[05.37] Drugs for TB V2.1.pdf

More than 90%

What is the proportion of initial infections with M. tuberculosis that leads to containment of the disease?

Containment

What occurs when macrophages ingest M. tuberculosis?

Reactivation

What may occur in less than 10% of those who initially contained the disease, leading to dissemination and transmission?

Acute disease

What outcome may develop, especially for those who are immunocompromised, following infection with M. tuberculosis?

Slow growth

What characteristic of mycobacteria contributes to antibiotics active against rapidly growing cells being relatively ineffective?

Two years

How long may TB disease have to be treated if caused by resistant organisms?

Dormancy

What characteristic of mycobacteria allows them to be completely resistant to many drugs or killed only very slowly?

Lipid-rich cell wall

What feature of mycobacteria makes them impermeable to many agents?

Intracellular pathogens

How are mycobacteria classified, requiring drugs to penetrate cells like macrophages to reach them?

10^9
tubercle bacilli

Approximately how many tubercle bacilli do TB lesions often contain?

Resistant mutants are readily selected

What consequence results if any anti-TB drug, such as Isoniazid, is given as a single agent?

1 bacillus in 10^6

What is the approximate probability of finding drug-resistant mutants for Isoniazid (INH) or Rifampicin (RIF) alone?

1 bacillus in 10^12

What is the approximate probability that a bacillus is initially resistant to both INH and RIF if they are combined?

Combination of two or more drugs

What strategy should be used to prevent the emergence of resistance during TB therapy?

Eradicate persistent organisms

What is the goal of prolonged TB treatment, administered for months to years?

6 months

How long is the TB treatment shortened to by adding Pyrazinamide (PZA) for the first 2 months?

Increases coverage for resistance

What benefit does the addition of Ethambutol provide to the treatment regimen?

Varying effectiveness of drugs on different TB subpopulations

Why is treatment with multiple drugs encouraged for TB?

Inside cavities

Which TB subpopulation site is characterized by an aerated, high PO milieu and rapid growth rate?

Intracellular Macrophage

Which TB subpopulation site is characterized by an acidic pH milieu due to phagosomes and slow growth?

HRS

Which first-line drugs are active against the TB subpopulation found inside cavities?

HRZ

Which first-line drugs are active against the TB subpopulation found inside closed lesions?

HRZE

Which first-line drugs are active against the TB subpopulation found within intracellular macrophages?

Isoniazid and Rifampicin

Which two first-line drugs are effective in all TB subpopulations?

Pyrazinamide

Which first-line drug is effective only in closed lesions and inside macrophages because it prefers an acidic milieu?

Streptomycin

Which first-line drug is effective only inside cavities (active mainly against extracellular tubercle bacilli)?

Isoniazid (H, INH)

Which first-line drug is structurally similar to pyridoxine?

Isoniazid (H, INH)

Which drug is considered the most active drug for TB?

Bactericidal

What is the activity type of Isoniazid against actively/rapidly growing bacilli?

Bacteriostatic

What is the activity type of Isoniazid against bacilli in the stationary phase?

Inhibits synthesis of mycolic acids

What is the mechanism of action of Isoniazid regarding the mycobacterial cell wall?

Prodrug

How is Isoniazid (INH) classified, requiring activation by an enzyme?

KatG (mycobacterial catalase-peroxidase)

Which enzyme activates INH inside the cell?

InhA (enoyl-acyl carrier protein reductase)

What enzyme, a component of the FAS II complex, does activated INH inhibit?

FAS II (fatty acid synthase type II) complex

Which complex involved in long-chain mycolic acid synthesis is inhibited by Isoniazid?

Mutations in InhA and KatG

What are two enzyme-related bases of Isoniazid resistance?

Prevention in drug uptake

What is one mechanism of Isoniazid resistance related to the cellular entry of the drug?

Readily absorbed from GIT

What is the absorption characteristic of Isoniazid?

Impairs absorption

What effect does taking food have on the absorption of Isoniazid?

Hepatic clearance

What is the primary clearance mechanism for Isoniazid?

N-acetyl transferase

What liver enzyme determines the acetylation rate (metabolism) of INH?

Fast acetylators

How are Filipinos typically characterized in terms of INH metabolism?

5 mg/kg/d

What is the typical daily dose for Isoniazid?

Pyridoxine (Vitamin B6)

What vitamin is recommended at 25-50 mg/day for patients predisposed to neuropathy while taking INH?

Latent TB

Besides active TB, for what condition is Isoniazid indicated (5 mg/kg/d for 6 months)?

Hepatitis

What is the most severe side effect of Isoniazid?

Elderly, alcoholic drinkers, pregnant and postpartum individuals, and patients taking Rifampicin

Name two groups of individuals at high risk for INH-induced hepatitis?

Peripheral Neuropathy

What common adverse reaction occurs in 10-20% of patients given INH dosages >5 mg/kg/day?

Relative pyridoxine (Vitamin B6) deficiency

What is the underlying cause of peripheral neuropathy associated with INH use?

Immunologic reactions (e.g., fever, skin rashes, Drug-induced SLE)

Name one adverse reaction category of INH other than hepatotoxicity or neuropathy.

Reduced metabolism of phenytoin

What is the effect of INH on phenytoin?

Rifampin

What is Rifampicin also known as?

Streptomyces mediterranei

Which organism produces the antibiotic Rifamycin, from which Rifampicin is derived?

Bactericidal

What is the activity type of Rifampicin against susceptible bacteria and mycobacteria?

Resistance rapidly emerges

What is the outcome if Rifampicin is used as a single drug for active infection?

Binds to the β-subunit of bacterial DNA-dependent RNA polymerase

What is the mechanism of action of Rifampicin?

Inhibits RNA synthesis (specifically mRNA transcription)

What is the resulting action after Rifampicin binds to the RNA polymerase?

rpoB

Mutations in which gene result in Rifampicin resistance?

Readily penetrates most tissues and phagocytic cells

What penetration characteristic allows Rifampicin to kill intracellular organisms?

3.5 hours

What is the half-life of Rifampicin?

Potent cytochrome P450 inducer

What important pharmacokinetic property does Rifampicin possess that affects the metabolism of other drugs?

Adequate CSF concentrations are achieved even in the absence of inflammation

What is a notable feature of Rifampicin's distribution?

Bile

How is Rifampicin eliminated from the body?

10 mg/kg/day

What is the typical daily dose for Rifampicin?

Alternative to Isoniazid

What role does Rifampicin play in the treatment of latent TB?

Leprosy and atypical mycobacterial infections

Name one other mycobacterial infection Rifampicin is effective against.

Meningococcal colonization

Rifampicin is effective in eradicating which specific type of colonization?

Harmless orange color to urine, sweat, and tears

What visually apparent, non-harmful side effect is caused by Rifampicin?

Soft contact lenses may be permanently stained

What is an implication of Rifampicin causing orange discoloration of tears?

Lower serum levels of anticoagulants, anticonvulsants, protease inhibitors, and contraceptives

What effect does Rifampicin's P450 induction have on these concurrent medications?

Nephritis, thrombocytopenia, cholestasis, hepatitis, and flu-like syndrome

What cluster of severe adverse effects may occur with Rifampicin, especially with intermittent dosing (<2x/week)?

Nicotinamide

Pyrazinamide is a relative of which compound?

Bacteriostatic (but may be bactericidal against actively dividing organisms)

What is the primary activity type of Pyrazinamide?

Active at acidic pH (5.5)

What is the optimal environment for Pyrazinamide activity?

Pyrazinoic acid

What is the active form of Pyrazinamide?

Pyrazinamidase (PncA)

Which enzyme converts PZA to its active form?

Inhibits the actions of fatty acid synthetase I (FAT I)

What is the mechanism of action of Pyrazinoic acid?

Short-chain mycolic acids

What does FAT I synthesize, which is necessary for the cell wall?

Mutations in PncA or impaired uptake of PZA

What are two causes of resistance to Pyrazinamide?

8-11 hours

What is the half-life of Pyrazinamide?

Metabolized by the liver and metabolites are renally cleared

What are the metabolic and clearance pathways for Pyrazinamide?

25 mg/kg/day

What is the typical daily dose for Pyrazinamide?

Sterilizing agent

What clinical term is used to describe Pyrazinamide's role in the first 2 months of therapy, targeting residual intracellular organisms?

Relapse

Pyrazinamide is active against organisms that may cause what condition?

Hepatotoxicity

What is the most common serious adverse reaction of Pyrazinamide?

Hyperuricemia

What metabolic adverse effect of PZA may provoke gouty arthritis?

Arthralgia

What musculoskeletal adverse effect is caused by PZA?

Synthetic, water-soluble, heat-stable compound

What are the chemical properties of Ethambutol?

Bacteriostatic

What is the activity type of Ethambutol?

Inhibits mycobacterial arabinosyl transferases

What is the mechanism of action of Ethambutol?

Involved in the polymerization reaction of arabinoglycan

What is the function of the arabinosyl transferases inhibited by Ethambutol?

Overexpression of emb gene products or mutations within the embB structural gene

What causes resistance to Ethambutol?

4 hours

What is the half-life of Ethambutol?

Accumulates in renal failure

Under what condition must the dose of Ethambutol be halved?

When the meninges are inflamed

When does Ethambutol cross the blood-brain barrier?

4 drug combination therapy

When is Ethambutol primarily given for tuberculosis treatment?

Atypical mycobacterial infections

Besides TB, for what other type of infection is Ethambutol used?

Retrobulbar neuritis

What is the most common serious adverse reaction of Ethambutol?

Loss of visual acuity and red-green color blindness

What are the specific symptoms of retrobulbar neuritis caused by Ethambutol?

Periodic visual acuity testing

What screening should be performed when using a higher dosage of Ethambutol (25 mg/kg/day)?