Pharmacology of antimicrobial treatment for Level IV and Bsc Nursing students

This power point lecture prepared for level Iv nursing students.

1. Chemotherapeutic agents By Nimona B . [email protected] pharmacology and toxicology course team 5/9/2018 By Nimona B.(NB NB) 1

2. Basic principles of antimicrobial therapy Antimicrobial a re drugs used to prevent or treat microbial infections. A re among the most commonly used and misused of all drugs. Widespread and irrational use of antimicrobial agents  Emergence of antibiotic-resistance The most desirable property of an antimicrobial agent Selective toxicity The ability of an antibiotic to kill or suppress microbial pathogens without causing injury to the host . It is the property that makes antibiotics valuable. 5/9/2018 By Nimona B.(NB NB) 2

3. How is selective toxicity achieved? Unique structure: Bacterial cell wall Penicillins and cephalosporins Unique enzyme/metabolic pathways: F olate biosynthesis in bacteria sulfonamides inhibit an enzyme needed to make folic acid. 5/9/2018 By Nimona B.(NB NB) 3

4. Selective toxicity cont … Structural difference: R ibosomal subunits for protein bacterial and mammalian ribosomes are not identical, and hence we can make drugs that disrupt function of one but not the other. Enzymatic difference: enzymes involved in DNA synthesis Biochemical difference: lipid constituents of biological membrane 5/9/2018 By Nimona B.(NB NB) 4

5. Classification of antimicrobial agents Based on susceptible organisms Antibacterial Narrow spectrum Broad spectrum Antiviral Antifungal Antiprotozoal / antiparasites Antihelmentics 5/9/2018 By Nimona B.(NB NB) 5

6. Spectrum of antimicrobial drugs Narrow spectrum Agents acting only a single or limited number of microorganisms E.g . Sulphonamides , Benzyl penicillins, streptomycine Broad spectrum When effective against wide range of MO ( Gm + and Gm -, ricketsia , chlamidia , mycoplasma) E.g . Tetracycline, chloramphenicol 5/9/2018 By Nimona B.(NB NB) 6

7. And also classified Bacteriostatic: Level of antimicrobial activity that inhibits the growth of bacteria. e.g. sulphonamides , tetracyclines Bactericidal: kill the microorganism directly. e.g. Penicillins, cephalosporins , aminoglycocides etc. NB. Bactericidal agents are less dependent on body defense mechanism for final eradication of Mos. DOC when body defense mechanism is deficient . Concomitant administration of bactereostatic and bactreocidal agents decreases the action of bactereocidal agents.B /c bactreocidal agents kill MOs during when bacteria is actively dividing or synthesizing. 5/9/2018 By Nimona B.(NB NB) 7

8. Resistance to antimicrobial agents Drug resistance is the phenomenon that susceptibility of pathogenic microorganisms to drugs becomes lower or even loses after the microorganisms contact with drugs many times. Use of broad spectrum antibiotics promotes the emergence of drug-resistant microbes . Can be minimized by using a combination of antimicrobials. 5/9/2018 By Nimona B.(NB NB) 8

9. Combinations of antimicrobial drugs Advantages For empirical therapy of an infection in which the cause is unknown For treatment of polymicrobial infections To enhance antimicrobial activity (i.e., synergism) for a specific infection To prevent emergence of drug resistant microorganism. Disadvantages I ncreased risk of toxicity from two or more agents, S election of multiple-drug-resistant microorganisms E radication of normal host flora with subsequent super infection Increased cost to the patient. 5/9/2018 By Nimona B.(NB NB) 9

10. Classification… Based on MOA antibacterials can be classified as Cell wall synthesis inhibitors , e.g. - lactam antibiotics, cycloserine , vancomycin , and bacitracin Agents that act directly on the cell membrane of the microorganism , e.g. Polymyxin , nystatin and amphotericin B Agents that affect ribosomal protein synthesis (e.g., CAF, TTCs, erythromycin, clindamycin , aminoglycosides) Agents that affect bacterial nucleic acid metabolism, such as the rifamycins and the quinolones The antimetabolites , including trimethoprim & sulfonamides 5/9/2018 By Nimona B.(NB NB) 10

11. Mechanisms of Antimicrobial Action 5/9/2018 By Nimona B.(NB NB) 11

12. Inhibitors of cell wall synthesis Β- lactam antibiotics Penicillins, cephalosporins , Monobactams , carbapenems Vancomycine B acitracine 5/9/2018 By Nimona B.(NB NB) 12

13. Cont …. Mechanism of Action Inhibit synthesis of bacterial cell wall by binding to penicillin binding proteins (PBP) in bacterial cell wall. This binding produces a defective cell wall that allows intracellular contents to leak out , destroying the micro-organism. Differ in anti-bacterial spectrum, route of administration, suseptiblity in B-lactamase and adverse effects. 5/9/2018 By Nimona B.(NB NB) 13

14. Cont … Resistance Resistance to penicillins and other – B lactams is due to one of four general mechanisms: I nactivation of antibiotic by B –lactamase . most common M odification of target PBPs I mpaired penetration of drug to target PBPs E fflux 5/9/2018 By Nimona B.(NB NB) 14

15. Penicillins First antibiotic discovered by Alexander Fleming in 1928. When first developed, had to be given parentrally because it was destroyed by gastric acid. Unless inflammation present, therapeutic levels can not be achieved in CSF. Except naficillin , all penicillins are excreted in high concentration through kidney. 5/9/2018 By Nimona B.(NB NB) 15

16. Classification of penicillins 5/9/2018 By Nimona B.(NB NB) 16

17. Crystalline penicillin Poor across BBB, crosses the placenta, enter breast milk. Time to peak plasma concentration after I.M is 30 minutes. Spectrum- gram + ve , N. gonorrhoeae , Some anaerobes Spirochets ( Treponema pallidum ) Use- congenital syphilis (syphilis present in utero and at birth, and occurs when a child is born to a mother with syphilis). Dose: 50,000 I U/kg IM a day in a single dose for 10 days. 5/9/2018 By Nimona B.(NB NB) 17

18. Benzathine penicillin Duration of action is 1-4 weeks. Absorption through IM Spectrum- similar to crystalline penicillin Uses S treptococcal URTI( tonsilitis )-once monthly P rophylaxis of recurrent rheumatic fever E arly and late syphilis(weekly for three weeks) 5/9/2018 By Nimona B.(NB NB) 18

19. B-lactamase resistant penicillins ( Oxacillin , Naficillin and Cloxacillin ) Cloxacillin Acid resistance and penicillinase resistant- effective against penicillinase producing gram positive S.aureus . Adequately absorbed orally, IV Food affects absorption Should be given 1 hr before or 2 hr after food. Dose 250—500 mg PO q6h. Use- Pneumonia due to S.aureus , osteomyelitis, septic arthritis, mastitis (breast infection) 5/9/2018 By Nimona B.(NB NB) 19

20. Broad spectrum penicillins (Amino penicillins) Cidal for gram + ve and gram – ve bacteria Ineffective against B-lactamase producing staphylococci and gonococci Amoxacillin - similar to ampicillin except; more rapidly and completely absorbed from the GIT absorption is less affected by food Ampicillin has low oral absorption and food decrease the absorption 5/9/2018 By Nimona B.(NB NB) 20

21. Amino penicillins… Has less incidence of diarrhea. Has longer duration of action Amoxicillin- 250—500 mg PO q8h Ampicillin-250-500 mg PO q6h Ampicillin sodium 1-12 g/d IM, IV in divided doses of q4-6h Therapeutic uses- Bronchitis , tonsilitis , UTI, otitis media, pneumonia, sinusitis. PUD(H. pylori)- Amoxicillin 1g BID+ Omeprazole 20 mg BID+ Clarithromycin 500 mg BID. 5/9/2018 By Nimona B.(NB NB) 21

22. Amino penicillins… Ampicillin- M eningitis (listeria monocytogenes ) P neumonia (gram – ve ) with gentamicin Hepatic encephalopathy- due to its capacity to reduce gastric ammonia production in basal and betazole -stimulated gastric secretion . Bile (biliary tract infection) 5/9/2018 By Nimona B.(NB NB) 22

23. Extended spectrum penicillins Carpenicillin , ticarcillin F or gram + ve & gram – ve like pseudomonas and proteus species and E. coli. Pseudomonas- combined with aminoglycosides or fluoroquinolones . Carpenicillin - used for UTI and prostatitis caused by susceptible pathogens, but resistant to aminopenicillins 5/9/2018 By Nimona B.(NB NB) 23

24. Beta lactamase inhibitors β- Lactamase is family of enzyme produced by bacteria(E. coli, S. aureus , H. infleuenza , N. gonorrhea, klebsella , enterobacter ) that inactivate β- lactam antibiotics. β- lactamase inhibitors are drugs with β -lactam structure but little antibacterial activity C lavulanic acid Vs amoxacillin , sulbactam Vs ampicillin/ amoxacillin and tazobactam Vs piperacillin 5/9/2018 By Nimona B.(NB NB) 24

25. Penicillins: Adverse Effects Allergic reactions occur in 0.7% – 8% of treatments urticaria , pruritus, angioedema, bronchoconstriction 10% of allergic reactions are life-threatening and 5 % of these are fatal Hepatotoxcity with naficillin and oxacillin Bleeding tendency with carpenicillin , piperacillin nausea , vomiting, diarrhea, abdominal pain Super infection with broad spectrum (due to suppression of normal flora). Irritation at the site of injection CI- hypersensitive patients. 5/9/2018 By Nimona B.(NB NB) 25

26. Cephalosporins Classified in to 4 generations based on Chronological sequence of development Spectrum First generation cephalosporins Cephalexin - given orally Cause irritation if given parentrally Cefazolin , cefalotin - parentral (IM/IV) Good activity against G+ and modest activity against G- ve (except MRSA) 5/9/2018 By Nimona B.(NB NB) 26 Giuseppe Brotzu July 1945.

27. First generation… Not effective against enterobacter , pseudomonas, and serratia species Cefazolin is a drug of choice for surgical prophylaxis Cephalothin –resistant to ß-lactamase Excellent in the treatment of soft tissue and skin infection(s. aureus , s. pyrogens ) 5/9/2018 By Nimona B.(NB NB) 27

28. Second generation cephalosporins Cefuroxime (PO, parentral ) Cefaclor , cefprozil -PO Cefotetan , cefamandole , cefoxitin (IV), C efotaxime , ceftazidime , ceftozoxime - parentral Spectrum - very good activity for gram – ve and anaerobic organisms and less activity for gram + ve . Ceftzidime effective against gram + ve and gram – ve including P. aeruginosa . 5/9/2018 By Nimona B.(NB NB) 28

29. Third generation cephalosporins Ceftriaxone ( parentral ) Cefdinir , cefixime , cefpodoxime – PO Useful for meningial infections Penetrate inflammed meninges to reach CSF Has activity against H. infleuenzae , N. meningitidis and S. pneumoniae Spectrum- gain gram – ve and lose gram + ve activity as they move from 1st to 3rd generations 5/9/2018 By Nimona B.(NB NB) 29

30. 4th generation cephalosporins cefepime , cefepirome Active against G + ve and – ve Highly resistant to penicillinase Active against streptococci and staphylococci (but not against MRSA) Used for P. aeruginosa and enterobacter infection Dosage must be reduced with renal impairment( cefepime ) SEs: Hypersensitivity reaction , Kidney toxicity- cephalotin Diarrhea- cefoperazone , Super infection. Bleeding tendency (3 rd generation cephalosporin) 5/9/2018 By Nimona B.(NB NB) 30

31. Contraindication Previous severe anaphylactic reaction to a penicillin(cross reactivity) Cephalosporin allergy Delayed reactions are more common than immediate allergic reactions with anaphylaxis, bronchospasm and urticaria . 5/9/2018 By Nimona B.(NB NB) 31

32. Carbapenems ( imipenem ) Are broad spectrum, bactericidal, B-lactam antibiotics Given parentrally and distributed widely Active against B-lactamase producing species Indication- infection caused by resistant organisms Adverse effect- cross reactivity, seizure. Painful upon IM administration Add lidocaine in IM solution. 5/9/2018 By Nimona B.(NB NB) 32

33. Monobactams ( azactam ) Active against gram- ve bacteria including enterobacteriaceae and P. aeruginosa . Active against B-lactamase producing gram – ve species Gram + ve and anaerobic bacteria are resistant to monobactam . Indications – UTI, LRTI, systemic/skin infection Adverse effect- cross reactivity 5/9/2018 By Nimona B.(NB NB) 33

34. Vancomycin Not beta-lactam antibiotic. Inhibitor of bacterial cell wall synthesis U sed for treatment of multiple drug resistant organisms. B acteriocidal for gram-positive bacteria including ß-lactamase producing staphylococci. G- ve bacteria are resistant to vancomycin poorly absorbed from the intestinal tract S hould be administered IV 5/9/2018 By Nimona B.(NB NB) 34

35. Cont … Uses Sepsis Endocarditis Caused by MRSA Poor penetration through BBB Adverse effects Irritates tissue at injection site, chills and fever. Ototoxicity and nephrotoxicity - increased risk when administered along with Aminoglycosides. 5/9/2018 By Nimona B.(NB NB) 35

36. Bacitracin Active against Gm+ve microorganisms Inhibit bacterial cell wall synthesis It is markedly nephrotoxic if administered systemically, thus limited to topical use like skin,wound or mucous membrane infections. Adverse Effects Significant nephrotoxicity with systemic administration, skin sensitization may occur on topical use. 5/9/2018 By Nimona B.(NB NB) 36

37. Anti metabolites - sulfonamides and trimethoprim Sulfonamides - bacteriostatic Systemic sulfonamides Short acting agents - Sulfisoxazole Intermediate acting – Sulfamethoxazole & sulfadiazine Long acting - Sulfadoxin Topical sulfonamide Mafenide acetate, Silver sulfadiazine, Sulfacetamide 37 5/9/2018 By Nimona B.(NB NB)

38. Anti metabolites- Sulfonamides Bacteria rely on their ability to synthesize folic acid from Para amino benzoic acid (PABA). Sulfonamides have similar structure with PABA and inhibit the synthesis of folic acid 38 5/9/2018 By Nimona B.(NB NB)

39. Sulfonamides cont… Therapeutic uses UTI ( Sulfisoxazole : high solubility, achieve effective concentration & less expensive) Other uses Trachoma ( sulfacetamide ) Toxoplasmosis & malaria - Sulphadiazine / sulphadoxine + pyrimethamine . Ulcerative colitis – Sulfasalazine Skin burn infections – Mafenide acetate and silver sulfadiazine 39 5/9/2018 By Nimona B.(NB NB)

40. Sulfonamides cont… Adverse effects Crystaluria In acidic urine, sulfonamides are insoluble and may precipitate, forming crystalline deposits that can cause urinary obstruction. (prevent???) Hyper sensitivity reaction Contraindication Infants <2 months old and pregnant women due to kernicterus (yellow pigmentation of the basal ganglia and other nerve cells in the spinal cord and brain). 40 5/9/2018 By Nimona B.(NB NB)

41. Trimethoprim A potent inhibitor of bacteria dihydrofolate reductase . Trimethoprim exhibit antimicrobial spectrum similar to the sulfonamides Usually compounded with sulfamethoxazole (Co- trimoxazole ) Combination has synegestic effect(bactericidal) 5/9/2018 By Nimona B.(NB NB) 41

42. Cotrimoxazole ( sulfamethoxazole & trimethoprim) Uses UTI due to enterobactericiae Chronic bronchitis due to pneumococci and H. infleuenzae Shigelosis and salmonella. P neumocystis carnii pneumonia ( Px and Tx ) A cute otitis media Dose - 160 mg TMP/800 mg SMZ PO q12h (Adult). Infant/Children- ( 8mg TMP/40mg SMZ )/kg in two divided doses. 5/9/2018 By Nimona B.(NB NB) 42

43. Protein synthesis inhibitors D ivided in to two groups Bacteriostatic (Chloramphenicol, Macrolides, Clindamycine and tetracyclines ). B actericidal (Aminoglycosides) Bacteria have two ribosomal subunits; 30S and 50S whereas in the mammalian ribosome the subunits are 60S and 40S. 5/9/2018 By Nimona B.(NB NB) 43

44. Tetracyclines ( Tetracycline , Chlortetracycline , Doxy -cycline, Oxytetracycline and Minocycline ) Spectrum: Broad spectrum bacteriostatic Active against G+ve and G- ve but P. aeruginosa develop resistance. Ricketsial , Chylamydia, mycoplasma, protozoa MOA: Mechanism Enter microorganism by passive & active transport Act by binding 30s ribosome  prevent addition of amino acid to growing peptide 5/9/2018 By Nimona B.(NB NB) 44

45. Tetracyclines … Absorption will decrease when they are taken with antacid and diary products (form chelation – non absorbable). TTCs should be taken on an empty stomach except doxycycline and minocycline . Short acting(6-8hr)- Tetracycline and Oxytetracycline Long acting(18hr)- Doxycycline and Minocycline 5/9/2018 By Nimona B.(NB NB) 45

46. Tetracyclines … Use Cholera Doxycycline 100mg po bid for 03 days Tetracycline 500mg po Qid for 3-5 days Malaria combined with other anti malarial drugs ( Inhibit mitochondrial protein synthesis and nucleic acid synthesis of plasmodium ). Severe and complicated P. falciparum Doxycycline 200mg po Qid for 7 days + Quinine Prophylaxis for chloroquine resistant Doxycycline 100mg po daily + chloroquine 300mg once weekly Acne – doxyccline 100 mg po bid for 2 weeks. 5/9/2018 By Nimona B.(NB NB) 46

47. Tetracyclines … Mycoplasma infection (M. pneumonia – atypical pneumonia). Relapsing fever ( an infection transmitted by a lice or tick and characterized by repeated episodes of fever). TTC 500mg po stat, the same dose can be repeated the following day. Trachoma - chlamidia trachomatis TTC eye oint , 1% twice daily for 6-8 week Doxycycline 100mg twice daily for 7 days Typhus TTC 250mg Qid for 7 days Doxycycline 100mg po bid for 7 days 5/9/2018 By Nimona B.(NB NB) 47

48. Tetracyclines … STD Genital ulcer syndrome and syphilis In penicillin allergy Doxycycline 100mg po bid for 7 days Pelvic inflammatory disease Doxycycline 100mg po bid for 14 days Urethral or vaginal discharge syndrome Doxycline 100mg po bid for 7 days 5/9/2018 By Nimona B.(NB NB) 48

49. Tetracyclines … Adverse Effect GI effect – Nausea, Vomiting and Diarrhea. avoided by taking it with food Food decrease the rate not the extent Bone and Teeth TTC strongly bind to Ca deposit in bone and teeth Bone - growth inhibition Teeth - discoloration Hepatotoxicity Renal toxicity ( except doxycycline ) 5/9/2018 By Nimona B.(NB NB) 49

50. Tetracyclines … Contraindication Pregnancy and under 8yrs(interfere with bone and tooth development). Renal failure Resistance- Cells become resistant to tetracycline by at least three mechanisms:  enzymatic inactivation of tetracycline ,  efflux, and ribosomal protection . 5/9/2018 By Nimona B.(NB NB) 50

51. Chloramphenicol (CAF) Are broad spectrum, bacteriostatic antibiotic Active against aerobic and anaerobic G+ and G- Active against Mycoplasma, Ricketssial, Chylamydia Distribute to most tissue and body fluid (readily cross the placenta and breast milk) MOA: Interfere with the attachment of RNA on the 50S ribosome unit and prevents elongation step in protein synthesis. 5/9/2018 By Nimona B.(NB NB) 51

52. USES (Chloramphenicol) Meningitis Best for H. influenza (100mg/kg QID for 7- 14 days). Trachoma Thyphoid fever 250mg – 500mg QID for 7 days. Thyphus 250mg – 500mg QID for 7 days . Anaerobic infection Lung abscess - inflammation of lung parenchyma which results in tissue necrosis Usual dosage: 50-100mg/kg/day in 4 divided doses 5/9/2018 By Nimona B.(NB NB) 52

53. Chloramphenicol… Adverse Effect Bone marrow suppression → aplastic anemia Hyper sensitive reactions - Rash, fever GIT upset - Nausea, vomiting and diarrhea Super infection → Oral or vaginal candidiasis 5/9/2018 By Nimona B.(NB NB) 53

54. Chloramphencol … Gray baby syndrome - Occurs in neonates Neonates lack effective conjugating enzymes for degradation of CAF, consequently it may accumulate resulting in gray baby syndrome Vomiting, diarrhea, flaccidity, hypothermia and an ashen gray color of the skin which has a 40 % mortality 5/9/2018 By Nimona B.(NB NB) 54

55. Macrolides Erythromycin, Clarithromycin, Azithromycin Azithromycin & Clarithromycin- Semisynthetic derivative of Erythromycin Have better oral absorption and Longer t 1/2 Fewer GI side effects and are expensive Azithromycin - Highly active against chlamydia and Hemophilus influenza Slightly less active than erythromycin & clarithromycin against staphylococci and streptococci Mechanism - Inhibition of protein synthesis via binding to 50s ribosomal RNA 55 5/9/2018 By Nimona B.(NB NB)

56. Macrolides… Clinical uses Respiratory and skin infection Bronchitis, CAP (Atypical pneumonia). Genital ulcer syndrome Erythromycin 250-500mg po Qid for 7-10 days Clarthromycin 1000mg daily for 7 days Tetanus due to Clostridium tetani ERM 500mg po Qid for 10 days + diazepam, cpz Tonsilitis - For penicillin allergy patients ERM 250mg po Qid for 5 days Clarithromycin 250mg po bid for 10 days 5/9/2018 By Nimona B.(NB NB) 56

57. Macrolides… Non gonococcal urethritis and cervicitis due to C. thrachomitis Azathromycin1g as stat dose Sinusitis Clarithromycin 500mg bid for 14days H. pylori infection Clarithlormycin 500mg bid combined with omeprazole and amoxicillin Uncomplicated skin and skin structure infection Clarithromycin 250mg po bid for 7-14days 5/9/2018 By Nimona B.(NB NB) 57

58. Macrolides… C. trachomatis Azithromycin 1gm as single dose N. gonorrhea Azithromycin 1gm as single dose SEs: GI intolerance ,Hepatotoxicity ,Cardiac arrhythmia Resistance to macrolides Encoded on the Chromosome Encoded on plasmids: efflux. 5/9/2018 By Nimona B.(NB NB) 58

59. Aminoglycosides ( Gentamicin , Neomycin, Amikacin , Streptomycin, Kenamycin , Tobramycin ) MOA B ind to the 30-S ribosomal subunit Decrease initiation of protein synthesis. C ause misreading of genetic code I ncorporation of wrong amino acid, leading to altered protein. P rotein is some times toxic to the bacteria 5/9/2018 By Nimona B.(NB NB) 59

60. Aminoglycosides… Pharmacokinetics - Absorbed very poorly from GIT, well absorbed after IM injection They are highly polar compounds that don’t enter cells readily Can't cross BBB and excreted unchanged rapidly by glomerular filtration. Indications: m ostly used against gram -v e enteric bacteria Alm ost always used in combination with β -lactam antibiotic to extend coverage to include gram- ve & + ve pathogens and to take advantage of the synergism between these two classes of drugs 5/9/2018 By Nimona B.(NB NB) 60

61. Aminoglycosides… Adverse effect Ototoxicity Auditory damage (tinnitus, hearing loss) Vestibular damage ( Loss of balance ) Nephrotoxicity - Injure cells of proximal renal tubule Neuromuscular blockade - Weakness of respiratory musculature Aminoglycosides prevent internalization of Ca 2+ in presynaptic axon  decrease release of Ach 5/9/2018 By Nimona B.(NB NB) 61

62. NA synthesis inhibitors Ciprofloxacin, Norfloxacin , Moxifloxacin , enoxacin , lemofloxacin , levofloxacin, ofloxacin , pefloxacin Well absorbed after oral administration Renal excretion – Accumulation can occur in renal failure. Mechanism of action Block bacterial DNA synthesis by inhibiting bacterial DNA gyrase (introduce negative supercoiling) and topoisomerase IV (separate replicated chromosomal DNA in to the respective daughter cells) during cell division. 5/9/2018 By Nimona B.(NB NB) 62

63. Filoroquinolones … Spectrum Norfloxacin is the least active against G+ve and G- ve Ciprofloxacin, enoxacin , lemofloxacin , levofloxacin, ofloxacin & pefloxacin Possess excellent activity against G- ve including enterobacteriaceae , pseudomonas, haemophilus species., Neisseria species, Campylobacter Possess moderate to good activity against G+ve Methicillin susceptible strains of staphyloccoci , streptococci & enterococci tend to be less susceptible 5/9/2018 By Nimona B.(NB NB) 63

64. Filoroquinolones … Flouroquinolones also have activity against Mycoplasma & chlamdiae , legionella species and Mycobacteria. Therapeutic uses: UTI even when caused by multi drug resistant bacteria Resistant RTI GIT infections ( bacterial diarrhea) Infections of soft tissues, bones and joints Gonoccocal infections Chlamidial uretritis or cervicitis 5/9/2018 By Nimona B.(NB NB) 64

65. Floroquinolones … SEs Nausea , vomiting and diarrhea Occasional effects - Headache, dizziness, insomnia, skin rash Floroquinolones may damage growing cartilage Not routinely recommended for patients under 18 years of age, nursing mothers and pregnant women. 5/9/2018 By Nimona B.(NB NB) 65

66. ANTIMYCOBACTERIAL DRUGS 5/9/2018 By Nimona B.(NB NB) 66

67. Antimycobacterial drugs Tuberculosis (TB) is a chronic infectious disease caused in most cases by Mycobacterium tuberclae and some times by Mycobacter bovis Classification Pulmonary TB Extrapulmonary TB TB of lymph nodes (TB-lymphadenitis) Bone TB Intestinal TB TB meningitis 67

68. Antimycobacterial drugs cont… Mycobacterial infections - Most difficult of all bacterial infections to treat because; They are resistant to many drugs The mycobacterial cell wall is impermeable to many drugs Substantial proportion of mycobacterial organisms are intracellular residing within macrophages and inaccessible to drugs Reasons for drug combination To delay / reduce resistance To shorten duration of therapy Rapid reduction of bacterial load  fast recovery & ↓ communicability 68

69. Antimycobacterial drugs cont … Antimycobacterial drugs can be divided into three groups: Drugs used in the treatment of tuberculosis. Drugs used in the treatment of atypical mycobacterial infection. Drugs used in the treatment of leprosy. 5/9/2018 By Nimona B.(NB NB) 69

70. Drugs Used in Tuberculosis Drugs used in the treatment of tuberculosis can be divided into two major categories: First-line drugs. Superior in efficacy and possess an acceptable degree of toxicity. Isoniazid , Rifampin , Pyrazinamide Ethambutol , Streptomycin Second- lin drugs More toxic and less effective; Ethionamide , aminosalicylic acid , Cycloserin , amikacin , kanamycin, capreomycin , rifamycins ( rifapentine , rifabutin ) 5/9/2018 By Nimona B.(NB NB) 70

71. Isoniazid (INH) Most active drug for the treatment of tuberculosis caused by susceptible strains. Isoniazid inhibit synthesis of mycolic acids which is an essential components of mycobacterial cell wall. Not effective for dormant mycobacterial. It is bactericidal in actively growing mycobacteria. Narrow spectrum of action limited to mycobacteria. Low resistance 5/9/2018 By Nimona B.(NB NB) 71

72. INH… Readily absorbed from the GIT. Metabolized by acetylation in the liver. N- acetyltransferase , genetically determined The dose need be adjusted in severe hepatic insufficiency. Metabolites and a small amount of unchanged drug are excreted mainly in the urine. Clinical uses: Used in the treatment and prevention (prophylaxis) of tuberculosis . 5/9/2018 By Nimona B.(NB NB) 72

73. INH… Adverse effects Allergic reactions (fever, skin rashes) Drug induced hepatitis - Elderly, if used with rifampin and alcohol Peripheral neuropathy - Reversed by administration of vit B6 Due to relative pyridoxine deficiency Likely to occur in slow acetylators & patients with predisposing factor (malnutrition, alcoholism, diabetes, AIDS & Uremia) Convulsion , Optic neuritis, psychosis----reversed by vit B6 5/9/2018 By Nimona B.(NB NB) 73

74. Rifampin Rifampin binds bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Rifampin is bactericidal for mycobacteria. Rifampin is well absorbed orally. It is a potent cyp450 enzyme inducer. The serum concentration of protease inhibitors, Nevirapine, ketoconazole and warfarin decreased by 50% on co-administration. 5/9/2018 By Nimona B.(NB NB) 74

75. Rifampin… Administered together with INH, Ethambutol , or other antituberculous drug. It is an alternative to INH for prophylaxis in patients who are unable to take INH. Adverse effects: Red-orange discoloration of different body fluids. Flu-like syndrome (fever, chills, ataxia) Liver toxicity 5/9/2018 By Nimona B.(NB NB) 75

76. Ethambutol Inhibits synthesis of mycobacterial cell wall. well absorbed from the gut. Accumulated in renal failure patients. (adjust the dose). The higher dose is recommended for treatment of tuberculous meningitis (cross BBB poorly). The most common serious adverse event is retrobulbar neuritis - inflammation of the optic nerve which makes objects appear blurred ( red-green color blindness). Hyperuricemia: gouty arthritis may result. 5/9/2018 By Nimona B.(NB NB) 76

77. Pyrazinamid Pyrazinamide requires an acidic environment to exhibit its activity. Thus, pyrazinamide is highly effective on intracellular mycobacteria. Pyrazinamide is a prodrug . The mycobacterial enzyme pyrazinamidase converts pyrazinamide to pyrazinoic acid , the active form of the drug. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport. 5/9/2018 By Nimona B.(NB NB) 77

78. Pyrazinamide… Major adverse effects of pyrazinamide include Hepatotoxicity , nausea, vomiting, fever Hyperuricemia acute gouty arthritis. 5/9/2018 By Nimona B.(NB NB) 78

79. Streptomycin P enetrates into cells poorly. A ctive mainly against extracellular tubercle bacilli. C rosses the BBB and achieves therapeutic concentrations with inflamed meninges. E mployed principally in: Individuals with severe, possibly life-threatening forms of tuberculosis (meningitis and disseminated disease) T reatment of infections resistant to other drugs. 5/9/2018 By Nimona B.(NB NB) 79

80. Streptomycin… SEs i) Ototoxicity- drugs get concentrated in labrynthine fluid, both vestibular & cochlear damage. ii) Nephrotoxicity iii) Neuromuscular Paralysis - Ach release, sensitivity of post synaptic receptors. iv) Sterile abscess at the injection site 5/9/2018 By Nimona B.(NB NB) 80

81. Combination Chemotherapy of Tuberculosis The duration of therapy for a patient with tuberculosis depends upon the severity of the disease the organ affected and the combination of agents. There are two phases in the treatment of tuberculosis the intensive phase , which lasts 8 weeks, makes the patients noninfectious. The continuation phase , which lasts 4 months or more and at least two drugs should be taken. 5/9/2018 By Nimona B.(NB NB) 81

82. Type of patient Duration of treatment Regimen Category-1 1.New sputum positive 2.Seriously ill, sputum negative, Pulmonary TB Intensive phase (2months) Continuation phase (4months) INH+RMP+ETB+PZA INH+RMP Category-2 Retreatment group 1.Relapse 2.Treatment failure Intensive phase (3months) Continuation phase (5months) INH+RMP+ETB+PZA INH+RMP+ETB Category-3 1.New smear negative pulmonary TB 2.Extrapulmonary TB Intensive phase(2months) Continuation phase(4months) INH+RMP+PZA INH+RMP Regimens: 5/9/2018 By Nimona B.(NB NB) 82

83. MDR-TB disease R esistance to both isoniazid and rifampin results in the development of what is known as multidrug-resistant tuberculosis (MDR-TB). Patients with confirmed MDR-TB disease must receive second line anti-TB drugs. 5/9/2018 By Nimona B.(NB NB) 83

84. Prevention of Tuberculosis INH prophylaxis (IPT) Isoniazid is given to individuals with latent infection with Mycobacterium tuberculosis. In these patients at high risk of active TB, prophylaxis is recommended to prevent active disease prophylaxis consists of oral isoniazid , 300 mg daily or twice weekly, for 6 months in adults. Those who cannot take isoniazid should be given rifampin , 10 mg/kg daily, for 4 months. 5/9/2018 By Nimona B.(NB NB) 84

85. Drugs used in Leprosy Leprosy is caused by mycobacterium leprae . C an be treated with dapsone , rifampin, clofazimine , ethionamide , etc. Because of increasing reports of dapsone resistance, treatment of leprosy with combinations of the drugs is recommended. 5/9/2018 By Nimona B.(NB NB) 85

86. Dapsone ( diaminodiphenylsulfone ) Most widely used drugs in the treatment of leprosy. MOA: Inhibits folate synthesis. Resistance can emerge in large populations of M leprae . the combination of dapsone , rifampin, and clofazimine is recommended. well absorbed from the gut and widely distributed throughout body fluids and tissues. Excretion into urine is variable, and most excreted drug is acetylated. 5/9/2018 By Nimona B.(NB NB) 86

87. Dapsone … SEs Gastrointestinal intolerance, fever, pruritus, and rashes occur. Erythema nodosum often develops during dapsone therapy in lepromatous leprosy. Erythema nodosum leprosum (ENL) may be suppressed by corticosteroids. Hemolysis and methemoglobinemia can occur. 5/9/2018 By Nimona B.(NB NB) 87

88. Antiretroviral (ARV) Drugs HIV is a retrovirus Contains two strands of RNA Contains reverse transcriptase and integrase . Integrase helps in the insertion of HIV DNA into host DNA Infects CD4, helper T cells and macrophages—immune system cells 5/9/2018 By Nimona B.(NB NB) 88

89. Acquired I mmuno Deficiency S yndrome (AIDS) It is essentially a disease of the immune system A ffects CD4 lymphocytes R esults in progressive and crippling immuno -deficiency state. E xposes infected individuals to various types of infections and the development of malignancies. 5/9/2018 By Nimona B.(NB NB) 89

90. Life cycle of HIV 1. Attachement : The virus uses gp120 to bind to the CD4 receptors of T-lymphocytes and chemokine co-receptors ( CXCR5, CXCR4 ). 2. Fusion: Binding of gp120 with the receptors makes the gp41 to unfold and inserts its endings in to the cell membrane. Uncoating : The virus removes its protein coat immediately after it enters in to the cell. 3. Reverse transcription: Reverse transcriptase makes a double stranded DNA copy of the viral RNA. 5/9/2018 By Nimona B.(NB NB) 90

91. Life cycle… 4. Integration: The viral integrase cuts the ends of the newly synthesized DNA, transports it to the nucleus & fuses it with the host DNA. Viral DNA becomes part of the CD4 cell’s DNA with in the nucleus transforms the cell in to a factory for making more HIV. 5. Completed DNA is transcribed and translated( creates complex HIV proteins). These HIV proteins are not infectious. 5/9/2018 By Nimona B.(NB NB) 91

92. Life cycle… 6. Protease enzyme cuts each complex protein chain in to smaller functional proteins that can be used to build the new virus ( eg . the core, the envelope). 7. Functional proteins are stuck together to form new HIV virus . 8. Budding off virus can then leave the CD4 cell and enter the plasma to infect new host cell. 5/9/2018 By Nimona B.(NB NB) 92

93. Life cycle… Targets of HIV are CD4 cells, macrophages and monocytes. 100 billion viruses are produced per day and 1 billion CD4 cells are destroyed and rebuilt each day until the immune system is too weak to do so. Normal CD4 count is above 800 but declines by 30-90 cells per year. 5/9/2018 By Nimona B.(NB NB) 93

94. Primary Goals of ART Reduce HIV-related morbidity and prolong survival Improve quality of life Restore and preserve immunologic function Maximally and durably suppress viral load Prevent vertical HIV transmission

95. Classification of Antiretroviral Drugs Nucleoside reverse transcriptase inhibitors (NRTIs), Non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease inhibitors (PIs). Entry /fusion inhibitors, and Integrase inhibitors (Raltegravir) 5/9/2018 By Nimona B.(NB NB) 95

96. Nucleoside reverse transcriptase inhibitors (NRTIs) 5/9/2018 By Nimona B.(NB NB) 96 Zidovudine (AZT/ZDV) Didanosine (DDI) Zalcitabine (DDC) Stavudine (D4T) Lamuvidine (3TC) Abacavir (ABC) Emtricitabine (FTC) Tenofovir (TDF)

97. Nucleoside reverse transcriptase inhibitors (NRTIs) Nucleoside reverse transcriptase inhibitors (NRTIs) Block HIV replication and therefore infection of new cells, but have little effect on cells already infected with virus 5/9/2018 By Nimona B.(NB NB) 97 Drugs Viral targets Mode of action Zidovudine Reverse Transcriptase Phophorylated by cellular enzymes Competitively inhibits viral DNA synthesis or cause chain termination Didanosine Zalcitabine Stavudine Lamivudine Abacavir

98. Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) Inactivate reverse transcriptase enzyme by binding adjacent to its active site and inducing a conformational change. 98 Drugs Viral Target Mode of action Nevirapine Reverse Transcriptase Not phophorylated Non-competitively inhibition of viral DNA synthesis (lock enzyme active site) Delavirdine Efavirenz

99. Protease Inhibitors Protease is required for the production of a mature infectious virus 99 Drugs Viral Target Mode of action Saquinavir Protease Bind to protease active site, inhibiting its action Prevent maturation of new viral particles Indinavir Ritonavir Nelfinavir Amprenavir Kaletra

100. Entry/Fusion inhibitors 5/9/2018 By Nimona B.(NB NB) 100 Enfuvirtide Binds to the gp41 subunit of the viral envelope glycoprotein, prevent the conformational changes required for the fusion of the viral and cellular membranes. Maraviroc Binds specifically and selectively to the host protein CXCR5 , one of two chemokine receptors necessary for entrance of HIV into CD4+ cells.

101. Anti-retroviral drugs… NRTl's Zidovudine (ZDV, AZT) 300 mg twice daily Stavudine (d 4 T) 40 mg twice daily Lamivudine (3TC) 150 mg twice daily Didanosine ( ddl ) 400 mg once daily Abacavir (ABC) 300 mg twice daily Tenofovir (TDF) 300 mg once daily Emtricitabin (FTC) 200 mg once daily Zalcitabine ( ddC ) 0.75mg three time daily 101

102. Anti-retroviral drugs cont… NNRTl's Efavirenz (EFV) 600 mg once daily Nevirapine (NVP) 200 mg once daily for 14 days, then 200 mg twice daily (induces its own metabolism). Protease inhibitors Nelfinavir (NFV) 1250 mg twice daily Indinavir /ritonavir (IDV/r) 800mg/100 twice daily Lopinavir /ritonavir (LPV/r) 400 mg/100 mg twice daily Saquinavir/ritonavir (SQV/r) 1000 mg/100 mg twice daily 102

103. NRTIs Zidovudine (AZT, ZDV) The triphosphate form is a competitive inhibitor of deoxythymidine triphosphate for binding to reverse transcriptase. Additionally, it acts as a chain terminator in the synthesis of proviral DNA. H as in vitro activity against HIV-1, HIV-2, and the human T cell lymphotropic viruses(X-4 tropic viruses). 5/9/2018 By Nimona B.(NB NB) 103

104. Zidovudine (AZT, ZDV) Pharmacokinetics Available in intravenous and oral formulations. well absorbed (63%), distributed to most body tissues and fluids, including the cerebrospinal fluid. Zidovudine is eliminated primarily by renal excretion. Zidovudine is available in a fixed-dose combination with lamivudine, either alone or in combination with abacavir. 5/9/2018 By Nimona B.(NB NB) 104

105. Zidovudine (AZT, ZDV) Adverse Reactions The most common adverse effect is myelosuppression resulting in neutropenia Lipoatrophy appears to be more common in patients receiving zidovudine . Less frequent adverse effects include thrombocytopenia, acute cholestatic hepatitis, and myopathy (infection of muscle). 5/9/2018 By Nimona B.(NB NB) 105

106. Lamivudine (3TC) Oral bioavailability exceeds 80% and is not food-dependent. Most of the drug is eliminated unchanged in the urine. Potential side effects are headache, insomnia, fatigue, and GI discomfort , though these are typically mild. Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another; therefore, their concurrent use should be avoided if possible. 5/9/2018 By Nimona B.(NB NB) 106

107. Didanosine ( ddI ) Major toxicity D ose dependent pancreatitis Other toxicities peripheral neuropathy, diarrhea, hepatotoxicity, headache, and irritability. A rise in uric acid during therapy with didanosine may precipitate attacks of gout in susceptible individuals. 5/9/2018 By Nimona B.(NB NB) 107

108. Common ADRs of NRTIs Lactic acidosis (All NRTI’s) characterized by weakness, GI disturbances, fatigue, hypotension, and shortness of breath . Lipodystrophy (All NRTI’s) Myopathy  Zidovudine (AZT) Peripheral neuropathy  d4T, ddI , ddC ( zalticabine ). pancreatitis  3TC, ddI , ddC Anemia  AZT Retinopathy  ddI Hypersensitivity reactions ABC 5/9/2018 By Nimona B.(NB NB) 108

109. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) Efaverenz (EFV) It is the only NNRTI approved for once-daily dosing Use - Approved for the therapy of HIV infection of adults and children Also used for postexposure prophylaxis Induces CYP 450 enzyme – Have drug interaction with many drugs 5/9/2018 By Nimona B.(NB NB) 109

110. NNRTI… SE – Rash, ↑ liver enzymes and serum cholesterol CNS effects - Dizziness, headache, insomnia, drowsiness, euphoria, agitation, impaired cognition, nightmares, vivid dreams, and hallucinations These effects often subside after several weeks to months of therapy Can be taken during pregnancy 5/9/2018 By Nimona B.(NB NB) 110

111. NNRTI… Neverapine I nduces CYP 450 enzyme Use - Approved for the treatment of HIV infection in adults and children as part of a combination therapy SE – increase SE when CD4 count is high Rash, fever, nausea, fatigue, headache, ↑ liver enzymes Fatal hepatic toxicity and skin reaction CI - Not to be administered with ketoconazole, rifampin, or rifabutin 5/9/2018 By Nimona B.(NB NB) 111

112. Highly active ART (HAART) - Combination Rationale for combination To delay resistance emergence To reduce toxicity of individual drugs To improve adherence 112 ↑Effectiveness

113. Anti-retroviral Regimen First line ART regimen in adults and adolescents Preferred   - Two NRTI + 1 NNRTI TDF+FTC+EFV = Triple Fixed Drug Combination (FDC) ZDV+3TC+EFV= double FDC +EFV ZDV+3TC+NVP = triple FDC Others TDF/3TC/NVP ABC/3TC/EFV or ABC/3TC/NVP ABC/3TC/ZDV = ABC + double FDC 113

114. Anti-retroviral regimens… First line and second line ART regimen in adults and adolescents 114

115. Factors to Consider in Selecting Initial ART Regimen Comorbidity Patient adherence potential Convenience (e.g., pill burden, dosing frequency, and food and fluid considerations ) Potential adverse drug effects and drug interactions with other medications Pregnancy Gender and pretreatment CD4 T-cell count if considering nevirapine

116. Post exposure prophylaxis (PEP) PEP – Short term ART to reduce the likelihood of HIV infection after potential exposure either occupationally or through sexual intercourse. Doses for post-HIV exposure Low risk - ZDV 300 mg twice daily + 3TC 150 mg twice daily or combivir 1 tab twice daily for 28 days High risk - ZDV 300 mg twice daily +3TC 150 mg twice daily+ EFV 600 mg once daily ( Combivir 1 tab twice daily + EFV 600 mg once daily) for 28 days LPV/r 400 mg/100mg twice daily can be given in place of EFV 116

117. Prevention of Mother to child transmission To prevent transmission to the child (PMTCT) Giving the infant either NVP or ZDV for four to six week after birth. Mother – TDF + 3TC + EFV or ZDV + 3TC+EFV 117

118. ANTI FUNGAL DRUGS 5/9/2018 By Nimona B.(NB NB) 118

119. Introduction Pathogenic fungi of animals and humans are generally filamentous molds or intracellular yeasts . The fungal cell wall contains chitin and polysaccharides making it rigid, and acts as a barrier to drug penetration. The cell membrane contains ergosterol , which influences the efficacy and the risk of drug resistance. Most antifungal agents are fungistatic with infection-clearance largely dependent on host response. 119

120. Classification of antifungal drugs Based on chemical structures: The classes include P olyene macrolides, Imidazoles , Fluorinated pyrimidines , Benzo -furans and Iodides. Based on their sites of action: E ither systemic or topical antifungal drugs. Miscellaneous classifications: Organic acids and their salts and other inorganic salts. 120

121. Polyene Macrolides antifungals Polyene macrolides antifungals were isolated from various species of Streptomyces . Examples include; Amphotericin B, Nystatin Pimaricin ( natamycin ) 121

122. Mechanisms of polyene macrolides Polyene macrolides bind to sterols ( ergosterol ) in the cell membrane of susceptible fungi. This creates a transmembrane channel, changing membrane permeability and thus allowing leakage of intracellular components. Amphotericin B may also act as an immunopotentiator . 122

123. Indications and dose rates Amphotericin B is used for the treatment of systemic mycotic infections. Nystatin is indicated for the treatment of mucocutaneous or intestinal candidiasis. Pimaricin is used in therapeutic management of mycotic keratitis . 123

124. Adverse effects, toxicity and drug interactions Oral administration of nystatin can lead to anorexia and GIT disturbances Amphotericin B cause nephrotoxicity after IV infusion . The drug may also cause anorexia , nausea, vomiting, hypersensitivity and drug fever. Rifampin may potentiate the amphotericin B activity. Amphotericin B should be contraindicated during therapy with aminoglycosides ( nephrotoxicity ). 124

125. Imidazole antifungal drugs Imidazoles antifungals contains imidazole ring in their chemical structures. Some imidazoles also have antibacterial, antifungal, antiprotozoal , and anthelmintic activity . Examples of imidazole derivatives used as antifungals are; c lotrimazole , miconazole , econazole , ketoconazole, itraconazole , and fluconazole. 125

126. Mode of action of imidazole antifungal drugs Imidazoles block the synthesis of ergosterol , the primary cell sterol of fungi thereby altering the cell membrane permeability of yeasts and fungi. They also impair enzymes required for fatty acid synthesis and also cause toxic concentrations of hydrogen peroxide to develop intracellularly due to changes in oxidative and peroxidative enzyme activities. This results in cell membrane and internal organelle disruption and cell death. 126

127. Activity and clinical uses: Ketoconazole DOC for Paracoccidioides and backup for Blastomyces and Histoplasma Oral use in mucocutaneous candidiasis or dermatophytose Fluconazole DOC for esophageal and invasive candidiasis and coccidioidomycoses Prophylaxis and suppression in cryptococcal meningitis Itraconazole DOC in blastomycoses and sporotrichoses Backup for several other mycoses and candidiasis Clotrimazole and miconazole Used topically for candidal and dermatophytic infections 5/9/2018 By Nimona B.(NB NB) 127

128. Imidazoles … Adverse effects Anorexia , nausea and vomiting (they are dose-dependent and patients receiving high doses may require antiemetics ). Gynecomastia , decreased libido, impotence, menstrual irregularities (with ketoconazole, due to blockade of adrenal steroid synthesis) Hepatitis (is rare, but can be fatal) Hypokalemia , hypertension ( itraconazole ) Azoles are potent teratogenic drugs in animals. 5/9/2018 By Nimona B.(NB NB) 128

129. Other Antifungals Griseofulvin Active only against dermatophytes (orally, not topically) MOA: D epositing in newly formed keratin and disrupting microtubule structure Side effects: Headache , thrush, peripheral neuritis, photo toxicity. Potentiates ethanol 5/9/2018 By Nimona B.(NB NB) 129

130. ANTIPROTOZOAL DRUGS 5/9/2018 By Nimona B.(NB NB) 130

131. 1 . Malaria Malaria is the most important of the transmissible parasitic diseases. Over 90 million cases occur each year . Malaria is an acute infectious disease caused by four species of the protozoal genus Plasmodium. Plasmodium falciparum is the most dangerous species, causing an acute, rapidly fulminating disease that is characterized by persistent high fever, orthostatic hypotension, and massive erythrocytosis (an abnormal elevation in the number of red blood cells accompanied by swollen, reddish limbs). 5/9/2018 By Nimona B.(NB NB) 131

132. Parasite life cycle An anopheline mosquito inoculates plasmodium sporozoites to initiate human infection . Circulating sporozoites rapidly invade liver cells, and exoerythrocytic stage tissue schizonts mature in the liver. Merozoites are subsequently released from the liver and invade erythrocytes. Only erythrocytic parasites cause clinical illness. Sexual stage gametocytes also develop in erythrocytes before being taken up by mosquitoes, where they develop into infective sporozoites . 5/9/2018 By Nimona B.(NB NB) 132

133. Treatment of malaria depends on; Type of malaria Knowledge of regional resistance Severity of illness (oral vs. intravenous) Age of patient

134. Drug Classification Tissue schizonticides : eliminate developing or dormant liver forms ; Blood schizonticides : act on erythrocytic parasites ; Gametocides : kill sexual stages and prevent transmission to mosquitoes . Radical cure : eliminate both hepatic and erythrocytic stages. Not available. 5/9/2018 By Nimona B.(NB NB) 134

135. Chloroquine For treatment and chemoprophylaxis since the 1940s. Oral use and parenteral use. Antimalarial Action: Highly effective blood schizonticide . Moderately effective against gametocytes of P vivax , P ovale , and P malariae but not against those of P falciparum. Not active against liver stage parasites. 5/9/2018 By Nimona B.(NB NB) 135

136. Chloroquine … Does not eliminate dormant liver forms of P vivax and P ovale , and for that reason Primaquine must be added for the radical cure of these species. MOA: Concentrating in parasite food vacuoles , preventing the biocrystallization of the hemoglobin breakdown product, heme , into hemozoin , and thus eliciting parasite toxicity due to the buildup of free heme . 5/9/2018 By Nimona B.(NB NB) 136

137. 5/9/2018 By Nimona B.(NB NB) 137 Mechanism of action of chloroquine

138. Chloroqiune … SEs Usually very well tolerated Pruritus, GI disturbance, headache, malaise, blurring of vision, and urticaria Rare : hemolysis in G6PD-deficient persons, impaired hearing, agranulocytosis , alopecia, bleaching of hair, hypotension. Large IM injections or rapid IV infusions : severe hypotension and respiratory and cardiac arrest. 5/9/2018 By Nimona B.(NB NB) 138

139. Quinine & Quinidine First-line therapies for falciparum malaria. Oral administration and parenteral administration. Higher plasma levels and half-life in infected persons, but toxicity is not increased, apparently because of increased protein binding. MOA: is unknown, they may act like chloroquine . 5/9/2018 By Nimona B.(NB NB) 139

140. Quinine & Quinidine Quinine: Is rapid-acting, highly effective blood schizonticide against the 4 species of human malaria parasites. Quinine ( i.v. ) has been used as the drug of choice for cerebral malaria and other forms of complicated malaria 20mg/kg(loading dose) diluted in 5 % dextrose saline and infused i.v over 4 hrs. Switch oral:10 mg /kg 8 hrly to complete a 7 day course Quinidine : parenteral treatment of severe falciparum malaria. Continuous IV infusion; cardiac monitoring (can cause cardiac arrhythmia). 5/9/2018 By Nimona B.(NB NB) 140

141. Adverse Effects Cinchonism : Tinnitus (perception of sound) Headache, Nausea, Dizziness, Flushing, Visual Disturbances Black water fever rare severe illness marked hemolysis , Hypersensitivity reactions Hypoglycemia Too-rapid IV infusions : Severe hypotension IV Quinidine : ECG abnormalities.

142. Mefloquine Used in chloroquine -resistant strains of P falciparum and other species. Is chemically related to quinine. Can only be given orally because severe local irritation occurs with parenteral use. Has strong blood schizonticidal activity against P falciparum and P vivax , it is not active against hepatic stages or gametocytes. MOA: is unknown. 5/9/2018 By Nimona B.(NB NB) 142

143. MEFLOQUINE… GI disturbance, Rash, Dizziness, Leukocytosis, Thrombocytopenia, Aminotransferase Elevations Arrhythmias , bradycardia . Considered safe in young children and throughout pregnancy. 5/9/2018 By Nimona B.(NB NB) 143

144. Primaquine Eradicate hepatic stages of all human malaria parasites. Chemoprophylaxis against all malarial species. It is the only available agent active against the dormant stages of p vivax and p ovale . Gametocidal against the 4 human malaria species. Acts against erythrocytic stage parasites, but this activity is too weak to play an important role. MOA: is unknown. 5/9/2018 By Nimona B.(NB NB) 144

145. Primaquine … Adverse effects: anorexia, nausea, abdominal cramps H aemolytic anaemia , especially in patients with genetic deficiency of erythrocyte glucose-6-phosphate dehydrogenase (G6PD ). Subjects should be tested for G6PD and, in those that are deficient, the risk of haemolytic anaemia is greatly reduced by giving primaquine in reduced dose. 5/9/2018 By Nimona B.(NB NB) 145

146. Halofantrine & Lumefantrine 5/9/2018 Against erythrocytic (but not other) stages of all four malaria species. MOA: unknown. SEs: GI disturbance, cough, rash, headache, pruritus, and elevated liver enzymes, dose-related prolongation of QT and PR intervals . By Nimona B.(NB NB) 146

147. Artemisinin & Its Derivatives Analogs are: Artesunate (water-soluble; oral, IM, IV and rectally), Artemether (lipid-soluble; oral, IM, and rectally), Dihydroartemisinin (water-soluble; oral). They are very rapidly acting blood schizonticides against all human malaria parasites, no effect on hepatic stages. 5/9/2018 By Nimona B.(NB NB) 147

148. Artemisinin & Its Derivatives… MOA: The parasite when it infects a RBC, it consumes Hgb within its digestive vacuole, liberating free heme , The iron in heme interacts with Artemisinin producing reactive oxygen radicals which damage the parasite leading to its death Artemisinin - based combination therapy is now the standard for treatment of uncomplicated falciparum malaria in nearly all areas endemic for falciparum malaria. SEs : GI disturbance, dizziness, neutropenia, anemia , hemolysis, elevated liver enzymes, allergic reactions. 5/9/2018 By Nimona B.(NB NB) 148

149. Drugs for Amebiasis Amebiasis Is due to infection with E. histolytica Asymptomatic intestinal infection ( 90%) Mild to moderate colitis Severe intestinal infection ( dysentery) Ameboma ( An inflamed, tumorlike , spreading nodule that occasionally develops in chronic amebiasis , often in the wall of the colon ) . Liver abscess Other extraintestinal infections. 5/9/2018 By Nimona B.(NB NB) 149

150. Life cycle of Amebiasis

151. Classification of anti-amoebic drugs Luminal amebicides : for treating intestinal infections.( Diloxanide Furoate , Iodoquinol , Paromomycin , Metronidazole .) Tissue amebicides : used to destroy amoebae that have invaded tissue, rapidly absorbed into the bloodstream and transported to the site of infection.( Metronidazole, Tinidazole ). For amebic liver abscess : .( Metronidazole, Tinidazole , Diloxanide Furoate ). 5/9/2018 By Nimona B.(NB NB) 151

152. Metronidazole & Tinidazole Metronidazole is an antibiotic, amebicide , and antiprotozoal. Effectively eradicates intestinal and extraintestinal tissue infections. (drug of choice in the treatment of extraluminal amebiasis ) It kills trophozoites but not cysts of E histolytica Tinidazole : appears to have similar activity and a better toxicity profile than metronidazole, and it offers simpler dosing regimens MOA: Disruption of DNA synthesis as well as nucleic acid synthesis 5/9/2018 By Nimona B.(NB NB) 152

153. Metronidazole & Tinidazole … Clinical use: Amoebiasis , Giardiasis, Trichomoniasis , Anaerobic infections, Pseudomembranous enterocolitis, H. pylori – induced peptic ulcer, Oral infections SEs GI disturbance, Dry mouth, Metallic taste, headache, dizziness, dark urine. Metronidazole has a disulfiram -like effect , so that N/V, flushing & tachycardia can occur if alcohol is ingested during therapy. 5/9/2018 By Nimona B.(NB NB) 153

154. Metronidazole and Tinindazole .. Contra-indications : First trimester of pregnancy Chronic alcoholism 5/9/2018 By Nimona B.(NB NB) 154

155. Diloxanide furoate Effective luminal amebicides , Used with metronidazole to treat serious intestinal and extraintestinal infections, by unknown mechanism . Dose: 500mg TID for 10 days. A/E: GI disturbance, Headache, Rash, Pruritus ( severe itching of the skin). 5/9/2018 By Nimona B.(NB NB) 155

156. Paromomycin It is an aminoglycoside antibiotic used as a luminal agent and may be superior to diloxinde in asymptomatic infection. Not significantly absorbed from the GIT MOA: inhibition of protein synthesis Adverse effects: abdominal pain and diarrhea 5/9/2018 By Nimona B.(NB NB) 156

157. ANTHELMENTHIC DRUGS 5/9/2018 By Nimona B.(NB NB) 157

158. 158

159. N ematodes A ) Intestinal round worms Ascaris lmubricoides (common round worm) Enterobius vermicularis (pinworm) Trichuris trichuria (whipworm) Strongyloids stercoralis (threadworm)  Strongyloidiasis Ancylostoma duodenale & Necator americanus (hookworm) B) Tissue round worms Trichinella spiralis . ( Trichinosis) Dracunculus medinensis ( guineaworm )  Dracunculiasis 5/9/2018 By Nimona B.(NB NB) 159

160. Flat worms Cestodes (tape worms ) Tenia saginata (Beef tapeworm) Tenia solium (Pork tapeworm), Cysticercosis (Pork tapeworm) Hymenolepis nana (Dwarf tapeworm) Diphyllobothrium latum (Fish tapeworm ) T rematodes /flukes (leaf-like ) Schistosoma mansoni Schistosoma hematobium Schistosoma Japonicum Paragonimus species  Paragonimiasis Fasciolopsis buski Fasciola hepatica Clonorchis sinensis 5/9/2018 By Nimona B.(NB NB) 160

161. Anthemlentic Anthelmintics are classified based upon their chemical structures. Piperazines : eg. Diethylcarbamazine citrate, Piperazine citrate. Benzimidazoles : eg . Albendazole , Mebendazole , Thiabendazole . Heterocyclics : eg . Oxamniquine , Praziquantel . Natural products: eg . Ivermectin , Avermectin . Vinyl pyrimidines : eg . Pyrantel , Oxantel . Amide : eg . Niclosamide . Nitro derivative: eg . Niridazole . Imidazo thiazole : eg . Levamisole . 5/9/2018 By Nimona B.(NB NB) 161

162. Benzimidazoles ALBENDAZOLE : It is a major drug for the treatment of ( intestinal nematodes) like; Ascariasis,Trichuriasis,Strongyloidiasis , Enterobius vermicularis (pinworm), Nector americanus , & Ancylostoma duodenale (Hookworms) infections . MOA: Inhibits microtubule synthesis and glucose uptake It has larvicidal effects on cysticercosis , ascariasis , and hookworm infection. Also, ovicidal in ascariasis , ancylostomiasis (hookworm), trichuriasis 5/9/2018 By Nimona B.(NB NB) 162

163. Albendazole … Adverse effects: In short term use there is no significant adverse effects. In long term use : abdominal distress, headache, fever, fatigue, alopecia , increased liver enzymes , pancytopenia. Blood counts and LFT should be carried out regularly. Not given during pregnancy and in hypersensitive people. Safety in children is not established in children below 2 years of age. 5/9/2018 By Nimona B.(NB NB) 163

164. Mebendazole Synthetic benzimidazole Wide spectrum antihelminthic   activity Low incidence of side effects Mechanism of action: Binds with β tubulin of microtubules   & inhibit its synthesis a worm becomes immobile & dies slowly Pharmacokinetics Poorly  absorbed (< 10%) Absorption increased with fatty meal Highly protein bound -PPB >90% Half life  : 2-6 hrs. Rapidly metabolized in liver & mostly renaly   excreted 5/9/2018 By Nimona B.(NB NB) 164

165. Mebendazole … Therapeutic Uses Tablet should be chewed before swallowing. Drug of choice for: Pinworm Infections ( enterobiasis ) (single dose of 100 mg once, repeated after 2 weeks) Round worm infection ( Ascariasis ) Whip worm infection( Trichuriasis ) Hookworm infections Intestinal capillariasis -200 mg twice daily for 21 days Also used as alternative drug for: Taeniasis Trichinosis 5/9/2018 By Nimona B.(NB NB) 165

166. Mebendazole … Drug Interactions Enzyme inhibitors (Cimetidine) increase drug levels Enzyme inducers (phenytoin) decrease drug levels Contraindications Pregnancy children < 2 yrs age 5/9/2018 By Nimona B.(NB NB) 166

167. PYRANTEL PAMOATE It is a broad- specturm antihelminthic It is not effective against trichuriasis (whipworms) and trichostrongylus orientalis . Pharmacokinetics: It is poorly absorbed orally. Active mainly against luminal organisms. Half of the drug is excreted unchanged in the feces. 5/9/2018 By Nimona B.(NB NB) 167

168. PYRANTEL PAMOATE Mechanism of Action Depolarizing neuromuscular blocking agent. It blocks NM transmission. Increases Acetyl choline release and inhibits Acetyl choline esterase Both effects result in increased acetylcholine at NMJ. Spastic paralysis Worm becomes immobile & expelled out 5/9/2018 By Nimona B.(NB NB) 168

169. PYRANTEL PAMOATE… Uses Pinworm, A scariasis , Hookworm, T richostrongylus orientalis Dose:  11 mg/kg. For Ascaris   and hookworm, single dose is effective, while for pinworm infection, dose is repeated after 2 weeks. Contraindications Pregnancy Children < 2 yrs age 5/9/2018 By Nimona B.(NB NB) 169

170. Piperazine Only used for the treatment of ascariasis . It is readily absorbed orally and excreted in urine Mechanism of action: It causes paralysis of ascaris by blocking acetylcholine at the myoneural junction, expelling the live worm by normal peristalsis . Treatment is continued for 3-4 days or repeated after one week in case of heavy infections. 5/9/2018 By Nimona B.(NB NB) 170

171. Piperazine … Adverse effects: GI disturbances Neurotoxicity , allergic reactions serum sickness like syndrome Contraindications Epilepsy or chronic neurologic disease Impaired liver or kidney functions Pregnancy Malnutrition 5/9/2018 By Nimona B.(NB NB) 171

172. Drug treatment for tape worm( cestodes ) infection Niclosamide Praziquantel Albendazole 5/9/2018 By Nimona B.(NB NB) 172

173. NICLOSAMIDE It is useful for the treatment of adult tape worm ( cestodes ) infestation Mechanism of action: Adult worm is rapidly killed by inhibition of the oxidative phosphorylation or stimulation of ATPase activity. has no effect on ova. Clinical uses: T. Saginata (Beef tape worm),T. solium (pork tapeworm), fish tapeworm. Hymenolepis nana, H diminuta and Dipylidium caninum 5/9/2018 By Nimona B.(NB NB) 173

174. NICLOSAMIDE… Adverse effects: Mild, infrequent and transitory GI disturbances Alcohol consumption should be avoided Not indicated in children under 2 years of age or pregnancy. 5/9/2018 By Nimona B.(NB NB) 174

175. praziquantel For Schistosome , Trematode , Cestode infections, swallowed without chewing because their bitter taste can induce vomiting. Undergoes extensive first-pass metabolization Adverse effects Headache, Dizziness, N/V/D Pruritus , Arthralgia, myalgia, Mild and transient elevations of liver enzymes MOA: Immobilize microfilariae- alters their surface structures- Displace the from the tissues- Makes them susceptible to destruction by host defense mechanism. 5/9/2018 By Nimona B.(NB NB) 175

176. Worms ( helminths ) Drug of choice Tapeworms (cestodes) Niclosamide or Praziquantel or Albendazole Roundworms (nematodes) Enterobius vermicularis (pinworm) Ascaris lumbricoides Trichuris trichiura (whipworm) Trichinella spiralis (trichinellosis) Strongyloides stercoralis Necator americanus (hookworm) Ancylostoma duodenale Onchocerca volvulus (Onchocercosis) Wuchereria bancrofti (Elephantiasis) Mebendazole or Pyrantel Mebendazole or Pyrantel Mebendazole or Albendazole Mebendazole and Thiabendazole Thiabendazole Mebendazole or Pyrantel Mebendazole , Pyrantel , or Albendazole Ivermectin Diethylcarbamazine Flukes (trematodes) Schistzoma (Schistozomes) Praziquantel

177. 5/9/2018 By Nimona B.(NB NB) 177