Dr. Roane Antimycobacterials EXAM 3 Flashcards
What is tuberculosis known for?
White plague (paleness of patients), consumption (pt lose weight)
Synonym for Hansens disease
Leprosy
Which patient population is associated with Mycobacterium Avium/intracellulare?
Immunocompromised patients
What are the first-line drugs for Tuberculosis?
-Ethambutol
-Isoniazid
-Pyranizamide
-Rifampin/Rifapentine
-Streptomycin (aminoglycoside - only injectable)
What does Rifampin, Rifabutin, Rifapentine have in common?
Similar structure
Which diseases can be treated with Rifampin?
-Tuberculosis
-Leprosy
Is Tuberculosis transmissible in latent patients?
No, but w/o treatment they may develop the disease at some point in their life
What prevents the TB bacteria from spreading within the alveola tissue?
Granuloma contains of macrophages and other immune cells
-> When the Granuloma breaks open the TB bacteria multiplies and causes the disease
Where in the body are TB bacteria found?
-In the lungs: pulmonary
-other parts of the body (via the bloodstream): Extrapulmonary
Why is Mycobacterium tuberculosis hard to treat?
-mycolic acid (fatty acid, waxy) on the cell wall: less susceptible to antibiotics
-slow growing
-Resistance may occur -> more than one drug is required
What are the important drug targets for Mycobacteria tuberculosis?
-Synthesis of Mycolic acid (fatty acid, waxy) on the outer cell wall
-Synthesis of the arabinogalactan (sugar-chain)
-Inhibition of protein synthesis
How to test for tuberculosis?
-Mantoux test (skin test)
-A positive test means that the body has produced antibodies against tuberculosis (have been exposed to the bacteria; doesn’t mean you have the disease!
How does the tuberculosis bacteria get to the brain?
Through lymphatics
-can infect any tissue in the body
What does Granuloma look like on the tissues?
-Caesation: “cheese”-like tissue
What is the recommended treatment for latent TB infections?
changed recently from long-term Monotherapy of Isoniazid to a short-course regimen
-Isoniazid + Rifapentine (3mo, 1xweekly)
-Rifampin (4mo, daily)
-Isoniazid - Rifampin (3mo, daily)
What does TDR or XDR mean?
MDR: Multi-drug-resistant TB
TDR: Totally-drug-resistant tuberculosis
XDR: broadly drug-resistant TB
How many drugs are required to treat TB?
-At least 2 bacteriocidal drugs
-usually Isoniazid and Rifampin
-compliance is an issue
MOA of Isoniazid
-Inhibits bacterial enzymes
-The exact cidal MOA is unknown, more cidal when the bacteria is rapidly dividing
-pro-drug -> that is activated by bacterial enzymes -free radical is formed -> formation of an adduct -> inhibits mycolic acid
-disrupts the synthesis of mycolic acid (cell wall)
Form of Resistance of Tuberculosis
-Failure to activate the pro-drug
-Neutralize active compound (catches free radicals and prevents its effect?)
Which patient should be treated with caution when INH is used?
-Patients with liver disease
-INH itself also damages the liver
Adverse effects of Isoniazid
-Hepatitis
->increases with age and rifampin
-> No alcohol allowed
-> Threshold for acetaminophen toxicity is lower
-Peripheral neuritis (tingling - corrected by pyridoxine V6 supplement)
-other neurological effects, rash, fever
What is a major route of Metabolism of INH?
Hepatic acetylation
-Slow acetylators are common, more common
in Mediterainean peoples
What part of the population is vulnerable to INH use?
-Hispanic, African-American
How can the adverse effect of peripheral neuritis (pins and needle tingling) be treated?
pyridoxine V6 supplement (similar structure)
Which enzyme is inhibited by Isoniazide and what is the effect?
-Monooxidase
-anti-depressive effect
Which INH-relative drug led to the discovery of Isocarboxazid?
-Iproniazid
-Isocarboxazid (MOA inhibitor treating depression)
Which disease is known to be treated with Rifampin?
-Leprosy
-also: May treat mycobacterium avium-intracellulare, seen in AIDS patients
MOA of Rifampin
Blocks prokaryotic DNA-dependent RNA
polymerase
Where is Rifampin derived from?
-Soil Streptomyces
-belongs to the family of rifamycins (rifapentine, rifabutin and rifaximin)
Mechanism of Resistance of the Bacteria against Rifampin
Mutations -> lowering of the affinity
-Not All or one, varies in affinity for the target
Pharmacokinetics and side effects of Rifampin
-Penetrates tissues well
-Active orally
-Enterohepatic circulation
-Major p450 induction
-Urine, feces, tears, and sweat are colored orange-red
What is a characteristic of rifampin’s metabolism?
It accelerates its own metabolism by inducing CYP450, as well as the metabolism of other drugs
-dose may have to be increased??
does CYP450 metabolism lead to more metabolites, hence more side effects??
-patients are often concerned about the efficacy of oral contraceptives when taking Rifampin
What are the side effects of Rifampin?
-Fever, rash, N/V, liver damage
-Caution in patients with liver problems, alcoholics, elderly
How does Pyrazinamide (PZA) work in the body?
-orally synthetic agent
-needs to be activated by the bacteria -> converted into pyrazonic acid with bacterial pyrazinamidase
-resistant bacteria lack pyrazinamidase
What can be caused by the intake of PZA, INH, and Rifampin?
-liver dysfunction in 1-5% of patients
-gout (elevation of uric acid)
How does Ethambutol work?
-orally active
-bacteriostatic
-inhibits arabinogalactans synthesis in the cell wall
-no resistance when used in Combination
What are the side effects of Ethambutol?
-Optic neuritis (eye pain)
-Blurred vision
-Loss of red/green color discrimination
Other drugs to treat Mycobacteria
-Streptomycin and other Aminoglycosides
-Capreomycin (a cyclic peptide)
-Macrolides (azithromycin)
-Fluoroquinolones (ciprofloxacin or others)
Which anti-TB drug showed promising results when tested against MDR tuberculosis strains in a study?
-Tebepenem, oral carbapenem
-alone: MIC range of 0.125 to 8 μg/ml
-with clavulanate: 2 μg/ml or less
Which drugs are recommended by a recent protocol for patients with a low bacterial count?
Rifapentine and Moxifloxacin
Which drug is the first new anti TB drug in 40 years?
Betaquiline (Sirturo)
-MOA: inhibts mycobacterial ATP synthetase
-T1/2= about 55 days
Which drug would lower the plasma level of Betaquiline due to drug interaction with CYP3A4?
Rifampin: CYP3A4-inducer
decrease Betaquiline leves by 50%
Which drug would increase the plasma level of Betaquiline due to drug interaction with CYP3A4?
Ketoconazole: CYP-inhibitor
increase Betaquiline leves by 25%
What is in the Black Box Warning of Betaquiline?
prolonged QT interval
-> Also for FQ and clofazamine
What is the new drug Pretomanid used for?
- txt of MDR-TB in combination with Linezolid and betaquiline
-Pretomanid inhibits mycolic acid synthesis
-Betaquiline inhibits bac. ATP synthetase
-Linezolid inhibits protein synthesis at the
ribosome
What is BPaL referred to?
combination of Pretomanid, betaquiline, and Linezolid
What is Leprosy?
-not highly contagious infection of M. leprae
-multi-drug therapy: 6-24 months
-Hansen’s Disease
Which drugs are used to treat Leprosy?
-Dapsone (sulfonamide-like PABA-antagonist)
-Clofazimine
-Rifampin
-in combination for 6-24 months
Side effect of Dapsone
-hemolytic anemia (red blood cell die), especially in patients with G6P-DH deficiency
-G6P-DH is involved in making ribose sugars and NADPH
Side effect of Clofazimine
-phenazine dye, produces toxic free radical that inhibits DNA template function
-dyes patient to reddish-brown
(Rifampin colors fluids red)
What is the consequence of Leprosy?
Sensory nerve damage -> patients can’t feel injuries -> infection -> Lost body parts
