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Pharmacology > Antimycobacterial Drugs > Flashcards

Antimycobacterial Drugs Flashcards

1
Q

antimycobacterial drugs are used for the treatment of

A
  1. tuberculosis
  2. atypical mycobacteria infections
  3. leprosy
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2
Q

what First line drugs are used to treat tuberculosis

A

-Isoniazid, Pyrazinamide, Rifampin, Ethambutol, streptomycin

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3
Q

what Second-line Drugs are used to treat tuberculosis

A

p-Aminosalicylic acid

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4
Q

what drugs are used to treat atypical Mycobacteria infections

A

-Isoniazid, Ethambutol, Rifampin, Erythromycin, Ciprofloxacin, various Cephalosporins

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5
Q

late stages of AIDS are associated with what

A

disseminated M avium complex infection (includes the presence of M. avium and M. intracellular),

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6
Q

what drugs are used to treat disseminated M avium complex infections

A

-clarithromycin plus ethambutol and rifabutin

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7
Q

what drugs are used to treat m. leprae

A

Dapsone, Clofazimine

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8
Q

what are the general considerations for the drug treatment of mycobacteria infections

A
  • M. infections intrinsically resistant to most antibiotics
  • notorious ability to develop resistance
  • slow growth rate: can also be dormant
  • intracellular location
  • lipid-rich cell wall is impermeable to many drugs
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9
Q

what is the treatment period for M. infections

A

treatment for periods of drug therapy longer than that of other infectious diseases

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10
Q

all M. Tuberculosisis initial isolates should be tested for what

A

susceptibility to drugs

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11
Q

should drugs be used in combination to treat Tuberculosis

A

-yes, use combined drug therapy with at least 2 drugs to which organism is susceptible

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12
Q

TB therapy requires use of

A
  • a multi-drug regiment with agents active against the clinical isolate
  • susceptibility test of initial isolates should always be obtained
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13
Q

what does the American Thoracic Society and the CDCP recommend for the initial treatment of TB

A
  • give 4 drugs: isoniazid, rifampin (or other rifamycin), pyrazinamide and ethambutol or streptomycin
  • after susceptibility of the clinical isolate has been determined, patients with drug-susceptible isolates can be treated with isoniazid and rifampin
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14
Q

what is the prevalence of INH resistant TB

A

~10%

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15
Q

what is the treatment of TB in HIV patients

A

use of rifampin-based regimes given clinical responses similar to that obtained in HIV-free TB patients

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16
Q

what are the first line drugs

A

Based of Efficacy

  • isoniazid (INH; generic)
  • rifampin (rifadin)
  • pyrazinamide (generic)
  • ethambuto (myambutol)
  • streptomycin (generic)
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17
Q

when are the second line drugs used

A

only if there are resistant organisms to first line drugs or other overriding considerations

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18
Q

what is the primary reason for the use of drug combinations in the treatment of TB

A

-to delay the emergency of resistance to INDIVIDUAL drugs

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19
Q

Isoniazid (INH) is a hydrazide of what

A

isonicotinic acid

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20
Q

Isoniazid acts only upon

A

Mycobacteria

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21
Q

what is the most active drug available for the treatment of TB casued by M. susceptible strains

A

Isoniazid

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22
Q

Isoniazid is less effective for the treatment of diseases caused by

A

atypical M. species

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23
Q

isoniazid are small molecules, structurally similar to

A

pyridoxine

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24
Q

Isoniazid is a prodrug, what does that mean

A 
After activation (by mycobacterial catalase
peroxidase KatG), has lethal effect by forming a covalent complex with an acyl carrier protein (AcpM) and a beta-ketoacyl carrier protein synthetase (KasA), blocking mycolic acid synthesis killing the cell
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25
Q

resistance to INH has been associated with various mutations, what are they

A
  1. over-expression of inhA gene encoding an NADH-dependent acyl carrier protein reductase
  2. mutation or deltion of the katG gene
  3. promoter mutations resulting in over-expression of ahpC, a putative virulence gene involved in cell protection from oxidative stress
  4. Mutations in kasA
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26
Q

inhA overproducers express — level resistance to INH and cross resistance to —

A

low

ethionamide

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27
Q

KatG mutants express — level INH resistance and often are not cross-resistant to —-

A

high

ethionamide

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28
Q

what are the pharmacokinetics of Isoniazid

A
  • well absorbed after oral administration, reaching peak plasma levels within 1-2 hrs
  • widespread distribution in body fluids and tissues, including brain, CSF, caseous TB lesions and phagocytic cells
  • active against intra- and extracellular organisms
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29
Q

what converts N-Acetylated to N-acetylisoniazid

A

liver N-acetyltransferase

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30
Q

how are N-acetylizoniazid + isonicotinic acid + little unchanged drugs eliminated

A

in the urine

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31
Q

Acetylisoniazid/isonizaid ratio is genetically determined by what

A

INH acetylation rate

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32
Q

INH average plasma conc. in rapid acetylators is

A

~1/3 to 1/2 of that in slow acetylators, with average t1/2 of >1hr and 3hr, respectively

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33
Q

are there therapetuic consequence of INH when using appropriate daily dosing

A

no, weekly NIH dosing (rapid acetylators) or malabsorption may result in subtherapetutic levels

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34
Q

when is INH the drug of choice (DOC)

A

when single agent used a chemoprophylaxis in individuals at greatest risk for developing active disease after being infected

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35
Q

what is the typical adult dose of INH

A

300 mg/once/d

  • should be adjusted in serious infection (single 900 mg twice/w) in combination with a second agent (600 mg rifampin)
  • dose modified in malabsorption of use of drug combinations
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36
Q

what is the recommended dose of Pyridoxine for those at risk of developing neuropathy (eg. slow acetylators)

A

25-50mg/d

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37
Q

what is the most common major toxic effect occuring with INH

A

INH-induced clinical hepatitis

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38
Q

risk of INH depends on what

A

age

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39
Q

who is at the greatest risk of developing INH-induced clinical hepatitis

A

alcoholics and possibly during pregnancy and the post-partum period

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40
Q

peripheral neuropathy caused by INH is seen in what % of patients

A

10-20% pts given dosages > 5 mg/kg/d

infrequent with standard 300 mg/d adult dose

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41
Q

INH neuropathy is due to what

A

a relative pyridoxine deficiency

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42
Q

INH neuropathy is more likley to occur in

A

-slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS and uremia

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43
Q

INH promotes the excretion of

A

pyridoxine

-this is revered by administration of pyridoxine 10 mg/d

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44
Q

what are the side effects of pyridoxine adminsitration of 10mg/d

A

-CNS side effects include memory loss, psychosis and seizures, allergic rxns

45
Q

Rifampin is a semisynthetic analog of what

A

the antibiotic rifamycin, present cross-resistance to other rifamycin derived drugs
eg. rifabutin, but not to other classes of antibiotics

46
Q

rifampin is effective against what

A
  • various bacteria, including bactericidal against M

- binds to the beta subunit of bacterial DNA dependent RNA polymerase, inhibiting RNA synthesis

47
Q

resistance to Rifampin results from

A

one of several point mutations in rpoB, the gene for the beta subunit of RNA polymerase, resulting in reduced rifampin binding to RNA polymerase

48
Q

does human RNA polymerase bind to Rifampin

A

no! Nor is human RNA polymerase inhibited by in

49
Q

describe the pharmacokinetics of Rifampin

A

-well absorbed after oral administration, which decreases when taken with meals or PAS acid

50
Q

how is Rifampin excreted

A

-into bile, undergoes enterohepatic recirculation and eliminated mostly in feces as a deacylated metabolite

51
Q

what dose of Rifampin should be administered to patients with active TB

A

600 mg/d + INH or other anti-TB drugs to prevent emergence of drug resistant mycobacteria

52
Q

Rifampin penetrates mostly

A

tissues and fluids, including phagocytic cells

-therapeutic CSF levels reached only in the presence of meningeal inflammation

53
Q

in combination with other drugs, rifampin 600 mg/d or twice/w 6 months is effective in treating

A

some atypical M. infections and leprosy

54
Q

Rifampin is a single drug alternative to

A

INH prophylactic treatment in patients with latent TB unable to take INH or when exposed to a case of active TB caused by INH-resistant, rifampin-susceptible M. strain

55
Q

what color does Rifampin give to urine, feces, saliva, sweat, tears and contact lenses

A

-a harmless red orange color, producing patients anxiety

56
Q

what are the side effects of Rifampin

A

light-chain proteinuria and occassionally rash, nephritis, jaundice, and hepatitis

57
Q

intermittent adminstration (>2w) of Rifampin causes

A

flu-like syndrome

eg. fever, myalgias, thrombocytopenia

58
Q

what does Rifampin strongly induce

A

most cytochrome P450 isoforms increasing the elimination rate, this lowering serum levels or numerous drugs
eg. methadone, oral anticoagulants, some anticonvulsants

59
Q

what is the antimicrobial activity of ethambutol

A

bacteriostatic agent

60
Q

MOA of ethambutol

A

inhibits mycobacterial arabinosyl transferases enzymes, encoded by the embCAB operon, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell

61
Q

ethambutol resistance is due to what

A

mutations resulting in over expression of emb gene products or within the embB structural gene

62
Q

what are the pharmacokinetic properties of ethambutol

A
  • well absorbed from GI, peak plasma levels reached within 2 hr, excreted in feces and urine
  • it accumulates in renal; can cause renal failure
  • reaches CSF only if menigeal inflammation
63
Q

when does rapid resistance to ethambutol occur

A

if used alone

64
Q

Ethambutol should be combined with

A

INH or rifampin

65
Q

ethambutol is effective against

A

M. TB strains

sensitivity of other M. variable

66
Q

what is the most common serious side effect of Ethambutol

A
  • is dose-related retrobulbar neuritis resulting in loss of visual acuity and red-green color blindness
  • it disappears after drug discontinuation
67
Q

what are contraindications of Ethambutol

A

-in children too young to permit assessment of visual acuity and red-green color discrimination

68
Q

Ethambutol is a synthetic analog of

A

nicotinamde

-converted to pyrazinoic acid (active form of the drug) by mycobacterial pyrazinamidase which is encoded by pncA

69
Q

resistance of Ethambutol occurs due to

A

mutation in pncA, blocking drug conversion to its active form, or by decreasing drug uptake which develops rapidly

70
Q

what are the pharmacokineics of Ethambutol

A
  • well absorbed from GI, widely distributed including inflamed meninges and macrophages
  • peak serum levels reached within 1-2 hrs and t1/2 ~ 10 hrs
71
Q

what are the major adverse effects of Ethambutol

A
  • effects include hepatotoxicity
  • GI disturbance and hyperuricemia (common)

*this is not a reason to stop therapy unless patients suffers acute gout attack

72
Q

Ethambutol is used together with

A

INH and rifampin in short course regimes (6 months) as a “sterilizing” agent to prevent relapse

73
Q

TB bacilli rapidly develops resistance to

A

pyrazinamide

74
Q

Streptomycin is an effective treatment of

A

M. tuberculosis, M. avium complex and M. kansaii, other M. species are resistant to this drug

75
Q

function of streptomycin

A

inhibits most tubercle bacilli

76
Q

what are the pharmacokinetic properties of streptomycin

A
  • poor penetration into cells and is effective mainly against extracelllular tubercle bacilli
  • used when injectable (IV or IM) therapy is recommended
    eg. meningitis (crosses the BBB achieving therapeutic levels with inflamed meninges) and disseminated infection, or when TB is resistant to other drugs
77
Q

resistance to streptomycin is due to

A
  • a point mutation in the rpsL gene, encoding the S12 ribosomal protein gene
  • or the rrs gene encoding the 16S ribosomeal rRNA, this altering the ribosomal binding site
78
Q

what are the side effects of Streptomycin

A

dose-related

oto- and nephrotoxicity

79
Q

what are the common SE of Streptomycin

A
  • vertigo and hearing loss, may become permanent

- risk increasing in the elderly and in patients with impaired renal functions

80
Q

what regime must be given with Streptomycin

A
  • a multidrug regime to prevent emergency of resistance

- treatment continue for several months and dosage should be adjusted during the course of therapy

81
Q

M. Tuberculosis: Second line drugs are considered only if

A
  1. resistance occurs to first-line drugs
  2. failure of recommended conventional therapy
  3. adverse effects limiting conventional therapy
  4. ability to deal with these drugs toxicity
82
Q

function of ethionamide

A

inhibits mycolic acid synthesis

83
Q

what are the SE of Ethionamide

A

GI irriation, neurophaties and liver toxicity

84
Q

function of Capreomycin

A
  • protein synthesis inhibitor

- give IM for the treatment of drug-resistant TB

85
Q

what are the SE of Capreomycin

A

oto-and nephrotoxic

86
Q

function of cycloserine

A

inhibits cell wall synthesis

87
Q

what are the side effects of Cycloserine

A

peripheral neuropathies and CNS depression and psychotic rxn

88
Q

what is aminosalicyclic acid (PAS)

A

folate synthesis antagonist

89
Q

what are the side effects of PAS

A

GI irritation and hypersensitivity rxn

90
Q

what drugs are used in combination in multidrug resistance M. tuberculosis

A

Kanamycin, amikacin, Fluoroquinolones (ciprofloxacin, levofloxacin), Linezolid (see slide 32)

91
Q

most mycobacterial infections are due to

A

“atypical” mycobacteria: M. kansaii, M. marinum, M. avium compex etc

92
Q

are atypical mycobacteria communicable from person to person

A

NO

93
Q

M. species are less responsive to M. tuberculosis to

A

anti-TB drugs (isoniazid, ethambutol, rifampin); however, they may respond to antibiotics not active against M. tuberculosis
eg. erythromycin, ciprofloxacin, various cephalosporins

94
Q

active infection of TB should be treated with

A

a multidrug regime to achieve optimal results in the shortest period of time, while minimizing the development of resistance

95
Q

late stages of AIDS are commonly associated with

A

disseminated M. avium complex infections, which includes the presence of M. avium and M. intracellulare

96
Q

what are the recommended treatments of late stages of AIDS

A

clarithromycin plus ethambutol and rifabutin

97
Q

leprosy is caused by

A

M. leprae

98
Q

Leprosy is characterized by

A

cutaneous lesions causing disfiguration and peripheral nerve damage

99
Q

what is used to treat Leprosy

A

Dapsone (and other sulfone-like agents) are closely related to sulfonamides and they competitively inhibit folate synthesis

100
Q

what are the pharmacokinetic properties of Dapsone

A
  • well absorbed from the GI

- widely distributed in the body t1/2 of 1-2d, eliminated in the urine (use with dose adjustment in kidney failure)

101
Q

Dapsone becomes significantly concentrated in the — of patients with M leprae skin infections

A

skin

102
Q

what are the side effects of Dapsone

A
  • hemolysis, particularly in G-6-PD deficiency pts
  • erythema nodosum leprosum responds to corticosteroids
  • FDA approved thalidomide for the treatment of this condition
  • may cause irreversible neuropathy
103
Q

to avoid resistance to Dapsone, treatment should be combined with

A

rifampin and clofazimine

104
Q

what is an alternative to dapsone

A

Clofazimine

105
Q

what are the pharmacokinetic properties of Clofazimine

A

-has a erractic absorption rate
-stored in skin and reticuloendothelial tissues from were it is slowly released
t1/2~2 months

106
Q

when is Clofazimine used

A

in sulfone-resistant leprosy or for sulfone intolerant pts

107
Q

what are the side effects of Clofazimine

A

skin discolouration from red brown to nearly black

108
Q

see slide 39

A

see slide 39

Pharmacology (23 decks)

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