Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

HSHD Block 3 > Antimycobacterial drugs > Flashcards

Antimycobacterial drugs Flashcards

1
Q

Why are mycobacteria so difficult to kill

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Primary TB drugs and course (time)

A

Isoniazid, Rifampin, Ethambutol, Pyrazinamide, Streptomycin, “RIPES”

3-4 drugs for 6 months

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the rifamycins

A

rifampin, rifapentine, rifabutin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Rifamycins MOA

A

They enter the acid-fast bacillus (AFB) in a concentration-dependent manner, reaching steady state within about 15 minutes.

They act by binding the beta-subunit of DNA-dependent RNA polymerase and form a stable complex that blocks chain formation in RNA synthesis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Dosing strategy for rifampin

A

Rifampin has a strong post antibiotic effect; goal is thus usually to increase peak plasma concentration rather than time above MIC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Rifampin interactions

A

Absorption can be prevented with food and other medications, so it must be taken on empty stomach.

It has very complex pharmacokinetics, including the ability to induce its own metabolizing enzymes in the p450 system, and thus Rifampin interacts with many drugs.

Poor CNS absorption

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Rifampin adverse effects

A

Orange discoloration of skin, urine, feces, saliva, tears, contact lenses

-Severe hepatic problems if preexisting liver disease, liver enzymes must be monitored on this medication

-Hypersensitivity reactions, including autoimmune reactions

-Major player in drug interactions;

Therapeutic failure of other drug as metabolism of other drugs is induced

Induction favors secondary pathways that cause increased production of toxic metabolites with some drugs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Who should get isoniazid

A

Isoniazid (INH) is a primary TB drug; this means that all patients who have susceptible M. tuberculosis should get this drug unless they have a direct contraindication or allergy.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Isoniazid chemistry

A

The prodrug isoniazid is metabolized in humans by NAT2 isoforms to its principal metabolite, N-acetyl isoniazid, which is excreted by the kidney.

100% bioavailability with good CNS penetration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Isoniazid MOA

A

Isoniazid diffuses into mycobacteria where it is “activated” by KatG (oxidase/peroxidase) to the nicotinoyl radical, which reacts spontaneously with NAD+ or NADP+ to produce adducts that inhibit important enzymes in mycolic acid and nucleic acid synthesis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Isoniazid and B6

A

INH is chemically very similar to vitamin B6, pyridoxine, and inhibits enzymes and reactions requiring B6 in mammalian cells as a result, which is a major source of toxicity. This toxicity can be usually prevented by giving pyridoxine (B6) with the drug.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Isoniazid resitance mechanism

A

Resistance due to mutations or deletions in KatG gene (most important) or efflux pumps, and there is evidence that development of one leads to development of the other form of resistance.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Isoniazid metabolism

A

It is metabolized via acetylation (NAT2 enzyme), different genes (autosomal dominant) determine how fast or slow it will be acetylyzed and removed.

This is the most important characteristic that determines efficacy of treatment (in vivo efficacy) with INH for TB that demonstrates sensitivity in lab cultures to the drug

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Isoniazid toxicities

A
  • Isoniazid hepatitis (have to monitor liver enzymes)
  • ANCA+ vasculitis, arthritis, or other hypersensitivity syndromes
  • methemoglobinemia
  • Peripheral neuritis and neurotoxicity due to dihydrofolate reductase inhibition in mammalian cells and resulting B6 (pyridoxine) deficiency. Neurotoxicity manifests as seizures, encephalopathy, and psychosis; all are preventable if the patient is given supplemental B6.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

INH toxicity relationship to metabolism

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is INH overdose syndrome

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Ethambutol MOA

A

It inhibits arabinosyl transferase III, an enzyme in the pathway for cell wall synthesis specific to mycobacteria only (due to the manufacture of glucans in cell wall.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Ethambutol dosing

A

Ethambutol is 80% bioavailable and redistributes so that rate of decline in serum concentration is much faster soon after the dose is taken than subsequently. Dosing strategies of higher, intermittent doses are thus used.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Ethambutol metabolism

A

This drug is metabolized by the alcohol dehydrogenase group of enzymes

20
Q

Ethambutol adverse effects

A

It has the unique adverse effect of loss of red/green vision, particularly at higher doses and with longer therapy, so you must test with vision cards during treatment and discontinue drug if this occurs. You must also test prior to treatment as this finding also occurs naturally in 6-8% of natal males as a genetic trait

21
Q

Pyrazinamide MOA

A

This little bitty molecule is “activated” by acidic conditions within edges of TB cavities and is also a first line TB drug.

First, the bacillus deaminates the drug PZA to the molecule POA- and transports it out of bacillus; resistance to drug is thus caused by alterations in deamination enzyme, pyrazinamidase.

Then, the molecule POA- is protonated in the acidic environment of the TB cavity edge to POAH,

Which is then is lipid-soluble and reenters bacillus and is able to kill the bacillus somehow.

22
Q

Pyrazinamide Mechanism of killing

A
  • Inhibition of mycolic acid synthesis in POA- form
  • Reduction of intracellular pH from H+ liberated in POA- form
  • Disruption of membrane transporters in POAH form
23
Q

Pyrazinamide absorption and metabolism

A

This drug has good oral absorption and 20-fold accumulation in lung epithelial lining fluid, making it one of those special cases where specific tissue concentration is much higher than measured serum concentration. Kind of uniquely, there are “slow absorbers” and “fast absorbers

24
Q

Pyrazinamide adverse effects

A

Liver injury is the most serious side effect and most prevalent with higher doses than currently used. Must monitor AST and ALT on this drug and stop the drug if they rise. This drug should be avoided altogether in liver impairment.

This drug does causes hyperuricemia; may precipitate gout attacks in folks who are susceptible.

25
Q

Cycloserine MOA

A

analogue of d-alanine that inhibits reactions in which d-alanine is incorporated into cell wall.

Great CNS penetrance

26
Q

Cycloserine contraindications and adverse effect

A

It very commonly causes neuropsych symptoms, giving it the nickname “psych-serine,” and is contraindicated in patients with a serious psychiatric history or history of seizures.

27
Q

Para-aminosalicyclic acid MOA

A

Mechanism of action is unknown, although we do know it is a P-aminobenzoic acid (PABA) analogue

28
Q

PAS adverse effects

A

10-30% of patients who take it have adverse effects that are bad enough to stop the drug, with GI effects or rashes/immune reactions predominating.

29
Q

Dapsone MOA

A

This drug is a PABA analogue that competitively inhibits dihydropterate synthetase in the prokaryotic folate pathway, blocking the same enzyme as sulfa drugs. This drug is active against many bacteria, protozoa, and fungi.

It is also anti-inflammatory due to inhibition of the respiratory burst and scavenging of free radicals and thus is used as primary therapy for some inflammatory diseases

30
Q

Dapsone adverse effects

A

This drug causes some degree of hemolysis in most patients, methemoglobinemia is also common as both pathways use PABA to scavenge/detoxify oxidative damage and molecules.

Due to the risk of hemolysis, you must test for G6PD deficiency prior to use; it will precipitate severe hemolysis in these folks

31
Q

What is clofazimine

A

This drug is a fat-soluble riminophenazine dye. It was discontinued in 2005 but listed/approved as an orphan drug (Orphan Drug Act) when we run out of other TB options.

32
Q

Clofazimine MOA

A

Its MOA unknown, but it appears to have anti-inflammatory as well as anti-mycobacterial properties.

33
Q

Clofazimine adverse effect

A

accumulation of the dye molecules; it causes reddish-black discoloration of skin and secretions and can cause crystalline deposition in GI tract, liver, lymph nodes.

34
Q

Bedaquiline MOA

A

targets subunit C of ATP synthase of mycobacteria, stopping bacillary energy metabolism and depleting reserves of cellular energy.

35
Q

Bedaquiline black box warning

A

black box warning was created that indicated possible unexplained death as well as QT prolongation. It is only licensed for use when resistance to other agents makes it necessar

36
Q

Pretomanid MOA

A

This drug is an nitroimidazopyran class. It inhibits mycolid acid and protein synthesis and also generates reactive nitrogen species (NO) that augment killing.

This drug is structurally similar to metronidazole, the “dirty bomb” that only affected bacterial cells by generating reactive species that caused oxidative damage, and is selective for TB because it must be activated by mycobacteria

37
Q

Use of pretomanid

A

It has favorable bioavailability, metabolic, and drug interaction/side effect profile, and is licensed for use in multidrugresistant-TB.

38
Q

Role of aminoglycosides in TB

A

Streptomycin is a first line TB drug

39
Q

Aminoglycosides MOA and resistance

A

Like the other aminoglycosides, it needs oxygen to get transported into the cell and acidic environments inactivate the drug.

Resistance occurs when multiple mutations causing changes to ribosomal binding site or RNA transferases or efflux pumps work synergistically together.

40
Q

Fluoroquinolone use in TB

A

Moxifloxacin’s C8 halogen and C8 methoxy groups greatly decrease the rapidity of development of resistance; currently being studied for replacement for ethambutol or INH in treatment regimens for TB.

41
Q

TB in the population

A

1/3 of the world’s population is infected with TB, 10% of these infected people will develop active TB.

Only 10% of people with the infection develop the actual clinical disease, the rest just have dormant mycobacteria hiding out that never cause a problem. However, active TB does a lot of damage, lets the disease spread, and is hard to treat. So, we’d like to find the infected people and treat their dormant infections before they actually get sick.

42
Q

How does the TB skin test work

A

This test injects purified protein derivative from TB into the DERMIS, where the dendritic cells take it up and signal the immune system. If that person has bee infected previously with TB, a type IV hypersensitivity reaction takes place, causing swelling and firmness of the dermis and (which is called induration) and redness of the epidermis, which we really don’t care about

Must wait 48 hours

43
Q

3 forms of reaction on TB skin test

A

The ability of the immune system to produce a robust response can be impaired in some populations and the test is not perfect, so there are 3 categories of the test used based on the diameter of the induration

44
Q

Steps if TB skin test is positive

A

When your TB skin test is positive, you will have to get a chest x-ray to look for active TB. If your chest x-ray shows active TB, you will get sputum culture and have full treatment for TB based on that result.

If your chest x-ray is reassuring, you will still be diagnosed with latent TB and then will have to take anti-TB drugs for at least 6 months! This is called TB prophylaxis

45
Q

TB prophylaxis course

A

It requires treatment with only 1 or 2 drugs, not 4 drugs like folks with active TB.

  • INH orally daily or twice weekly for 6 months (9 mos in kids)
  • Rifampin daily for 4 months (6 mos in kids)
46
Q

Course for active TB

A

Use sputum culture to guide therapy

  • Multidrug therapy always used; 4 drugs for 2 mos, 2 drugs for 4 mos
  • INH, pyrazinamide, rifampin, ethambutol, streptomycin are all first-line
  • Everybody on INH gets B6 continuously
  • Direct Observed Therapy
47
Q

Resistiant TB classifications

A
  • MDR TB is defined as resistant to INH AND rifampin, is about 1% of untreated TB in USA, this rate rises to 15% of isolates in previously treated patients who did not eradicate the TB
  • XDR-TB is defined as also resistant to Fluoroquinolones and second-line drugs

HSHD Block 3 (5 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions