(Ch 41) Antimycobacterial Drugs (Tuberculosis & Leprosy) Flashcards
- Drugs for Tuberculosis*
- Name 5 Drugs:*
- Isoniazid
- Rifampin (RIFADIN)a
- Ethambutol (MYAMBUTOL) • Pyrazinamide
- Streptomycin
- Amikacin
- Drugs for Mycobacterium avium-intracellulare Infections*
- name 1:*
• Azithromycin (ZITHROMAX)b
- Drugs for Leprosy*
- Name 4:*
- Dapsone
- Rifampin (RIFADIN)
- Clofazimine (LAMPRENE) • Thalidomide (THALOMID)
- Effective treatment of TB required*
- -the drug regimen and Protocol is used ?*
- and*
- -How long?*
Multidrug Therapy
Protocol: (DOT) directly obsereved therapy (observe each drug administration for adherence of Pt’s)
and
at least 6 months to eradocate the pathogen
Define Mycobacteria
What diseases does it cause
“acid-fast bacilli”
cause a variety of diseases:
TB, leprosy, and localized or disseminated
M. avium-intracellulare infections
- The goals of TB therapy*
- Name: 3*
- to kill tubercle bacilli rapidly
- to eliminate persistent bacilli and prevent relapse
- to prevent disease transmission
- Is Isolation of patients with TB in single-person rooms important:*
- yes/no?*
- how long?*
Isolation of patients with TB in single-person rooms is essential until sputum cultures are negative
and
extended isolation may be required to prevent the spread of drug-resistant strains
Which organism causes tuberculosis?
- bacterium*
- Mycobacterium tuberculosis.*
What makes tuberculosis difficult to treat?
Name 3 major complicating factors:
- Mycobacterium tuberculosis is an intracellular organism.
- Theorganism grows very slowly. Consequently infections are often chronic, and therapy may be required for as long as 2 years.
- Resistance to drugs develops rapidly.
Why is tuberculosis treated with multiple drugs?
Multiple drugs are used to delay the emergence of resistant strains of the organism.
- What are the five first-line pharmacological treatment options fortuberculosis?*
- “RIP ESther”*
- Isoniazid (INH)
- Rifampin
- Pyrazinamide
- Ethambutol
- Streptomycin
ISONIAZID (Laniazid)
How does it work: MOA
- Isoniazid is believed to act by inhibiting the enzymes enoyl acyl carrier protein reductase (InhA) and a β-ketoacyl ACP synthase (KasA).*
- These enzymes are essential for the synthesis of mycolic acids, which are unique to the mycobacterial cell walls.*
ISONIAZID (Laniazid)
ROA:
The drug is readily absorbed orally and parenterally. Absorption is impaired, however, if isoniazid is taken with aluminum-containing antacids.
ISONIAZID (Laniazid)
How does resistance to the drug occur?
A mutation or deletion of the katG gene results in underproduction of the mycobacterial enzyme needed for isoniazid to become biologically active. A mutation in the InhA enzyme can also cause resistance.
ISONIAZID (Laniazid)
What is this drug’s distribution?
Isoniazid penetrates all body fluids, cells, and caseous material. Therefore it is able to act on intracellular mycobacteria.
- ISONIAZID*
- State the metabolism of the drug.*
metabolized in the liver by N-acetylation.
The rate of acetylation shows a genetic variance among humans; it can be as fast as 1 hr or as slow as 3 hr.
ISONIAZID
How does isoniazid affect the cytochrome P-450 system?
inhibits this system;
the drug therefore increases plasma levels of drugs such as:
phenytoin,
benzodiazepines,
warfarin.
- ISONIAZID*
- adverse effects.*
1. Peripheral neuritis—Most commonly paraesthesias of the hands and feet.
This is thought to be caused by isoniazid’s action in binding and inactivating pyridoxine (vitamin B6).
Vitamin B6 supplementation can minimize this problem.
2. Hepatotoxicity—Jaundice and hepatitis
can be severe. LFTs must be monitored.
3. Rashes and skin eruptions
- Neurological problems such as convulsions in patients prone to seizures
ISONIAZID
When is isoniazid given alone?
In most cases isoniazid is given along with other drugs.
However, for prophylactic treatment of skin test converters and for close contacts of patients who have active disease, isoniazid is given alone.
-Isoniazid-
Can you use isoniazid in pregnant patients?
No!
- This drug crosses the placenta*
- and*
- may cause peripheral neuritis in newborns.*
Peripheral Neuritis
Define:
disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord.
Damage to peripheral nerves may impair sensation, movement, gland or organ function depending on which nerves are affected; in other words, neuropathy affecting motor, sensory, or autonomic nerves result in different symptoms.
RIFAMPIN (Rifadin)
MOA?
Rifampin inhibits the β-subunit of DNA- dependent RNA polymerase.
It suppresses RNA synthesis by blocking chain initiation.
NOTE: Rifabutin and rifapentine are in the same family of drugs as rifampin and work similarly to rifampin.
- RIFAMPIN (Rifadin)*
- What is the metabolism of this drug?*
Rifampin is metabolized by and induces the cytochrome P-450 system.
Therefore other drugs such as ketoconazole and warfarin may require higher dosages to maintain therapeutic concentrations.
- Does* Rifabutin induce cytochrome P-450
- Why or why not?*
Rifabutin does not induce the cytochrome P-450 system as much as rifampin and therefore is used in tuberculosis-infected HIV patients
who are taking
protease inhibitors.
RIFAMPIN (Rifadin)
In what other setting is rifabutin used?
It is used as prophylaxis against
Mycobacterium Avium Complex (MAC).
MAC also can be treated with a combination of ethambutol
rifabutin
clarithromycin
azithromycin.
- RIFAMPIN (Rifadin)*
- State the clinical indications for rifampin*
- in addition to the treatment of*
tuberculosis.
Prophylaxis of meningitis caused by Haemophilus influenzae and Neisseria meningitidis
Leprosy—used in combination with dapsone
Legionnaires’ disease—used in combination with erythromycin
RIFAMPIN (Rifadin)
- What is the absorption and distribution*
- of the drug?*
is orally absorbed.
It easily penetrates into all tissue cells and fluids, including the CNS.
RIFAMPIN (Rifadin)
Through decreased permeability
or
a mutation in the mycobacterial DNA- dependent RNA polymerase.
Rifampin
State the adverse effects.
Urine, sweat, tears, and other secretions may become red-orange in color.
(Rifampin—Red-orange)
Rash, fever, nausea, and vomiting are common.
A flu-like syndrome with chills, fever, and myalgias may develop in patients who use rifampin once or twice weekly.
PYRAZINAMIDE
When is this drug used?
For short-course (≤ 6 months)
treatment of tuberculosis in combination with
isoniazid** and **rifampin
Pyrazinamide
What is the absorption and distribution
of this drug?
Pyrazinamide is
orally absorbed and distributed to most body tissues, including the CNS.
Pyrazinamide
State the MOA.
The target of pyrazinamide appears to be the mycobacterial fatty acid synthase I gene
involved mycolic acid synthesis.
- Pyrazinamide*
- What are pyrazinamide’s adverse effects?*
- Hepatotoxicity*
- Gout* due to the inhibition of uric acid
secretion
and
Arthralgia and myalgia (most common)
Arthralgia
Define:
literally means joint pain
Define
Myalgia
Muscle pain
ETHAMBUTOL (Myambutol)
What is the clinical use of this drug?
Ethambutol is almost always used against
M. tuberculosis,
also used against
M. avium and M. kansasii
ETHAMBUTOL (Myambutol)
How does it work?
Ethambutol inhibits the enzyme arabinosyl transferase,
which is involved in the synthesis of
arabinogalactan (an essential component of the mycobacterial cell wall)
- ETHAMBUTOL (Myambutol)*
- State the absorption and distribution of the drug.*
It is well absorbed orally
and
distributes into all cells, including the CNS.
- ETHAMBUTOL (Myambutol)*
- Is this drug bacteriostatic or bacteriocidal?*
Ethambutol
is the only first-line drug
that is bacteriostatic.
Ethambutol
What are the adverse effects?
- Optic neuritis* or other visual disturbances (decreased visual acuity, red-green color blindness)
- Gout* due to a decrease in uric acid secretion
Rash, fever
- STREPTOMYCIN*
- What is the classification of this drug?*
Streptomycin is an aminoglycoside
STREPTOMYCIN
What is the MOA?
Streptomycin binds to the 30S ribosomal subunit, causing
a misinterpretation of the genetic code.
Streptomycin
State the clinical indication for streptomycin.
Treatment of life-threatening tuberculosis in combination with other first-line drugs
Streptomycin
What are streptomycin’s adverse effects?
Ototoxicity
Nephrotoxicity—usually reversible
What is the preferred recommendation
for the initial treatment of
active TB?
A 2-month regimen of
pyrazinamide
INH
rifampin
and
4- month regimen of INH and rifampin
for a total of 6 months
Name the second-line agents used
in the treatment of
tuberculosis.
- Ethionamide
- Aminosalicylicacid (PAS)
- Cycloserine
- Fluoroquinolones (moxi or gatifloxacin)
- Macrolides (Azithromycin)
Why are second-line drugs considered
second line agents?
They are lower in efficacy and higher in toxicity* or they *are active against atypical strains of mycobacterium.
They are used only if the patient cannot tolerate the first- line drugs or if the strain is resistant to them.
What organism causes leprosy?
Mycobacterium leprae
- What are the pharmacological treatment options*
- for leprosy?*
Dapsone,
clofazimine,
rifampin.
Usually all three of them are used concomitantly.
DAPSONE
How does dapsone work?
It is related to the sulfonamides
and
inhibits folate biosynthesis by
acting as a competitive antagonist of PABA.
PABA
Define:
PABA - Para aminobenzoic Acid
is an intermediate in the synthesis of folate by bacteria, plants, and fungi.
DAPSONE
What is this drug’s route of administration?
PO (orally)
Dapsone
What is the metabolism of this drug?
It undergoes acetylation in the liver.
Dapsone
How is it used?
Dapsone is used* in *combination with
rifampin and clofazimine to treat leprosy.
It is also used in the treatment and prophylaxis of Pneumocystis carinii pneumonia
Pneumocystis carinii
define:
a yeast-like fungus of the genus Pneumocystis.
The causative organism of Pneumocystis pneumonia, it is an important human pathogen, particularly among immunocompromised hosts
S/S: may develop over several days or weeks
may include: shortness of breath and/or difficulty breathing (of gradual onset), fever, dry/non-productive cough, weight loss, night sweats, chills, and fatigue.
- DAPSONE*
- What are the adverse reactions?*
- GI irritation*
- Methemoglobinemia*
- Hemolysis* (dose-related) especially in patients with GGPD deficiency
- Drug-induced lupus erythematosus*
Methemoglobinemia
define:
- -condition of elevated methemoglobin in the blood-*
- Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis).
- Complications may include seizures and heart arrhythmias.
Methemoglobin
define
is a hemoglobin in the form of metalloprotein,
in which the iron in the heme group is in the Fe3+ (ferric) state,
not the Fe2+ (ferrous) of normal hemoglobin. Methemoglobin cannot bind oxygen,
which means it cannot carry oxygen to tissues
- G6PD deficiency*
- define:*
Glucose 6 phosphate dehydrogenase (G6PD) deficiency is a hereditary condition in which red blood cells break down (hemolysis) when the body is exposed to certain foods, drugs, infections or stress.
What causes G6PD deficiency?
It occurs when
a person is missing or has low levels of the enzyme glucose-6-phosphate dehydrogenase.
What is the G6PD enzyme
responsible for?
This enzyme helps red blood cells work properly.
Symptoms during a hemolytic episode may include dark urine, fatigue, paleness, rapid heart rate, shortness of breath, and yellowing of the skin (jaundice)
CLOFAZIMINE (Lamprene)
How does this drug work?
Clofazimine binds to DNA
and
inhibits its replication.
Clofazimine
How is this drug given?
Orally
Clofazimine
What are the adverse effects?
A distinctive reddish-brown discoloration of the skin
GI irritation (nausea, vomiting, diarrhea)
