Multi-Systems: Antimycobacterial Drugs Flashcards
Inhibits Dihydropterorate Synthetase?
PABA –| |–> –> DHF –> THF –>Nucleotides + DNA
Dapsone
Bacteriostatic
- Dapsone is an analog of Para-aminobenzoic acid (PABA) that inhibits Dihydropteroate Synthase
- Dapsone has the SAME Mechanism of Action as
- Sulfonamides
- Human don’t synthesize Folate de novo, so…. this drug is highly specific for Microorganisms
Clinical use of Dapsone?
-
Mycobacterium leprae (Leprosy)
- As a component of combination therapy w/
- Rifampin
- Clofazimine
- As a component of combination therapy w/
-
Pneumocystis jiroveci Pneumonia (PCP)
- Prophylaxis
- Treatment
What are the SEs of Dapsone?
-
Hemolysis in pts. w/ G6PD deficiency
- or If > 200 mg/day
-
Methemoglobinemia
- Results from the presence of iron in the ferric form instead of the usual ferrous form ( > 1% - 15%)
- Chocolate brown color in Blood
- GI intolerance
- Fever
- Rash
- Erythema nodosum leprosum may develop resistance, Fast developing
Antimycobacterial that inhibits the Synthesis of
mRNA from Nucleotides + DNA?
Nucleotides + DNA –| |–> mRNA
Bactericidal or Bacteristatic?
Rifampin
Bactericidal against both Intracellular and Extracellular bacteria?
Antimycobacterial that inhibits
DNA-dependent RNA polymerase?
Rifampin
Bactericidal - readily penetrates Macrophages
Clinical use of Rifampin?
-
Mycobacterium tuberculosis
- Combo therapy, NEVER USE ALONE
-
Mycobacterium leprae
- Combo therapy
- Dapsone
- Clofazimine
- Combo therapy
- Prophylaxis for H influenza and N meningitis (Staph)
What are the 4 R’s of Rifampin?
- RNA Polymerase inhibitor
- Red / Orange Body fluids
- Rapid resistance if used alone
-
Ramps up CYP450 system
- Very important in HIV Patients
- Dramatically increases the Concentration of
* *Protease Inhibitors (PIs)**
SEs of Rifampin?
-
Hepatotoxicity
- Jaundice, Rashes, Thrombocytopenia
- Nephritis
-
Red-Orange
- Tears
- Saliva
- Urine
- Feces
Inhibits the Synthesis of Mycolic acid?
Bacteriostatic or Bactercidal?
(component of mycobacterial cell wall)
Isoniazid
- Bacteriostatic - Resting cells
- Bactericidal - Dividing cells
What is the Enzyme req’d to activate Isoniazid?
Catalase-peroxidase enzyme KatG
Isoniazid is a pro-drug and must be activated
Clinical use of Isoniazid?
- Mycobacterium tuberculosis
- ONLY DRUG that can be used ALONE
as Prophylaxis against TB - Given w/ Pyridoxine (Vitamin B6) to prevent Peripheral neuropahty
- Capable of penetrating Macrophages
- Inactivated by Acetylation
What are the SEs of Isoniazid (INH)?
-
INH - Injuries Neurons and Hepatocytes
- Peripheral and Central Neuropahty
-
Hepatitis
- Older pts. and Alcoholics
- Hemolysis in G6PD-deficient individuals
- Systemic Lupus Erythematous (SLE)-like Syndrome
-
Inhibits Phenytoin Metabolism
- Anticonvulsant - Seizure
A prodrug that inhibits Synthase I,
Synthesis of Fatty Acid Precursors of Mycolic acid?
Pyrazinamide
MUST BE activated by Pyrazinamidase
Combo therapy - Short Term - 6 months
Clinical use of Pyrazinamide?
Mycobacterium Tuberculosis
SEs of Pyrazinamide?
- Hepatitis
-
Hepatotoxicity
- Not for Liver disease or Gout pts.
- Asymptomatic Hyperuricemia
- Arthralgias
Inhibits Arabinosyl Transferase?
(enzyme required for Synthesis of Arabinogalactan, a component of Cell wall)
Ethambutol
Mycobacteriostatic
Clinical use of Ethambutol?
- Combo therapy to treat
- M tuberculosis
- M avium-intracellulare
(Bacteriostatic)
SEs of Ethambutol?
- Hepatotoxicity
- Optic Neuritis
- Red-Green Color Blindness
- Decreased visual acuity
- AVOID giving to Children
- E(ye)thambutol
1st Line Treatment Rx for Anti-Mycobacteria?
and
What is the mechamism for each?
“RIPE”
-
Rifampin
- inhibits Bacterial DNA dependent RNA polymerase
no mRNA
- inhibits Bacterial DNA dependent RNA polymerase
-
Isoniazid - activated by KatG enzyme (cat. peroxidase)
- inhibits Syn. of Mycolid acids (cell wall
-
Pyrazinamide
- inhibits Fatty Acid Synthase I –>
-
Ethambutol
- inhibits Arabinosyl transferase
–> No syn. of Arabinan (Arabinogalactan)
- inhibits Arabinosyl transferase
2nd Line Treatment Rx for Anti-Mycobacterial?
(usually added for multi-drig resistant Tb)
“FACES”
- Fluoroquinolones
- Aminosalicyclic Acid (PAS)
- Cycloserine
- Ethionamide
- Streptomycin
Fluoroquinolones?
- Inhibits DNA Gyrase (Topoisomerase II) and Topoisomerase IV
- SE:
-
Stevens-Johnson Syndrome
- Epidermis seperates from Dermis
- Nausea, Vomiting, Headache, Seizure, Tendonitis, Photosensitivity
-
Stevens-Johnson Syndrome
Aminosalicyclic Acid (PAS)?
- Similar to Sulfonamides
- Inhibition of PABA conversion by Dihydropteroate synthase
- Bacteriostatic
- Excreted in Urine - High Concentrations
- Crystalluria prevented by keeping Urine Alkaline
- GI symproms
- Drug Fever
- Joint pain
- Rash
- Granulocytopenia
Cycloserine?
- Similar to Vancomycin - Irreversible inhibitor of Alanine Racemase and D-Ala-D-Ala Synthetase
-
Partial agonsit at NMDA receptors
- Significant CNS side-effects (25%)
- Excreted in the Urine
Ethionamide?
- Inhibits the Synthesis of Mycolic acids
- Same as Isoniazid
-
Poorly tolerated
- Gastric Irritation
- Metallic taste
- Neurologic Symptoms
- Rapid resistance Development
- No cross reactivity w/ Isoniazid
Streptomycin?
- First approved Clinically effectiv Rx for Mycobacteria
- Does NOT enter the cells readily
- -> Bacteriostatic
- Binds 30S subunit –> Prevents Reading of mRNA
- ONLY FOR SEVERE CASES
- Can cause Otototoxicity and Nephrotoxicity
- It is an Aminoglycoside
Rx for the Mycobacterium Leprae (Leprosy)
(Hanson’s Disease)
- Multi-drug Theray Req’d
- (2) Major Categories
- Paucibacillary (PB) < 5 Lesions
- -> Rx: Dapsone and Rifampin
- **Multibacillary (MB) > 6 Lesions
- ->Rx:DapsoneandRifampinandClofazimine**
Clofazimine?
- Acts Very Slowly
- Up to 50 days after the Therapy is started
- Mechanism unknown
- Oral Availability is Variable
- Can accumulate in Tissues
- Slow Secretion into the Bile
- GI intolerance and Red Discoloration of the Skin
