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
2
Q
TB
A
Tuberculosis
3
Q
BCG
A
- Bacillus of Calmette and Guerin vaccine
- Contains live, attenuated preparation of the BCG strain of Mycobacterium bovis
4
Q
MAC
A
- M. avium mycobacterium
- Contains M. avium and M. intrecellulare
5
Q
NTM
A
Non-tuberculosis mycobacterium
6
Q
PPD
A
- Purified Protein Derivative
- Intradermal tuberculin testing
- Cell-free purified protein fraction obtains from human strain of Mycobacterium tuberculosis
7
Q
Mycobacterial Infections + Organisms
A
- Tuberculosis - Mtb
- Leprosy - M. leprae
- MAC => chronic cough, SoB, fatigue
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
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
10
Q
Pulmonary TB Disease
A
- Symptoms: fever, cough, night sweats, weight loss, fatigue, hemoptysis, decreased appetite
- Respiratory smears are usually culture positive (~50%)
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
12
Q
5 Principles of TB Treatment
A
- Multiple drugs MUST be used
- Drug sensitivity testing is mandatory
- Single daily dosing of drugs is preferred
- Prolonged therapy is necessary (>6 mo)
- Monitoring for patient compliance and toxicity is required (DOT)
13
Q
Initiation Phase
A
- Bactericidal, intensive phase
- Use: isoniazid, rifampin, pyrazinamide, and ethambutol
- Administer for 2 months
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
15
Q
TB First Line Agents
A
-Greatest level of efficacy with acceptable toxicity
Drugs
- Isoniazid (INH)
- Ethambutol (EMB)
- Pyrazinamide (PZA)
- Rifampin (RIF)
RIPE!!!
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
Pyrazinamide
- 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
Pyrazinamide ADME
- Well absorbed
- Widely distributed, CSF
- Hepative metabolism
- Excreted in urine (DOSE ADJUST)
27
Pyrazinamide AE
- Liver injury with jaundice, rarely fatal
- Don't use with decreased liver function
- Monitor LFTs
28
Rifampin MoA
- Binds to B-subunit of bacterial DNA-dependent RNA polymerase
- Inhibits RNA synthesis
- Bactericidal
29
Rifampin ADME
- 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
Rifampin Toxicity
- 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
MDR TB
- 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
Bedaquiline
- Sirturo
- 1st new TB drug in over 40 years
- MoA: inhibits proton pump for mycobacterial ATP synthase
- Hepatic metabolism
- Feces excretion
33
Bedaquiline Boxed Warnings
- Increased mortality
| - QT prolongation
34
Pretomanid
- 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
