Anti-Tb Drugs Flashcards
Discuss the characteristics of mycobacteria
- resistant to most antibiotics- lipid-rich cell wall
- Lay dormant
- Intracellular pathogens- drugs need to penetrate the cell
- High chance of developing resistance which is why multi-drug tx. is used
What are the fist line agents and which agent is no longer part of this
H (INH) RZE
Inoniazid
Rifampicin
pyraminazide
ethambutol
Streptomycin
Explain the relationship between ioniazid and pyrazinamide
When ioniazide used alone it cures 95 to 98% of TB cases over 9 months. When pyrazinamide is added for the first 2 months, case reduced in 6 months
Explain the fist line TB regimen for uncomplicated TB in adults/children >8 years and younger= 8 years
- 2HRZE/4HR
- 2HRZ/4HR
Explain the drug regiment for complicated TB in children =< 8 years old
2HRZE/4-7HR
Explain some characteristics of Isoniazid and MOA
- Structurally similar to pyridoxine
- Most active drug treatment of TB
- Bactericidal against multiplying bacteria
- Bacteriostatic against non-dividing bacteria
- Penetrate into macrophages
Inhibits the synthesis of mycolic acids (essential for cell walls) unique to mycobacterium
- Prodrug activated by KatG
explain the mechanisms of resistance regarding Ioniazid
- Mutation mechanisms
- Mutation or deletion of KatG gene (ioniazid won’t be activated)
- Cross resistance with ethionamide
Explain the pharmacokinetics of ioniazid
- rapidly absorbed from the GIT within 1-2 hrs
- Diffuses into all bodily fluids and tissue (CNS and CSF)
Acetylation by N acetyl-transferase
Inhibits metabolism of phenytoin and carbamazepine
Discuss the clinical uses of ioniazid
max 10mg/kg, 300 mg day for adult
Primary tuberculosis, miliary TB
single agent in latent TB
Pyrioxidine supplementation is essential to prevent neurotoxicity
Discuss the adverse effects of ioniazid
- SLE (immunological reaction and skin rashes)
- Hepatotoxicity (20-40%)
- Peripheral neuropathy
4 CNS toxicity- psychosis, memory loss and seizures
SHIPP
Discuss the characteristics of rifampicin
Semisynthetic derivative of rifamycin
Rifamycin is produced by streptomyces mediterranei
Explain the antimicrobial activity of rifampicin
Gram positive and gram negative cocci
Some enteric bacteria
Mycobacteria , H. influenzae, Staph aureus,
Chlamydia, certain viruses
Leprosy, severe legionaires’ disease, chemoprophylaxis of meningococcal meningitis, severe staphylococcal infection
Explain the mechanism of action of rifampicin
- Inhibits RNA synthesis
- Penetrates most tissues including phagocytotic cells
- Kill organisms inaccessible by other drugs (lung cavities)
Explain the pharmacokinetics of rifampicin
- well absorbed orally
- Distributes widely in body fluids
- highly protein bound
Even with renal or hepatic failure, dosage does not need to change
Explain the mechanism of resistance for rifampicin
- RNA polymerase mutations that prevent the binding of rifampicin to the RNA polymerase
- Drug-resistant mutants present in the mycobacterial population
NO CROSS RESISTANCE WITH OTHER DRUGS ONLY TO RIFAMYCIN DERIVATIVES
Explain the clinical uses of rifampicin
Latent tuberculosis (monotherapy or combination with pyrazinamide
Bacterial
- Single drug prophylaxis in place of ioniazid
infections (Staph aureus, H influenza, legionella, chlamydia
Prophylaxis against H. influenza type B
explain the adverse reactions of rifampicin
FAT HI
Flushing
Acute tubular necrosis
Thrombocytopenia
Hepatic toxicity
Influenza-like symptoms e.g. chills, fever, wheezing
Red orange discoloration of urine or tears
Explain the drug interactions with rifampicin
- strong enzyme inducer
- Increases elimination of many drugs
- Warfarin, steroid contraceptives, analgesics, antidiabetic agents, phenytoin, and protease inhibitors. elimination is enhanced. The drug does need to be increased
- Induces its own metabolsim, half life decreases as weeks progress
Explain the properties of pyrazinamide
- Derivative of nicotinamide
- Only treatment of TB
- Inactive at neutral pHm activated at pH of 5.5
- converted to pyazinoic acid (active form)–> mycobacterial pyrazinamidase
- Effective against persisters, prevents relapses
Explain the MOA of pyramid
- exact mechanism of action not known
- Inhibits synthesis of fatty acids required for synthesis of mycolic acid
- Inhibits mycobacterial cell wall
- resistance develops easily
Explain the adverse reactions with pyrazinamide
- Hepatotoxicity
- Hyperuricemia (gouty attacks and high uric acid levels)
- Nausea, vomiting and fever
CONTRAINDICATED IN PREGANCY
Explain the antimicrobial action of ethambutol
- No effect on other organisms other than mycobacteria
- Crosses the blood-brain barrier when meninges are inflamed
- Used only for the treatment of tuberculosis and meningitis
Explain the MOA of ethambutol, when does resistance develop, when does it accumulate?
- inhibits mycobacterial cell wall synthesis
- Inhibits arobinosyl transferase (important in polymerisation of aribinoglycan)
- When used alone
- renal failure
Explain the adverse effects of ethambutol and the testing that needs to take place as well as contraindications
Optic neuritis
- loss of visual acuity
- red-green colour blind
- Peripheral vision loss
regular visual acuity tests is required
Avoided in patients with impaired vision or children too young for visual testing
Explain the MOA, Pharmacokinetics and adverse effects of streptomycin
Inhibits protein synthesis by binding to the S12 ribosomal unit
Active extracellularly
IM or IV
Ototoxicity and nephrotoxicity, vertigo and hearing loss
When will second-line agents be used?
- Resistance to first line agents
List the second line agents, their MOA and adverse effects
- Ethionamide
- Similar to ioniazid
- Inhibits synthesis of mycolic acid - Amikacin and kanamycin
Multidrug resistant TB
Amikacin= MAC (mycobacterium avium complex)
Macrolides
Limited activity against TB, used for MAC prevention
Fluoroquinolones
TB and MDR TB
What are the principles of TB treatment
Kill a large number of actively multiplying bacilli
Treat persisters (semidormant bacilli)
Prevent drug resistance with multiple therapy
