Antituberculosis Drugs Flashcards
Why combination of drugs is better than single drugs?
State the example combination of drugs.
Single drugs will developed resistance.
Combination of drugs will reduce the resistance and prolonged the chemotherapy of tuberculosis.
Example: Isoniazid & Rifampin
What is the first line of drugs?
What is the second line of drugs?
In treating tuberculosis.
First line of drugs have high efficacy and low toxicity.
Second line of drug have low efficacy and high toxicity or both.
List the first line of drugs in tuberculosis.
- Isoniazid
- Rifampin
- Pyrazinamide
- Ethambutol
- Streptomycin (previously)
List the second line of drugs in tuberculosis.
- Macrolides : Clarithromycin & Azithromycin
- Fluoroquinolones : Ciprofloxacin
- Para-amino salicylic acid
- Cycloserine
- Amikacin/capreomycin
Isoniazid is tuberculocidal or tuberculostatic?
Tuberculocidal
MOA of isoniazid
- Isoniazid is a prodrug activated by a mycobacterial catalase-peroxidase (KatG).
- Isoniazid targets the enzyme acyl carrier protein reductase (InhA) and beta-ketoacyl-ACP synthase, which are essential for the synthesis of mycolic acid.
- inhibiting mycolic acid leads to a disruption in the bacterial cell wall
Mechanism of resistance of isoniazid
- Mutation of KatG
- Mutation of the acyl carrier protein
- Over expression of the target enzyme InhA.
Cross resistance may occur between isoniazid and ethionamide.
Isoniazid acts on what organisms?
Intracellular and extracellular organisms
Pharmacokinetic of isoniazid
- readily absorbed after oral administration
- absorption is impaired if taken with food especially hight fat meal.
- it diffuses into all body fluids, cells and caseous material
- drug concentration in the cerebrospinal fluid (CSF)
- undergoes N-acetylation and hydrolysis, resulting in inactive products.
- excretion is through glomerular filtration and secretion.
Adverse effects of isoniazid
- Peripheral neuropathy (paraesthesia of the hands and feet) due to pyridoxine deficiency. But, can be avoided by supplementation of 25 to 50mg per day of pyridoxine (vitamin B6).
- Hepatitis
- CNS: seizures & convulsions
- Hypersensitivity : rashes & fever
- Nystagmus & ataxia (due to inhibition of metobolism of carbamazepine & phenytoin)
Fast acetylator and slow acetylator will develop what disease?
Fast acetylator : Hepatotoxicity
Slow acetylator : Neuropathy (treat with vitamin B6)
Rifampin is tuberculocidal or tuberculostatic?
Tuberculocidal
MOA of Rifampin
-it blocks RNA transcription by interacting with the beta subunit of mycobacterial DNA-dependent RNA polymerase.
Mechanism of resistance of Rifampin
-Mutation in repo B causes the reduced affinity for the drug
Lippincott :
-mutations in the affinity of the bacterial DNA-dependent RNA polymerase gene for the drug
Pharmacokinetic of Rifampin
- adequate absorption after oral administration.
- distribution occurs to all body fluids and organs.
- concentrations attained in the CSF are variable.
- the drug is taken up by the liver and undergoes enterohepatic recycling.
- it induce cytochrome P450 enzymes and transporters
- elimination of Rifampin and its metabolites is primarily through the bile and into the feces, small percentage is cleared in the urine.
Adverse effects of Rifampin
- Nausea
- Vomitting
- Rash
- Hepatitis due to liver failure (rare)
- Flu-like syndrome: fever, chills and myalgia
- Hemolytic anemia
- Shock
- Renal failure
- Orange discolouration in urine
Other uses of rifampin
- leprosy
- prophylaxis of H. Influenza & meningococcal meningitis
- MRSA
- Legionella
- diptheroids
- brucella
Pyrazinamide is tuberculocidal or tuberculostatic?
Weakly tuberculocidal but more active in acidic medium
Pyrazinamide acts on which organism?
Intracellular organism
MOA of pyrazinamide
Mechanism of action of pyrazinamide is unclear.
Short answer: inhibit mycolic acid synthesis and interacts with different fatty acid synthase encoding gene.
Long answer:
-it is thought to enter mycobacteria tuberculosis by passive diffusion and enzymatic ally hydrolyzed by pyrazinamidase to pyrazinoic acid (active form of drugs)
-the metabolite inhibit Mycobacterium fatty acid synthase-I enzyme and disrupts mycolic acid synthesis which is essential for mycobacterial cell wall.
Mechanism of resistance of pyrazinamide
-Mutation of pnc A gene
Pharmacokinetics of pyrazinamide
- absorbed orally
- widely distributed
- metabolised in liver
Adverse effect of pyrazinamide
- Hepatotoxicity
- Hyperuricemia
- Arthralgia
- Flushing
- Rashes
- Fever
Drug interaction of pyrazinamide
-oral contraceptives, digoxin, warfarin, theophylline, steroids, metoprolol, ketoconazole, fluconazole
Ethambutol is tuberculocidal or tuberculostatic?
Tuberculostatic
MOA of ethambutol
It inhibits arabinosyl transferase-an enzyme important for the synthesis of mycobacterial cell wall
Resistance of ethambutol
-alterations in the drug target gene
Pharmacokinetics of ethambutol
- absorbed orally
- excreted by glomerular filtration and tubular secretion
Adverse effects of ethambutol
- Optic neuritis
- Nausea
- Rashes
- Fever
- Hyperuricemia
- Peripheral neuritis
Streptomycin is tuberculocidal or tuberculostatic?
Tuberculocidal
Streptomycin acts on which organism?
Extracellular organism only
MOA of streptomycin
Binds to 30S ribosomes and inhibit protein synthesis
Adverse effect of streptomycin
- Ototoxicity (loss of hearing)
2. Nephrotoxicity
Adverse drug reaction for Miscellaneous
- Hepatotoxicity
- Exfoliative dermatitis
- Stevenson Johnson’s syndrome
- Bone marrow depression
- Nausea
- Anorexia
- Abdominal discomfort /pain
What is Directly observed therapy (DOT)?
- the patients take their medication while being supervised and observed.
- DOT shown to decrease drug resistance and mortality rate
- improved cure rates
