Chapter 50 - Antimycobacterial Drugs (TB) Flashcards
What is the classification of Antituberculosis drugs ?what drugs are in each class?
Classified as 1st line and 2nd line Drugs.
1st line (RIPE): 2nd line drugs:
- Rifampicin. - Streptomycin
- Isoniazid - Capreomycin
- Pyrazinamide. - Kanamycin
- Ethambutol. - Ethionamide
- Cycloserine
- P-amino salicylic acid
- Amikacin - Rifabutin. - Clarithromycin
To what drug is Isioniazid structurally similar ?
Pyridoxine
What side effect of Isioniazid warrants prompt stoppage?
- Drug induced Hepatitis
What is the MOA of Isioniazid ?
It is bacteriostatic to resting bacteria, but is a killer to dividing bugs. Can penetrate macrophages
- It is activated by KatG, (bacterial catalase -Peroxidase)
- It’s activated form forms covalent bond with Acyl carrier protein(AcpM) and KasA (beta-ketoacyl carrier protein synthetase)
- This stops Mycolic acid formation
Acylation of Isioniazid is genetically determined. True or False ?
True.
A person can be a fast or slow acylator
Isioniazid inhibits many CYP 450 enzymes causing increases in drugs such as ….
Phenytoin, Carbamazepine, and Benzodiazepines
What is the dosage daily of Isioniazid in adults and Children ?
- 300mg OD
2. 5mg/kg/d
What are the side effects of Isioniazid?
Classified as immunologic and Direct toxicity .
- Immunological: Fever, rash and Drug induced SLE
- Direct toxicity : Hepatitis (drug induced),Peripheral neuropathy (Pyridoxine treatable, 25mg-50mg/d)
CNS: memory loss, Psychosis, Ataxia, Seizures
Miscellaneous: HEMATOLOGIC disturbances, Pyridoxine deficiency anemia, Tinnitus and GI discomfort.
Isioniazid is the most active TB Drug ?
True.
Rifampin/Rifampicin ,Rifabutin and Rifapentine are derivatives of ?
Semisynthetic derivatives of Rifamycin. Produced by Amycolatopsis rifamycinca
Rifampicin is active against gram positives and negatives (Neisseria and Haemophilus)
True.
MOA of Rifampicin is by binding to the β subunit of the DNA dependent RNA polymerase thereby blocking RNA synthesis. It is bacteriocidal
True.
Rifampicin cannot penetrate into macrophages .
False. It penetrates
Rifampicin is excreted in feces and urine ?
Yes.
Rifampin concentration reaches high levels in the CSF in meningeal inflammation.
TRUE
Rifampin imparts an orange colour to urine, sweat and even tears ?
Yes.
Is Rifampin active against Leprosy ?
Yes
What non Mycobacterium uses are available for Rifampin?
Treating and prophylaxis against staphylococcus
Prophylaxis again Hib.
Side effects of Rifampicin include….
Orange colouring of body fluids
Hepatitis
Rash, thrombocytopenia, AKI, cholestatic jaundice
Ethambutol is a soluble , heat-stable compound. What is the MOA of Ethambutol?
- Inhibits Mycobacterium Arabinosyl transferase (embCAB Operon encoded)
- The enzyme is responsible for the polymerisation of Arabinoglycan an essential cell wall component.
By what means is Ethambutol execreted ?
Renal System. Doses should be reduced in failure.
MAC and M. Kansasii can be treated with Ethambutol ?
TRUE.
What is the most common side effect of Ethambutol ?
- Retrobulbar neuritis, leading to reduced visual acuity and red-green color blindness (mostly dose related)
Not to be used in young children.
To what drug is Pyrazinamide related ?
Nicotinamide
Pyrazinamide is active at alkaline pH ?
False. It is inactive at neutral pH but active at 5.5
Pyrazinamide is taken up by macrophages and exerts it’s activity within the acidic Lysosomes ?
True
What is the MOA of Pyrazinamide?
1. Pyrazinamide is converted to Pyrazinoic acid (Pyrazinamidase). The acid disrupts mycobacterium cell membrane metabolism and transport functions.
How is Pyrazinamide execreted ?
In urine. Metabolism is in the Liver
Adverse reactions of Pyrazinamide ?
- Hepatotoxicity
- Nausea/Vomiting
- Drug fever, photosensitivity
- Hyperuricemia
When are 2nd line TB drugs used ?
- When there is resistance to 1st line drugs
- Failure of clinical response to conventional therapy
- Serious treatment-limiting adverse reactions
What class of drugs does Streptomycin belong to ?
.Streptomycin is an Aminoglycoside
What is the mechanism of action of Streptomycin ?
It is an irreversible inhibitor of protein synthesis.
- Porrins passively carry the aminoglycoside across the outer membrane.
- Drug is actively transported across the cell membrane into the cytoplasm. (Oxygen dependent)
- The aminoglycosides bind the 30S ribosomal protein subunit causing :
- Inhibition of initiation complex of peptide formation
- Causes misreading of mRNA
- Break up of polysomes into nonfunctional monosomes.
Streptomycin is injectable, both IM and IV ?
True
What is the major concern with Streptomycin usage ?
It is Ototoxic (vertigo and deafness May occur and be permanent. Toxicity is dose related and high in elderly people)
The first drug with a new MOA to be approved for TB use since 1971 is ?
Bedaquiline.
What is the MOA of Bedaquiline ?
Inhibits ATP synthase In Mycobacterium
What are some side effects with the use of Bedaquiline ?
Nausea/ athralgia headache
- Cardiotoxicity (QT prolongation)
- Hepatotoxicity
Rifapentine and Rifabutin are Rifabutin are related to Rifampin ?
True
Levofloxacin, and Moxifloxacin are better at treating TB than Ciprofloxacin ?
True.
How component do Flouroquinolones inhibit ?
- DNA Gyrase
Linezolid can inhibit intracellular pathogens and is useful in MDR TB. What are it’s side effects?
Bone marrow suppression
Irreversible P. Neuropathy, optic neuropathy
Amikacin is good at treating DR TB ?
True
Ethionamide is chemically related to Isoniazid and also blocks mycolic acid synthesis. Is it active against non TB mycobacterium?
Yes
