MicroB Antimicrobials 4. Anti-Tuberculosis Agents Flashcards
Ethambutol inhibits the […] enzyme encoded by the […] gene
- interferes with the polymerization of arabinose into arabinogalactan, the principal polysaccharide on the mycobacterial cell wall.
- This affects the integrity of the Mycobacterium tuberculosis cell wall and thus facilitates the entry of lipophilic antibiotics, like rifampicin and levofloxacin.
Resistance to Ethambul arises due to mutations in the […]B gene
Ethambutol inhibits the arabinosyltransferase enzyme encoded by the embB gene
- interferes with the polymerization of arabinose into arabinogalactan, the principal polysaccharide on the mycobacterial cell wall.
- This affects the integrity of the Mycobacterium tuberculosis cell wall and thus facilitates the entry of lipophilic antibiotics, like rifampicin and levofloxacin.
Resistance to Ethambul arises due to mutations in the embB gene
TLDR ethambutol inhibits cell wall synthesis by inhibiting enzyme encoded by embB gene
Ethambutol is causes […] toxicity!!!
and also […]
Ethambutol is causes visual toxicity!!!
and also hyperuricemia/gout
Decrease in visual acuity, red green colour blindness, blurring, central scotoma (is an area of partial alteration in the field of vision consisting of a partially diminished or entirely degenerated visual acuity that is surrounded by a field of normal)
First line anti TB drugs are Mnemonic: “RIPEs”
- R[…]
- I[…]
- P[…]
- E[…]
- S[…]
For prophylaxis, only R and I are given.
First line anti TB drugs are Mnemonic: “RIPEs”
- Rifampicin
-* Isoniazid*
- Pyrazinamide
- Ethambutol
- Streptomycin
For prophylaxis, only **R and I **are given.
Isoniazid DDI
Isoniazid is an […] of the cytochrome P450 (CYP450) system families. This inhibitory effect of isoniazid can […] the plasma concentrations of anticonvulsants such as phenytoin, and oral anticoagulants
Isoniazid DDI
Isoniazid is an inhibitor of the cytochrome P450 (CYP450) system families. This inhibitory effect of isoniazid can increase the plasma concentrations of anticonvulsants such as phenytoin, and oral anticoagulants
Isoniazid should NOT be taken concomitantly with foods rich in tyramine and histamine
IMPT CYP Inhibitors to memorize!!!
- Isoniazid (Anti-TB)
- Erythromycin (Macrolides) (crows)
- Ciprofloxacin (Fluoroquinolones) (flowers)
- SSRIs (like fluoxetine)
- Grapefruit products (like juice)
Ritonavir
Azoles (Antifungals)
Omeprazole
ethanol (acute)
Isoniazid is a prodrug
- that is activated by the […] enzyme of M tuberculosis
- The activation of isoniazid produces oxygen derived free radicals that can inhibit the formation of […] of the bacterial cell wall, cause DNA damage and, subsequently, the death of the bacillus
Resistance to isoniazid include
- mutations to the […] enzyme, and/or
- mutations of the regulatory genes involved in […] synthesis
Isoniazid is a prodrug
- that is activated by the catalase peroxidase enzyme of M tuberculosis
- The activation of isoniazid produces oxygen derived free radicals that can inhibit the formation of mycolic acids of the bacterial cell wall, cause DNA damage and, subsequently, the death of the bacillus
Resistance to isoniazid include
- mutations to the catalase peroxidase enzyme, and/or
- mutations of the regulatory genes involved in mycolic acid synthesis
Principals of TB treatment
- Treatment of tuberculosis needs to be […] to ensure the killing of these slowly growing / semi dormant organisms which, if not fully eradicated, may cause relapse.
- Giving a single drug will select for a population that is resistant to this drug after a period. Hence monotherapy must be […] in active TB.
- Before starting tuberculosis treatment,
- assess […] for pyrazinamide
- assess […] and […] for ethambutol - Treatment for TB is initiated if sputum obtained for […] stain for […] is positive
Principals of TB treatment
- Treatment of tuberculosis needs to be prolonged to ensure the killing of these slowly growing / semi dormant organisms which, if not fully eradicated, may cause relapse.
- Giving a single drug will select for a population that is resistant to this drug after a period. Hence monotherapy must be avoided in active TB.
- Before starting tuberculosis treatment,
- assess liver enzyme for pyrazinamide
- assess visual acuity and colour vision for ethambutol - Treatment for TB is initiated if sputum obtained for Ziehl-Neelsen stain for AFB is positive
Pyrazinamide are usually
- avoided in patients with […] disease
- Used with decreased dose in patients with […] failure (pyrazinamide metabolite elimination by kidney, metabolite can accumulate)
Pyrazinamide are usually
- avoided in patients with liver disease
- Used with decreased dose in patients with kidney failure (pyrazinamide metabolite elimination by kidney, metabolite can accumulate)
Probenecid, rifampicin, isoniazid, can potentiate the toxic effects of pyrazinamide
TLDR these drugs are very nephrotoxic
Pyrazinamide is a prodrug
- converted into its active form […] by the microbial enzymes […]
- Accumulation of […] in bacterial cytoplasm decreases the intracellular […] to levels that cause the […] of critical pathways necessary for the survival of the bacteria.
Resistance to pyrazinamide results from mutations in the […] and prevents pyrazinamide from being converted into its active form.
Pyrazinamide is a prodrug
- converted into its active form pyrazinoic acid by the microbial enzymes pyrazinamidase
- Accumulation of pyrazinoic acid in bacterial cytoplasm decreases the intracellular pH to levels that cause the inactivation of critical pathways necessary for the survival of the bacteria.
Resistance to pyrazinamide results from mutations in the gene which encodes the pyrazinamidase enzyme and prevents pyrazinamide from being converted into its active form.
Pyrazinamide is the most effective drug in eliminating […] bacilli which are responsible for bacteriological relapse.
Pyrazinamide is the most effective drug in eliminating persistent bacilli which are responsible for bacteriological relapse.
This activity of pyrazinamide allows the duration of the treatment with rifampicin, isoniazid and pyrazinamide to be reduced to six months. Otherwise it is 9 months
Rifampicin and isoniazid, the two main tuberculosis drugs, are […] cleared by the kidneys or by haemodialysis.
Rifampicin and isoniazid, the two main tuberculosis drugs, are NOT cleared by the kidneys or by haemodialysis.
No dose adjustment is needed in patients with renal impairment
Rifampicin DDI
Rifampicin is known to induce certain […] enzymes . Therefore, rifampicin can increase the metabolism of numerous drugs that are partially or completely metabolized by CYP450 when these drugs are administered concomitantly with rifampicin.
Rifampicin DDI
Rifampicin is known to induce certain cytochrome P450 enzymes . Therefore, rifampicin can increase the metabolism of numerous drugs that are partially or completely metabolized by CYP450 when these drugs are administered concomitantly with rifampicin.
The above mentioned drugs include warfarin, corticosteroids, hormonal contraceptives (patients should be advised to use non hormonal methods during rifampicin therapy) and HIV protease inhibitors.
IMPT CYP inducers to memorize!!
- Rifampicin (Anti TB)
- Carbamazepine/phenytoin (Anti Epileptic)
- St John’s Worts (Over the counter)
- Alcohol (chronic drinker)
- Cigarette smoker
Rifampicin inhibits the gene transcription of mycobacteria by blocking the […] , which prevents the bacillus from synthesizing mRNA and protein, causing cell death.
Resistance to rifampicin occurs due to […], which encodes the RNA polymerase beta chain.
Rifampicin inhibits the gene transcription of mycobacteria by blocking the **DNA dependent RNA polymerase **, which prevents the bacillus from synthesizing mRNA and protein, causing cell death.
Resistance to rifampicin occurs due to mutations in the gene, which encodes the RNA polymerase beta chain.
Rifampicin undergoes […] metabolism and is rapidly eliminated in the bile (~65%).
Rifampicin undergoes hepatic metabolism and is rapidly eliminated in the bile (~65%).
Similar to pyrazinamide,Ethambutol and its metabolites can accumulate in patients with […] failure.
Similar to pyrazinamide,Ethambutol and its metabolites can accumulate in patients with kidney failure.
Dose reduction needed.
When prescribing isoniazid, pyridoxine (vit B6) supplement should be given to
- […], both mother and baby (breastfeeding) and infant should be monitored for jaundice
- prevent B6 deficiency for those at risk of […]
When prescribing isoniazid, pyridoxine (vit B6) supplement should be given to
- Pregnant women, both mother and baby (breastfeeding) and infant should be monitored for jaundice
- prevent B6 deficiency for those at risk of peripheral nephropathy
B9 is folic acid/folate btw
Following absorption from the gastrointestinal tract, pyridoxine is converted in the liver to a coenzyme, pyridoxal phosphate (active form of Vitamin B 6 ), that is involved in many metabolic processes.
Isoniazid interferes competitively with pyridoxine metabolism by inhibiting the formation of the active form of vitamin B6 , and hence often results in peripheral neuropathy.
