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840 > Mycobacterial Agents Pharmacology > Flashcards

Mycobacterial Agents Pharmacology Flashcards

1
Q

Mtb

A
  • Mycobacterium tuberculosis
  • Slow-growing, aerobic bacteria with lipid-rich cell wall
  • Can remain dormant for long periods of time
  • Mycolic acid makes up 60% of cell wall, relatively impermeable
  • Intracellular - lives inside non-activated macrophages
  • Need to use multiple or combination drugs to decrease emergence of resistant strains
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2
Q

TB

A

Tuberculosis

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3
Q

BCG

A
  • Bacillus of Calmette and Guerin vaccine

- Contains live, attenuated preparation of the BCG strain of Mycobacterium bovis

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4
Q

MAC

A
  • M. avium mycobacterium

- Contains M. avium and M. intrecellulare

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5
Q

NTM

A

Non-tuberculosis mycobacterium

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6
Q

PPD

A
  • Purified Protein Derivative
  • Intradermal tuberculin testing
  • Cell-free purified protein fraction obtains from human strain of Mycobacterium tuberculosis
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7
Q

Mycobacterial Infections + Organisms

A
  • Tuberculosis - Mtb
  • Leprosy - M. leprae
  • MAC => chronic cough, SoB, fatigue
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8
Q

Active Tuberculosis

A
  • Becomes active if immune system doesnt prevent growth
  • These bacteria begin to multiply in the body => active TB disease
  • Can be spread to others
  • Localized = lungs, Disseminated = Fulminant
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9
Q

Latent TB Infection

A
  • LTBI
  • Exposed to bacteria but becomes inactive
  • Lives in body but becomes active later
  • Many who have LTBI never develop active TB
  • No symptoms or physical findings that suggest TB
  • Respiratory smear/culture will be negative
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10
Q

Pulmonary TB Disease

A
  • Symptoms: fever, cough, night sweats, weight loss, fatigue, hemoptysis, decreased appetite
  • Respiratory smears are usually culture positive (~50%)
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11
Q

Asymptomatic Diagnosis

A
  • Based on immune response to Mtb antigens
  • PPD Skin test: purified protein derivative, delayed hypersensitivity
  • QuantiFERON - TB-Gold standard, blood test, immune cell memory resposne
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12
Q

5 Principles of TB Treatment

A
  1. Multiple drugs MUST be used
  2. Drug sensitivity testing is mandatory
  3. Single daily dosing of drugs is preferred
  4. Prolonged therapy is necessary (>6 mo)
  5. Monitoring for patient compliance and toxicity is required (DOT)
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13
Q

Initiation Phase

A
  • Bactericidal, intensive phase
  • Use: isoniazid, rifampin, pyrazinamide, and ethambutol
  • Administer for 2 months
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14
Q

Continuation Phase

A
  • Sterilizing/continuation phase
  • Use: isoniazid and rifampin
  • Continued for 4-7 months IF cavitation on chest x-ray, positive acid fast bacillus smear, and positive culture
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15
Q

TB First Line Agents

A

-Greatest level of efficacy with acceptable toxicity

Drugs

  • Isoniazid (INH)
  • Ethambutol (EMB)
  • Pyrazinamide (PZA)
  • Rifampin (RIF)

RIPE!!!

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16
Q

Isoniazid

A
  • Inhibits synthesis of mycolic acids
  • Primary agent in therapeutic/prophylactic programs
  • Bactericidal
  • Enters phagocytic cells of the host and kills bacilli
17
Q

Isoniazid + Pro-drug

A
  • Pro-drug activated inside mycobacterium
  • Enters via passive diffusion and is then activated by katG
  • Becomes a range of radicals/reactive species that attacks multiple targets including mycolic acid synthesis
  • Other targets: Lipid peroxidation, DNA damage, and NAD metabolism
  • Resistance: mutations in katG or inhA promotor region (increased expression)
18
Q

Isoniazid ADME

A
  • Orally absorbed that can be interfered with by aluminum containing antacids
  • Hepatic acetylation for metabolism that determines [drug] and half-life
  • Excreted in urine (don’t adjust for renal impairment)
19
Q

Isoniazid + AE

A
  • Allergic rxns
  • Peripheral neuropathy at high doses
  • Elevated hepatic enzymes (more common)
  • Box warning: INH induced hepatitis (rare) - monitor monthly (LFTs)
20
Q

Isoniazid + Peripheral Neuropathy

A
  • INH metabolites attach to inactive vitamin B6
  • Vitamin B6 (pyridoxine) used to produce GABA
  • When deficient, this could cause seizures and peripheral neuropathy
  • Supplement with pyroxidine
21
Q

Ethambutol

A
  • Inhibits mycobacterial cell wall synthesis but enhances activity of lipophilic drugs mainly
  • Inhibits arabinosyl transferase which blocks polysaccharide synthesis and mycolic acid transfer to cell wall
  • Enhances activity of lipophilic drugs like RIF
22
Q

Ethambutol ADME

A
  • Orally absorbed, aluminum antacids can interfere
  • Hepatic metabolism
  • Excreted in urine: DOSE ADJUST
23
Q

Ethambutol Toxicity

A
  • Optic neuritis is most common AE
  • Results in diminished visual acuity and loss of red/green discrimination
  • Decreased ureate excretion => Gout if predisposed
24
Q

Ethambutol Alternative

A
  • Streptomycin
  • Inhibits protein synthesis (binds to 30S ribosome, aminoglycoside)
  • Poorly absorbed orally
  • Not distributed in CSF, good otherwise
  • Dose adjust with renal impairment, excrete urine
  • Neuro and nephrotoxic
25
Q

Pyrazinamide

A
  • Enters Mtb as a pro-drug by passive diffusion
  • Converted to POA by nicotinamidase/pyrazinamidase
  • Disrupts intracellular pH and membrane transport (exact MoA unresolved)
26
Q

Pyrazinamide ADME

A
  • Well absorbed
  • Widely distributed, CSF
  • Hepative metabolism
  • Excreted in urine (DOSE ADJUST)
27
Q

Pyrazinamide AE

A
  • Liver injury with jaundice, rarely fatal
  • Don’t use with decreased liver function
  • Monitor LFTs
28
Q

Rifampin MoA

A
  • Binds to B-subunit of bacterial DNA-dependent RNA polymerase
  • Inhibits RNA synthesis
  • Bactericidal
29
Q

Rifampin ADME

A
  • Oral administration (food/antacids decrease)
  • Distributes to all body fluids and organs, includes CNS
  • Induces hepatic mixed-function oxidases, increases its own and other drugs’ metabolism (contraceptives)
  • Fecal elimination, orange-red discoloration
  • Tears may permanently stain contacts red/orange
30
Q

Rifampin Toxicity

A
  • STRONG inducer of CYP1A2, 2C9, 2C19, and 3A4
  • Flu-like symptoms, skin rashes, and itching, jaundice/hepatitis, hepatic enzyme elevation
  • Potential DDI, includes several HIV protease inhibitors
31
Q

MDR TB

A
  • Multidrug resistant TB
  • Resistant to at least two of the best anti-TB drugs, isoniazid and rifampicin
  • XDR (extensively DR) is rare, same as MDR as well as resistant to any FQ and at least one of the three injectable second-line drugs
32
Q

Bedaquiline

A
  • Sirturo
  • 1st new TB drug in over 40 years
  • MoA: inhibits proton pump for mycobacterial ATP synthase
  • Hepatic metabolism
  • Feces excretion
33
Q

Bedaquiline Boxed Warnings

A
  • Increased mortality

- QT prolongation

34
Q

Pretomanid

A
  • Approved in 2019 for XDR TB
  • Nitroimidazole drug
  • Blocks mycolic acid synthesis
  • Use in combination with Bedaquiline and Linezolid
  • AE: peripheral neuropathy, acne/rash, low blood sugar, vomiting, diarrhea, liver inflammation
  • 16 hour half life
  • Excreted in urine

840 (17 decks)

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