Antimycobacterial drugs (2) Flashcards
Mycobacteria
• Species:
- M. tuberculosis- tuberculosis
– M. bovis- bovine tuberculosis
FYI
– M. kansasii - resembles tuberculosis
– M. marinum - granulomatous cutaneous disease
– M. avium complex (avium/intracellulare) - pulmonary disease or
disseminated infection in AIDS
– M. scrofulaceum - cervical adenitis in children
– M fortuitum - abscess, sinus tract, ulcer, bone, joint, tendon infection
– M. ulcerans - skin ulcers
– M. chelonae - abscess, sinus tract, ulcer, bone, joint, tendon infection
– M. leprae - leprosy
• aerobic, non motile, rod shaped bacteria
• very slowly growing
• can be dormant
• hydrophobic (lipid-rich) cell wall (difficult to penetrate)
• intracellular pathogen • (not obligate)
• resistancy
• special inflammation – acidicpH
– lowO2
– cavernes
Anti-tuberculotic drugs
where and how they reach the lesion
Anti-tuberculosis drugs travel
• from blood vessels enter
• the interstitial space of granulomas and then
• penetrate and accumulate in immune cells, including within subcellular organelles, such as the phagolysosome, where intracellular bacilli can reside.
Finally, the drugs
• permeate the pathogen to reach their molecular target.
In necrotic granulomas and cavities, drugs must diffuse through
• caseum in the absence of vascularization and active transport systems to reach
• extracellular bacilli that are present in the necrotic centre.
antituberculotics are able to travel in the caseum and penetrate the lipid wall !!!!!!!!
First line drugs for tuberculose
Isoniazid (INH) Rifampin (RA) Pyrazinamide (PZA) Ethambutol (ETB) Streptomycine (not good kinetics)
second line drugs for tuberculose
Ethionamide Cycloserine!!! Paraaminosalicylic acid (PAS) Kanamycine!!!!!, amikacin Capreomycin Fluoroquinolons Rifabutin Linezolid Bedaquiline Delamanid
for actively growing bacteria
therapeutic specificities
isoniazid
for dormant bacteria
therapeutic specificities
rifampin (RA),
pyrazinamide (PZA),
ethambutol (ETB)
therapeutic specificities
- long term treatment (6 months-2 years)
- social problems
- drugs are given always in combination
- the drugs are well absorbed after oral administration and have a good distribution (exceptions: aminogylcosides, Capreomycine)
common therapeutical protocol (drug combination and duration)
(therapeutic specificities)
- INH+RA+PZA+ETB– first 2 months
* INH+RA–4 months after ward
Isoniazid
- Bactericide for actively growing bacterias, bacteriostatic for dormant bacterias
- Mechanism of action: inhibits synthesis of mycolic acid •
Inhibitor of CYP450 enzymes
Pharmacokinetics:
• pro drug, (activation by catalase)
well absorbed given orally, iv. adm. is possible as well • excellent tissue distribution
• 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)
• Adverse effects:
• hepatotoxicity, alcohol enhances its prevalence, more common in rapid
acetylators
• Neurologic problems, more common in slow acetylators
• peripheralneuritis, paresthesias (rarely headache, memoryl oss, psychosis, seizures)
• duetoB6-deficiency(INH binds to pyridoxine and blocks pyridoxal-5- phosphate formation - coenzyme of various enzymes).
Neurotoxicity due to pyridoxine (vitamin B6) deficiency – insomnia, muscle twitching,
Sideroblastic anemia
Drug-induced lupus
- Acute hemolysis in G6PD
deficient patients
- AG metabolic acidosis
Mechanism of resistance: deletions in katG gene (encodes catalase needed for INH bioactivation)
- Most important drug used in tuberculosis treatment; component of most drug regimens
- Prophylaxis (see indications)
Rifampin
• Bactericide, inhibits RNA polimerase
Inhibits DNA-dependent RNA polymerase
(transcription inhibitor)
• Spectrum: M. tuberculosis, M. leprae, Neisseria meningitidis, Haemophilus
influenzae, pox viruses
• Pharmacokinetics:
• well absorbed orally, good distribution (including phagocytic cells, abscesses, lung cavities), metabolized in the liver (accelerates its own metabolism)
Enterohepatic cycling
- Partial hepatic metabolism,
excreted in feces both intact and metabolised
• Adverse effects:
- hepatotoxicity (enzyme elevation, rarely hepatitis) - orange discoloration of urine, tears, sweat
- rarely neurologic problems
- Nephrotoxicity (proteinuria, nephritis)
- Skin rash
- Thrombocytopenia
• 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)
In combination with
vancomycin, active against
MRSA and PRSP
Mechanism of resistance: alteration of the polymerase enzyme
• Interactions
- strong enzyme inducer
- CYP3A4, CYP1A2, CYP2C9, CYP2C19, CYP2D6 - accelerates its own metabolism
Pyrazinamide
• Bactericide (lecture), pyrazinoic acid is formed and inhibits cell membrane functions, dysrupts energy metabolism
(notes: Bacteriostatic
- Mechanism of resistance: mutations in gene encoding enzymes involved in drug activation)
- Oral
- Prodrug
- Partial hepatic metabolism,
eliminated in urine both intact
and metabolised - Plasma T1/2 increases in
renal/hepatic impairment
• Adverse effects:
- hepatotoxicity
- hyperuricaemia
- Non-gout polyarthralgia
- Skin rash
- To be avoided in pregnancy
• Clinical indications:
- in combination for the short term regimen (synergic effect with INH and rifampin. Thanks to Pyrazinamide it was possible to reduce the original 1 year long therapy to 6 months
- as a substitute of INH in case of INH resistancy
Ethambutol
• Bacteriostatic, inhibits mycobacterial arabinosyl transferases → inhibited bacterial cell wall synthesis
Inhibits synthesis of arabinogalactan
• Pharmacokinetics
- well absorbed orally (alcohol decreases)
- Eliminated unchanged in urine (dose adjustment in renal impairment)
Mechanism of resistance: alteration of drug target
• Adverse effects:
- Dose-dependent visual disturbances
- 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, confusion
• Clinical indications:
- early intensive therapy, in combination
Streptomycin
Aminoglycoside
(protein synthesis inhibitor)
• Bactericide, concentration-dependent killing action (antibacterial effect is increased proportionally above the MIC
Toxicity of aminoglycosides is both concentration-dependent and time-dependent
Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
• Mechanism of action: protein synthesis inhibitor
Bind to the 30S ribosomal subunit
- Parenteral
- T1/2 2-3 h’
- Renal elimination (directly proportional
to creatinine clearance) - Dose reduction in renal impairment
- Requires monitoring of drug plasma
concentrations (due to narrow TI) - Dosing regimens consist of 2-3 times daily (traditionally), or once-daily
- Plasmid-encoded inactivating enzymes (acetylation of the drug)
- Alteration of ribosomal binding site
- Intrinsic resistant (failure of drug to penetrate into the cell) → all anaerobes
• 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
Resistant tuberculosis, used in combination regimens
- Treatment of life-threatening associated diseases (meningitis, miliary dissemination, end-organ TB)
• Pharmacokinetics
- only parenteral administration (2-3*/week i.m.) - does not enter CNS
• Adverse effects
- nephrotoxicity: proteinuria, acidosis, hypokalemia, acute tubular necrosis
- ototoxic
- Neuromuscular blockade → botulism-like blockade at high doses (Ach release ↓), may result in respiratory paralysis (treatment with Ca2+ and neostigmine)
- Allergic skin reaction → contact dermatitis (most common with neomycin)
- Teratogenicity → fetal ototoxicity
second line drugs, clinical indications
Clinical indications
• resistance to first-line agents
• failure of clinical response to conventional therapy
• treatment limiting adverse drug reactions
Cycloserine
2nd line antituberculotic, no other use due to side effects
• inhibits alanine racemase and cell wall synthesis
notes: Cell wall active antibiotics
(cyclic analogue of D-ala → inhibits peptidoglycan synthesis)
• Adverse effects
- severe central nervous system side effects: tremor, acute
psychosis, seizures; peripheral neuropathy.
