1、1,SYSTEMS PHARMACOLOGY Chemotherapy of Infection: Part I,Dr Dhaya PerumalLondon Metropolitan UniversityDept. Health & Human SciencesTower Building: Room T13-10Telephone: 020 7133 4195d.perumallondonmet.ac.uk,2,Pathogenic (Infectious) Organisms,Are those organisms that cause diseases in human beings/
2、 animalsTypes of pathogenic organisms:1. MicrobesBacteria, fungi and viruses 2. Parasites Protozoa and helminthes (worms),3,Chemotherapeutic agents,Are naturally occurring or chemically synthesized substances intended to be toxic for the pathogenic organisms but innocuous to the hostAim- To treat ac
3、ute, severe, persistent or progressive infectious disease,4,Factors contributing to microbial threats to health,Microbial adaptation and change Human susceptibility to infection Climate and weather Changing ecosystem Human demographics and behaviour Economic development and land use International tr
4、avel and commerce,5,Factors contributing to microbial threats to health (Contd.),Technology and Industry Breakdown of Public Health Measures Poverty and Social Inequality War and famineLack of Political will Intent to harm (e.g. weapons of mass destruction),6,Classic Definition: Antibiotic,(from Gre
5、ek, anti against, bios life) A natural substance, or derivative of a natural substance, which when taken in small doses will either kill or prevent the growth of a microorganism, but will not seriously harm the person taking it,7,Antibiotic-producing microorganisms,Penicillium and Cephalosporium Bet
6、a-lactam antibiotics: penicillin and cephalosporinActinomycetes, Streptomyces speciesTetracyclines AminoglycosidesMacrolides ChloramphenicolBacillus species Polypeptide antibiotics: polymyxin and bacitracin,8,Definition (Modified): Antibiotics/Antibacterials/Antimicrobials,Any chemical compound used
7、 to kill or inhibit the growth of infectious organisms, particularly bacteria and fungiAll antibiotics share the property of selective toxicity: they are more toxic to an invading microorganism than to the animal/human host,9,Choice of suitable drug,Two considerations: 1. Patient - history of allerg
8、y- renal/hepatic function- susceptibilty to infection- ability to tolerate by mouth- severity of illness- ethnic origin- age- other medication- pregnancy, breast-feeding, OC use,10,Choice of suitable drug contd.,2. Known or likely causative organism- antibacterial sensitivityFinal choice depends on
9、microbiological, pharmacological and toxicological properties,11,Rational approach to selecting drug,Example: to treat UTI in a pregnant patient who has nausea. The organism found to be resistant to ampicillin but - sensitive to nitrofurantoin (can cause nausea)- gentamycin (only by injection and av
10、oided in pregnancy)- tetracycline (dental discolouration)- trimethoprim (teratogenic) and - cefalexin Safest in pregnancy is penicillins and cephalosporins Therefore cefalexin indicated for this patient,12,Spectrum of Activity,A. Broad spectrum of activityAn antimicrobial drug that is effective agai
11、nst a large variety of microorganisms ADVANTAGES: A high degree of efficacy against an unidentified pathogen DISADVANTAGES:A high likelihood of the drug also destroying the friendly/helpful bacteria making up an individuals normal microbial flora,13,Spectrum of Activity (Contd.),B. Narrow spectrum o
12、f activityAn antimicrobial drug that is effective against only a relatively small subset of bacteria,14,Effects of Antimicrobials,A. Bactericidal (kill)Interaction results in an irreversible disruption or binding cell death B. Bacteriostatic (inhibit growth)Interaction effect involves lower affinity
13、 binding and is reversible when the antibacterial is removed from the environment,15,DIAGNOSTIC STAINING TECHNIQUE,Gram Positive Bacteria : BLUE Gram Negative Bacteria : RED,16,17,DIAGNOSTIC STAINING TECHNIQUE (Contd.),Ziehl-Neelsen Stain (Acid-fast bacteria)Bacteria + Carbofuchsin (bring to boil 3
14、times) HCl + Alcohol (1-2 min) Alkaline methylene blue (3 min)RESULT:- Acid-fast bacilli: RED- Other bacteria: BLUE,18,Spectrum of Antibacterials,Gram Negative Bacteria Acid fast BacteriaAerobic requires oxygen Anaerobic does not require oxygen,19,Sensitivity Test,Antibiotic sensitivity determined b
15、y size of inhibition zone,20,Mode of action of antibacterials,21,Bacterial cell wall structure,Gram Negative,Gram positive,22,Mode of action of antibacterials,Inhibition of cell wall synthesis Disruption of cell membrane function Inhibition of protein synthesis Inhibition of nucleic acid synthesis A
16、ction as antimetabolites,23,Major modes of action of drugs,24,A. Inhibition of cell wall synthesis,Most bacteria have peptidoglycan-based cell walls (mammals do not) Successful cell wall synthesis by these bacteria is impossible in the absence of peptidoglycan synthesis In the absence of cell wall i
17、ntegrity, most bacteria are susceptible to osmotic lysis,25,26,27,Beta-lactam antibiotics: Penicillins and Cephalosporins,Stereochemically related to D-alanyl-D-alanine, which is a substrate for the last step in peptidoglycan synthesis Block the final transpeptidation (cross-linkage of pentapeptide
18、side chains),28,29,30,Glycopeptides: Vancomycin,covalently bind to the terminal two D-alanine residues at the free carboxyl end of the pentapeptide Sterically hinder the elongation of the peptidoglycan backbone,31,Polypeptide: Bacitracin,Blocks the dephosphorylation of the lipid carrier Cycloserine
19、by competitive inhibition, the drug prevents the addition of the two terminal alanines to the initial tripeptide side-chain on N-acetylmuramic acid,32,B. Disruption of cell membrane function,Damage to cytoplasmic membrane Increase permeability by disorganizing the structure or inhibiting the functio
20、n of bacterial membranes- Polymyxins- Nystatin- Amphotericin B- Imidazoles,33,C. Inhibition of protein synthesis,The bacterial ribosome and the animal ribosome differ structurally Inhibition of some step in the complex process of protein synthesis Attack on specific ribosomesTetracyclinesInterferes
21、with the attachment of t-RNA to m-RNA-ribosome complex preventing the addition of new amino acids to the growing peptide chain,34,Protein synthesis,35,C. Inhibition of protein synthesis (Contd),Chloramphenicol - Binds to the 50S portion and inhibits formation of peptide bondsMacrolides, Fusidic Acid
22、 - Binds to the 50S portion and prevents the translocation of ribosome along mRNA Aminoglycosides - Changes the shape of the 30S portion causing the misreading of code on mRNA,36,37,D. Inhibition of nucleic acid synthesis,Quinolones - Inhibit DNA gyrase activity (DNA gyrase topoisomerase II- is esse
23、ntial for DNA replication and allows supercoils to be relaxed and reformed)Rifampicin Inhibit RNA synthesis by inhibiting DNA-dependent RNA polymerase,38,E. Action as antimetabolites,Inhibit the bacterial enzymes required for the synthesis of folic acid (tetrahydrofolic acid, THF)Sulfonamides: struc
24、turally similar to para aminobenzoic acid (PABA), the substrate for the first enzyme in the THF pathwayTrimethoprim: structurally similar to dihydrofolate (DHF) and competitively inhibits the second step in THF synthesis mediated by the DHF reductase,39,SIDE-EFFECTS,Toxicities: inability of drug to
25、completely distinguish host physiology from pathogen physiologyAllergiesNormal flora disruptions,40,Antibiotic Resistance,1. Evasion - The organism may enter or be present in an antimicrobial-resistant state such that all members of a population are destroyed by the antimicrobial except those that h
26、appen to be in the resistant state (e.g. endospores),41,Antibiotic Resistance Contd.),2. organism may become mutated such that the site of action of the antimicrobial is no longer affected by it (a mutation affecting ribosome structure) typically resistant to only a single type of antibiotic,42,Anti
27、biotic Resistance (Contd.),3.Extrachromosomal antibiotic resistance (acquired antibiotic resistance) Is associated with resistance (R) plasmids Does not involve the mutation within a given bacteria to antibiotic resistance but instead the acquisition of resistance plasmids from other bacteria Involv
28、es an inactivation of the antibiotic or a prevention of entry rather than a change in the structure of the antibiotic target,43,The “Super Bug” Issue,MRSA (methicillin-resistant Staphylococcus aureus) Resistance developed against - Beta-lactam antibiotics- Aminoglycosides (Streptomycin)- Macrolides-
29、 Chloramphenicol- Sulphonamides (Sulpamethoxazole + Trimethoprim)- Rifampicin- Fusidic Acid- Quinolones Vancomycin was the last resort against it but resistance has also developed,44,Limiting Antibiotic Resistance,Should be employed only when necessary (now often used indiscriminately and to excess)
30、 High concentrations of drug should be maintained over long periods (i.e. taking all of ones pills over prescribed duration of treatment) Two antibiotics administered simultaneously may be capable of synergism when necessary,45,Combinations of antimicrobial agents,Necessary when:- Treating a life-th
31、reatening infection- Preventing the emergence of resistance- Treating a mixed infection- Enhancing antibacterial activity- Using lower concentrations of a toxic drug,46,Common Uses of Antibiotics,a. Gastro-intestinal system (Invasive salmonellosis, Typhoid fever, Biliary tract, Peritonitis) b. Cardi
32、ovascular system (Endocarditis) c. Respiratory system (Chronic bronchitis, Pneumonia) d. Central nervous system (Meningitis caused by Meningococci, Pneumococci, Haemophilus influenzae, Listeria) e. Urinary tract (Acute pyelonephritis or prostatitis, Lower urinary tract infection),47,Common Uses of A
33、ntibiotics (Contd.),f. Genital system (Syphilis, Gonorrhoea, Uncomplicated genital chlamydial infection, Urethritis or pelvic inflammatory disease) g. Blood (Septicaemia, Meningococcal septicaemia) h. Musculoskeletal system (Septic arthritis, Osteomyelitis) i. Eye, ear, nose and oropharynx (Conjunct
34、ivitis, Sinusitis, Otitis media, Throat, Dental infection) j. Skin (Acne, Cellulitis, animal/insect bite),48,Common antibacterials,Beta-lactam Antibiotics A. Penicillins Natural penicillins Penicillinase-resistant penicillin Amino Penicillin Antipseudomonal Penicillin,49,1. Natural Penicillins,Penic
35、illin G (Benzyl) Penicillin G sodium/potassium Penicillin G procaine Penicillin G benzathine Penicillin V (Phenoxymethyl-),50,2. Penicillinase-Resistant Penicillins,Cloxacillin Orbenin Dicloxacillin Diclocil Methicillin Pyopen Nafcillin Oxacillin,51,3. Amino Penicillins (broad spectrum),Amoxacillin
36、(Amoxil) Ampicillin (Penbritin) Bacampicillin (Penglobe) Pivmecillinam Pivampicillin,52,4. Antipseudomonal Penicillins,Carbenicillin indanyl sodium (Geopen) Mezlocillin Piperacillin (Pipracil) Ticarcillin (Timentin),53,Beta-lactamase,54,Beta-lactamase inhibitors,1. Fixed Combination Only- Clavulanic
37、 Acid- Tazobactam2. Free combination possible- Sulbactam,55,B. Cephalosporins,a. Ist generation b. 2nd generation - with Haemophilus influenzae and Bacteroides fragilis activity c. 3rd generation - with Pseudomonas aeruginosa activity d. 4th generation,56,a) Ist generation,Parenteral form - Cephalot
38、hin (Keflin)- Cefazolin (Cefamezin)- Cefaprin (Lopitrex)Oral form - Cefadroxil (Duracef)- Cephalexin (Keflex, Ceporex)- Cephradine (Velosef),57,b). 2nd generation,Parenteral form - Cefmetazole (Cefmetazon)- Cefonicid (Monocid)- Cefoperazone (Cefobid)- Cefoxitin (Mefoxin) Oral form - Cefaclor (Ceclor
39、)- Cefamandole (Mandol)- Cefetamet pivoxil (Globocef)- Cefprozil (Procef)- Cefuroxime axetil (Zinnat)- Loracarbef (Lorabid),58,c). 3rd generation,Parenteral form - Cefotaxime (Claforan)- Ceftazidime (Fortum)- Ceftriaxone (Rocephin)Oral form - Cefixime- Cefpodoxime Proxetil (Banan)- Ceftibuten (Cedax
40、),59,d). 4th generation,Parenteral Form - Cefepime (Maxipime)- Cefpirome (Cefrom),60,Tetracyclines,Cause dental staining and hypoplasia; Absorption is affected by milk, iron preparations, antacids (Ca2+, Mg2+, Fe2+ ions); Drug of choice for chlamydia, rickettsia, brucella and spirochaete; E.g. Tetra
41、cyclines - Doxycycline (Vibramycin), Minocycline (Minocin), Oxytetracycline (Terramycin), Tetracycline (Achromycin),61,Quinolones,For complicated urinary tract infections (Not recommended for those aged 12 years)a. Nalidixic Acid - Nalidixic Acid (Wintomylon), Pipemidic Acid (Urotractin) b. Fluoroqu
42、inolones - Ciprofloxacin (Ciproxin), Levofloxacin (Cravit), Lomefloxacin (Maxaquin), Moxifloxacin (Avelox), Norfloxacin (Lexinor), Ofloxacin (Tarivid),62,Extended spectrum,Pefloxacin (Peflacine) Sparfloxacin (Zaglam) Trovafloxacin (Trovan),63,Macrolides,Azithromycin Clarithomycin Roxithromycin Eryth
43、romycin,64,Sulphonamides,Sulfadiazine Sulfamethoxazole Sulfisoxazole Trimethoprim + Sulfamethoxazole,65,Aminoglycosides,Usually in parenteral form Can cause serious ototoxicity and nephrotoxicity Amikacin (Amikin) Gentamicin (Garamycin) Kanamycin (Kanamycin) Netilmycin (Netromycin) Streptomycin Tobramycin (Nebcin),66,Chloramphenicol,Reserved for typhoid fever Causes serious blood disorderLincosamides Clindamycin (Dalacin-C) Pseudomembranous colitis (antibiotic associated) Lincomycin (Lincocin),
