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Flashcards in topic 13 Deck (21):
1

How do mycobacteria grow? How does that affect treatment?

Mycobacteria grow slowly, and the diseases are usually chronic. The invading organisms are hard to eradicate.

The duration of therapy tends to be months and years. Therefore, resistant bacterial strains and manifestation of drug toxicities during the therapy are common problems

The therapy entails many different groups of drugs in combination regimen.

2

What is the mechanism of isoniazid? cidal or static?

It inhibits the synth of mycolic acid, an unique component of mycobacterial cell wall.

It does not inhibit other bacterial growth, and it is bactericidal during the log-phase growth of mycobacteria and bacteriostatic for the resting organisms.

3

what is the admin, absorp, distrib, metab, and elimin of isoniazid?

Given orally it is readily absorbed from GI and diffuses into all body fluids including CSF.

Metabolized by the Liver.
The major portion of a dose is excreted in the urine in 24 hrs, and the main metabolic product is inactivated acetylated isoniazid.

4

What factors determine the extent of hepatotoxicity caused by isoniazid? What is done to prevent it?

Fast vs. slow acetylators: Slow acetylators are more likely to have hepatotoxicity. Fast acetylators may need more frequent doses.

Likelihood of hepatotoxicity increases with age

Likelihood also increases when taking rifampin.

Liver is monitored monthly.

5

What precautions must be taken if isoniazid is used for prophylactic purposes

It is frequently used prophylactically, but for people over 35, they must be monitored regularly (liver function)

6

Other than hepatotoxicity, what other side effects are caused by isoniazid? How does it happen? What can be caused to prevent it?

Isoniazid can also cause peripheral neuritis and other neurological disorders, if pyridoxine (vitamin B6) is NOT given concomitantly.
- occurs in about 20 % of the patients without supplemental pyridoxine.

Isoniazid causes peripheral neuritis by inhibiting pyridoxine kinase and therefore pyridoxine phosphate formation.

Pyridoxine phosphate- co-factor for formation of several neurotransmitters:

GABA
Norepinphrine
5-hydroxytryptamine

7

What is the mechanism of action of pyrazinamide?

It inhibits synth of mycolic acid. Bactericidal.

8

What is the admin, absorp, distrib, metab of pyrazinamide?

Given-orally and is widely distributed into body tissues and fluids. Good CSF penetration, with therapeutic level attained (85-100 % of serum level attained).

Metabolized to pyrazoic acid (active metabolite).

9

What is the main adverse effect of pyrazinamide? What precautions are taken?

Due to its proclivity to hepatotoxicity (even more than isoniazid), It is recommended for a component of short term (up to 6 months) multiple drug therapy.

Liver function tests should be given before and
during therapy.

Should not be given to patients with impaired
hepatic function

10

What are other adverse effects of pyrazinamide?

Frequent:

Mild polyarthralgias occurs
in 70% of patients;

hyperuricemia due to block of renal
excretion of uric acid in all patients.

11

What is the mechanism of ethambutol? What is its admin, absorp? What is its most significant untoward effect? What precautions are taken?

Given orally and is well absorbed (80%).

Inhibits mycolic acid insertion into cell wall.

Bacteriostatic.

The most significant untoward effect is optical neuritis.Visual acuityand red-green discrimination must be tested before the beginning of and during the therapy. The therapy is not recommended for patients younger than 5 years old, because of the unreliability of the results of these tests.

Patients with impaired renal function accumulate ethambutol, and dosage adjustment may be necessary.

12

What is the mechanism of action of rifampin, rifambutin?

It inhibits initiation of RNA chain rather than the elongation (DNA Dependent RNA Polymerase), more so in prokaryotes than eukaryotes.

13

What is the admin, absorp, distrib of rifampin, rifabutin? What happens to urine, saliva, etc.?

Oral administration produces adequate plasma level, and penetrates into all body compartments including CSF.

Imparts orange-red color to urine, saliva, tears, feces and sweat, etc.

14

What is the most serious adverse effect of rifampin/rifabutin?

Rifampin can cause hepatitis in patients receiving isoniazid or who are alcoholics or who have a history of liver disease.

15

What effects does rifampin/rifabutin have in P450? Which has more effects? What is an example of that?

Rifampin is a both a substrate and potent inducer of CYP3A4. Other CYPs as well.

Notably, it may decrease the efficacies of oral contraceptives, glucocorticoids, anticoagulant of the coumarin type, methadone, HIV protease inhibitors.

Rifampin> Ribabutin:

Rifampin is contraindicated in patents taking most HIV protease inhibitors, since it decreases levels by ~80%.

Patients can be switched to rifabutin which is a less potent inducer of CYP3A4 and decreases protease inhibitors levels to lesser degree e.g. 20-40%.

16

What is the mech of action of clofazamine?

treatment of leprosy. Evidence indicates that clofazimine binds to DNA, and inhibits the template function of DNA.

17

What is the admin, absorp, excretion of clofazamine?

Given orally and is 20-70% absorbed .
Widely distributed including CNS.

Excreted in feces as unabsorbed drug and via hepatic excretion. Little is excreted in the urine

18

What is the main side effect of clofazamine? What precautions should be taken?

Patients under the therapy may develop pink to brownish-black discoloration of skin, cornea, retina and urine ( up to 75-100% with prolonged use, first noted in 1-4 weeks, resolves 6-12 months after drug is stopped). Abdominal pain also occurs.

The CDC does not recommend use of clofazimine
in pregnancy, especially in the first trimester.

19

What is the mechanism of action of dapsone? What is its absorp, distrib, admin?

Given orally completely absorbed and widely distributed in body tissue including CSF.

The mechanism of action is similar to that of other sulfonamides it inhibits dihydropteroatesynthethase

20

What are the untoward effects of dapsone?

Untoward effects are similar to those of other sulfonamides including anorexia and nausea.

Hemolysis is rare at normal doses. More common among those with G6PD deficieny. More common at higher doses.

(c) High potential to develop allergy.

(d) Sulfone syndrome (rare): fever, malaise, exfoliative dermatitis, hepatic necrosis, lymphadenopathy, and hemolytic anemia w/ methemoglobinemia (stephens johnson syndrome and toxic epidermal necrolysis).

21

What are the drug interactions of dapsone?

(a) Rifampin decreases dapsone serum levels by 7-10 fold when rifampin is administered daily.

(b) Primaquine increases increased risk of hemolysis in patients with G6-PD deficiency.