CHEMOTHERAPY

1. CHEMOTHERAPY Dr. Rajendra Nath Professor

2. CHEMOTHERAPY The term Chemotherapyis used for the drug treatment of parasitic infections in which parasites ( e.g. Virus ,Bacteria , Protozoa , Fungi & Worms) / invading cells are selectively destroyed or removed without significant injury to the host.

3. CHEMOTHERAPY (CANCER CELLS – they are host cells but considered as invading cells or parasite since they escape from the regulating devices , which govern normal cells .As they are very similar to host cells so difficult to tackle ) Differential toxicity: based on the concept that the drug is more toxic to the infecting organism than to the host

4. CHEMOTHERAPY Antibiotics – They are antibacterialsubstances produced by various species of micro-organisms ( Bacteria , Fungi & Actinomycetes ) that suppress the growth of other microorganism . • Majority of antibiotics are based on naturally occurring compounds • or may be semi-synthetic or synthetic

5. CHEMOTHERAPY Natural Sources of Antibiotics A. Fungus –1. Penicillin - Penicillium notatum & P. crysogenum 2. Cephalosporins – Cephalosporium acremonium 3. Griseofulvin – P. griseofulvum

6. CHEMOTHERAPY B. Bacteria C. Actinomycetes 1. Bacitracin – 1. Streptomycin - B. Subtilis Streptomyces griseus 2. Polymyxin – B. polymyxa 2. Chlortetracycline- 3. Colistin – S. aureofaciens B. colistinus 3. Chloramphenicol - S. venezuelae 4. Erythromycin- S. erythreus

7. CHEMOTHERAPY Antibacterial term includes the synthetic drugs e.g.- Sulfonamides & Quinolones . Antimicrobials- include both antb.s as well as synthetic drugs History – The Ancient Hindus treated Leprosy withChaulmoogra oil.

8. CHEMOTHERAPY (The earliest use of antibiotics was probably in the treatment of skin infections with moldy curd by the ancient Chinese . Modern antibiotics can be traced to the work of Louis Pasteur who observed that the in vitro growth of one microbe was inhibited when another added to culture ,Pasteur called this phenomenon as antibiosis )

9. CHEMOTHERAPY in 16th century – Mercury for Syphilis was used . in 17th century – Cinchona bark was used against Malaria . Modern rational chemotherapy begin when Ehrlich said that Aniline dyes selectivelystained bacteria in tissuemicroscopic prep.

10. CHEMOTHERAPY & could selectively kill them .(He discovered Arsphenamine –Salvarsan , an arsenical comp. for Tt. Of Syphilis ) - He also invented the term ‘Chemotherapy’ in 1906. -Antimalarials Primaquine & Mepacrine were developed from dies . - In 1935 first Sulfonamide linked with dye Prontosil was introduced by Domagk.

11. CHEMOTHERAPY It causes a revolution in scientific & medical field as many cases of severe bacterial infections were treated successfully .

12. CHEMOTHERAPY In 1928 Flemingaccidentally rediscover the long known ability of Penicillium fungi to suppress the growth of bacterial culture but could not purify it .

13. CHEMOTHERAPY In 1939 Florey & Chain prepared Penicillin & confirmed its remarkable lack of toxicity. subsequently other antibiotics were came into being by another group of microbes called Actinomycetes e.g. Streptomycin by Walksmanin 1944 ( Actinomycetes proved to be the important source

14. CHEMOTHERAPY of antibiotics & soon Tetracyclines , chloramphen.& Erythromycin emerged ) For above discoveries all three gps of scientists were awarded Noble prize for medicine.

15. CHEMOTHERAPY Classification : Based on chemical structure & mech. of action- i) Agents that inhibit synthesis of bacterial cell wall e.g. – β lactum class – Penicillin ,Cephalosporin , Carbepenem etc. - other dissimilar antb.s e.g. -

16. CHEMOTHERAPY Cycloserine , Vancomycin & bacitracin ii) Agents that act directly on the cell membrane of the micro-organism increasing their permeability & leading to leakage of intracellular components. e.g. – Polymixin , Nystatin & Amphotericin -B .

17. CHEMOTHERAPY iii) Agents that disrupts funct. of 30S or 50S ribosomal subunits to reversibly ↓ protein synthesis ( Bacteriostatic) e.g. – Chloramphenical , Tetracycline , Erythromycin etc. iv) Agents that bind to 30S ribosomal

18. CHEMOTHERAPY subunit & alter protein synthesis (Bactericidal) e.g.- Aminoglycosides. v) Agents that affect bact. nucleic acid metabolism e.g.- Rifampicin which ↓ RNA-Polymerase & Quinolones which ↓DNA- Gyrase / Topo-isomerases

19. CHEMOTHERAPY vi) Antimetabolites - e.g.-Trimethoprim & Sulfonamides which blocks essential enzyme of folate metabolism.

20. CHEMOTHERAPY

21. CHEMOTHERAPY Other Classification : Antimicrobial agents ( AMA ) can also be classified broadly as under : • Bacteriostatic – those that act primarily by arresting bacterial multiplication e.g. Sulfonamides , Tetracyc.s & Chloramphenicol.

22. CHEMOTHERAPY ii) Bactericidal– those which act primarily by killing of bact. such as – Penicillins, Cephalosporins , Aminoglycosides, INH &

23. CHEMOTHERAPY Rifampicin etc. they act more on rapidly dividing organisms This classification is arbitrary because most bacteriostatic drugs can act as bactericidal on high concentrations.

24. CHEMOTHERAPY Principles of Antimicrobial Chemotherapy 1.Make a diagnosis – As precisely as possible - Define the site of infection • The micro-organism responsible & their sensitivity to drugs

25. CHEMOTHERAPY It is advisable that all related biological samples (e.g.-Blood , Pus , Urine, CSF, Sputum etc.) should be taken before starting treatment. Once antibiotic has been administered isolation of the underlying organism may be inhibited & its place may be taken by resistant , colonizing bact.

26. CHEMOTHERAPY which obscure the true causative pathogen . 2.Removal of barriers for cure : - lack of free drainage of abscess . - obstruction in urinary or respiratory tract. - Infected I.V. catheters .

27. CHEMOTHERAPY 3.Decision that whether chemoth. isreally necessary : As a general rule acute inf.s require chemoth. while other measures are moreimportant for resolution of chronic inf.s e.g. - chr. abscess or empyma need drainagealong with chemotherapy

28. CHEMOTHERAPY 4. Select the best drug :To select a few pearls from the big ocean of anti-microbials is indeed the need of the day. a.) Specificity - AM activity should match that of the infecting organism. Indiscriminate use of broad spectrum antibiotics promote AM resistance & encourage opportunistic inf.s

29. CHEMOTHERAPY (in absence of precise identification of responsible microbe, best guess chemoth. of broad spectrum most often be given ) -Simplest , least expensive & useful of all rapid methods of identification – Gram stain can be used to identify the presence of bacteria & its morphological feature . Spectrum of cover should be narrowed once the causative organism have been identified .But it should be changed only after adequate trial ( usually 3 days ) .

30. CHEMOTHERAPY - Rapid diag. tests- -Gram –ve or Gram +ve staining of body secretions . - Ziehl Neelsen’s staining for acid fast bacteria.

31. CHEMOTHERAPY -Polymerase chain reaction ( nucleic acid detection assay ) for reliable therapy . Modification of treatment can be made laterif necessary in light of C/S tests ( Tt. should be changed after 2-3 days) .

32. CHEMOTHERAPY - b)Route of administration : Parenteral therapy ( I.M. or I.V. ) is preferred for serious inf.s (to achieve high conc. then switch on to oral therapy) & in cases having vomiting/ diarrhea etc. Topical – in cases of skin inf.s , ant . nasal , mouth & eye inf.s

33. CHEMOTHERAPY bi) Pharmacokinetic Factors : Absorption -polar cations are poorly absorbed e.g. Aminogl.s - inactivation in GIT , e.g. Penicill.s - Presence of divalent ions e.g. Ca , Mg , Al ↓ Tetracycl.s & Quinol.s absorption .

34. CHEMOTHERAPY Distribution : Natural barriers limit the entry to the sites like brain , bones & prostate . Chosen drug is not capable of reaching the site of infection in adequate amount e.g.- 1. By crossing BBB as Penicill.s & Aminog.s .

35. CHEMOTHERAPY 2. Prostate – many drugs do not cross the prostatic epithelium so difficult to treat prostatitis bii) Pharmacodynamic factors : AM.s can exhibit – CONCENTRATION & TIME DEPENDENT EFFECTS AM drugs exhibit various conc.& time dependent effects that influence their clinical efficacy , dosage & frequency of administration e.g.

36. CHEMOTHERAPY • Minimal inhibitory conc. ( MIC ) – Lowest conc. of a drug that ↓ bacterial growth . 2. Conc. Dependent killing ( CDK ) – Some Aminoglycosides ( Tobramycin ) & some Fluoroquinolones ( Ciprofloxacin) exhibit CDK against a large gp . of Gram –ve bacteria e.g. P. aeuroginosa & members of family Enterobacteriaceae . 3. Post antibiotic effect ( PAE ) - After removal of AB drug from bact. culture, evidence of a persistent effect on bact. growth may exist , this is known as PAE e.g. Penicil.-against G+ve & Aminog. for G-ve . It is due to post antb, leukocyte enhancement i.e. increased sensitivity to the phagocytic & bacteriological action and altered bacterial morphology and decrease rate of growth due to sub- inhibitory concentration .

37. CHEMOTHERAPY c) Host factors- i) History of previous ADRs ii) Critical determinant of the therapeuticeffectiveness of AM agents is the functional states of host defense mech. ( in an immunocompetent patient a static drug may be sufficient . If host defenses are impaired cidal drugs are essential for the cure )

38. CHEMOTHERAPY There may be generalized impairment of host defenses as in Diabetes, Leukemia , Lymphoma , AIDS , Steroid & immunosuppressant therapy. There may be

39. CHEMOTHERAPY a) Inadequacy of type , quality & quantity of the immunoglobulins b) Alteration of the cellular immune system or a qualitative / quantitative defect in phagocytic cells which may result in therapeutic failure despite

40. CHEMOTHERAPY the use of appropriate & effective drugs . ABs may affect hostdefenseacting as biologic response modifiers : 1. With no effect on host defense – β – lactams . 2. Inhibition of immune syst.-Tetracyc.

41. CHEMOTHERAPY 3. Synergy with immune syst. – Macrolides & Quinolones . 4. Increased immune function- some of Cephalosporins. Immune system plays impt. role in final elimination of microbes therefore drugs that ↑ immune func. are preferr.

42. CHEMOTHERAPY c-ii) Age – Mech . of elimination esp. renal exc. & hepatic metabolism are poorly developed in the new born and cause disastrous consequences e.g. – Grey baby syndrome caused by Chloramphenicol.

43. CHEMOTHERAPY -Elderly – excrete drug with less efficacybecause of ↓ creatinineclearance. They also metabolize drug less rapidly. c-iii) Renal & Hepatic function : When renal &/ or hepatic function are impaired the dose of the AMA

44. CHEMOTHERAPY ( especially having low safety margin) need to be modified e.g. following antb need dose reduction in renal failure pts. - Aminoglycosides - Amphotericin B - Cephalosporins - Vancomycin

45. CHEMOTHERAPY - Metronidazole - Co- trimoxazole & Fluroquinolones Drugs should not be given- -Nitrofurantoin -Nalidixic acid -Tetracyc. ( except Doxycyc.) - Cephalothine & Cephaloridine

46. CHEMOTHERAPY Drugs to be avoided / used in low doses in Liver disease – -Erythromycin estolate - Tetracyclines - Nalidixic acid -Pyrazinamide ,Isoniazid &Rifampicin - Chloramphenicol etc.

47. CHEMOTHERAPY c-iv) Pregnancy – All AMA should be avoided in pregnancy due to the risk to the foetus ( Penicillins , , most of the Cephalosporins & Erythromycin are safe & can be given when especially needed ) . c-v) Genetic factor : Primaquine , Chloramphenicol , Sulphonamides & Fluroquinolones can produce hemolysis in G-6 PD deficient pts .

48. CHEMOTHERAPY d.) Local factors – presence of pus , low pH & other confined spaces like – pleural space , CSF , urine & anaerobic condition can reduce AM action e.g.Aminoglycosides

49. CHEMOTHERAPY • Presence of foreign body in the infected site ↓ AMA e.g. – prosthetic cardiac valves , joints , pacemaker, vascular grafts & shunts . They promote formation of a bact. biofilm that impairs phagocytosis.

50. CHEMOTHERAPY • Presence of intracellular pathogen e.g.- Salmonella, Brucella , Listeria & M. tub. as they are protected from the actions of AB agents .