antimycobacterial drugs Flashcards
First line drugs:
First line drugs: Isoniazid (INH) Rifampin (RA) Pyrazinamide (PZA) Ethambutol (ETB) Streptomycine
Second line drugs:
Second line drugs: Ethionamide Cycloserine Paraaminosalicylic acid (PAS) Kanamycine, amikacin Capreomycin Fluoroquinolons Rifabutin Linezolid
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
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
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
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
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
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
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
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
Kanamycin- second line
- Aminoglycoside
* used rarely, mainly in case of streptomycin resistancy
Amikacin- second line
Amikacin
• Aminoglycoside
• active mainly against M. tuberculosis (poor effect against M. kansasii), used in the case of multiresistancy
Capreomycin (seocnd line) mechanism used against adverse? 2 adminstration
- protein synthesis inhibitor
- used against multiresistant M. tuberculosis strains
- nephro- and ototoxic
- administrated parenterally
Fluoroquinolons (Second line)
name 4 drugs and which is it used against.
- Ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin
* in combination against M. tuberculosis
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)
