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Flashcards in antimycobacterial drugs Deck (20):
1

First line drugs:

First line drugs:
Isoniazid (INH)
Rifampin (RA)
Pyrazinamide (PZA)
Ethambutol (ETB)
Streptomycine

2

Second line drugs:

Second line drugs:
Ethionamide
Cycloserine
Paraaminosalicylic acid (PAS)
Kanamycine, amikacin
Capreomycin
Fluoroquinolons
Rifabutin
Linezolid

3

Isoniazid:
Cidic or static?
Mechanism?
antimicrobial activity? 2
Pharmacokinetics: Given (2 methods), tissue distribution?
Adverse effect? 3

Isoniazid
• Bactericide for actively growing bacterias, bacteriostatic for dormant bacterias

• Mechanism of action: active metabolites inhibit synthesis of mycolic acid by blockade of enzymes and carrier proteins.

• Antimicrobial activity: M. tuberculosis, M. kansasii

• in combination it is recommended for of all type of tuberculosis

• Pharmacokinetics:
• pro drug,
• well absorbed given orally, iv. administration is possible as well
• excellent tissue distribution: high concentration in liquor and in tuberculous granuloma
• it is acetylated in the liver (T1/2 =1 h in the case of fast and T1/2 =3 h in the case of slow acetylators) • elimination by the urine.

• Adverse effects:
1) hepatotoxicity, dose dependent, alcohol enhances it prevalence. More common in rapid acetylators.

Neurologic problems:
1) peripheral neuritis, paresthesias (rarely headache,
memory loss, psychosis, seizures)
• due to B6 -deficiency (INH binds to pyridoxine and blocks pyridoxal-5-phosphate formation - coenzyme of various enzymes). • More common at slow acetylators, it is reversed by adding
pyridoxine
3) muscle cramps, fever, rashes

4

Rifampin
Static or cidic?
Mechanism?
which bacteria? which other microbes?
administration method?
Metabolized? Elimination?
ADverse effects- 3
Clinical indications- enough...

Rifampin
• Bactericide
• Mechanism of action: inhibits RNA polimerase (RNA- and protein synthesis↓ ), long postantibiotic effect
• Spectrum:
1) M. tuberculosis, M. kansasii, M. marinum, M. avium, M. leprae,

2) Neisseria meningitidis, Haemophilus influenzae, pox 3) viruses

• Pharmacokinetics:
• well absorbed given orally
• good distribution (including phagocytic cells, abscesses, lung cavities), therapeutic level in the liquor • metabolized in the liver (accelerates its own metabolism)
• hepatic (is saturable) and renal elimination.

Rifampin
• Adverse effects:
- hepatotoxicity (enzyme elevation, rarely hepatitis)
- orange discoloration of urine, tears, sweat
- rarely neurologic problems

• Clinical indications:
- mainly in combination! (resistancy)
- the most effective antituberculotic
- leprosy (in combination with dapsone or clofazimine)
- in monotherapy for the profilaxis of contacts in Meningococci, H. influenzae infections
- highly resistant staphylococcal infections (endocarditis, osteomyelitis - in combination with ciprofloxacine).

• Interactions
-strong enzyme inducer
- CYP3A4, CYP1A2, CYP2C9, CYP2C19, CYP2D6
- accelerates its own metabolism
- it will cause increased elimination of cumarins, hormonal
contraceptives, corticosteroids, cardiac glycosides, barbiturates,
methadon, chloramphenicol, ketoconazole, protease inhibitors,
some anticonvulsants

5

Pyrazinamide
cidic or static
Mechanism
Spectrum
Pharmacokinetics: administration and excretion.
Adverse effects: 2
Inidcation

Pyrazinamide

• Bactericide
• Mechanism of action: in the bacteria pyrazinoic acid is formed and inhibits cell membrane functions, dysrupts energy metabolism
• Spectrum: M. tuberculosis

• Pharmacokinetics
- good oral absorbtion
- well distributed in the body, penetrates BBB
- metabolized in the liver
- excreted by the urine

• Adverse effects:
- hepatotoxicity
- hyperuricaemia

• Clinical indications:
- in combination for the short term regimen (synergic effect with INH and rifampin, thank to Pyrazinamide it was possible to reduce the original 1year long therapy to 6 months
- as a substitute of INH in case of INH resistancy

6

Ethambutol
cidic or static,
Mechanism:
spectrum
Kinetics:
adverse effects and indications:

Ethambutol
• Bacteriostatic
• Mechanism of action: inhibits mycobacterial arabinosyl transferases → inhibited arabinoglycan formation → inhibited bacterial cell wall synthesis

• Spectrum: M. tuberculosis, M. kansasii, M. avium (usually resistant)

• Pharmacokinetics
- well absorbed orally (alcohol decreases)
- accumulates in the alveolar macrophages, enters CNS
- excreted mainly unchanged by the urine

Adverse effects:
-retrobulbar neuritis (loss of visual activity, red-green
color blindness, scotomas) - periodic visual control
(every month!)
- other rare side effects: nausea, joint pain, headache,

allergy
• Clinical indications:
- early intensive therapy, in combination

7

streptomycin (first line)
cidic or static
Mechanism
Spectrum 1
Kinetics: 2
Adverse: 2

Streptomycin
• Bactericide

• Mechanism of action: protein synthesis inhibitor • Spectrum: M. tuberculosis, not effective against intracellularly residing
bacterias, acts only against mycobacterias in open caverns or bronchi
M. kansasii and M. avium are resistant •

Pharmacokinetics
- only parenteral administration (2-3*/week i.m.)
- does not enter CNS

• Adverse effects
- nephro- and ototox

8

ethionamide (second line)
Mechanism
Spectrum 3
Kinetics: 4
adverse effects: 3

Ethionamide (related to isoniazide)
• Mechanism of action: inhibits mycolic acid synthesis
• Spectrum: M. tuberculosis, M. kansasii, M. avium

• Pharmacokinetics
- good oral absorbtion
- enters CNS
- metabolized in the liver
- eliminated by the urine

• Adverse effects
- hepatotoxicity
- gastrointestinal side effects
- allergy

9

Cycloserine (second line)
Mechanism
Spectrum:
Kinetics: 3
adverse: 2

• Mechanism of action: D-Ala analogue, inhibits alanine racemase and cell wall synthesis.

• Spectrum: M. tuberculosis, effective againts INH and streptomycin resistant strains.
Active against many G+ and G- bacteria but because of its toxicity it is used only for the treatment of tuberculosis

• Pharmacokinetics
- well absorbed orally
- enters CNS
- partly metabolized

• Adverse effects
- severe central nervous system side effects: tremor, acute psychosis, seizures;
- peripheral neuropathy

10

Paraaminosalicylic acid (PAS) (Second line)
Mechanism
Static or cidic
Spectrum
kinetics: 3
adverse effects: 3

Paraaminosalicylic acid (PAS)
• Mechanism of action: inhibits folate synthesis (structural analog of PABA)
• Bacteriostatic
• Spectrum: M. tuberculosis, resistancy is rare
• Pharmacokinetics
- well absorbed orally
- good distribution
- metaboliztion mainly by acetylation
• Adverse effects
- gastrointestinal (ulcer, nausea, diarrhea)
- central nervous system
- hypersensitivity reactions

11

Kanamycin- second line

• Aminoglycoside
• used rarely, mainly in case of streptomycin resistancy

12

Amikacin- second line

Amikacin
• Aminoglycoside
• active mainly against M. tuberculosis (poor effect against M. kansasii), used in the case of multiresistancy

13

Capreomycin (seocnd line)
mechanism
used against
adverse? 2
adminstration

• protein synthesis inhibitor
• used against multiresistant M. tuberculosis strains
• nephro- and ototoxic
• administrated parenterally

14

Fluoroquinolons (Second line)
name 4 drugs and which is it used against.

• Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin
• in combination against M. tuberculosis

15

Rifabutin
what is it and when is it used

• similar to Rifampin, less potent enzyme inducer
• indicated in place of rifampin for treatment of tuberculosis in patients with
HIV infection (less interactions)

16

Linezolid
mechanism?
indication
kinetics?
adverse: 2

Linezolid
• Mechanism of action: protein synthesis inhibitor
• Clinical indications: in case of multiresistant and atypical mycobacterias
• well absorbed orally
• adverse effects at long term therapy: bone marrow suppression,
neuropathy

17

atypical myco treatments...

• M. kansasii - ciprofloxacin, clarithromycin, ethambutol, INH, rifampin, cotrimoxazole (trimethoprim-sulfamethoxazole)
• M. marinum - amikacin, clarithromycin, ethambutol, doxycycline,
minocycline, rifampin, cotrimoxazole
• M. scrofulaceum - amikacin, erythromycin (macrolides), rifampin,
streptomycin, surgery
• M. avium complex (avium/intracellulare) - amikacin, azithromycin,
clarithromycin, ciprofloxacin, ethambutol, rifabutin
• M. chelonae - amikacin, doxycycline, imipenem, macrolides, tobramycin
• M fortuitum - amikacin, cefoxitin, ciprofloxacin, doxycycline, ofloxacin, cotrimoxazole
• M. ulcerans - INH, streptomycin, rifampin, minocycline, surgery

18

leprosy drugs

dapsone,
rifampin
clofazimine

19

dapsone
static or cidic
mechanism:
Kinetics: 2
Also used in?
Adverse: 3

bacteriostatic
mechanism: inhibits folic acid synthesis (inhibits dihydropteroate synthase).
Kinetics: Taken orally andexcreted in urine

Also used in pneumonia caused by pneumocystis jirovecii immuno suppressed patients.

adverse:
Hemolysis (especially in G6pD def. patients).
Methemoglobineaemia
Erythema nodosum

20

clofazimine
Mehcanism
Used in case of ?
Cidic or cidial
Adverse effects:

unknown mechanism (may involve DNA binding).
Used in case of dapsone resistance.
Bactericidal
adverse effects: black and brown discoloration of the skin.