Chemotherapeutic Drugs - General Considerations - Ximei Wu Dept. of Pharmacology,

1. Chemotherapeutic Drugs - General Considerations - Ximei Wu Dept. of Pharmacology, School of Medicine, Zhejiang University

2. Overview • Chemotherapy • Chemotherapeutic agents • Antimicrobial drugs / Anti-infective Agents Antibacterial drugs Antifungal drugs Antiviral drugs • Antiparasitic durgs • Antineoplastic / anticancer drugs

3. Adverse effects Resistance Pharmacokinetics Therapeutic Effects Host Factors： patient’s age, gender, constitution, hepatic, renal function pathogenicity Immunological responses

4. ideal antimicrobial drugs • High sensitivity • Nontoxic or low-toxic (safety) • Nonresistance • Satisfied pharmacokinetic properties • Good price

5. Terminology 1. Antibacterial drugs 2. Antibiotics 3. Bacteriostatic drugs 4. Bactericidal drugs 5. Antibacterial spectrum 6. Chemotherapetic index (CI) 7. Minimum inhibitory concentration (MIC) 8. Minimum bactericidal concentration (MBC) 9. Concentration Dependent killing 10. Post antibiotic effect (PAE) 11. Time-dependent killing

6. Terminology • Antibacterial drugs • kill bacteria and arresting its growth • antibiotics and synthetic antimicrobial agents such as sulfonamides and quinolones.

7. Terminology 2. Antibiotics • produced by various species of microorganisms (bacteria, fungi , actinomycetes) • suppress the growth of other microorganisms.

8. Terminology • 3. Bacteriostatic drugs • inhibit the growth of microorganisms • e.g. Sulfonamides, Tetracycline • 4. Bactericidal drugs • kill microorganisms • e.g. Penicillin, Aminoglycosides

9. Bactericidal vs Bacterostatic

10. Terminology 5. Antibacterial spectrum • Narrow • Broad 6. Chemotherapetic index (CI) • CI= LD50 / ED50 • CI= LD5 / ED95

11. Pharmacological effect Toxic effect Lether effect TD50 ED95 LD5

12. 9. Concentration Dependent killing: situation in which the bactericidal activity of a drug depends by how much the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. aminoglycosides and quinolones 10. Time-dependent killing: situation in which the bactericidal activity of a drug depends how long the drug concentration exceeds the Minimum inhibitory concentration of the organism in question. e.g. b-lactams and vancomycin 11. Post antibiotic affect (PAE) : Persistence of suppression of bacterial growth after limited exposure to an antimicrobial agent. e.g. aminoglycosides

13. Mechanism of Action 1. inhibit synthesis of bacterial cell walls 2. affecting permeability of cell membrane and leading to leakage of intracellular compounds 3. inhibit protein synthesis 4. affect bacterial nucleic acid metabolism 5. block essential enzymes of folate metabolism

14. 1 2 4 3 5 Antibacterial Targets

15. Bacterial Resistance

16. OM Penicillinase b-lactam Inactive IM Penicillin Acetylation Phosphorylation Kanamycin Adenylyation Resistance: mechanisms, pathways 3. Active efflux e.g. Tetracycline resistance 1. Enzymatic inactivation e.g. b-lactamase 4. Decreased permeability e.g. Porin mutations - cephalosporin 5. Target alteration Streptomycin resistance penicillin binding proteins Enzymatic modification e.g. Aminoglycoside modification

17. Bacterial Resistance • Intrinsic resistance – Inherent features ，usually expressed by chromosomal genes • Acquired resistance – emerge from previously sensitive bacterial populations – Caused by mutations in chromosomal genes – Or by acquisition of plasmids or transposons

18. The transfer of Resistance genes • Mutations • Transduction • Transformation • Conjugation

19. Mutations May occur in the gene encoding i) The target protein ii) A protein involved in drug transport iii) A protein important for drug activation iv) A regulatory gene or promoter affecting expression of the target, a transport protein, or an inactivating enzyme.

20. Transduction

21. Conjugation • Transformation

23. Multi-drug resistance MDR (略) • Methicillin-resistant coagulase negative staphylococci, • MRCNS • PBP-2a • Penicillin-resistant streptococcus pneumoniae, PRSP • PBP-1a, PBP-2a, PBP-2x, PBP-2b • Active efflux system • Vancomycin-resistant Enterococcus, VRE • PBP avidity ↓ • van-A, van-B, van C-1, van C-2, van D, van E

24. Multi-drug resistance MDR (略) • 4. The 3rd generation-cephalosporins -resistant • Extended spectrumβ-lactamases, ESBL • Class I chromosone mediated β-lactamases • Carbapenem -resistant • OprD porin • 6. Quinolone-resistant escherichia coli, AREC • Active efflux system

25. Antimicrobial drugs classification According to bio-activity • Anti G+ antibiotic • Anti G- antibiotic • Broad-spectrum antibiotic • Anti mycobacterium antibiotic • Anti anaerobe antibiotic • β- lactamase inhibitor

26. According to the chemical structure： • β-lactams: Penicillins; Cephalosporins; • Aminoglycosides; • Macrolides; Lincosamides ;Vancomycins • Tetracyclines; Chloramphenicol 5. Quinolones 6. Sulphonamides 7. Nitrofurans 8. Antimycobacterial agents 9. others: Oxazolidinones; Streptogramins

27. Antituberculous Drugs

28. Antituberculous Drugs • First-line agents： Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin • Second-line agents： Para-aminosalicylic Ethionamide Amikacin Capreomycin Fluoroquinolones

29. Isoniazid 1．Antituberculous activity • Bacteriostatic & bactericidal for tubercle bacilli • Remarkably selective for mycobacteria • Resistance mutants occurs easily when given as the sole drug. • Be active against both extracelluar and intracellular tubercle bacilli. • Penetrating into phagocytes, Diffusing readily into all body fluid and tissues, including caseous material.

30. 2．Mechanism of action • Inhibiting synthesis of mycolic acids – the essential components of mycobacterial cell walls. • The Bacterial Cell Wall Gram Positive Gram Negative Mycobacteria Peptidoglycan Mycolate Porin Cytoplasmic membrane Acyl lipids LAM Outer membrane proteins

31. Isoniazid 3．ADME • Absorbed from the gastrointestinal tract readily. • Distributed widely in all body fluids and tissues. • Metabolism, especially acetylation by liver N-acetyltransferase, is genetically determined (slow acetylators，rapid acetylators, and middle acetylators). • Excreted mainly in the urine.

33. Isoniazid 4．Clinical Uses • Combination with rifampicin or second-line agents, used for severe infections with M tuberculosis. • As a single agent, indicated for prevent and treatment of active tuberculosis of early stage. • Allergic reactions: rashes, systemic lupus erythematosus, etc. • Hepatotoxicity • Peripheral neuritis (slow acetylators, the structure of isoniazid is similar to that of pyridoxine, Vit B6) • CNS toxic effects • GI effects 5．Adverse reactions

34. Rifampicin 1. Antibacterial activity • Broad-spectrum • Resistance mutants occurs easily, if used alone. • Bactericidal for mycobacteria. • Penetrates most tissues and into phagocytes.

35. DNA template DNA template 2．Mechanism of action • Binding strongly to the b subunit of bacterial DNA-dependent RNA ploymerase • Inhibiting RNA synthesis. 3．Mechanism of resistance • Resistance results from one of several possible points in the gene for b subunit ofRNA polymerase. These mutation prevent binding of rifampicin to RNA polymerase.

36. Rifampicin 4．ADME • Absorbed well after oral administration. The absorption is attenuated by food and para-aminosalicylic (PAS). • Distributed widely, even in CSF when meninges is infectious. • Metabolized in liver by deactylation, and rifampicin is a enzyme inducer. • Excreted mainly through the liver into bile, then undergoes enterohepatic recirculation.

37. Rifampicin 5. Clinical Uses • mycobacterial infections • other indications 6. Adverse reactions • GI effects • Cholestatic jaundice or hepatitis • Hypersensitive reaction • Causing a harmless orange color in urine, sweat, tear, and contact lenses.

38. Ethambutol 1．Antimycobacterial actvity • Nearly all strain of M. tuberculosis are sensitive. • Be bactericidal to intercellular and extrecellular M. tuberculosis. • Ethambutol inhibits mycobacterial arabinosyl transferases, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. • Resistance to ethambutol is due to mutations resulting in overexpression of mycobacterial arabinosyl transferases. 2．Clinical Uses • Treatment for tuberculosis of various forms when given concurrently with isoniazid. 3．Adverse reactions • Retrobulbar neuritis. • Hypersensitive reactions. • GI upset, rash, fever, headache, etc.

39. Pyrazinamide • Bactericidal (in vitro a slightly acidic pH). • Well absorbed (p.o.), widely distributed. • Resistance for Pyrazinamide develops fairly readily, but there is no cross-resistance with other antituberculous drugs. • Adverse reactions hepatotoxicity, GI reactions, drug fever, and hyperuricemia (acute gouty arthritis).

40. Streptomycin • The first effective drug to treat tuberculosis. • in treatment of life-threatening forms of tuberculosis, eg, meningitis and disseminated disease, and in treatment of infections resistant to other drugs. • Resistance to Streptomycin developed easily when it is used alone. • Given simultaneously to prevent emergence of resistance and toxic reaction.

41. The principle for using antituberculous drugs • Treatment should be initiated with antituberculous drugs early. • Be initiated with combination of antituberculous drugs . • be continued for a long time (6-9 months). e.g. 2HRZ/4HR and 2SHRZ/4HRE