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Exam 1 Drugs DPPHuckT > Anti-TB > Flashcards

Anti-TB Flashcards

1
Q

what are the five drugs used to treat Mycobacterium Tuberculosis

A

The five primary drugs used to treat sensitive strains of Mycobacterium tuberculosis are isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin.

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2
Q

the only drug that can be used in monotherapy for treatment of TB and in this case it’s used as prophylaxis for people who are living in the vicinity of someone who has been designated to have active TB.

A

isoniazid

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3
Q

What is the mechanism of action of isoniazid?

A

Isoniazid is bactericidal to Mycobacterium tuberculosis

isoniazid inhibits mycolic acid synthesis and thus cell wall synthesis in Mycobacterium tuberculosis. This is what gives isoniazid its bactericidal activity

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4
Q

what is the structure of isoniazid and it can only be bacteriocidal when?

A

This is what gives isoniazid its bactericidal activity but it can only be bactericidal if it’s a growing culture of Mycobacterium tuberculosis.

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5
Q

the bactericidal activity of isoniazid requires 2 steps what are they?

A
  1. Activation of INH
  2. Complex of activated INH with NADH
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6
Q

what does Mycobacterium contain that is significant to the activation of isoniazid

A

Mycobacterium tuberculosis turns INH from a prodrug into an active drug. Mycobacterium tuberculosis have a catalase-peroxidase (KatG) that can activate the prodrug.

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7
Q

how does the Kat G activate the prodrug?

A

A. The catalase-peroxidase can remove two amines from the prodrug INH which makes that site have a negative charge. So the prodrug INH will be turned into isonicotinic acyl anion which is chemically reactive.

B. The catalase-peroxidase can also catalyze another slightly different chemical reaction where the two amines on the prodrug are still lost but this time you instead have at that site an unpaired electron. So in this case the catalase-peroxidase turns the prodrug into isonicotinic acyl radical which is a chemically reactive compound

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8
Q

what are the two forms of activated isoniazid

A

isonicotinic acyl anion or isonicotinic acyl radical

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9
Q

what does mycobacterium tuberculosis do to the isonicotinic acyl radical or anion?

A

In short: it complexes it with NADH and it is formed in the active site of an enoyl acyl carrier protein reductase (ACP reductase)

Mycobacterium tuberculosis complexes activated INH (either isonicotinic acyl anion or isonicotinic acyl radical) with NADH. This is a non-enzymatic reaction and it actually occurs at a site on the ACP reductase enzyme. The activated isonicotinic acyl-NADH complex inhibits an enzyme in Mycobacterium tuberculosis needed for mycolic acid synthesis. So isonicotinic acyl-NADH can bind to the active site of an acyl carrier protein (ACP) reductase present in Mycobacterium tuberculosis in order to inhibit it. ACP reductase is responsible for reducing a double bond in the growing fatty acid chain and if this function is inhibited by isonicotinic acyl-NADH, Mycobacterium tuberculosis cannot create the mycolic acids necessary for its replication

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10
Q

what are the resistant mechanisms to INH?

A

mutation is only chromosomal

  1. Mutations in KatG catalase-peroxidase resulting in lowered affinity for isoniazid
  2. Deletion of KatG
  3. Mutations in INHA which lower affinity for NADH and result in decreased ability to covalently bond INH with NADH

some M. tuberculosis strains have secondary mutations in the ACP reductase enzyme which lowers its affinity for NADH. This lowered affinity for NADH by the ACP reductase results in a decreased ability to covalently bond activated INH with NADH. So even though you have an active INH molecule, it can’t interact appropriately with the NADH and you wind up with no ability to interfere with the synthesis of mycolic acid.

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11
Q

what is the pharmacokinetics of INH

A

penetrates well in cells, it can enter pleural and ascitic fluid and caseous material; enters CSF and crosses the placenta

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12
Q

the excretion of INH is

A

7 to 95% of dose is excreted by the kidneys within 24 hrs, mostly as metabolites

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13
Q

INH can be metabolized two ways. What are those two ways called?

A

How does INH get metabolized? There are so called rapid acetylators and slow acetylators

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14
Q

how much of the parent compound is excreted by slow vs fast acetylaters

A

Rapid acetylators excrete 4% of the INH dose as the unmodified parent compound while slow acetylators excrete 13% of the INH as the parent compound

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15
Q

what is the first step in metabolism of INH

A

INH first gets acetylated by N-acetyl transferase where an acetyl group is added to the free amine to form acetyl isoniazid. This is a conjugation reaction that requires acetyl CoA as a cofactor and is not cytochrome p450 dependent. Rapid acetylators excrete 44% of the INH dose as acetyl isoniazid while slow acetylators excrete 34% of the INH dose as acetyl isoniazid

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16
Q

how much of acetyl isoniazid is excreted by the rapid vs slow acetylators? Also what are the two things that are needed to catalyze the first step

A

This is a conjugation reaction that requires acetyl CoA as a cofactor and is not cytochrome p450 dependent. Rapid acetylators excrete 44% of the INH dose as acetyl isoniazid while slow acetylators excrete 34% of the INH dose as acetyl isoniazid

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17
Q

the second step in the metabolism of INH is the

A

metabolism of acetyl isoniazid to isonicotinic acid and monoacetyl hydrazine via hydrolysis

Acetyl isoniazid is susceptible to hydrolysis like many other acetylated compounds are. So there are esterases that will break the acetyl isoniazid open. What happens is that the hydrolysis of acetyl isoniazid doesn’t occur where the acetyl group was added but instead is at the other end of the molecule. When the hydrolysis occurs, acetyl isoniazid is turned into two compounds called isonicotinic acid and monoacetyl hydrazine.

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18
Q

how much of isonicotinic acid and monoacetyl hydrazine is excreted via slow vs fast acetylators

A

Rapid acetylators excrete 48% of their INH dose as these two compounds while slow acetylators excrete 32% of their INH dose in these two forms. Monoacetyl hydrazine appears to be involved in one of the toxic effects of INH

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19
Q

a minor reaction can occur with INH. explain that

A

There is a minor reaction where the free amine on unmodified INH is not acetylated but is instead modified by other kinds of groups that are added to it forming hydrazones. These hydrazones are relatively innocuous.

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20
Q

how much is excreted via slow vs fast acetylators in the minor reaction of the metabolism of INH

A

Rapid acetylators excrete 4% of the INH dose as hydrazones while slow acetylators excrete 21% of the INH dose as hydrazones

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21
Q

Slow acetylators are what kind of trait

A

Slow acetylation is a recessive trait

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22
Q

if you actually looked at the rate of clearance in the sputum of Mycobacterium tuberculosis, the clearance does occur more rapidly in a

A

in a slow acetylator since they have more of the INH available

But this doesn’t usually affect the clinical outcome in such a way that slow acetylators on INH will get better than fast acetylators

23
Q

what are the fast lives of slow vs fast acetylators

A

In slow acetylators, INH has a half-life of around 3 hours. Slow acetylators who take INH actually have a more rapid anti-mycobacterial response

24
Q

what are the 3 features of slow acetylators?

A
  1. Exhibit greater risk for isoniazid toxicity:

Peripheral neuropathy

  1. Exhibit more drug interactions
  2. More rapid anti-mycobacterial response
25
Q

what are the three general adverse effects of INH

A

Hypersensitivity: various rashes

Peripheral Neuropathy: increased excretion of pyridoxine, axon trminal degeneration, supplement with B6 to reduce risk, slow acetylators are at more risk

CNS toxicity: dizziness, ataxia, concvulsions (individuals with seizure disorders)

26
Q

The most serious side effect associated with INH use is a risk of

A

hepatotoxicity. The risk for INH induced hepatotoxicity is related to acetylation status as well as the patient’s age.

27
Q

why is age important when talking about INH induced hepatotoxicity

A

The older the patient is, the greater the risk there is for development of INH induced hepatotoxicity. The reasoning behind this is that as you get older, your ability to repair damage gets reduced. The monoacetyl hydrazine is a reactive chemical and it will combine with amino acids on proteins. In most cases when monoacetyl hydrazine reacts with a protein, the protein will become degraded and replaced. But as you get older your ability to do that is diminished. So it’s felt that the older you are, the greater the risk there is for damage to proteins due to INH use which then eventually leads to hepatonecrosis

28
Q

exact age profile of INH induced hepatotoxicity

A
  1. If the patient is under 20 years old, INH induced hepatotoxicity is very rare.
  2. If the patient is 20-34 years old, they have a 0.3% chance of getting INH induced hepatotoxicity.
  3. If the patient is 35-49 years old, they have a 1.2% chance of getting INH induced hepatotoxicity.
  4. People greater than 49 years old have a 2.3% chance of getting INH induced hepatotoxicity
29
Q

what is the problem with slow acetylation

A

INH induced hepatotoxicity isn’t really related to your acetylation status if you’re a fast acetylator. However slow acetylators don’t make as much monoacetyl hydrazine yet there is some evidence that they are more at risk for INH induced hepatotoxicity. The reasoning for that doesn’t have so much to do with the amount of INH present but rather the duration of exposure to INH. So if you’re a slow acetylator, you’re not removing INH or its metabolites as quickly and thus there’s going to be more time available for the formation of monoacetyl hydrazine which reacts with protein

30
Q

what are some of the drug interactions with Slow acetylators

A
  • drug interaction with phenytoin where INH interferes with the metabolism of phenytoin (anti-epileptic) which results in ataxia and other significant CNS impairment
  • interferes with disulfiram metabolism so that disulfiram persists longer. So if someone was taking disulfiram and INH, when they stop taking the disulfiram it’s going to persist for a longer period of time. Therefore the risk of disulfiram interacting with alcohol is much lengthier if you’re taking INH
  • drug interaction with oral anticoagulants
31
Q

Slow acetylation can also causes

A

drug induced lupus erythmatosus

32
Q

which drugs are associated with the interaction with INH in dru-induced lupus erythmatosus

A

Procainamide and Hydralazine

33
Q

is a large substance with a molecular weight of 823, second most commonly used drug agains TB and is highly lipid soluble

A

rifampin

34
Q

what is the mechanism of action and resistance for rifampin

A
  1. inhibts DNA dependent RNA polymerase leading to suppression of chain initiation
  2. Selective toxicity is conferred by the poor affinity for the mammalian enzyme
  3. Resistance occurs when binding site on polymerase is altered so that rifampin cannot bind to the B-subunit(chromosomal mutation)
35
Q

what is the spectrum of activity for Rifampin

A

Mycobacterium tuberculosis as well as some atypical strains

prophylaxis of meningococcal and H influenzae infections

36
Q

Rifampin exhibits what type of pharmacokinetics

A

absorbed well orally, well distributed, effective concentations in the CNS,

37
Q

how can you delay the absorption of rifampin

A

p-aminosalicyclic acid

38
Q

how is rifampin metabolized and excreted

A

undergoes enterohepatic circulation; de-acetylated form is not absorbed from the intestine

primarily biliary excretion

39
Q

the de-acetylated form of rifampin is

A

not absorbed from the intestine

40
Q

acetyl group on rifampin, once it is removed, it

A

it doesn’t undergo enterohepatic circulation anymore.

41
Q

what is the half life of rifampin and which patients should you keep an eye on

A

plasma half-life is 2-5 hrs and may be prolonged in hepatic insufficiency

42
Q

what are the adverse reactions due to use of rifampin

A

GI complaints

Mild, self-limiting rash

asymptomatic elevation of liver enzymes

hepatitis with jaundice

colors all bodily excretions and secretions orange red

43
Q

if intermitted therapy of rifampin is given what may happen

A
  1. Unfortunately those high doses of rifampin caused an increased risk of allergic reactions such as drug fever and flu-like symptoms in 20% of patients.
  2. Some patients, due to the high doses of rifampin given, had eosinophilia and rarely hemolytic anemia or thrombocytopenia. Therefore intermittent therapy with rifampin is not performed anymore.
44
Q

drug interactions of rifampin include

A

Rifampin is an inducer of microsomal MFO(induce cyP450 enzymes).

Decreases the effectiveness of

oral contrceptives(methadone), oral anticoagulants(quinidine), digitoxin(ketoconazole), glucoccorticoids(propranolol), oral hypoglycemics(metoprolol)

45
Q

what are the characteristics of pyrazinamide

A

it is bactericidal, orally acitve, well distributed, and hepatotoxic

46
Q

pyrazinamide is activated by the

A

pyrazinamide is activated by the Mycobacterium tuberculosis so that it turns into pyrazinoic acid

47
Q

the 5-hydroxy pyrazinoic acid metabolite interferes with

A

uric acid excretion

48
Q

which primary TB drugs is bacteriostatic

A

ehambutol

49
Q

what is the mechanism of ethambutol

A

it inhibits arabinosyl transferase which is necessary for polymerization of arabinogalactan cell wall components

50
Q

ethambutol is concentrated in

A

red blood cells

51
Q

ethambutol is absorbed well

A

orally

52
Q

what is the form of excretion for ethambutol and what is the half life

A

excreted in urine, 50% as parent compound and half-life is 8 hrs

53
Q

what are the adverse effects of ethambutol

A

optic neuritis which is dose dependent

allergic reactions are rare: dermatitis arthralgia

hyperuricemia

Exam 1 Drugs DPPHuckT (8 decks)

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