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Basic principles of chemotherapy,The Development of Chemotherapy,Molecular basis of chemotherapy ,Biochemical reaction as potent targets,Antimicrobial Drugs,Mechanisms of action of Antibacterial Drugs,Aminoglycosides,Macrolides,Tetracyclines,Chloramphenicol,Sulphonamides,Antibacterials – Competitive Inhibitors,Quinolones (GABA antagonists),Antiviral Drugs,Drugs that Inhibit Nucleic Acid Synthesis
Nucleoside and Nucleotide Analogs
aminoglycosides, antibacterials – competitive inhibitors, antimicrobial drugs, antiviral drugs, basic principles of chemotherapy, biochemical reaction as potent targets, chloramphenicol, drugs that inhibit nucleic acid synthesis
nucleosi, macrolides, mechanisms of action of antibacterial drugs, molecular basis of chemotherapy, quinolones (gaba antagonists), sulphonamides, tetracyclines, the development of chemotherapy,

Basic principles of chemotherapy,The Development of Chemotherapy,Molecular basis of chemotherapy ,Biochemical reaction as potent targets,Antimicrobial Drugs,Mechanisms of action of Antibacterial Drugs,Aminoglycosides,Macrolides,Tetracyclines,Chloramphenicol,Sulphonamides,Antibacterials – Competitive Inhibitors,Quinolones (GABA antagonists),Antiviral Drugs,Drugs that Inhibit Nucleic Acid Synthesis
Nucleoside and Nucleotide Analogs
aminoglycosides, antibacterials – competitive inhibitors, antimicrobial drugs, antiviral drugs, basic principles of chemotherapy, biochemical reaction as potent targets, chloramphenicol, drugs that inhibit nucleic acid synthesis
nucleosi, macrolides, mechanisms of action of antibacterial drugs, molecular basis of chemotherapy, quinolones (gaba antagonists), sulphonamides, tetracyclines, the development of chemotherapy,

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Basic Principles of Chemotherapy

  1. 1. BASIC PRINCIPLES OF CHEMOTHERAPY Mr. Vijay Salvekar Dept. of Pharmacology GRY Institute of Pharmacy, Borawan
  2. 2. CHEMOTHERAPY: Is a term that applies to the use of both natural and synthetic chemicals to interfere with the functioning of the foreign cell population. The Synthetic chemical substances used to inhibit or destroy microorganisms. (ie bacteria). The term is used for both treatment of cancer and treatment of Infection.
  3. 3. 19th Century LOUIS PASTEUR & ROBERT KOCH: Identified bacteria as causative agent of disease. (Germ theory) (Now know what is causing disease, need to find out how to stop it) 1877 Pasteur: Soil bacteria injected into animals made Anthrax harmless 1888 de Freudenreich: Isolated product from bacteria with antibacterial properties. Toxic and The Development of Chemotherapy
  4. 4.  Early 20th century  1904: Paul Ehrlich is pioneer researcher found that the dye trypan red was effective against Trypanosoma (sleeping sickness)  Arspheniamine against syphilis  1st antibacterial, only cured syphilis.  Systemic infection : Blood stream  Enunciated : 1906 Therapia Sterilizans Magna  Published :Magic Bullet
  5. 5. Paul Ehrlich: Quinine : Malaria Various Dyes (Gentian Violet); Disinfectants Heavy Metals : Antimicrobial Agents Fight against systemic infection and acknowledged as the Father Of Chemotherapy
  6. 6.  Sulfa drugs:  1927: Domagk discovered that the dye Prontosil Red was effective against staphlococcal and streptococcal infections; later in 1935 it was found that Protonsil red was converted to sulfonamide in the body  Penicillin  Produced by Penicillium notatum  Discovered in 1928 by Fleming  Method of mass production developed in late 1930s - early 1940s by Chain and Florey
  7. 7.  Streptomycin  Produced by Streptomycin griseous  Discovered in 1944 by Waksman after screening 10,000 soil isolates  Following its discovery was the discovery of other antibiotics produced by soil microbes, including chloramphenicol, neomycin, terramycin, and tetracyclin by the early 1950s
  8. 8. •Selective toxicity •Ability of chemical strike selectively at foreign cell and harm them without causing significance damage to host cells. •Drug must inhibit microorganism at lower concentrations than those that produce toxic effects in humans •No Chemotherapy is completely safe
  9. 9. CHEMOTHERAPEUTIC INDEX: •Maximally Parasitotropic •Minimally Organotropic
  10. 10. Antibiotic : A chemical that is produced by one microorganism and has the ability to harm other microbes. Bacteriostatic activity: Ability of compound to inhibit the growth and multiplication of organism. Bacteriocidal activity: Actually killing effect on the microorganism Antibiotic spectrum: Broad Narrow
  11. 11.  Selective toxicity  Therapeutic dose  Toxic Dose  Therapeutic Index  Side Effects  Narrow-Spectrum  Broad Spectrum  Cidal vs Static  Minimal Inhibitory Concentration  Minimal Lethal Concentration
  12. 12.  1- Wrong Diagnosis 2- Wrong Choice Of Drug 3- Wrong Dose 4- Development Of Resistance 5- Infections With More Than One Organism 6- Presence of Pus ,Blood ,Necrotic Tissues .
  13. 13. Microbs: Bacteria, viruses, fungi, Parasites: Protozoa, helminths Living Organism Are Classified : Prokaryotic : Cell Without Nuclei. Ex. Bacteria Eukaryotic : Cell With Nuclei ex. Protozoa, fungi,helminths 
  14. 14. Bacteria cause more infectious disease than any other parasites. Simplicity well-developed cell structure .
  15. 15. •Synthesis Of The Main Type Of Macromolecules
  16. 16. BIOCHEMICAL REACTION AS POTENT TARGETS Class I reaction: Not Promising Targets : 2 Reason 1st :- No Diffence b/w Bacteria And Human Cell Mechanism for Obtaining Energy {Glucose} ex. By EMP Pathway And TCA Cycle 2nd :- Glucose Pathway Blocked and Other Coumpound Used By Bacteria{ AA , Lactate}
  17. 17. Class II Reaction : Better / Potent Target • Essential Amino Acid Responsible For Growth Ex. Synthesis Of Folate : Required For DNA Synthesis In Human: Obtain From Diet/Not Sythesise In Bacteria: Synthesis Own Folate
  18. 18. CLASS III REACTION : Good Target { Macromolecules }With Selective Toxicity Formation of skeleton , Protect from osmotic disruption{3 to 5 times}
  19. 19. 1.Inhibition of bacterial cell wall synthesis/Peptidogylcan
  20. 20. Bacterial Cell Wall: Peptidoglycan
  21. 21. www.uccs.edu/
  22. 22. Cell Membrane semipermiable Function With Very Selective Permiability { Tripple Layered Lipoprotien Structure } Locate: b/w cytoplasm and cell wall Function:maintain Osmotic Pressure And Barrier Rapid Release Of Small Molecules From Interior Barrier b/w External ATM Increase Permiability :Result Cell {Disorganizing Cell Function}
  23. 23. Protein synthesis DNA mRNA Protein transcription translation Ribosome is a protein factory in bacteria takes mRNA in and produces proteins from them. Bacterial ribosome has 2 parts: 30S binds to mRNA to translate mRNA into amino acids, which form Proteins 50S required for Peptide Elongation
  24. 24. • 3 phases from mRNA to protein Initiation Elongation Termination Disruptive effect on many essential bacterial functions leading to cell death
  25. 25. 1. Inhibition The Synthesis of The Nucleotides: for class II reaction 2.Altering The Base Pairing Properties of The Templet: Framshaft mutation= misreading addition of extra base
  26. 26. 3.Inhibiting Either DNA or RNA Polymerase: Drugs bind to Guanine in DNA and block the movement of RNA polymerase prevent transcription leads to inhibit protein synthesis 4.Inhibition Of DNA Gyrase: chromosome fold around RNA core Supercoiling by DNA gyrase {Topoisomerase II}
  27. 27. 5.Direct Effect On DNA Itself: covalent bond with base{Prevent Replication} Only for cancer chemo. Not for antibacterial agents
  28. 28.  Ability of the drug to reach the site of infection  Route of administration  Rate at which the drug is eliminated from the body  Susceptibility of the pathegen to the drug  Level of the drug must exceed the pathogen’s MIC value at the site of infection
  29. 29. 1. Allergic Reactions: some people develop hypersensitivities to antimicrobials 2. Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects 3. Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers
  30. 30.  Selectively toxic to microbe but nontoxic to host.  Soluble in body- tissue distribution .  Remains in body long enough to be effective - resists excretion and breakdown.  Shelf life.  Does not lead to resistance.  Cost not excessive.  Hypoallergenic.  Microbiocidal rather than microbiostatic.
  31. 31.  Mechanisms of Drug resistance  Origin of Drug Resistance in a microbial population  Drug resistance genes on chromosomes and plasmids  Transmission of resistance genes between bacteria
  32. 32. 30S 1 3 2 GTP 1 2 3 GTP Initiation Factors mRNA 3 1 2 GTP 30S Initiation Complex f-met- tRNA Spectinomyci n Aminoglycoside s 1 2 GDP + Pi 50S 70S Initiation Complex AP
  33. 33. GTP AP Tu GTP Tu GDP Ts Ts Tu + GDP Ts Pi P A Tetracycline AP Erythromyci n Fusidic Acid Chloramphenico l G GTP G GDP + Pi G GDP AP + GTP
  34. 34.  Chemicals used to treat microbial infections  Before antimicrobials, large number of people died from common illnesses  Now many illnesses easily treated with antimicrobials  However, many antimicrobial drugs are becoming less useful
  35. 35.  Chemotherapeutic agent=  Antimicrobial drug=  Different types of antimicrobial drugs:  Antibacterial drugs  Antifungal drugs  Antiprotozoan drugs  Antihelminthic drugs
  36. 36.  Most modern antibiotics come from species of microorganisms that live in the soil  To commercially produce antibiotic: 1. Select strain and grow in broth 2. When maximum antibiotic concentration reached, extract from medium 3. Purify 4. Chemical alter to make it more stable
  37. 37.  Cause greater harm to microorganisms than to host  Chemotherapeutic index: lowest dose toxic to patient divided by dose typically used for therapy
  38. 38.  Bacteriostatic: inhibit growth of microorganisms  Bactericidal: Kill microorganisms
  39. 39.  Antimicrobial medications vary with respect to the range of microorganisms they kill or inhibit  Some kill only limited range : Narrow-spectrum antimicrobial  While others kill wide range of microorganisms: Broad-spectrum antimicrobial
  40. 40.  Combinations are sometimes used to fight infections  Synergistic: action of one drug enhances the activity of another or vice versa.  Antagonistic: activity of one drug interferes with the action of another.
  41. 41. 1. Allergic Reactions: some people develop hypersensitivities to antimicrobials 2. Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects 3. Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers
  42. 42.  Some microorganisms inherently resistant to effects of a particular drug  Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes (more later).
  43. 43.  Selectively toxic to microbe but nontoxic to host.  Soluble in body- tissue distribution – BBB.  Remains in body long enough to be effective - resists excretion and breakdown.  Shelf life.  Does not lead to resistance.  Cost not excessive.  Hypoallergenic.  Microbiocidal rather than microbiostatic.  Concerns suppression of normal flora - antibiotic associated colitis with Clostridium difficule and it’s toxins or Candida albicans.
  44. 44. 1. Inhibit cell wall synthesis 2. Inhibit protein synthesis 3. Inhibit nucleic acid synthesis 4. Injury to plasma membrane 5. Inhibit synthesis of essential metabolites
  45. 45.  Irreversibly inhibit enzymes involved in the final steps of cell wall synthesis  These enzymes mediate formation of peptide bridges between adjacent stands of peptidoglycan  b-lactam ring similar in structure to normal substrate of enzyme  Drug binds to enzyme, competitively inhibit enzymatic activity
  46. 46.  Some bacteria produce b-lactamase- enzyme that breaks the critical b-lactam ring  b-lactam drugs include: penicillins and cephalosporins
  47. 47.  Acid-labile.  Gram+ bacteria.  So, take phenoxymethylpenicillin.  Large Vd, but penetration into brain: poor, except when the meninges are inflammed.  Broad spectrum penicillins: amoxicillin and ampicillin are more hydrophillic and therefore, are active against gram- bacteria.
  48. 48. Penicillinase-resistant penicillins – Flucloxacillin Indicated in infections caused by penicillinase- producing pen-resistant staphlococci. Has an isoxazolyl group at R1  sterically hinders access of the enzyme to the β-lactam ring. Less effective than benzylpen. So, should be used only for pen-resistant infections. Well-absorbed orally, but in severe infections, should be i.v. and not alone. Staphlococci aureas-resistant strains to flucloxicillin and MRSA (methicillin-resistant Staph aureas) – increasing problem.
  49. 49.  Ampicillin and amoxicillin – very active against non-β- lactamase-producing gram+ bacteria.  Because they diffuse readily into Gram- bacteria, also very active against many strains of E. coli, H. influenzae, and Salmonella typhimurium.  Orally, amoxicillin is better because absorption is better.  Ineffective against penicillinase-producing bacteria (e.g., S. aureus, 50% of E. coli strains, and up to 15 % of H. influenzae strains.  Many baterial β-lactamases are inhibited by clavulaic acid ± amoxicillin (co-amoxiclav)  antibiotic is effective against penicillinase-producing organisms.  Co-amoxiclav indicated in resp and UT infections, which are confirmed to be resistant to amoxicillin.
  50. 50.  Used for treatment of meningitis, pneumonia, and septicemia.  Same mech and p’col as that of pens.  May  allergic rxn and cross-reactivity to pen.  Similar to pens in broad-spectrum antibacterial activity. Cedadroxil (for UTI) in case of antibact resist. Cefuroxime (prophylactic in surgery) – Resistant to inactivation by β-lactamases and used in severe infections (others ineffective). Ceftazidine – wide range of activity against gram- including Pseudomonas aeruginosa), but is less active than cefurozime against gram+ bact (S aureus). Used in meningitis (CNS-accessible) caused by gram- bacteria.
  51. 51.  Not well absorbed orally.  Inhibits peptidoglycan formation.  Active against most gram+ organisms.  I.v. treatment for septicemia or endocarditis caused by MRSA.  Used for pseudomembranous colitis (superinfection of the bowel by Clostridium difficile – produces a toxin that damages the colon mucosa)
  52. 52. Antibacterial Drugs that Inhibit Cell Wall Synthesis
  53. 53.  Target ribosomes of bacteria  Aminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translation  Tetracyclines: bind to 30S subunit blocking attachment of tRNA.  Macrolides: bind 50S subunit and prevents protein synthesis from continuing.
  54. 54.  Against many gram- and some gram+.  Narrow TI – very potentially toxic.  Most important adverse side-effect: VIIIth cranial n. (ototoxicity) and kidney damage.  Resistance – several mechs: inactivation of the drug by acetylation, phos, or adenylation, Δ envellope to prevent drug access, and Δ the binding site of the 30S subunit (streptomycin only).
  55. 55.  Gentamicin – used for acute, life-thretening gram- infections. Has synergism with pen and van and combo.  Amikacin – used for bact that are gent-resistant.  Netilmicin – less toxic than gentamicin.  Neomycin – too toxic for parenteral use. Used for topically for skin infections and orally for sterilizing bowel before surgery.  Streptomycin – active against Mycobacterium tuberculosis. But bec of its ototoxicity, rifampicin replaces.  Rifampicin – resistance develops quickly alone; so, with TB, combine with isoniazid, ethambutol, and pyrazinamide for the 1st 2 mos of treatment, followed by another 4 mos with rifampicin and isoniazid.
  56. 56.  Very safe drugs.  Ususally given orally.  Erythromycin and clarithomycin  Effective against gram- bact and can be used as an alt to pen-sensitive patients, esp in infections caused by streptococci, staphylococci, pneumococci, and clostridia.  Don’t cross the BBB – ineffective against meningitis.  Resistance- occurs bec of plasmid-controlled Δ of their receptor on the 50S subunit.  Erythromycin – in high doses, may cause nausea and vomiting (less so with clarithromycin and azithromycin).  Azithromycin – very long t1/2 (~40-60 hr) and a single dose is as effective in treating chlamydial non-specific urethritis as tretracycline admin over 7 days,
  57. 57.  Broad-spectrum.  Penetrate microorganisms well.  Sensitive organisms accumulate it through partly passive diffusion and partly through active transport.  Resistant organisms develop an efflux pump and do not accumulate the drug.  Genes for tet-resistance transmitted by plasmids.  Closely assoc with those for other drugs to which the organisms will also be resistant (e.g., sulphonamides, aminoglycosides, chloramphenicol).  Tets bind to Ca in growing bones and teeth  can discolor teeth. So, should be avoided in children < 8 yrs old.
  58. 58.  Broad-spectrum.  Serious side-effects: bone marrow aplasia, suppression of RBCs, WBCs, encephalopathy, optic neuritis.  So, periodic blood counts required, esp in high doses.  Large Vd, including CNS.  Inhibits the actions of other drugs and may incr the actions of phenytoin, sulphonlureas, and warfarin.  Neonates cannot met the drug rapidly  accum  ‘grey baby’ syndrome (pallor, abdominal distension, vomiting, and collapse).
  59. 59. Antibacterial Drugs that Inhibit Protein Synthesis
  60. 60.  Target enzymes required for nucleic acid synthesis  Fluoroquinolones: inhibit enzymes that maintain the supercoiling of closed circular DNA  Rifamycins: block prokaryotic DNA-dependent RNA polymerase from initiating transcription
  61. 61.  Sulfadiazine well-absorbed orally. Used to treat UTIs.  But many strains of E. coli are resistant.  So, use less toxic drugs instead.  Adverse effects: allergic rxns, skin rashes, fever.  Trimethoprin – used for UTIs and Resp TIs  Co-trimoxazole (trimethoprin + sulfamethoxazole) – used mostly for pneumonia, neocarditis, and toxoplasmosis.
  62. 62.  Sulfonamides (Sulfa drugs)  Inhibit folic acid synthesis  Broad spectrum Figure 5.7
  63. 63. Figure 20.13
  64. 64.  Inhibit DNA gyrase.  Nalidixic acid – used only for UTIs.  Ciprofloxin (6-fluoro substituent) that greatly enhances its effectiveness against both gram- and gram+ bacteria. Well-absorbed both orally and i.v. Eliminated largely unchanged by the kidneys. Side-effects (headache, vomiting, nausea) are rare; but convulsions may occur.
  65. 65.  Wide-spectrum  Metronidazole – against anaerobic bacteria and protozoan infections.  Tinidazole – longer duration of action.  Diffuses into the organism where the nitro group is reduced  chemically reactive intermediates are formed that inhibit DNA synthesis and/or damage DNA.
  66. 66.  Polymyxin B: binds to membrane of G- bacteria and alters permeability  This leads to leakage of cellular contents and cell death  These drugs also bind to eukaryotic cells to some extent, which limits their use to topical applications
  67. 67.  Competitive inhibition by substance that resembles normal substrate of enzyme  Sulfa drugs
  68. 68.  Very few antiviral drugs approved for use in US  Effective against a very limited group of diseases  Targets for antiviral drugs are various points of viral reproduction
  69. 69.  Amantadine – interferes with replication of influenza A by inhibiting the transmembrane M2 protein that is essential for uncoating the virus. - Has a narrow spectrum; so, flu vaccine is usually preferable.  Zanamivir – inhibits both influenza A and B neuraminadase. Decr duration of symptoms if given within 48 hr of the onset of symptoms. Prophylactic in healthy adults.  Immunoglobulins – Human Ig contains specific Abs against superficial Ags of viruses  can interfere with their entry into host cells. Protection against hepA, measles, and rubellla (German measles).
  70. 70.  Acyclovir- used to treat genital herpes  Cidofovir- used for treatment of cytomegaloviral infections of the eye  Lamivudine- used to treat Hepatitis B
  71. 71.  HSV and VZV contain a thymidine kinase (TK) that  acyclovir to a monophosphate phosphorylated by host cell enzymes to acycloguanosine triphosphate, which inhibits viral DNA pol and viral DNA synthesis.  Selectively toxic (TK of uninfected host cells activates only a little of the drug).  Viral enzymes have a much higher affinity than the host enzymes for the drug.  Effective against HSV, but does not eradicate them.  Need high doses to treat shingles.
  72. 72.  Quite toxic (neutropenia) –so, given only for severe CMV infections in immunosuppressed patients.  CMV is resistant to acyclovir because it does not code for TK.
  73. 73.  Currently implies a drug used to treat HIV  Tenofovir- nucleotide reverse transcriptase inhibitor  Zidovudine- nucleoside analog – inhibits RT of HIV and is only used orally for AIDS. - Activated by triple phosphorylation and then binds RT (with100X affinity than for cellular DNA pols). - Incorporated into the DNA chain, but lacks a 3’OH; so another nucleoside cannot form a 3’-5’-phosphodiester bond  DNA chain elongation is terminated. -Severe adverse effects: anemia, neutropenia, myalgia, nausea, and headaches.  Stavudine, didanosine, zalcitabine – among other NRTIs.  Nevirapine, efavirenz – Non nucleoside RTIs - denature RT.
  74. 74. Life Cycle of HIV
  75. 75. HIV gp41-mediated fusion and enfuvirtide (T-20) action – Prohibits HIV entry
  76. 76.  Zanamivir (Relenza) and Oseltamivir phosphate (Tamiflu)- inhibitors of the enzyme neuominidase  Used to treat influenza  Indinavir- protease inhibitors. Inhibit the synthesis of essential viral proteins (e.g., RT) by viral-specific proteases.
  77. 77.  Cells infected by a virus often produce interferon, which inhibits further spread of the infection  Alpha-interferon - drug for treatment of viral hepatitis infections
  78. 78. 1. Bacteria spread on surface of agar plate 2. 12 disks, each with different antimicrobial drug, placed on agar plate 3. Incubated- drugs diffuse outward and kill susceptible bacteria 4. Zone of inhibition around each disk 5. Compare size of zone to chart
  79. 79.  Drug resistance limits use of ALL known antimicrobials  Penicillin G: first introduced, only 3% of bacteria resistant  Now, over 90% are resistant
  80. 80. 1. Inactivating enzymes that destroy the drug (e.g., β- lactamases). 2. Decreased drug accumulation (e.g., tet). 3. Altering the binding sites (e.g., aminoglycosides and erythromycin). 4. Development of alternative metabolic pathways (sulphonamides ( dihydropteroate synthease) and trimethoprim (dihydrofolate reductase).
  81. 81. 1. Spontaneous Mutation: happen as cells replicate – Within a pop, there will be some bact with acquired resistance. The drug then elim the sensitive organisms, while the resistant ones proliferate. 2. Gene Transfer or Transferred resistance: Usually spread through conjugative transfer of R plasmid ( may be virally mediated).
  82. 82. 1. Responsibilities of Physicians: must work to identify microbe and prescribe suitable antimicrobials, must educate patients 2. Responsibilities of Patients: need to carefully follow instructions
  83. 83. 3. Educate Public: must understand appropriateness and limitations of antibiotics; antibiotics not effective against viruses 4. Global Impacts: organism that is resistant can quickly travel to another country - in some countries antibiotics available on non- prescription basis - antibiotics fed to animals can select for drug- resistant organisms
  84. 84.  Scientists work to find new antibiotic targets in pathogens  Discovery of new and unique antibiotics is necessary

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