramycin , amikacin , streptomycin, azithromycin , aztreonam , cephalexin , cefotaxime , cephamandole , cefepime , ceftriaxone , ceftazidime , cefpirome , imipenem , chloramphenicol , cotrimoxazole , ciprofloxacin, norfloxacin , trimethoprim ,……. ………………………………………………………………………………………………………………………………………………….. hundreds of different antimicrobial agents on the market.


Terminology 6 Chemotherapy – U se of drugs to treat infections and malignancy. (Antimicrobials and Antineoplastic agents) Pharmacodynamic agents- D rugs regulating physiological process of body and act on the body cells. Chemotherapeutic agents- S electively acting against microbes or malignant cells. (Don’t touch body cells) Antimicrobials – U sed in treating infectious diseases. Antibiotics – P roduced from microbes to inhibit or kill other microbes . (Antimicrobials from microbes) All antibiotics are antimicrobials but all antimicrobials are not antibiotics

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Bacteriostatic - Stop the growth of bacteria Bactericidal- Kill the bacteria PAE- Post antibiotic effect Minimum Inhibitory Concentration (MIC)- Which stops the growth Minimum Bactericidal Concentration (MBC)- Which kills by 99.99% (Bactericidal -less value of MBC-MIC, Bacteriostatic - more value of MBC-MIC)

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Prebiotics - Stimulate the growth of intestinal commensals and prevent multiplication and establishment of pathogenic bacteria. Lactulose , Lactitol , Inulin Probiotics - Live microbial substances used as supplements to maintain or improve the intestinal bacterial flora. Lactobacilli and Bifidobacteria

Gram positive & Gram Negative:

Gram positive & Gram Negative Gram positive bacteria have thick cell wall Peptidoglycan directly accessible from environment Gram negative bacteria have Thin cell wall Surrounded by inner and outer membrane Of lipopolysaccharide , phospholipids, and proteins Outer membrane is a barrier to diffusion of antibiotics Limited antibiotics may diffuse through porins

Historical Perspectives:

Historical Perspectives Chenopodium - for intestinal worms Mouldy curd – for boils Chaulmoogra oil- for Leprosy Mercury – for Syphilis Cinchona Bark- for Malaria

Historical perspectives:

Historical perspectives Pasteur- (1877) Phenomenon of antibiosis Paul Ehrlich- (1906) Father of Chemotherapy, Coined term chemotherapy Domagk- (1935) Discovery of sulfonamides ( Prontosil to sulphanilamide ) Fleming, Chain, Florey- Penicillin (1929, 39, 41) from penicillium Waksman- Streptomycin, from actinomycetes , Coined term antibiotic

Introduction of Class of antimicrobial agents (SPECTM) :

Introduction of Class of antimicrobial agents (SPECTM) 1935 - Sulphonamides 1941 - Penicillins 1944 - Aminoglycosides 1945 - Cephalosporins 1949 - Chloramphenicol 1950 - Tetracyclines 1952 - Macrolides 1956 - Glycopeptides 1957 - Rifamycins 1959 - Nitroimidazoles 1962 - Quinolones 1968 - Trimethoprim 2000 - Oxazolidinones 2003 - Lipopeptides

Antimicrobial Classification:

Antimicrobial Classification Chemical structure Mechanism of Action Organism type Spectrum of activity Static or Cidal Origin of antimicrobials

Chemical Classification (Public Loves GOOD Quality BATSMAN):

Chemical Classification ( P ublic L oves GOOD Q uality BATSMAN ) P olypeptides - Polymyxin , Colistin , Bacitracin P oyene antibiotics- Nystatin , Amphotericin -B, Hamycin L incosamide - Lincomycin , Clindamycin G lycopeptides - Vancomycin , Teicoplanin O xazolidinone - Linezolid O thers----------------- Riampicin , Griseofulvin , etc Di aminopyrimidines - Trimethoprim , Pyrimethamine Q uinolones - Nalidixic acid, ciprofloxacin B eta- lactam - Penicillins , Cephalosporins , Monobactams , Carbapenems A minoglycosides - Streptomycin, Gentamycin T etracyclines - Oxytetracycline , Doxycycline S ulphonamides - Sulfadiazine, Sulfamethoxazole , M acrolides - Erythromycin, Clarithromycin A zoles- Fluconazole , Clotrimazole N itroimidazoles - Metronidazole , Tinidazole N icotinic acid derivatives- Isoniazide , Pyrizinamide , Ethionamide N itrobenzene derivaties - Chloramphenicol N itrofuran derivatives- Nitrofurantoin , Furazolidone

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Organism affected Anti-viral Anti-bacterial Anti-fungal Anti- protozoal Anthelmintic Sources Fungi- Penicillin Cephalosporins Griseofulvin Bacteria- Polymyxin B Colistin Bacitracin Actinomycetes - Most common Aminoglycosides , Tetracyclines , Chloramphenicol Macrolides

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Spectrum Narrow Penicillin G Streptomycin Erythromycin Broad Tetracycline Chloramphenicol Extended Ampicillin Amoxicillin Most…….. Bacteristatic Sulfonamides and Trimethoprim Tetracyclines Macrolides (Erythromycin) Chloramphenicol Ethambutol Nitrofurantoin Bactericidal Cotrimoxazol Penicillins Cephalosporins Aminoglycosides Vancomycin , Daptomycin Fluroquinolones (ciprofloxacin) INH, Rifampicin , Pyrazinamide Polymixins , Bacitracin Metronidazole

Spectrum (Narrow, Broad, Extended):

Spectrum (Narrow, Broad, Extended)

Mechanism of action:

Mechanism of action Cell Wall synthesis inhibition- Beta- lactams , Vancomycin , Cycloserines Cell membrane Leakage- Polypeptides, Polyenes Folate Synthesis inhibition- Sulfonamides, Pyrimethamine , Cotrimaxazole , PAS, Ethambutol DNA gyrase and Topoisomerase inhibition- Fluroquinolones RNA polymerase inhibition- Rifampicin ,, Protein Synthesis Inhibition- (ATT) Aminoglycosides , tetracyclines , Chloramphenicol , Macrolides , Clindamycin, Linezolid

Differences between human cells Vs Bacterial Cells (Makes the antibacterial selective):

Differences between human cells Vs Bacterial Cells (Makes the antibacterial selective) Human cells don’t posses wall ( Peptidoglycans = peptides + sugar ) Human cell membrane is different ( Bacteria Contain Hypanoids in place of Sterol) Human cells take preformed dihydrofolic acid ( no need of PABA in human) Dihydrofolic acid reducatase enzyme is different ( thousand time affinity) Topoisomerase II are different (in bacteria IV, DNA Gyrase ) DNA dependent RNA polymerase is different Ribosome 60S subunit (in bacteria 50S) Ribosome 40S subunit (in bacteria 30S) 1 2 3 4 5 6 7 8

Cell Wall:

Cell Wall Beta Lactams

Protein Synthesis:

Protein Synthesis Chloramphenicol - Macrolides - Erythromycin, Azithromycin etc. Aminoglycosides . Gentamicin , Amikacin , etc.

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DNA gyrase belongs to a class of enzymes called DNA topoisomerases Topoisomerases (the study of geometrical properties and spatial relations unaffected by the continuous change of shape or size of figures ) of the DNA, resulting in a chemical isomer of the wound or unwound DNA strands. DNA gyrase , often referred to simply as  gyrase , also known as DNA topoisomerase IV. (in human Topoisomerase II ) Enzyme  that relieves strain while double-strand  DNA  is being unwound by  helicase . Causing negative supercoiling of the DNA. DNA gyrase is particularly unique because it is the only topoisomerase that can both relax positively supercoiled DNA and introduce negative supercoils into the DNA (most topoisomerases only relieve the positively supercoiled DNA This process occurs in  prokaryotes  (in particular, in bacteria), whose single circular DNA is cut by DNA gyrase and the two ends are then twisted around each other to form supercoils .

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There are three main types of topology:  supercoiling , knotting, and  catenation . Outside of the essential processes of  replication  or  transcription , DNA must be kept as compact as possible, and these three states help this cause. However, when transcription or replication occurs, DNA must be free, and these states seriously hinder the processes. In addition, during replication, the newly replicated duplex of DNA and the original duplex of DNA become intertwined and must be completely separated in order to ensure genomic integrity as a cell divides. As a transcription bubble proceeds, DNA ahead of the transcription fork becomes overwound , or positively supercoiled , while DNA behind the transcription bubble becomes underwound , or negatively supercoiled . As replication occurs, DNA ahead of the replication bubble becomes positively supercoiled , while DNA behind the replication fork becomes entangled forming precatenanes . One of the most essential topological problems occurs at the very end of replication, when daughter chromosomes must be fully disentangled before mitosis occurs. Topoisomerase IIA plays an essential role in resolving these topological problems

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PABA Dihydrofolic acid Tetrahydrofolic acid Purines and Pyrimidines DNA And RNA DNA unwinding (DNA gyrase ) Threads sepeartion (Topoisomerase IV) DNA dependent RNA Polymerase tRNA + Amino Acids Ribosome unit (50S) Ribosome unit (30S) Protein Synthesis Dihydro -folic acid Synthetase Dihydro -folic acid reductase DNA multiplication mRNA Sulphonamides (PABA analogue and inhibitor of DHFAS) Trimethoprim and Pyrimethamine (inhibitor of DHFAR) Quinolones (Inhibitor of DNA gyrase and Topoisomerase IV) Rifampicin (inhibitor of DNA dependant RNA Polymerase) Chloramphenicol , Macrolides (50S) Aminoglycosides , Tetracyclines (30S)

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DNA unwinding (DNA gyrase ) Threads sepeartion ( Topoisomerase IV) PABA Dihydrofolic acid Tetrahydrofolic acid Purines and Pyrimidines DNA And RNA Dihydro -folic acid Synthetase Dihydro -folic acid reductase RNA Polymerase tRNA + Amino Acids Ribosome unit (50S) Ribosome unit (30S) Protein Synthesis mRNA Sulphonamides (PABA analogue and inhibitor of DHFAS) Trimethoprim and Pyrimethamine (inhibitor of DHFAR) Quinolones (Inhibitor of DNA gyrase and Topoisomerase IV) Rifampicin (inhibitor of DNA dependant RNA Polymerase) Chloramphenicol , Macrolides (50S) Aminoglycosides , Tetracyclines (30S) 3 4 5 6 7 8

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Cell Wall synthesis inhibition- Beta- lactams , Vancomycin , Cycloserines Cell membrane Leakage- Polypeptides, Polyenes PABA Dihydrofolic acid Tetrahydrofolic acid Purines and Pyrimidines DNA And RNA DNA unwinding (DNA gyrase ) Threads sepeartion ( Topoisomerase IV) RNA Polymerase mRNA tRNA + Amino Acids Ribosome unit (50S) Ribosome unit (30S) Protein Synthesis Dihydro -folic acid Synthetase Dihydro -folic acid reductase DNA multiplication Sulphonamides (PABA analogue and inhibitor of DHFAS) Trimethoprim and Pyrimethamine (inhibitor of DHFAR) Quinolones (Inhibitor of DNA gyrase and Topoisomerase IV) Rifampicin (inhibitor of RNA Polymerase) Chloramphenicol , Macrolides (50S) Aminoglycosides , Tetracyclines (30S) 1 2 3 4 5 6 7 8

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1 2 3 4 5 6 7 8

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ANTIBIOTICS Dose-dependent (With PAE) Time-dependent Antibacterial effect directly depends on their concentrations in the locus of in fection (high doses 1-2 times/24h) Aminoglycosides F lu or oq inolones Metronidazol Amphoter i cin B Effectiveness depends on a period of time, during which concentration in blood overwhelms MIC for a particular causative agent (constant i.v . infusion or 3-6 times/24h) Beta-lactames Glycopeptides Macrolides Tetracyclines Vancomycin

Post-Antibiotic Effect:

Post-Antibiotic Effect The capacity to inhibit the growth of bacteria after removal of the drug from the culture (body) P rovides additional time for the immune system to remove bacteria that might have survived antibiotic treatment before they can eventually regrow after removal of the drug.

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Cell mebrane Polypeptides and Polyenes Polymyxin , Colistin , Bacitracin , Nystatin , Amphotericin -B, Hamycin Cell Wall synthesis by acting on cross linking Penicillins , Cephalosporins , Monobactams , Carbapenems , Vancomycin , Teicoplanin , Cell wall synthesis by acting on inhibition of mycolic acid (Long Fatty acid present in mycobacterial family) Isoniazide , Pyrizinamide , Ethambutol Interfering with folic acid metabolism Sulphonamides - Sulfamethoxazole , Sulfadoxine , Diaminopyrimidines - Trimethoprim , Pyrimethamine DNA gyrase and topoisomerase IV inhibitors Quinolones - Nalidixic acid, ciprofloxacin, Ofloxacin , Pfloxacin , Gatifloxacin , Sparfloxacin Inhibition of DNA dependeant RNA Polymerase Rifampicin , Acting on 50S ribosome Macrolides - Erythromycin, Clarithromycin , Azithromycin , Roxithromycin , Chloramphenicol , Lincomycin , Clindamycin , Linezolid Acting on 30 S ribosome Aminoglycosides - Streptomycin, Gentamycin , Kanamycin , Amikacin , Tobramycin Tetracyclines - Oxytetracycline , Doxycycline Antibacterial - Co- trimoxazole Antimalarial - Co- trimazine 1 2 3 4 5 6 7 8 2

Mechanisms Of Resistance:

Mechanisms Of Resistance Resistance Intrinsic Acquired Mutation Transferred Conjugation Transformation Transduction Not Dangerous/ less clinical importance Dangerous/ clinical importance

Inherent Resistance (Not Much of clinical importance):

Inherent Resistance (Not Much of clinical importance) Bacteria naturally resistant e.g ., Gram-negative bacteria resistant to penicillins Genes transferred to the bacterial progeny. Bacteria may be resistant because No mechanism to transport the drug into the cell. Do not contain antibiotic’s target process or protein.

Acquired Resistance:

Acquired Resistance Due to exposure of antimicrobials Horizontal evolution: Resistance genes pass from resistant to nonresistant strain, Antibiotics- a selective pressure. Gene transfer mechanisms: Conjugation. Transduction. Transformation.

Cellular Resistance:

Cellular Resistance ATTACK OF THE SUPERBUGS: ANTIBIOTIC RESISTANCE By Grace Yim, Science Creative Quarterly. Jan 07

Mechanisms of Resistance:

Mechanisms of Resistance Enzyme-based resistance – Break down of antimicrobials. Ribosomal modifications – Methylation of ribosome interferes with antibiotic binding . Protein modifications – Mutations leave target protein unrecognizable to antibiotic Metabolic resistance – Overcome competitive inhibition by alternate pathway. Efflux– Pumps antimicrobials out.

Resistance to Antibiotics:

Resistance to Antibiotics

Resistance in some antibiotics:

Resistance in some antibiotics Beta- lactams : - Hydrolysis , mutant PBP Tetracycline: - Active efflux from the cell Aminoglycosides - Inactivation by enzymes Sulfonamides- Alternate pathway, Fluoroquinolones - Mutant DNA gyrase Chloramphenicol - Reduced uptake into cell Macrolides - RNA methylation, drug efflux

Factors favoring Resistance:

Factors favoring Resistance Prescription related factors: Overuse Early discontinuation Over continuation Less dose, duration Livestock doping : Animals exposure

Superbugs (Microorganisms with multiple resistance) :

Superbugs (Microorganisms with multiple resistance) MRSA - Methicillin - resistant Staphylococcus aureus VISA - V ancomycin intermediate resistant Staphylococc і VRE - Vancomycin - resistant enterococci ESBLs - Extended-spectrum beta- lactamases (microorganisms – resistant to cephalosporins and monobactams ) PRSP - Penicillin-resistant Streptococcus pneumoniae MRPA (MDR-PA)- Multidrug resistant Pseudomonas aeruginosa MRAB (MDR-AB) - Multidrug resistant Acinetobacter baumannii

Why worry?:

Why worry? MDRO are dangerous Difficult to treat More virulent Increase mortality and morbidity Resource-intensive More expensive and toxic antibiotics Increase length of hospitalization Increase demand for isolation-facilities

The number of new antibiotics is falling:

The number of new antibiotics is falling

General-Adverse effects of antimicrobials :

General-Adverse effects of antimicrobials Hypersensitivity reaction- Penicllins , Sulphonamides , Fluoroquinolones , Tetracyclines , Nitrofurantoin Skin rashes , Angioedema , Bronchospasm Anaphylaxis, Management with OASIS O xygen, A drenaline {Physiological antagonist of histamine} A ntihistaminics S teroid , I V fluid S upportive ,

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Gastrointestinal symptoms- Nausea, Gastric irritation , Anorexia , Flatulence , indigestion, Altered GI motility, Mouth ulcers, Glossititis , Stomatitis , Chelitis Esophagitis , Mal-absorption syndrome Tetracyclines , Quinolones , Ampicilline , Metronidazole

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Injectable Side effects- Pain, Abscess formation, Thrombo -phlebitis in case of IV Flushing, redness in case of rapid IV, Deficiency- V itamin B complex and Vitamin K , Deficiency of drugs which need entero -hepatic recirculation for their effect e.g . Oral contraceptives

Superinfections :

Superinfections New infection Most common organisms Pseudomonas Candida Proteus Clostridium difficle - Pseudomembranous Colitis Due to removal of inhibitory mechanisms ( Bacteriocins and competition for nutrition) Common C lindamycin , C otrimoxazole , C hloramphenicol , A mpicillin , T etracyclines (CAT) Immunosuppressant, Diabetes mellitus Abdominal surgery Treated by Metronidazole , Vancomycin , Bacitracin

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CNS- Headache, Irritability , Sedation , Tinnitus , Ataxia , Slurred speech, Blurring of vision, .

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Masking of infections- eg . Tt Gonorrhea mask Syphilis Idiosyncratic and Intolerance- Drug Fever- Electrolyte imbalance- Teratogenic - No antimicrobial is absolutely safe during pregnancy No one is Category A. Category B, C and D can be given under special situation. Category X absolutely contraindicated to pregnant

FDA Categorization of Drugs in Pregnancy:

FDA Categorization of Drugs in Pregnancy Category A (No antibiotic is under this) Controlled studies in women fail to demonstrate a risk Category B (Safe can be prescribed) Either animal-reproduction studies have not demonstrated or not confirmed in controlled studies in women Category C (Under special circumstance) Either studies in animals have revealed or studies in women and animals are not available. Category D (Under special circumstance with consent) There is positive evidence of human fetal risk, but the benefits may be acceptable despite the risk Category X (Not prescribed) Studies in animals or human beings have demonstrated fetal abnormalities and contraindicated

Antibiotics in Pregnancy:

Antibiotics in Pregnancy FDA Category Antibiotics in Category A B Penicillins , Cephalosporins , Carbapenems (except Imipenem ), Daptomycin , Vancomycin (oral), Clindamycin, Erythromycin, Azithromycin , Metronidazole (avoid first trimester), Nitrofurantoin , Acyclovir, Amphoterocin B, Ethambutol C Quinolones, Chloramphenicol, Clarithromycin, Imipenem, Linezolid, Trimethoprim/Sulfa (D if used near term), Vancomycin (IV), Rifampin, INH, PZA, PAS, Fluconazole, Caspofungin D Tetracyclines (Doxy, Tige, Mino), Voriconazole, Aminoglycosides (some put gentamicin as a category C) X Ribavarin

Specific Side effects of antimicrobials :

Specific Side effects of antimicrobials Bone marrow suppression- Chloramphenicol , Thrombocytopenia- Sulphonamides Cephalosporins , ( Cefamandole , Cefoperazone , Cefotetam ), Chloramphenicol Renal toxicity- Aminoglycosides , Tetracyclines except Doxycycline , Cephalothin , Talampicillin , Nitrofurantoin , Nalidixic acid, Amphotericin B, Vancomycin , Ethambutol , Flucytosine , Methacillin ,

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Hepatotoxicity - Rifampicin , Isoniazide (in fast acetylators due to accumulation of Acetyl – isoniazide and acetyl – hydrazine) Pyrazinamide , Tetracycline, Erythromycin estolate , Talampicillin , Nalidixic acid, Trovafloxacin Oxacillin , Photoxicity - Tetracyclines ( Demeclocycline , Doxycycline ), Quinolones ( Sparfloxacin )

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Ototoxicty - Aminoglycosides , Vancomycin Diabetes insipidus - Demeclocycline Neuromuscular block- Amino-glycosides, Polymyxin - B, Colistin (May cause respiratory paralysis in patients of Myasthenia gravis, Gaping of wound)

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Retinal damage- Chloroquine Neuropathy- Isoniazide - more in slow acetylators Due to increased excretion of pyridoxine in urine and Accumulated INH inhibits pyridoxine- kinase ( Pyridoxine Kinase converts pyridoxine to active form pyridoxyl phosphate) Polypeptide antimicrobials, Amphotericin B, Nitrofurantoin , Carbenicillin

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Haemolysis (G-6-PD deficiency), - X-Linked recessive. G-6-P-D is required for regeneration of NADPH. NADPH is required for reduction of oxidized glutathione Reduced glutathione protects –against oxidative injury In presence of pro-oxidants like Naphthalene, Methylene Blue, Beans ( Favism ) Drugs- S ulfa drugs, P rimaquine , I soniazide , N itrofurantoin , N alidixic acid, D apsone , Furazolidione , Quinolones , Chloramphenicol , Chloroquine , Aspirin, Haemolysis occurs G-6-P-D Glutathion reductase Glutathione Glutathione disulphide NADP NADPH S P I N D elivery

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Discolouration of Teeth and bone damage- Tetracyclines Redman (Red neck) Syndrome- Vancomycin , Teicoplanin , Discolouration of secretions (saliva, sweat, urine)- Rifampicin , Clofazimine , Nitrofurantoin Kernicterus - Sulphonamides , Rifampicin Flu-like syndrome- Rifampicin Antitestosterone effect- Ketoconazole (reduces synthesis of testosterone and estradiol which leads to gynaecomastia )

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Crystaluria - Sulphonamides Antianabolic effect- Tetracycllines Cholestatic jaundice- Erythromycin estolate , Nitrofurantoin , Fosfomycin , Optic neuritis- Ethambutol Tendon rupture- Fluroquinolones

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Hyperuricemia - Pyrazinamide (Gout) Jarisch Herxheimer Reaction- Penicillin in syphilis Neuromuscular blockadage - Amino-glycosides Alopecia- All anti-cancer drugs Fanconi’s Syndrome- (Renal toxicity)- Expiry date tetracyclines - due to toxic metabolites epitetracycline Teratogenic - Aminoglycosides , Tetracyclines Pulmonary eosonophilic syndrome- Tetracylines

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Pseudotumor cerebri - and bulging fontanelles - Tetracyclines Vestibular toxicity- Minocycline Disulfiram like reaction – ( G ood C hief M inister) G riseofulvin , C efoperazone , C efotetan , C efamandole , M etronidazole ,

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Grey Baby Syndrome- (Ashen Grey Cyanosis)- Chloramphenicol Pulmonary Fibrosis- Bleomycin, Nitrofurantoin Special- Gatifloxacin Prolongs QT interval and arrhythmia Hypo or hyperglycemia in patients of diabetes. Aminoglcosides have NONE side effects- N euromuscular block (more with Neomycin and Streptomycin), O totoxicity (Vestibular by Streptomycin, Gentamicin while Cochlear by Neomycin, Amikacin), N ephrotoxicity least with Streptomycin, E tc. Teratogenic) High dose of Ceftriaxone Pseudo-lithiasis (Gall bladder sludge)

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Mafenide Has carbonic anhydrase inhibitor activity- May alkalinize urine and cause acidosis Hyperventilation . 8-Hydroxy-quinoines ( Iodochloro-hydroxyquinol ,) SMON ( Subacute myelo -optic neuropathy) Arrhythmia- Quinolones , Macrolides Antianabolic effect (reduce protein synthesis)- Tetracyclines



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