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Anti-Infectives Exam 2 > Lecture 8 - Antitubercular agents > Flashcards

Lecture 8 - Antitubercular agents Flashcards

1
Q

1st line Antitubular Agents

A

RIPE

Rifamycins
Isoniazid
Pyrazinamide
Ethambutol

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2
Q

Rifamycins

A

Rifampin
Rifabutin
Rifapentine

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3
Q

Rifamycins MOA

A

Inhibit DNA dependent RNA polymerase

Bind to b-subunit of enzyme complex

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4
Q

Rifampin ADME properties

A

Widely distributed, highly lipophilic

Hepatic metabolism, 3-4hrs 1/2 life

mostly feces excreted some in urine

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5
Q

Rifabutin ADME properties

A

Widely distributed

Hepatic metabolism, 45hrs 1/2life

5 metabolites its metabolized to

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6
Q

Rifapentime ADME properties

A

High fat meals inc AUC & Max

Widely distributed

Hepatic metabolism, 17hr 1/2 life

Excreted mostly in feces 70/30

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7
Q

Big reason for choosing one Rifamycin over another?

A

DI

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8
Q

Rifampin DI

A

has a bunch

Warfarin = inc clot risk
Cyclosporine, Tacrolimus
HIV protease inhibitors + NNRT inhib

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9
Q

Rifabutin DI

A

way less DI, 50% of induction seen w/ rifampin

still has CYP3A4 tho

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10
Q

Rifapentine DI

A

more potent inducer than rifabutin but less than rifampin

rarely used

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11
Q

Rifampin Adverse Reactions

A

Hepatitis main issue

GI, rash, Genitourinary = change colors

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12
Q

Rifabutin Adverse Reactions

A

Rash, Urine discoloration, GI, some Hematologic

higher incidence

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13
Q

Rifapentine Adverse Reactions

A

Hepatic, Hematologic, Genitourinary

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14
Q

Rifampin role in therapy

A

1st line in pulmonary + extra pulmonary TB

resistance rapidly evolves if used alone

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15
Q

Rifabutin role in therapy

A

Rifampin alternative, as effective in drug susceptible TB

** used in pts w/ HIV if using protease inhibitors **

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16
Q

Rifapentine role in therapy

A

approved for once weekly use in INH in continuation phase of therapy w/ HIV neg patients

** Avoid in HIV + patients on antiretroviral therapy

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17
Q

Isoniazid (INH) MOA

A
  1. inhibit synthetic pathways of mycelia acid
  2. inhibit catalase-peroxidase enzyme
  3. Bactericidal ( against activity growing) and bacteriostatic (against non-replicating organisms0
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18
Q

Isoniazid (INH) ADME

A

well distributed, rapid absorption

excreted mostly in urine

Fast acetylators = lower 1/2 life
Slow acetylators = higher 1/2 life

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19
Q

Isoniazid (INH) Adverse effects

A

Hepatitis

Neurotoxic - peripheral neuropathy ~ 17% ( give Vit B to prevent)

Hypersensitivity reactions

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20
Q

Isoniazid Hepatitis risk factors

A 
Alcoholics
Preexisting liver damage
Reg women + women 3 months postpartum
Concomitant hepatotoxic agents
Active Hep B
HIV-seropositve pts on HAART
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21
Q

Isoniazid DI

A

Phenytoin
Theophylline
Clopidogrel

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22
Q

Isoniazid Role in therapy

A

1st line, indicated for all clinical forms of TB, used in combo

Used alone for latent TB

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23
Q

Pyrazinamide (PZA) MOA

A

Converted to pyrazinoic acid, lowering pH of environment

Inhibits fatty acid synthetase, involved in mycelia acid which are important for cell well

24
Q

Pyrazinamide (PZA) ADME

A

well absorbed, widely distributed

crosses inflamed meninges

Hepatic metabolism, 9-10hr 1/2 life

25
Q

Pyrazinamide (PZA) Adverse Reactions

A

Hepatotoxicity ~ 15% in trials in early trials at higher doses

GI - N/V
Urine retention ~ 50%
Gout

26
Q

Pyrazinamide (PZA) DI

A

Doesn’t have any really

BUT enhances hepatitis effects of Rifampin

27
Q

Pyrazinamide (PZA) Role in therapy

A

1st line, essential component of multi drug 6month therapy

** Pts have to be on PZA for 1st 2 months **

Primary resistance is low, but if resistant to INH/Rifampin will probs be resistant to PZA

28
Q

Ethambutol MOA

A

Interferes with cell wall biosynthesis

Inhibits arabinosyl transferase (EmbB)

29
Q

Ethambutol ADME

A

Well absorbed

Widely distributed

Hepatic metabolsim

excreted urine and feces

30
Q

Ethambutol Adverse Reactions

A 
Neuropathy
** Retrobulbar optic neuritis**
GI
Hyperuricemia
Hypersensitivity
31
Q

Retrobulbar optic neuritis

A

Bilateral blurry vision and red/green color vision
Slowly reversible
TIW admin reduces the risk

32
Q

Ethambutol DI

A

None

33
Q

Ethambutol Role in therapy

A

1st line, 4th drug of combo

protects against rifampin resistance, dropped once susceptibilities results are back

34
Q

TB Treatment Algo

A

If think they have TB, start on RIPE

Once susceptibilities back, E can be d/x if no drug resistance

P has to be on of 1st 2 months, can take off after for rest

**If dont get P in 1st 2 months, have to stay on therapy for 9 **

35
Q

Bedaquiline ( Diarylquinoline) MOA

A

Inhibits ATP synthase through inhibition of proton transfer chain required for energy generation

36
Q

Bedaquiline ( Diarylquinoline) ADME

A

Absorption inc w/ food
Large Vd
Hepatic metabolism

37
Q

Bedaquiline ( Diarylquinoline) Adverse effects

A

** Nausea ~ 38%
QTc prolongation
Black box for Cardiac toxicity/sudden death

38
Q

Bedaquiline ( Diarylquinoline) Black Box

A

“Only use when an effective treatment regime cannot otherwise be provided”

39
Q

Clofazimine MOA

A

Prodrug, originally anti-leporsy

exactly mechanism not well understood

causes accumulation of ROS radicals and cause cell death basically

40
Q

Clofazimine ADME

A

Absorption variable, inc w/ food
Highly Lipophilic
No hepatic metabolism

41
Q

Clofazimine Adverse effects

A

** Pigmentation changes = pink/brown/black color

GI = abdominal pain

42
Q

Clofazimine DI

A

QTc prolonging effects

43
Q

Cycloserine MOA

A

Inhibit bacterial cell wall synthesis by competing w/ amino acid (D-alanine) for incorporation into bacterial cell wall

44
Q

Cycloserine ADME

A

Mostly GI absorption
Widely distributed most body fluids
Hepatic metabolism
Highly urine excretion

45
Q

Cycloserine Adverse effects

A

Cardiac effects
CNS
Skin
Hepatic

46
Q

Cycloserine DI

A

Minimal

47
Q

Ethinamide MOA

A

Inhibits Peptide synthesis

results in impairment of cell wall synthesis

48
Q

Ethionamide ADME

A

essentially complete absorption
Widely distributed, Vd 93.5L
Prodrug, extensive hepatic metabolism

49
Q

Ethionamide Adverse effects

A 
Cardiovascular- ortho hypotension
CNs
SKin
Hepatic
GI
50
Q

Ethionamide DI

A

minimal

51
Q

Streptomycin MOA

A

Interferes w/ translation of mRNA transcripts

Bind to S12 protein, part of 30S complex

inhibits synthesis of mycobacterial proteins

52
Q

Streptomycin ADME

A

Usually given IM, PO poorly absorbed
Distributes into tissues/fluids except CNS
No hepatic metabolism
Urine excretion

53
Q

Streptomycin Adverse effects

A

Nephrotoxicity
Auditory + Vestibular toxicity
Hypersensitivity reactions

54
Q

Pretomanid MOA

A

Cell-wall lipid biosynthesis inhibitor

inhibition of mycelia acid synthesis
Formation of nitrogen reactive species

55
Q

Pretomanid ADME

A

Well absorbed
Distributes throughout body + CSF
Urine excretion

56
Q

Pretomanid Adverse effects

A 
Pretty high change of Peripheral neuropathy
Headache
GI
Musculoskeletal 
increased LFTs
57
Q

Therapy for MDR-TB

A
  1. pick 1 later-get Fluoroqinolone (Levo-/Moxifloxacin)
  2. Both Bedaquiline + Linezolid
  3. Both Clofazimine + Cycloserine/terizidone
  4. If cant get those 5 + susceptible, do Amikacin + Streptomycin
  5. If cant do injectable, do Delamanid, Pyrazinamide, Ethambutol

Anti-Infectives Exam 2 (8 decks)

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