health education

1. IX-CHEMOTHERAPY OF
INFECTIOUS DISEASES
1

2. General principles of antimicrobial therapy
 Definition:
a) Chemotherapy
» Use of drugs against invading organisms as
well as cancerous cells
b) Antimicrobial agent
» chemicals against invading organisms
c) Antibiotic
» A drug that is produced by one microorganism
and has the ability to harm other microbes
 Goal: Selective toxicity:
 Ability to injure or kill an invading microorganism
without harming the cells of the host. 2

3.  How is selective toxicity achieved?
 Biochemical differences that exist between
microorganisms and human beings.
 Example:
 Disruption of bacterial cell wall synthesis by
penicillins
 Classification of Antimicrobial Drugs
 Antibacterial, Antifungal , Antiviral, Antiparasites
3

4. ANTIBACTERIAL AGENTS
 Mechanisms of Antibacterial Action
1) Inhibition of cell wall synthesis
– penicillin, cephalosporin, cycloserine,
vancomycin, bacitracin, carbapenems
2) Increase in cell membrane permeability
– polyene antibiotics, polymixins
3) Inhibition protein synthesis
– aminoglycosides, chloramphenicol, tetracycline
4) Inhibition nucleic acid synthesis
– rifampicin, fluoroquinolones
5) Antimetabolites
– sulphonamides, trimethoprim 4

5.  Drug resistance
– Unresponsiveness of microorganism to antimicrobial
agents
 Mechanisms by which Resistance is acquired
A. Spontaneous mutation
B. Gene transfer
5

6.  Biochemical alterations leading to antimicrobial
resistance include:
A. Destruction of the drug by the organism
»β lactamase inactivates penicillins
B. Development of altered drug receptor
»Aminoglycosides, erythromycin, penicillin
C. Decreased drug entry
»Tetracycline
D. Development of alternate metabolic pathway
»Sulphonamides
6

7.  Bacteriostatic vs. bactericidal
Bacteriostatic
»arrest the growth and replication of bacteria at
serum levels achievable in the patient
Bactericidal
»kill bacteria at drug serum levels achievable in
the patient
7

8.  Misuses of Antimicrobial Drugs
A. Attempted Treatment of Untreatable Infection
B. Treatment of Fever of Unknown Origin
C. Improper Dosage—Too low or too high
D. Treatment in the Absence of Adequate
Bacteriologic Information
E. Omission of Surgical Drainage—Have limited
efficacy in presence of foreign material, necrotic
tissue, or pus
8

9. BETA-LACTAM ANTIBIOTICS AND OTHER INHIBITORS
OF CELL WALL SYNTHESIS
9

10. Penicillins
 Mechanism of action
– Inhibition of bacterial cell wall synthesis by inhibition
of transpeptidase.
10

11.  are bactericidal
 Mechanism of bacterial resistance
1) Inactivation of antibiotic by -lactamase:
common
2) Impaired penetration: from G-ves, absence of
porins
3) Modification of target penicillin binding sites
4) Presence of efflux pump
11

12.  Penicillin G
 AMS
a) G+ve cocci except penicillinase producing
staphylococci
b) some G+ve bacilli
c) G –ve cocci [N. meningitidis, N. gonorrhea]
d) Spirochetes [T.pallidum]
12

13.  Therapeutic uses
A. Drug of choice for
a) pneumonia or meningitis by Streptococcus
pneumonia
b) Pharyngitis by streptococcus pyogenes
c) Infectious endocarditis by streptococcus
viridians
B. Infection caused by G+ve bacilli
a) Gangrene by Cl. Perfringes
b) Tetanus by Cl. Tetani
c) Anthrax by B. anthracis
13

14. C. First choice for meningitis by N. meningitides
D. Drug of choice for the treatment of syphilis
E. Prophylactic applications
a) Syphilis in sexual partners
b) Benzathine penicillin G monthly for life in
recurrent rheumatic fever
c) Bacterial endocariditis
14

15.  Pharmacokinetics
– Penicillin G is available as salts [Na+, K+, Procaine,
Benzathine penicillin G]
– Penicillin G: orally ineffective due to gastric acid
– Distributes well to most tissues; Inflammation
increases distribution into CSF, joints, and eye
– Penicillin G is eliminated by tubular secretion [90%]
– Excretion delayed by probenecid
phenoxymethyl penicillin [penicillin V]
– Acid stable: given orally
– Used for streptococcal pharyngitis, prophylaxis of
rheumatic fever
– Not for serious infections
15

16.  PENICILLINASE RESISTANT PENICILLINS
 Cloxacillin , dicloxacillin, oxacillin , methicillin,
nafcillin
» Used against penicillinase producing strains of
staph.aureus and staph.epidermidis
» Emergence of staphylococcal strains [methicillin
resistant]: treated with vancomycin
16

17.  AMINOPENICILLINS
 ampicillin, amoxicillin, bacampicillin
 Antimicrobial spectrum
as penicillin G
plus G-ve bacilli [H.influenza, E.coli, Salmonella,
Shigella]
Ineffective against  lactamase producing bacteria
A. Ampicillin
 Therapeutic use
1. UTI, RTI
2. Shigellosis [but not amoxicillin]
3. Typhoid fever: less efficacious than Ciprofloxacin
4. Meningitis combined with 3rd generation 17

18.  Adverse effects
a. Diarrhea
b. Rashes
B. Amoxicillin
Oral absorption is better
Incidence of diarrhea is less
Less active against shigella
C. Bacampicillin: prodrug of ampicillin
18

19.  ANTIPSEUDUOMONAL PENICILLINS
 Carboxypenicillins
– Carbenicillin
»active against pseudomonas aeruginosa &
Indole positive proteus
– Ticarcillin
 Ureidopenicillins
– piperacillin, mezlocillin, Azlocillin
»active against pseudomonas, Klebsiella
pneumoniae
19

20.  BETA-LACTAMASE INHIBITORS
 Clavulinic acid, sulbactam, tazobactam
Inhibits bacterial -lactamases; have weak
antibacterial effect
 Most active against -lactamase produced by:
»S.aureus, H.infleunza, some
enterobacteriaceae, Bacteroid spp
Restore antibacterial activity of amoxicillin,
ampicillin, piperacillin, mezlocillin
20

21.  Amoxicillin-clavulinic acid [augmentin®]
 Therapeutic use
 acute otitis media [H.infleunza; B.catarrhalis];
 Sinusitis
 Lower RTI
 Skin infection [streptococci, staphylococci];
 Diabetic foot infection [staphylococci, aerobic
& anaerobic G-ve]
21

22.  ADVERSE EFFECTS OF PENICILLINS
 allergy, diarrhea ( ampicillin), rash(ampicillin)
 sodium overload, inhibition of platelet function
» ticarcillin
 antibiotic-associated colitis (pseudomembranous
colitis)
22

23. CEPHALOSPORINS
 Related both structurally and functionally to the
penicillins
23

24.  Mechanism of action
 Inhibition of cell wall synthesis
 Bactericidal
 Mechanisms of Bacterial Resistance
 Production of β-lactamases (cephalosporinases)
 Altered penicillin binding proteins (PBPs)
 Classification
 Four generation
 From 1st generation to 3rd generation
Increasing activity against G-ve & anaerobes
Increasing resistance to -lactamase destruction
Increasing ability to reach CSF 24

25.  FIRST GENERATION CEPHALOSPORINS
1. Excellent gram-positive coverage, some gram
negative coverage.
2. Do not cross the blood–brain barrier.
3. Useful for treating soft-tissue infections and for
surgical prophylaxis.
 Can often be used as an alternative to penicillin G.
25

26. Selected 1st generation cephalosporins
Generic Route Half
life(h)
Cephalexin oral 0.9
Cefadroxil oral 1.2
Cephradine Oral,iv/im 0.7
Cefazolin Iv/im 1.8
Cephalothin iv 0.6
26

27.  SECOND GENERATION CEPHALOSPORINS
1) Improved activity against Haemophilus
influenzae, Neisseria species, and Moraxella
catarrhalis.
2) Activity against gram-positive organisms is
weaker
 Overall, this generation is of limited usefulness
27

28.  THIRD GENERATION CEPHALOSPORINS
a)Less active than first generation against gram
positive cocci
b)Improved gram-negative coverage
c)Excellent activity against Neisseria
gonorrhoeae, N. meningitidis, Haemophilus
influenzae, and Moraxella catarrhalis.
d)Ceftriaxone has a long half-life that allows for
once-daily dosing.
28

29.  CEFTRIAXONE
– High efficacy in bacterial meningitis, multiresistant
typhoid fever, complicated UTI, abdominal sepsis,
septicaemias
 CEFTAZIDIME
– Excellent activity against G-ve including p.aeruginosa
– Penetrate CSF & txt of choice in meningitis due to p.
aeruginosa; given parenterally
29

30.  FOURTH GENERATION CEPHALOSPORINS
 Cefepime & cefpirome
a) More resistant to β–lactamases
b) Excellent gram-positive (including methicillin
sensitive Staphylococcus aureus) and gram
negative coverage (including Pseudomonas
aeruginosa).
30

31.  ADVERSE EFFECTS OF CEPHALOSPORINS
1) Allergic reactions
2) Antibiotic-associated colitis: superinfection
3) Bleeding tendency: hypoprothrombinemia
[methylthioterazole/MTT containing group -
Cefoperazone, cefotetan, cefmandole,
cefmetazole ]
4) Local effects: thrombophlebitis from iv
injection
31

32. OTHER INHIBITORS OF CELL WALL SYNTHESIS
 vancomycin
 Mechanism:
–Inhibit bacterial cell wall synthesis by
binding to peptidoglycan pentapeptide 
Transglycosylase inhibition  inhibition of
elongation of peptidoglycan & cross linking
 Spectrum:
–Against G+ve [staphylococcus aureus &
staph epidermidis including methicillin
resistant, & Cl.difficile]
 PKS:
–Not absorbed orally; given iv except
antibiotic induced colitis 32

33.  BACTERIOCIDAL INHIBITORS OF PROTEIN SYNTHESIS:
AMINOGLYCOSIDES
 Includes: Streptomycin, Gentamicin, Kanamycin,
Amikacin, Tobramycin, Sisomycin, Netilmicin &
others
 Mechanism of action
– The drug binds to 30s ribosomal subunit 
Protein synthesis inhibition
Block initiation complex of peptide formation
Induce misreading of mRNA
Promote polysome instability
33

34.  Mechanisms of Bacterial Resistance
a) Production of enzyme that can inactivate
aminoglycoside [phosphorylate, acetylate or
adenylate the drug]
b) Alteration of drug target site
c) Altered drug transport
 Antimicrobial spectrum
 Aerobic gram-negative organisms
 Eg Pseudomonas, Klebsiella, E. coli, others
 Pharmacokinetics
 Absorbed very poorly from intact GIT [i.m. &i.v.]
34

35. – Distribution limited to ECF
»Bind to renal tissue  nephrotoxicity
»ototoxicity
– Eliminated primarily by kidney
 ONCE DAILY DOSING
– 2-3 Equally divided doses [traditional]
– Once daily dosing may be preferred in certain
situations
efficacious as traditional multiple dose method
lower but not eliminate : nephrotoxicity & ototoxicity
simple, less time consuming & cost effective
does not worsen neuromuscular function
35

36.  Therapeutic uses
»used against G-ve enteric bacteria in bacteremia &
sepsis; TB
» used in combination with -lactam antibiotic to
increase coverage (G+) and synergism
 Adverse Effects of Aminoglycosides
1. Ototoxicity
2. Renal toxicity
3. Rarely neuromuscilar blockade
36

37. BACTERIOSTATIC INHIBITORS OF PROTEIN
SYNTHESIS
Tetracyclines
 Macrolides
 Lincosamides
 Chloramphenicol
37

38.  TETRACYCLINES
 Includes: oxytetracycline, tetracycline,
demelocycline, doxycycline, minocycline
 G+ve & G-ve aerobic & anerobic bacteria
 Spirochetes, Mycoplasma, Rickettsia, Chlamydia
& some protozoa
 Mechanism:
– Act by binding 30s ribosome  prevent addition
of aminoacid to growing peptide
 Microbial resistance
»decrease drug uptake
»acquisition of the ability to extrude TTCs
38

39. Major Indications Effective alternative
1. Chlamydial Infections - Acne, severe
Lymphogranuloma venereum - M. pneumoniae
Conjuctivitis - Nocardia
Trachoma - Rat-bite fever
Acute epididymitis - Syphilis
2. Ricketisial infections - Amebiasis
Typhus fever - P. falciparum
Rocky mountain spotted fever - Meningococcal disease
3. Other infections Prevention[minocycline]
Plague - Oral bowl preparations for
Tularemia In combination with aminglyco. Intestinal surgery
Brucellosis [TTC+ Neomycin]
Relapsing fever - tXt of inappropriate secretion
Cholera Of ADH [Demeclocycline]
Urethritis
39

40.  Adverse Effects of TTCs
1) GI Irritation: oral therapy burning, cramps
& NVD
– Administration of food with doxycycline or
minocycline ameliorate some of the
symptoms
2) Effect on bone & teeth
 Yellow or brown discoloration of teeth
 Hypoplasia of enamel
 Suppression of long bone growth in infants
 Doxycycline bind less with Ca2+  less
frequent dental changes
40

41.  MACROLIDES
 Includes: Erythromycin, Clarithromycin,
Azithromycin
 Erythromycin
– Mechanism:
»Inhibition of aminoacyl translocation
reaction & formation of initiation complex
Inhibition of protein synthesis via binding
to 50s ribosomal RNA;
 Resistance
a. Decrease permeability or active efflux
b. Production of esterase  hydrolysis
c. Modification of the ribosomal binding sites
41

42.  Pharmacokinetics
– enteric coated to prevent stomach acid
 Administration
»Oral, topical, Parentral [i.v., i.m.]
»Excretion: Primarly bile & faces
42

43. Therapeutic uses
Erythromycin, 1st
choice Alternative
Mycoplasma pneumonia Fluoroquinolone
Legionella pneumonia
Doxycycline + Rifampin or
cotrimoxazole
Diptheria Penicilline G
Pertusis Cotrimoxazole
Chlamydia trachomatis
[pneumonia;conjunctivitis]
Sulfisoxazole
Campylobacter jejuni
[Gastroenteritis]
Tetracycline
Bacillary angiomatosis Doxycycline
43

44.  adverse effects of erythromycin
a) GI effects: ANVD
b) Liver toxicity: estolate salts cause acute
cholestatic hepatitis due to hypersensitivity
reaction
 drug interaction
1) Erythromycin metabolites form inactive
complexes with CYP450  Increase level of
terfenadine or astemizole
2) Increase bioavailability of digoxin by
interfering with its inactivation in gut flora
44

45.  Azithromycin and Clarithromycin
 Semisynthetic derivative of Erythromycin
 Difference from erythromycin
a) Have better oral absorption
b) Longer t1/2
c) Fewer GI side effects
d) Are expensive
 Clarithromycin is similar with erythromycin
with respect to antibacterial activity & drug
interaction except:
» More active against M. avium complex
» Also activity against M. laprae &
Toxoplasma gondii
45

46.  Azithromycin is similar to clarithromycin except:
Less active against staphylococci & streptococci
Slightly more active against H. influenza
Highly active against Chlamydia
Long t1/2 [3days] permit once daily dosing
Free of drug interaction
46

47.  LINCOSAMIDES:
– Clindamycin
 Mechanism: similar to erythromycin
 Therapeutic use
–Infections that involve B. fragilis & penicillin
resistant anaerobic bacteria
–In combination with aminoglycosides/
cephalosporins to treat penetrating wounds
of the abdomen
–Infections on female genital tract
»Septic abortions
»Pelvic abscess
»Aspiration pneumonia 47

48. – Recommended instead of erythromycin for
prophylaxis of endocarditis
– Clindamycin + Primaquine in tXt of moderate or
severe PCP alternative to cotrimoxazole
– Clindamycin + Pyrimethamine for AIDS related
toxoplasmosis
 Adverse effects
nausea, diarrhea & skin rashes
Clindamycin associated colitis
48

49.  CHLORAMPHENICOL
 Mechanism
– binds 50s ribosome subunit  inhibiting
peptidyl transferase steps of protein
synthesis
–Bacteriostatic
 Antimicrobial spectrum: Broad spectrum
–Both aerobic &anaerobic G+ve & G-ve
–Rickethisiae
49

50. Indication of chloramphenicol
Indication Comments
Therapy of choice: None
Effective alternative
1. Bacterial meningitis For penicillin allergic patients
H. influenza
Streptococcus pneumoniae
Neisseria meningitis
2. Typhoid fever
3. Brain abscess
4. Rickethisial infections Preferred in pregnancy & child
Rocky mountain spotted fever
Typhus
50

51.  Adverse drug reactions
a) GI disturbance: NVD
b) Bone marrow disturbances
 Suppression of RBC production: dose related
c) Aplastic anemia: Idiosyncratic reaction
d) superinfection: including oropharyngeal
candidiasis
e) Gray baby syndrome [vomiting, cyanosis,
abdominal distension, circulatory collapse&
death]
 Result from decreased conjugation &
excretion
51

52. SULPHONAMIDES & TRIMETHOPRIM
 Sulphonamides
 Mechanism:
Inhibit bacterial growth by interfering with
microbial folic acid synthesis
Inhibit competitively the incorporation of PABA
during folic acid synthesis
52

53. 53

54.  Microbial resistance
Synthesis of PABA in amounts sufficient to
overcome sulphonamide mediated inhibition
Dehydropetroate synthetase  affinity to
sulphonamide
 Sulphonamide uptake
 Classification of sulphonamides
systemic sulphonamides
–short acting agents: sulfisoxazole
–Intermidiate acting: sulphamethoxazole
–Long acting : sulphadiazine
54

55.  Sulphonamide limited to GIT
» Succinylsulfathiazole & sulfasalazine
 Topical sulphonamide:
» Mafenide acetate
» Silver sulfadiazine
» Sulfacetamide
 Therapeutic uses
 Declined due to introduction of cidal antibiotic
with lower toxicity & development of resistance
1) UTI [Sulfisoxazole: high solubility, achieve
effective concentration & less expensive]
55

56. 2) Other uses
a) Nocardiasis
b) Trachoma [sulfacetamide]
c) Sulphadiazine/sulphadoxine + pyrimethamine:
to treat toxoplasmosis & malaria
d) Ulcerative colitis: sulfasalazine
 Adverse effects
1) hypersensitivity reactions
a) Mild [rash, fever, photosensitivity]
b) Severe [stevens-Johnson syndrome: lesion of
skin & mucus membrane, fever, malaise]
56

57. 2) Haematologic effect
a) Hemolytic anemia [Glucose 6 phosphate
dehydrogenase deficiency]
b) Agranulocytosis: leucopenia &
thrombocytopenia
4) Renal damage from crystalurea
57

58.  cotrimoxazole
 Trimethoprim and sulphamethoxazole
 Shows synergism
 Selected because of similarity in pharmacokinetics
 Mechanism: Inhibition of two sequential steps
 Therapeutic Uses
a) UTI: Caused by E.coli, Klebsiella, Enterobacter,
P.mirabilis
b) PCP: Txt of choice
c) Drug of choice for shigellosis
58

59. d) Other infections
 Acute otitis media & chronic bronchitis [H.
infleunza, streptococcus pneumonia]
 Urethritis & pharyngitis due to penicillinase
producing N. gonorrhoe
 Alternative to CAF for typhoid fever
 Pharmacokinetics
 TMP concentrates in the relatively acidic
milieu of prostate & vaginal fluids  effective
59

60.  Adverse effects
–Dermatologic
– GI: NV & stomatitis
–Hematologic:
»megaloblastic anemia; Leukopenia;
thrombocytopenia
–HIV pts with PCP: drug induced fever, rashes,
diarrhea
60

61. FLUOROQUINOLONES
– include ciprofloxacin, norfloxacin etc.
– active against broad spectrum of bacteria: mainly
G-ve, some G+ve and mycoplasma
– Mechanism of action
–Block DNA synthesis
 AMS- All the fluoroquinolones are bactericidal.
61

62. In general, they are effective against gram-
negative organisms such as the
Enterobacteriaceae, Pseudomonas species,
Haemophilus influenzae, Moraxella catarrhalis,
Legionellaceae, chlamydia, and mycobacteria
(except for Mycobacterium avium-intracellulare
complex).
They are effective in the treatment of gonorrhea
but not syphilis.
The newer agents (for example, levofloxacin and
moxifloxacin) also have good activity against some
gram-positive organisms, such as Streptococcus
pneumoniae.
62

63.  Resistance
»Alteration in DNA gyrase & topoisomerase IV
» Reduced ability to cross bacterial membrane
 Pharmacokinetics
Absorption- Well absorbed, food does not
reduce absorption
 Distribution
- Vd is high
- Concentration in prostate, kidney, bile,
lung, neutrophils/ macrophages exceed
serum concentration
63

64.  Elimination
–Ofloxacin & lomefloxacin: predominantly by
kidney
– Pefloxacin, sparfloxacin, trovafloxacin:
nonrenal pathway
– Most others have mixed excretion: renal &
nonrenal
 Ciprofloxacin
 Therapeutic uses
1)UTI: complicated and uncomplicated
2)GI infection & abdominal infection
64

65. a) Diarrhea caused by shigella, salmonella,
toxigenic E.coli, campylobacter
b) Peritonitis
3) Prostatitis
4) sexually transmitted diseases
a) N.gonorrhea
b) C.trachomatis
c) H. ducreyi
65

66. 5) RTI :
a) Respiratory tract infections [H.infleunza,
M.catarrhalis & Enteric G-ve bacteria]
b) Against agents for atypical pneumonia [M.
pneumoniae, C. pneumoniae, L. pneumoniae]
c) Exacerbation of chronic bronchitis
6) Skin & soft tissue infection
7) others [mycobacterial infection, for
nontubercular mycobacteria, typhus fever]
66

67.  Adverse effect
a) GIT: ANV & Abdominal discomfort
b) CNS: Head ache, dizziness, insomnia
67

68. ANTIMYCOBACTERIAL AGENTS:
 DRUGS FOR TUBERCULOSIS
 Treating mycobacterial infection present problems:
 they are slow growing microbes
 can also be dormant; resistant to many drugs
 lipid rich cell wall is impermeable to many agent
 a substantial portion is intracellular
Needs prolonged treatment
Drug toxicity & poor patient compliance
High risk of emergency of resistant bacteria
68

69.  individual antituberculous agents
First line drugs: superior efficacy & acceptable
toxicity
»isoniazide, rifampin, pyrazinamide,
ethambutol, streptomycin
Second line drugs: less efficacy, greater toxicity or
both.
– Used in combination with 1st line drug to treat
dissiminated TB & TB caused by resistant
organism
»PAS, kanamycin, capreomycin,
ethionamide, cycloserine
69

70.  ISONIAZID (INH/Isonicotinic hydrazide)
 Mechanism
–block mycolic acid synthesis
–bactericidal
 Pharmacokinetics
–Well absorbed p.o. or i.m.
–Distributed widely: CSF  20% of plasma conc.
Increased in meningeal inflammation
–Metabolised by acetylation
» Fast acetylation t1/2  1hr
» Slow acetylation t1/2  3hr
70

71.  Therapeutic Uses
1) component of all TB chemotherapeutic regimens
2) alone is used to prevent
a) transmission to close contact at high risk of
disease
b) progression of infection in recently infected,
asymptomatic individuals
c) development of active TB in immunodeficient
individuals
71

72.  Adverse effects
– Allergic reactions (fever, skin rashes)
– Direct toxicities
Drug induced hepatitis: high risk age, rifampin,
alcohol
Peripheral neuropathy
Reversed by administration of vit B6
 Other adverse effect
Convulsion
Optic neuritis reversed by vit. B6
Psychosis
72

73.  RIFAMPICIN
 Mechanism: binds to the -subunit of bacterial DNA
dependent RNA polymerase  inhibits RNA synthesis
 bactericidal
 Pharmacokinetics
well absorbed; distributed throughout the body
 excreted mainly through liver into bile
 Therapeutic uses
a) Mycobacterial infection
b) TB: Bacteriocidal for intra & extracellular bacteria
c) Leprosy
73

74.  Adverse effects
1) Hepatitis in pts with
– Preexisting liver disease, high dose,
alcoholics, elderly
2) Hypersensitivity reactions
– Fever, flushing, pruritis, thrombocytopenia,
interstitial nephritis
74

75. 3. Miscellaneous adverse reaction
– Harmless orange color appearing in urine,
saliva, tears, sweat
 Drug interaction
– is a microsomal enzyme inducer; enhances its own
metabolism as well as other drugs [warfarin, OTC,
Steroids, HIV protease inhibitors & ketoconazole]
75

76.  ETHAMBUTOL
 Mechanism: Inhibits cell wall synthesis by blocking
arabinosyl transferase  bacteriostatic
 Therapeutic use: TB
 Adverse effects
–optic neuritis
–Loss of visual acuity & red-green color blindness
–GI intolerance
–Hyperuricemia due to deceased uric acid
excretion
76

77.  PYRAZINAMIDE
Converted to pyrazinoic acid, active form of drug
 Therapeutic use: TB
 Adverse effects
GI intolerance, hepatotoxicity, hyperuricemia
77

78.  Drugs for leprosy
 Dapsone
 MOA
–structurally related to the sulfonamides
–inhibits folate synthesis via dihydropteroate
synthetase inhibiton
–is bacteriostatic for Mycobacterium leprae
–resistant strains are encountered
78

79.  Pharmacokinetics
–well absorbed from the gastrointestinal tract
and is distributed throughout the body, with
high levels concentrated in the skin.
–undergoes hepatic acetylation
–Both parent drug and metabolites are
eliminated through the urine
 Therapeutic use
–leprosy
–also employed in the treatment of
pneumonia caused by Pneumocystis jiroveci
in patients infected with the HIV
79

80.  Adverse effects
–hemolysis, especially in patients with
glucose 6-phosphate dehydrogenase
deficiency
–peripheral neuropathy
80

81.  Clofazimine
 MOA
–binds to DNA and prevents it from serving as
a template for future DNA replication
–May also generate cytotoxic oxygen radicals
that are also toxic to the bacteria
–is bactericidal to M. leprae
 Pharmacokinetics
–Following oral absorption, the drug
accumulates in tissues
–it does not enter the CNS
– Adverse effect
–Patients may develop a red-brown
discoloration of the skin 81

82.  Rifampin
 MOA
–blocks transcription by interacting bacterial
DNA-dependent RNA polymerase
 Therapeutic uses
• TB
• is the most active antileprosy drug at present
–to delay the emergence of resistant strains,
it is usually given in combination with other
drugs
82

83. ANTIPROTOZOAL DRUGS
83

84. TREATMENT OF MALARIA
 Malaria is an acute infectious disease caused by four
species of the protozoal genus Plasmodium
P. vivax, P. malariae, P. ovale, and P. falciparum.
P. falciparum and P. vivax malaria are the two
most common forms
P falciparum causes most of the serious
complications and deaths.
 effectiveness of antimalarial agents varies between
parasite species and between stages in their life cycles.
84

85. 85

86.  P falciparum and P malariae
– have only one cycle of liver cell invasion and
multiplication, and liver infection ceases
spontaneously in less than 4 weeks.
– Then multiplication is confined to the red blood cells
So, treatment that eliminates these species from the
red blood cells four or more weeks after inoculation
of the sporozoites will give cure.
 P vivax and P ovale
– sporozoites also induce in hepatic cells the dormant
stage (the hypnozoite) that causes subsequent
recurrences (relapses) of the infection.
Therefore, treatment that eradicates parasites from
both the red blood cells and the liver is required to
cure these infections.
86

87. Drug Classification
 The antimalarial drugs are classified by their
selective actions on the parasite's life cycle.
1. Tissue schIzonticides:
– eliminate tissue schizonts or hypnozoites in the
liver (eg primaquine)
2. Blood schIzonticides:
– act on blood schizonts (eg, chloroquine,
proguanil, pyrimethamine, mefloquine, quinine) .
87

88. 3. Gametocides
– destroy gametocytes in the blood (eg, primaquine
for P falciparum and chloroquine for P vivax, P
malariae, and P ovale
4. Sporonticidal agents
– make gametocytes non infective in the mosquito
(eg, pyrimethamine, proguanil).
88

89. Chloroquine
 Pharmacodynamics
» exact mechanism of action has not been known
» Mainly by inhibition of heme polymerase
–binding to heme ( released from hemoglobin
by the parasite) and prevention of its
polymerization in to less toxic hemozoin
causes parasite death and hemolysis
89

90.  blood schizonticidal: highly effective for all except
resistant falciparum species
 Gametocidal
 moderately effective against gametocytes of P.
vivax, P. ovale, and P. malariae
 but not against those of P falciparum
 not active against the preerythrocytic plasmodium
and does not effect radical cure.
90

91.  Pharmacokinetics:
– rapidly and almost completely absorbed from GIT
– more concentrated in parasitized cells:
– is rapidly distributed to the tissues including across
the placenta and also permeates the CNS
– Distributed widely and is extensively bound to body
tissues eg in the liver
– half-life of the drug is 6 to 7 days
91

92.  Clinical uses:
Acute Malaria Attacks
–Chloroquine is effective for acute attacks of P
vivax, P ovale, and P malariae and of malaria due
to nonresistant strains of P falciparum
Chemoprophylaxis
–Chloroquine is the preferred drug for prophylaxis
against all forms of malaria except in regions
where P falciparum is resistant to it
also effective in the treatment of extraintestinal
amebiasis
occasional use in rheumatoid arthritis b/c of its
antiinflammatory effect
92

93.  Adverse Effects:
– Gastrointestinal symptoms, mild headache, pruritus,
anorexia, malaise, blurring of vision, and urticaria
»an ophthalmologic examination should be
routinely performed
– depigmentation or loss of hair
 Contraindications:
– in patients with a history of liver damage, alcoholism,
or neurologic or hematologic disorders, psoriasis or
porphyria
»it may precipitate acute attacks of these diseases
93

94. Primaquine
 Pharmacodynamics:
» Has a metabolite that inhibits the coenzyme Q–
mediated respiratory chain of the exoerythrocytic
parasite
» The metabolites also cause hemolysis as toxicity
Against exoerythrocytic form
»eradicates primary exoerythrocytic forms of P.
falciparum and P. vivax and the secondary
exoerythrocytic forms of recurring malarias (P.
vivax and P. ovale).
 Primaquine is the only agent that can lead to radical
cures of the P. vivax and P. ovale malarias
94

95. Gametocidal
–Destroys the sexual (gametocytic) forms of all
four plasmodia in the plasma or
–Prevents the gamectocytes from maturing later
in the mosquito
 NB:- Primaquine is not effective against the erythrocytic
stage of malaria
–is often used in conjunction with a blood
schizonticide, such as chloroquine, quinine,
mefloquine, or pyrimethamine
95

96.  Pharmacokinetics:
– usually well absorbed after oral administration
– half-life is short, and daily administration is usually
required for radical cure and prevention of relapses.
 Clinical Uses:
– Terminal prophylaxis of vivax and ovale malaria.
– Radical cure of acute vivax and ovale malaria.
– Pneumocystis carinii pneumonia
96

97.  Adverse Effects:
– generally well tolerated
– infrequently causes nausea, epigastric pain,
abdominal cramps, and headache
»abdominal discomfort, especially when
administered in combination with chloroquine
– agranulocytosis is rare
– drug-induced hemolytic anemia in patients with
genetically low levels of glucose-6-phosphate
dehydrogenase can be lethal
97

98. Quinine
 Pharmacodynamics:
– Mechanisms of its antimalarial activity is not known
– It may poison the parasite’s feeding mechanism
– interferes with heme polymerization
blood schizonticide
rapidly acting, highly effective blood
schizonticide against the four malaria parasites
gametocidal
for P vivax and P ovale but not very effective
against P falciparum gametocytes
 reserved for severe infestations and for malarial strains
that are resistant to other agents, such as chloroquine
98

99.  Pharmacokinetics:
– Oral route- rapidly absorbed and is widely distributed
in body tissues
– Also given IV
 Clinical Uses:
1. Parenteral Treatment of Severe Falciparum Malaria
2. Oral Treatment of Falciparum Malaria Resistant to
Chloroquine
3. Prophylaxis
4. Other Uses: Quinine sulfate is also used for the
prevention and treatment of night time leg cramps
such as those resulting from arthritis, diabetes, and
varicose veins.
99

100.  Adverse Effects:
– often causes nausea, vomiting, hypoglycemia
– a less common effect such as headache, slight visual
disturbances, dizziness, and mild tinnitus which may
subside as treatment continues.
»are reversible and are not considered to be
reasons for suspending therapy
– Severe toxicity like fever, skin eruptions, GI
symptoms, deafness, visual abnormalities, central
nervous system effects (syncope, confusion)
 Quinine treatment should be suspended if a
positive Coombs' test for hemolytic anemia occurs.
 Contraindications:
– haemoglobinuria, optic neuritis and in patients
hypersensitive to quinine or quinidine
100

101. Proguanil and Pyrimethamine
 Pharmacodynamics:
 are dihydrofolate reductase inhibitors
blood schizonticides
–are slow acting blood schizonticides against
susceptible strains of all four malarial species.
Proguanil (but not pyrimethamine)
– has a marked effect on the primary tissue
stages of susceptible P falciparum
Pyrimethamine also acts as a strong sporonticide in
the mosquito's gut when the mosquito ingests it with
the blood of the human host
101

102.  Pharmacokinetics:
– slowly but adequately absorbed from the GIT
– Pyrimethamine has a half-life of about 4 days
 Clinical uses:
– Chemoprophylaxis
– Treatment of Chloroquine-Resistant Falciparum
Malaria
– Toxoplasmosis treatment
 Adverse Effects:
– In the high doses pyrimethamine causes
megaloblastic anemia, agranulocytosis and
thrombocytopenia
»leucovorin calcium is given concurrently 102

103. Sulfones and Sulfonamides
 Pharmacodynamics:
– inhibit dihydrofolic acid synthesis
– blood schizonticidal
»against P falciparum
»weak effects against P vivax
– are not active against the gametocytes or liver stages
of P falciparum or P vivax
 Sulfonamide/sulfone + pyrimethamine has synergistic
blockade of folic acid synthesis in susceptible plasmodia
 most used combinations are:-
Sulfadoxine with pyrimethamine (Fansidar)
dapsone with pyrimethamine (Maloprim)
103

104. Pyrimethamine – sulfadoxine (Fansidar)
 Pharmacodynamics:
effective against falciparum malaria
»Fansidar is only slowly active. Hence quinine
must be given concurrently in treatment of
seriously ill patients
not effective in the treatment of vivax malaria
 Pharmacokinetics:
– is well absorbed when given orally
– Average half-lives are about 170 hours for sulfadoxine
and 80-110 hours for pyrimethamine
104

105.  Clinical uses:
– Treatment of Chloroquine-Resistant Falciparum
– Fansidar is no longer used in prophylaxis because of
severe reactions
 Adverse Effects:
– sulfonamide allergy including the hematologic
(agranulocytosis) , thrombocytopenia,
photosensitivity , hepatitis, megaloblastic anemia etc
 Contraindications:
– contraindicated in patients who have had adverse
reactions to sulfonamides, pregnancy, in nursing
women
105

106. Mefloquine
 is chemically related to quinine
 like quinine, it can apparently damage the parasite's
membrane
 Pharmacodynamics:
 blood schizonticidal - against all plasmodia species
 Pharmacokinetics:
 It can only be given orally because intense local
irritation occurs with parenteral use.
 absorbed well after oral administration
 cleared in the liver
 elimination half-life varies from 13 days to 33 days
106

107.  Clinical uses:
For treatment of chloroquine-resistant and
multidrug-resistant falciparum malaria
also effective in prophylaxis against P. vivax, P. ovale,
P. malariae, and P. falciparum
 Adverse Reactions:
– frequency and intensity of reactions are dose-related
– In prophylactic doses
»GI disturbances, headache, dizziness, syncope,
and transient neuropsychiatric events
(convulsions, depression, and psychoses).
107

108. – In treatment doses
»the incidence of neuropsychiatric symptoms
(dizziness, headache, visual disturbances,
tinnitus, insomnia, restlessness, anxiety,
depression, confusion, acute psychosis, or
seizures) may increase
 Contraindications:
– A history of epilepsy, psychiatric disorders,
arrhythmia, sensitivity to quinine and the first
trimester of pregnancy
108

109. Atovaquone
 MOA
»involves inhibition of the mitochondrial
electron transport system in the protozoa
 is effective against erythrocytic and exoerythrocytic P.
falciparum
 has good activity against the blood but not the
hepatic stage of P. vivax and P. ovale
 pharmacokinetics
– poorly absorbed from the gastrointestinal tract, but
absorption is increased with a fatty meal
– Fecal excretion
– elimination half-life is 2 to 3 days 109

110.  Therapeutic use
the combination of atovaquone and proguanil is
used for the treatment and prophylaxis of P.
falciparum malaria
»Atovaquone and proguanil are synergistic and
are highly effective when combined and no
atovaquone resistance is seen
atovaquone is also used for the treatment and
prevention of P. carinii pneumonia
 Adverse effect
– Atovaquone is well tolerated
– rare instances of nausea, vomiting, diarrhea,
abdominal pain, headache, and rash of mild to
moderate intensity 110

111.  Doxycycline
– is generally effective against multidrug-resistant P
falciparum
– is active against the blood stages of Plasmodium
species but not against the liver stages
– In the treatment of acute malaria, it is used in
conjunction with quinine
111

112.  Halofantrine
– is an oral schizonticide for all four malarial species
– Excretion is mainly in the feces
 Lumefantrine:
– Availabe in fixed dose combination with artemether
as Coartem
– T 1/2  4.5 hrs
– Coartem is very effective for Rx of P falciparum
112

113. Artemisinin and its derviatives
– artemisinin, artemether, arteether, artesunate, artlinic
acid
– are potent and rapidly acting antimalarial drugs that
show relatively low human toxicity
 Mechanism of action
Act by interacting with heme to produce carbon-
centered free radicals that alkylate protein &
damage microorganelle & membranes of the
parasites
– active against blood stages, especially in patients with
severe manifestations, such as cerebral malaria and
chloroquine-resistant malarial infections
– have no effect on exoerythrocytic stage of the parasite
113

114.  Therapeutic use
 are most useful in treating life-threatening cerebral
edema
 for the treatment of severe, multidrug-resistant P.
falciparum malaria
 pharmacokinetics
 Oral, rectal, and IV preparations are available
 the short half-lives preclude their use in
chemoprophylaxis
 metabolized in the liver and are excreted primarily in
the bile
114

115.  Adverse effects
– include nausea, vomiting, abdominal pain and
diarrhea, but overall, artemisinin is remarkably safe.
– Extremely high doses may cause neurotoxicity and
prolongation of the QT interval.
115

116. Summary of Treatment and
prevention of malaria
All plasmodium species except chloroquine resistant
P falciparum
Chloroquine
chloroquine resistant P falciparum
Quininine + (pyrimethamine-sulfadoxine or
doxycycline )
Alternaive is mefloquine
Prevention of relapses: P vivax and P ovale only
Primaquine
116

117. Prevention of malaria
Chloroquine sensitive areas
chloroquine
Chloroquine resistant areas
mefloquine
In pregnancy
Chloroquine or mefloquine
117

118. Drugs used in amebiasis
 Amebiasis/also called amebic dysentery is infection
of the intestinal tract by the protozoan parasite
Entamoeba histolytica
 The parasite exists in two forms:
Cysts: can survive outside the body
Trophozoites: labile but invasive and do not
persist outside the body
 Trophozoites multiply in intestine and either invade
and ulcerate the mucosa of the large intestine or
simply feed on intestinal bacteria
»Adding antibiotics, such as tetracycline, to
the treatment regimen is one strategy for
treating luminal amebiasis
118

119.  The infection may present as:
Intestinal
a severe intestinal infection (dysentery), a
mild to moderate symptomatic intestinal
infection, an asymptomatic intestinal
infection
extraintestinal
liver abscess, or other type of extraintestinal
infection
 All of the antiamebic drugs act against Entamoeba
histolytica trophozoites, but most are not effective
against the cyst stage.
119

120.  Drug classification:
»Antiamebic drugs are classified as luminal, systemic,
or mixed (luminal and systemic) amebicides
according to the site where the drug is effective
I. luminal amebicides - act on the parasite in the lumen
of the bowel. Eg paromomycin, iodoquinol
II. systemic amebicides - are effective against amebas
in the intestinal wall and liver. Eg chloroquine,
emetine, dihydroemetine
III. Mixed amebicides - are effective against both the
luminal and systemic forms of the disease
» But luminal concentrations are too low for
single-drug treatment
» Eg metronidazole and tinidazole
120

121. Tissue amebicides
 eliminate organisms primarily in the bowel wall, liver,
and other extraintestinal tissues
 are not effective alone against organisms in the bowel
lumen
– Metronidazole, and tinidazole are highly effective
against amebas in the bowel wall and other tissues.
– Emetine and dehydroemetine also are effective on
organisms in the bowel wall and other tissues
– Chloroquine - active principally against amebas in
the liver.
121

122. Luminal Amebicides
 act primarily in the bowel lumen
– Diloxanide furoate
– Iodoquinol
– Tetracyclines, paromomycin and erythromycin
122

123.  Treatment of Amebiasis
Asymptomatic Intestinal Infection:
The drugs of choice, diloxanide furoate and
iodoquinol
Alternatives are metronidazole plus iodoquinol
or diloxanide.
Intestinal Infection:
The drugs of choice, metronidazole and a
luminal amebicide.
123

124. Hepatic Abscess:
The treatment of choice is metronidazole
An advantage of metronidazole is its
effectiveness against anaerobic bacteria, which
are a major cause of bacterial liver abscess.
Diloxanide furoate or iodoquinol should also be
given to eradicate intestinal infection whether or
not organisms are found in the stools.
Dehydroemetine and emetine are potentially
toxic alternative drugs.
124

125. Ameboma or Extraintestinal Forms of
Amebiasis:
–Metronidazole is the drug of choice
–Dehydroemetine is an alternative drug;
–chloroquine cannot be used because it does
not reach high enough tissue concentrations
to be effective (except in the liver).
–A simultaneous course of a luminal
amebicide should also be given.
125

126. Metronidazole
 Mechanism of Action:
– the nitro group is chemically reduced by the enzyme
pyruvate-ferredoxin oxidoreductase
»Reduced metronidazole disrupts replication and
transcription and inhibits DNA repair.
– Is both luminal and systemic amebicide
 Pharmacokinetics:
– Oral metronidazole is readily absorbed
– Has good distribution including the CSF, breast milk,
alveolar bone, liver abscesses, vaginal secretions, and
seminal fluid.
– The drug and its metabolites are excreted mainly in
the urine 126

127.  Clinical Uses:
– Metronidazole is active against amebiasis, urogenital
trichomoniasis, giardiasis
– anaerobic infections (gram –ve cocci, baciili, eg
Bacteroides species)
– drug of choice for the treatment of
pseudomembranous colitis by anaerobic gram +ve
bacili C difficile)
– also effective in the treatment of brain abscesses
caused by the above organisms
127

128.  Adverse effects:
– nausea, headache, dry mouth, or metallic tastes
occur commonly
– oral moniliasis (yeast infection of the mouth)
– rare adverse effects include vomiting, diarrhea,
insomnia, weakness, dizziness, stomatitis, rash,
urethral burning, vertigo, and paresthesias
– it has a disulfiram-like effect if taken with alcohol
– The drug is not recommended for use during
pregnancy.
128

129.  Other Nitroimidazoles
– Eg tinidazole
– with the exception of tinidazole, the other
nitroimidazoles have produced poor results than
metronidazole in the treatment of amebiasis
– Tinidazole is as effective as metronidazole, with a
shorter course of treatment, yet is more expensive
than generic metronidazole.
129

130. Chloroquine
– Chloroquine reaches high liver concentrations
– is used in combination with metronidazole and
diloxanide furoate to treat and prevent amebic liver
abscesses
– Chloroquine is not active against luminal organisms
Dehydroemetine and Emetine
– inhibit protein synthesis by blocking chain elongation
– the use of these drugs is limited by their toxicities
(dehydroemetine is less toxic than emetine)
– They should not be taken for more than 5 days
130

131.  Pharmacokinetics:
– IM injection is the preferred route
– stored primarily in the liver, lungs, spleen, kidneys
– slowly metabolized and excreted, and can accumulate
– are eliminated slowly via the kidneys
– half-life in plasma is 5 days
 Clinical Uses:
– Severe Intestinal Disease (Amebic Dysentery)
 Adverse Effects:
– Sterile abscesses, pain, tenderness, and muscle
weakness in the area of the injection are frequent
– They should not be used during pregnancy. 131

132. Diloxanide Furoate
– is directly amebicidal, but its mechanism of action is
not known
– Diloxanide furoate is the drug of choice for
asymptomatic infections.
– For other forms of amebiasis it is used with another
drug
132

133. Iodoquinol
– It is thought to inactivate essential parasite enzymes
– Iodoquinol is effective against organisms in the bowel
lumen but not against trophozoites in the intestinal
wall or extraintestinal tissues.
 Adverse Effects:
– Reversible severe neurotoxicity (optic atrophy, visual
loss, and peripheral neuropathy).
– Long-term use of this drug should be avoided
133

134. Antibiotics
 Erythromycin and tetracycline
– Do not have a direct effect on the protozoa
»Act on the normal flora
 Paromomycin
– is directly and indirectly amebicidal
134

135. Paromomycin Sulfate
– an aminoglycoside antibiotic
– only effective against the intestinal (luminal) forms
of E. histolytica and tapeworm
»b/c not significantly absorbed from the
gastrointestinal tract
– Paromomycin is an alternative drug for the
treatment of asymptomatic amebiasis.
– Paromomycin is both directly and indirectly
amebicidal
–Direct effect- leakage on cell membranes
135

136. Summary of amoeba treatment
 Assymptomatic cyst carriers
– Iodoquinol /diloxanide or paromomycin
 Diarhea/dysentry- extraintestinal
– Metronidazole +
Iodoquinol/diloxande/paromomycin
 Amebic liver abscess
– Chloroquine + metronidazole/emetine
136

137. Giardiasis
– Caused by Giardia lamblia
• has only two life-cycle stages:
–Trophozoite and the drug-resistant -cyst
– The trophozoites exist in the small intestine and
divide by binary fission.
– severe diarrhea can occur, which can be very
serious in immune-suppressed patients.
 Metronidazole- is a drug of choice
 Tinidazole – alternatetive
– Tinidazole 2 g given once
137

138. Trichomoniasis
– It is a genital infection produced by the protozoan
Trichomonas vaginalis
– Metronidazole – the drug of choice
– tinidazole - alternate drug
• Relapses occur if the infected person’s sexual
partner is not treated simultaneously
138

139. Leishmaniasis
 There are three types of leishmaniasis: cutaneous,
mucocutaneous, and visceral (kala-azar)
– L. donovani causes visceral leishmaniasis
– L. tropica and L. major produce cutaneous
leishmaniasis
– L. braziliensis causes South American mucocutaneous
leishmaniasis.
 leishmaniasis is transmitted by the bite of infected
sandflies
 the protozoa is taken by macrophages, multiply and kill
the macrophages
139

140.  sodium antimony gluconate (sodium stibogluconate)
»the drug of choice
 amphotericin B and pentamidine - alternative drugs
140

141. Sodium stibogluconate
 Exact mechanism is unknown
– Thought to inhibit glycolysis in the parasite
– It is proposed that reduction to the trivalent
antimonial compound is essential for activity
 it is not absorbed on oral administration
– must be administered parenterally
 Adverse effects include pain at the injection site,
gastrointestinal upsets, and cardiac arrhythmias.
141

142. Trypanosomiasis
 refers to two chronic and, eventually, fatal diseases
caused by species of Trypanosoma:
– African sleeping sickness
• Trypanosoma brucei gambiense and
Trypanosoma brucei rhodiense
»invades the CNS, causing an inflammation
of the brain and spinal cord that produces
eventually continuous sleep
– American sleeping sickness/Chagas' disease
• caused by Trypanosoma cruzi and occurs in
South America
142

143. Melarsoprol
– first-line therapy for advanced central nervous
system African trypanosomiasis
 Mechanism of action:
– The drug reacts with sulfhydryl groups of various
substances, including enzymes
 Pharmacokinetics:
– usually is slowly administered IV even though it is
absorbed from the GIT
– in contrast to pentamidine, adequate trypanocidal
concentrations appear in the CSF.
– The host readily oxidizes melarsoprol to a relatively
nontoxic
– The drug has a very short half-life and is rapidly
excreted into the urine
143

144.  Adverse effects:
– CNS toxicities are the most serious side effects
– Encephalopathy may appear soon after the first
course of treatment but usually subsides.
–It may, however, be fatal
– Hypersensitivity reactions and fever may follow
injection
– gastrointestinal disturbances, such as severe
vomiting and abdominal pain, can be minimized if
the patient is in the fasting state during drug
administration
– Hemolytic anemia has been seen in patients with
glucose 6-phosphate dehydrogenase deficiency.
144

145. Pentamidine isethionate
– active against T. brucei gambiense
»for which pentamidine is used to treat and
prevent the organism's hematologic stage
– However, some trypanosomes, including T. cruzi,
are resistant
 Mechanism of action:
– the drug binds to the parasite's DNA and interferes
with the synthesis of RNA, DNA, phospholipid, and
protein by the parasite.
– Also may act by inhibiting dihydrofolate reductase
145

146.  Pharmacokinetics:
– is not well absorbed from GIT
– Fresh solutions of pentamidine are administered IM
or as an aerosol
»intravenous route is avoided because of severe
adverse reactions, such as a sharp fall in blood
pressure and tachycardia
– Because it does not enter the CSF, it is ineffective
against the meningoencephalitic stage of
trypanosomiasis
– The drug is not metabolized, and is excreted very
slowly into the urine.
– Its half-life in the plasma is about 5 days
146

147. to treat and prevent the hematologic stage of
trypanosomiasis by T. brucei gambiense
an alternative drug to stibogluconate in the
treatment of leishmaniasis
treatment of systemic blastomycosis (caused by the
fungus Blastomyces dermatitidis)
treating infections caused by Pneumocystis jiroveci
»For patients who failed to respond to
trimethoprim-sulfamethoxazole or allergic to
sulfonamides
147

148.  Adverse effects:
– Serious renal dysfunction may occur, which
reverses on discontinuation of the drug.
– Other adverse reactions are hypotension,
dizziness, rash, and toxicity to beta 2 cells of the
pancreas
148

149. Nifurtimox
– has found use only in the treatment of acute T.
cruzi infections (Chagas' disease)
– Nifurtimox undergoes reduction and, eventually,
generates intracellular oxygen radicals, such as
superoxide radicals and hydrogen peroxide
–These highly reactive radicals are toxic to T.
cruzi, which lacks catalase
– Nifurtimox is administered orally, and it is rapidly
absorbed
149

150.  Adverse effects are common following chronic
administration, particularly among the elderly.
Major toxicities include immediate
hypersensitivity reactions such as anaphylaxis,
delayed hypersensitivity reactions such as
dermatitis , and gastrointestinal problems that
may be severe enough to cause weight loss.
Peripheral neuropathy is relatively common,
and disturbances in the CNS may also occur.
150

151. Suramin
– Used primarily in the early treatment and, especially,
the prophylaxis of African trypanosomiasis
»it is the drug of choice
– It is very reactive and inhibits many enzymes, among
them those involved in energy metabolism
»for example, glycerol phosphate dehydrogenase
– not absorbed from the intestinal tract and must be
injected intravenously
– It binds to plasma proteins and remains in the plasma
for a long time, accumulating in the liver and in the
proximal tubular cells of the kidney.
151

152. • The severity of the adverse reactions demands that the
patient be carefully followed, especially if he or she is
debilitated.
 Although infrequent, adverse reactions include:
– nausea and vomiting (which cause further
debilitation of the patient),
– shock and loss of consciousness,
– neurologic problems, including paresthesia,
photophobia, palpebral edema (edema of the
eyelids)
– Albuminuria tends to be common
– hematuria may occur and treatment should cease.
152

153. Benznidazole
 inhibits protein synthesis and ribonucleic acid synthesis
in the T. cruzi cells
 It is an alternative choice for treatment of acute phases
of Chagas’ disease
 benznidazole is recommended as prophylaxis for
preventing infections caused by T. cruzi among
hematopoietic stem cell transplant recipients because
treatment in potential donors is not always effective.
153

154. Toxoplasmosis
– caused by Toxoplasma gondii
– transmitted to humans when they consume raw or
inadequately cooked, infected meat
– An infected pregnant woman can transmit the
organism to her fetus.
– Cats are the only animals that shed oocysts, which
can infect other animals as well as humans.
154

155.  Pyrimethamine
– The treatment of choice
– At the first appearance of a rash, pyrimethamine
should be discontinued, because hypersensitivity to
this drug can be severe.
 sulfadiazine –pyrimethamine
– is also efficacious
– Leucovorin is often administered to protect against
folate deficiency
• Other inhibitors of folate biosynthesis, such as
trimethoprim and sulfamethoxazole, are without
therapeutic efficacy in toxoplasmosis.
155

156. ANTIFUNGAL AGENTS
 Fungal infections have increased in incidence and
severity in recent years
due to increase in the use of broad-spectrum
antimicrobials and the HIV epidemic
 antifungal drugs fall into two groups:
antifungal antibiotics- Amphotericin B,
Nystatin, Griseofulvin
synthetic antifungals- Flucytosine, Azoles
(imidazoles and triazoles)
156

157.  amphotericin B
– is antifungal antibiotic
– is a broad-spectrum antifungal agent
»against yeasts including; Candida albicans and
Cryptococcus neoformans; molds, Aspergillus
fumigatus
 MOA
– binds to ergosterol (a cell membrane sterol) and
alters the permeability of the cell by forming
amphotericin B-associated pores in the cell
membrane
157

158.  pharmacokinetics
– is poorly absorbed from the GIT
– Oral amphotericin B is thus effective only on fungi
within the lumen of the GI tract
 widely distributed in tissues, but only 2-3% of the
blood level is reached in CSF, thus occasionally
necessitating intrathecal therapy for certain types
of fungal meningitis
 Therapeutic use
– drug of choice for nearly all life-threatening
mycotic infections
– as the initial induction regimen for serious fungal
infections (immunosuppressed patients, severe
fungal pneumonia, and cryptococcal meningitis
with altered mental status).
158

159.  Adverse Effects
– fever, chills, muscle spasms, vomiting, headache,
hypotension (related to infusion), renal damage
associated with decreased renal perfusion (a
reversible) and renal tubular injury (irreversible).
– Anaphylaxis, liver damage, anemia occurs
infrequently.
159

160. Nystatin
– active against most Candida species
– is antifungal antibiotic
 MOA
– has similar structure with amphotericin B and has
the same pore-forming mechanism of action
 Pharmacokinetics
– too toxic for systemic use and is only used topically
– is not absorbed from skin, mucous membranes, or
the gastrointestinal tract
 Therapeutic use
– most commonly used for suppression of local
candidal infections
»in the treatment of oropharyngeal thrush,
vaginal candidiasis, and intertriginous candidal
infections. 160

161. Griseofulvin
 MOA
– is a fungistatic
– is antifungal antibiotic
 Pharmacokinetics
– fatty foods increase its absorption
– is deposited in newly forming skin where it binds to
keratin, protecting the skin from new infection
 Therapeutic use
– used is in the treatment of dermatophytosis
161

162.  Adverse effects
– allergic syndrome much like hepatitis
– drug interactions with warfarin and phenobarbital.
 Griseofulvin has been largely replaced by newer
antifungal medications such as itraconazole
162

163. Flucytosine
– synthetic antifungal agent
– spectrum of action is much narrower than that of
amphotericin B
»Active against Cryptococcus neoformans,
some Candida species, and the dematiaceous
molds that cause chromoblastomycosis
 MOA
– is related to fluorouracil (5-FU)
– inhibit DNA and RNA synthesis after being changed
163

164.  Pharmacokinetics
– well absorbed orally
– penetrates well into all body fluid compartments
including the CSF
 Therapeutic use
– with amphotericin B for cryptococcal meningitis
– with itraconazole for chromoblastomycosis
–chronic fungal infection of the skin,
producing wartlike nodules
 Adverse effects
– Bone marrow toxicity with anemia, leukopenia,
and thrombocytopenia are the most common
adverse effects
164

165.  Azoles
– synthetic compounds
 Classification
– can be classified as imidazoles and triazoles
imidazoles
»ketoconazole, miconazole, and clotrimazole
Triazoles
»itraconazole and fluconazole
 MOA
– reduction of ergosterol synthesis by inhibition of
fungal cytochrome P450 enzymes
– Have greater affinity for fungal than for human
cytochrome P450 enzymes
»Imidazoles exhibit a lesser degree of
specificity than the triazoles 165

166.  Antifungal spectrum
– active against many Candida species, Cryptococcus
neoformans, the endemic mycoses (blastomycosis,
coccidioidomycosis), the dermatophytes, and,
Aspergillus infections (itraconazole)
 Adverse Effects
– azoles are relatively nontoxic
– most common adverse reaction is minor GI upset
– Most azoles cause abnormalities in liver enzymes
166

167. Ketoconazole
– limited use because of the drug interactions,
endocrine side effects, and of its narrow therapeutic
range
 Therapeutic use
– in treatment of mucocutaneous candidiasis and
nonmeningeal coccidioidomycosis (mainly affects
the lung)
– also used in the treatment of seborrheic dermatitis
and pityriasis versicolor (Topical/ shampoo)
 Adverse Effects
– Interferes with biosynthesis of adrenal and gonadal
steroid hormones
–Endocrine effects such as gynecomastia,
infertility, and menstrual irregularities
– Inhibits hepatic enzyme cytochrome p450 167

168.  Clotrimazole and miconazole
often used for vulvovaginal candidiasis
Oral clotrimazole troches are available for treatment
of oral thrush
– In cream form, both agents are useful for
dermatophytic infections, including tinea corporis,
tinea pedis, and tinea cruris
– Absorption is negligible, and adverse effects are rare.
168

169.  Itraconazole
– available in an oral formulation
– absorption is increased by food and by low gastric pH
is the azole of choice in the treatment of
dermatophytoses and onychomycosis
– is the only agent with significant activity against
Aspergillus species.
169

170.  Fluconazole
– has good CSF penetration
– given IV or PO
– has the least effect on hepatic microsomal enzymes
– is the azole of choice in the treatment and
secondary prophylaxis of cryptococcal meningitis
– also effective for mucocutaneous candidiasis.
170

171. TREATMENT OF HELMINTHIC
INFECTIONS
 Three major groups of helminths (worms) the
nematodes, trematod, and cestodes infect humans
 Anthelmintic drugs are used to eradicate or reduce
the numbers of helminthic parasites in the intestinal
tract or tissues of the body.
 Most anthelmintics are active against specific
parasites; thus, parasites must be identified before
treatment is started.
171

172.  Drugs for the Treatment of Nematodes
 Nematodes
– are elongated roundworms
– cause infections of the intestine as well as the blood
and tissues.
172

173. Roundworms (nematodes)
– Ascaris lumbricoides (roundworm)
• First choice
–Albendazole/pyrantel pamoate/ mebendazole
• Alternative
–Piperazine
– Trichuris trichiura (whipworm)
• First choice
–Mebendazole/albendazole
• Alternative
–Oxantel/pyrantel pamoate
173

174. – Necator americanus (hookworm); Ancylostoma
duodenale (hookworm)
• First choice
–Pyrantel pamoate/mebendazole/ albendazole
– Strongyloides stercoralis (threadworm)
• First choice- Ivermectin
• Alternative - Thiabendazole, albendazole
– Enterobius vermicularis (pinworm)
• First choice- Mebendazole/pyrantel pamoate
• Alternative- Albendazole
174

175. – Trichinella spiralis (trichinosis)
• First choice - Mebendazole
– add corticosteroids for severe infection
• Alternative - Albendazole
–add corticosteroids for severe infection
– Trichostrongylus species
• First choice - Pyrantel pamoate/mebendazole
• Alternative - Albendazole
175

176. – Cutaneous larva migrans
»First choice - Albendazole or ivermectin
»Alternative - Thiabendazole (topical)
– Visceral larva migrans
»First choice - Albendazole
»Alternative - Mebendazole
– Angiostrongylus cantonensis
»First choice - Thiabendazole
»Alternative – Albendazole/mebendazole
176

177. – Wuchereria bancrofti (filariasis); Brugia malayi
(filariasis); tropical eosinophilia; Loa loa (loiasis)
»First choice - Diethylcarbamazine
»Alternative - Ivermectin
– Onchocerca volvulus (onchocerciasis)
• Ivermectin
– Dracunculus medinensis (guinea worm)
»First choice - Metronidazole
»Alternative – Thiabendazole/mebendazole
177

178. Mebendazole
 synthetic benzimidazole compound, is effective
against a wide spectrum of nematodes.
 drug of choice in the treatment of infections by:
– whipworm (Trichuris trichiura)
– pinworm (Enterobius vermicularis)
– hookworms (Necator americanus and
Ancylostoma duodenale) and
– roundworm (Ascariasis lumbricoides)
178

179.  Mechanism of action:
– bind to and interfere with the assembly of the
parasites' microtubules and also by decreasing
glucose uptake
– Mebendazole is nearly insoluble in aqueous solution.
Little of an oral dose (that is chewed) is absorbed by
the body, unless it is taken with a high-fat meal.
– It undergoes first-pass metabolism to inactive
compounds
– Mebendazole is relatively free of toxic effects,
although patients may complain of abdominal pain
and diarrhea. It is, however, contraindicated in
pregnant women
179

180. Pyrantel pamoate
 MOA- acts as a depolarizing, neuromuscular-blocking
agent, causing persistent activation of the parasite's
nicotinic receptors
The paralyzed worm is then expelled from the
host's intestinal tract
 along with mebendazole, is effective in the treatment
of infections caused by roundworms, pinworms, and
hookworms
 poorly absorbed orally and exerts its effects in the
intestinal tract
 Adverse effects are mild and include nausea, vomiting,
and diarrhea.
180

181. Thiabendazole
 affects microtubular aggregation
 is effective against strongyloidiasis caused by
Strongyloides stercoralis (threadworm), cutaneous
larva migrans, and early stages of trichinosis (caused
by Trichinella spiralis)
 the drug is readily absorbed on oral administration.
 It is hydroxylated in the liver and excreted in the
urine
181

182.  adverse effects
– most often encountered are dizziness, anorexia,
nausea, and vomiting
– central nervous system (CNS) symptoms
– erythema multiforme and Stevens-Johnson
syndrome that can be fatal
 contraindicated during pregnancy
182

183. Ivermectin
 Acts on the parasite's glutamate-gated Cl- channel
receptors
– Chloride influx is enhanced, and hyperpolarization
occurs, resulting in paralysis of the worm.
 drug of choice in the treatment of :
– onchocerciasis (river blindness) caused by
Onchocerca volvulus
– cutaneous larva migrans and strongyloides.
183

184.  The drug is given orally
 It does not cross the blood-brain barrier
– it is contraindicated in patients with meningitis,
because their blood-brain barrier is more
permeable and CNS effects might be expected
 also contraindicated in pregnancy
 The killing of the microfilaria can result in a Mazotti-
like reaction (fever, headache, dizziness, somnolence,
and hypotension)
184

185. Diethylcarbamazine
 used in the treatment of filariasis
– because of its ability to immobilize microfilariae
and render them susceptible to host defense
mechanisms.
 Combined with albendazole, diethylcarbamazine is
effective in the treatment of Wucheria bancrofti and
Brugia malayi infections
 It is rapidly absorbed following oral administration
with meals and is excreted primarily in the urine.
185

186.  Adverse effects
– are primarily caused by host reactions to the killed
organisms.
– The severity of symptoms is related to the parasite
load and include fever, malaise, rash, myalgias,
arthralgias, and headache.
– Most patients have leukocytosis
 Antihistamines or steroids may be given to ameliorate
many of the symptoms
186

187. Drugs for the Treatment of
Trematodes
 trematodes (flukes)
– are leaf-shaped flatworms
– generally characterized by the tissues they infect.
For example, they may be categorized as liver,
lung, intestinal, or blood flukes
187

188. – Schistosoma haematobium (bilharziasis)
–First choice - Praziquantel
–Alternative - Metrifonate
– Schistosoma mansoni
–First choice - Praziquantel
–Alternative - Oxamniquine
– Schistosoma japonicum
»Praziquantel
– Clonorchis sinensis (liver fluke); Opisthorchis
species
»Praziquantel and alternative is Albendazole
188

189. – Paragonimus westermani (lung fluke)
• First choice - Praziquantel
• Alternative - Bithionol
– Fasciolopsis buski (large intestinal fluke)
»Praziquantel or niclosamide
– Heterophyes heterophyes; Metagonimus
yokogawai (small intestinal flukes)
»Praziquantel or niclosamide
189

190. Praziquantel
– Permeability of the cell membrane to calcium is
increased, causing contracture and paralysis of the
parasite
 Trematode infections are generally treated with
praziquantel
– an agent of choice for the treatment of all forms
of schistosomiasis and other trematode infections
and for cestode infections like cysticercosis.
190

191.  pharmacokinetics
– rapidly absorbed after oral administration and
distributes into the cerebrospinal fluid
– The drug is extensively metabolized, resulting in a
short half-life
– The metabolites are inactive and are excreted
through the urine and bile
 adverse effects
– Commonly include drowsiness, dizziness, malaise,
and anorexia, as well as gastrointestinal upsets.
191

192. – The drug is not recommended for pregnant
women or nursing mothers.
– contraindicated for the treatment of ocular
cysticercosis, because destruction of the organism
in the eye may damage the organ
192

193. Drugs for the Treatment of Cestodes
 The cestodes, or true tapeworms
– typically have a flat, segmented body and attach to
the host's intestine
– Taenia saginata (beef tapeworm)
• First choice - Praziquantel or niclosamide
• Alternative - Mebendazole
– Diphyllobothrium latum (fish tapeworm)
–Praziquantel or niclosamide
– Taenia solium (pork tapeworm)
–Praziquantel or niclosamide
193

194. – Cysticercosis (pork tapeworm larval stage)
• First choice - Albendazole
• Alternative - Praziquantel
– Hymenolepis nana (dwarf tapeworm)
• First choice - Praziquantel
• Alternative
–Niclosamide
– Echinococcus granulosus (hydatid disease);
Echinococcus multilocularis
–Albendazole
194

195. Niclosamide
– inhibits the parasite's mitochondrial phosphorylation
of adenosine diphospate
– Anaerobic metabolism may also be inhibited
 the drug of choice for most cestode (tapeworm)
infections.
 Alcohol should be avoided within 1 day of niclosamide.
195

196. Albendazole
 inhibits microtubule synthesis and glucose uptake in
nematodes
– primary therapeutic application, however, is in the
treatment of cestodal infestations, such as
cysticercosis (caused by Taenia solium larvae) and
hydatid disease (caused by Echinococcus
granulosis).
196

197.  Pharmacokinetics
– Albendazole is erratically absorbed after oral
administration, but absorption is enhanced by a
high-fat meal.
– It undergoes extensive first-pass metabolism
– Albendazole and its metabolites are primarily
excreted in the urine
197

198.  Adverse effect
– When used in short-course therapy (3 days) for
nematodal infestations, adverse effects are mild
and transient and include headache and nausea.
– Treatment of hydatid disease (3 months) has a risk
of hepatotoxicity and, rarely, agranulocytosis
– Medical treatment of neurocysticercosis is
associated with inflammatory responses to dying
parasites in the CNS, including headache, vomiting,
hyperthermia, convulsions, and mental changes.
– should not be given during pregnancy or to
children under 2 years of age.
198