Pharm 11-10-00 9am Corey Ball
Dr Lombardini Brian Carreon
Antibiotics VI - Anti Tuberculosis Drugs (cont’d)
2.0 Isoniazid (INH)
- It is a derivative of nicotinic acid, analog of B6.
- MOA
- It affects peroxidases & catalases, so there is an increase in oxygen metabolites & the cell doesn’t function well.
- INH reacts with NAD + (it is an NAD analog) and perhaps inhibits dehydrogenases and has affects on carbohydrate metabolism.
-INH is best known to inhibit mycolic acid synthesis. TB bacteria are called Mycobacteria because they have mycolic acids in their cell wall. INH has an effect on the synthesis of mycolic acids, & thus disrupts the cell wall. Also affects DNA synthesis and lipid metabolism.
- Selective toxicity: INH is only good against Mycobacteria; it is useless against gram +/– organisms,
Protozoa or viruses.
- A one-day dose of INH will last for 7-9 days, so you don’t have to give it every day. However, you give INH with several other drugs that do have to be taken every day, so doctors usually prescribe all the drugs together for compliance reasons.
-Resistance mechanisms: (must use 2-4 drugs in combination, at a minimum)
-Catalases and peroxidases may change
-Mycobacterium can cleave off the hydrazine (-NH-NH2) group with a hydrazide enzyme, which
inactivates the drug. This is the most effective means of resistance.
- Mycobacterium can increase production of mycolic acid.
- Some of mycobacterium can survive with less of the mycolic acid in their cell wall
- Pharmacokinetics:
- Absorption: INH is absorbed well orally and has good distribution into the cerebral spinal fluid (about 50%).
- Metabolism: Host can inactivate isoniazid by acetylation (adding --CO--CH3 to the hydrazine).
- People are either slow or rapid acetylators. Give a population a standard test dose of INH, wait a few hours, and sample plasma levels. One group will have significantly higher INH levels than the rest. These are slow acetylators. They have an isoniazide half-life of 2-5 hours. The slow acetylators can be given the drug less frequently.
- The fast acetylators have a half-life of 70 minutes.
- Fast/Slow acetylators: Eskimos and Asians are usually fast acetylators. Europeans, European Jews, N. African Caucasians are mostly slow acetylators. He said Americans should be about 50/50.
- Clinical significance:
-Slow acetylators – there is a good chance of pyridoxine (vit B-6) deficiency, so they need to take vit B-6 as a supplement.
-Epileptics taking phenytoin (Dilantin) along with isoniazid will have a greater chance of developing toxicity to this drug, so reduce the levels of phenytoin while on INH.
- May only have to treat once a week, except there are problems of compliance.
- Isoniazid Toxicity:
- Leads to a vitamin B6 deficiency because B-6 looks like INH chemically.
- This deficiency could lead to peripheral neuropathies reversed by vitamin B6 ingestion
- Liver toxicities are increased by the consumption of alcohol -contraindication.
- Hepatitis associated with the age of pt with use of isoniazid prophalactically
- Those over the age of 35 show an increase in incidence of hepatitis with isoniazid (1.2% chance, 2.3% fr ages 35-50)
- Under age of 21, then not really a problem with hepatitis (0.3% chance)
- Those between 21 and 34 years of age, each case should be looked at on an individual basis; liver tests would need to be monitored.
- Therapeutic Use of Isoniazid (INH)
- Treatment is aimed at the active state of tuberculosis
- Used as the main drug in the combination therapy for TB—(Never Alone!)
- Prophylactic treatment for those displaying a positive skin test
-Cheap drug, good in cases of extended use.
3.0 Ethambutol
- also a primary anti-TB agent
- Relatively simple structure, which makes it inexpensive to make
- Only active against Mycobacterium—no general anti-bacterial effect.
- Mechanism of action:
- interferes with the synthesis of RNA
- interferes with mycolic acid synthesis
- Toxicity:
- Causes colorblindness, which is usually reversible
- Causes a loss of visual acuity which is also usually reversible
- Very rarely can cause a retro bulbar neuritis, which may not be reversible.
- Do extensive vision testing before putting them on this drug to make sure these pts did not have pre-existing visual problems.
- Do monthly check-ups to monitor these patients for toxicity.
- Should not be used for anyone under five years old
-Ethambutol replaced p-aminosalicylic acid (PAS) as a main drug for the treatment of TB. The problem with PAS was that most patients would get diarrhea for up to 6 months, so people would stop using it. Then they were only on one drug (INH), and monotherapy leads to the development of resistance.
4.0 Rifampin
- A much more complicated drug that is not able to be synthesized, therefore much more expensive.
- Therapeutic uses: (The first 3 are the most important)
- Used for the elimination of the meningococcal carrier state in TB
- Systemic TB
- TB meningitis
- The following are potential uses, or uses not employed in the US:
- Has effects against gram + and gram – bacteria
- Has activity against DNA viruses
- Potential use in cancer chemotherapy
- Potential use in fungal therapy
-Useful against leprosy
- MOA:
- inhibits DNA-dependent RNA polymerase and the synthesis of new RNA
-RNA polymerase made up of four subunits. The beta subunit is responsible for resistance due to a change in its structure
- Blocks the initiation of transcription, affects are early in the process. Rifampin forms a stable complex with the polymerase and DNA and blocks further initiation.
- Selectivity of Action
- Rifampin does not bind or inhibit mammalian polymerase activity (except in mitochondria, but in high concentrations only)
- Good for gram + and gram – but need a much higher dose for the gram – (but not used in US for these purposes)
- Pharmacokinetics
-Cannot be administered simultaneously with PAS, because PAS interferes with the absorption of rifampin (not really a problem since PAS is not used anymore except in resistant strains).
- Toxicity
- Very low
- Turns body fluids orange (sweat, tears, urine); more of a nuisance than a toxicity, but can stain clothing and such permanently
- There is also very rare association with hepatitis (1.6 deaths out of 50K uses)
- Rifampin is also known as a potent inducer of liver microsomal enzymes -decreases the half-lives of numerous drugs in several different classes, so you are under medicating if
you use these drugs along with rifampin.
5.0 Pyrazinamide
- A primary drug for the treatment of TB, but used to be a secondary agent. Also used to treat returning infections
- As with the other drugs, it should never be used alone, due to the greater chance of developing resistance
- Can cause some serious liver damage
- must check liver function often while taking pyrazinamide
- in the past, all patients taking this drug were hospitalized do to these liver problems, now
it is used as an out patient drug.
- Can cause hyperuricemia and worsen gout in certain pts
6.0 Secondary Antituberculosis Drugs
-Streptomycin
- must be injected, which may be too painful for some people to do every day
-Cycloserine
- cell wall inhibitor (D/L alanine racemase inhibitor)
- CNS toxicity, especially with the use of alcohol
- also associated with many other CNS problems like seizures, headaches, vertigo, confusion,
tremor, visual disturbances, patients committing suicide, etc.
-Ethionamide
- should be used in combination if you are resistant to primary agents
- associated with toxicities such as hepatitis, depression, hypotension, anorexia
-Capreomycin
- used if resistance or treatment failure occur
- can be used w/INH or ethambutol
- like an aminoglycoside - associated with auditory and renal dysfunction
-Viomycin
- same problems as capreomycin and other aminoglycosides
- renal function problems and electrolyte imbalance
- 8th cranial nerve problems
-Kanamycin
- another aminoglycoside
- not used much because of resistance of general bacteria, but is used for tuberculosis
- ototoxicity and renal toxicity are assoc w/ its use
-P-aminosalicyclic Acid (PAS)
- rarely used anymore because of GI problems
- associated with severe G.I. problems such as diarrhea –a problem for extended period of use
- inhibits folic acid synthesis (it’s a folic acid derivative, probably interferes with coupling enzyme)
- only effects mycobacteria
- interferes w/rifampin absorption
- inactivated by acetylation
- weak acid – drugs affecting acid secretions will affect its function
7.0 DRUG INTERACTIONS: only covered these 3
- 7.1 Isoniazid—Rifampin: liver toxicity
- 7.7 Rifampin—Oral contraceptives rifampin also has gram positive & gram-negative activity, so it wipes out the normal flora of the gut
- 7.8 Rifampin – Prednisolone – reduces corticosteroid activity
ANTILEPROSY DRUGS
1.0 Dapsone -perhaps interferes with folic acid synthesis
-Toxicities:
-GI problems
- Blood dyscrasias, anemias, methemoglobinemia
- Tx usually must continue for life, or at least extended periods (debated topic)
2.0, 3.0 Amithiozone and Clofazimine
- Other drugs related to leprosy
- Clofazomine associated with skin discoloration
4.0 Rifampin
5.0 Thalidomide
- Used to treat morning sickness in pregnant women
- 1960 in Germany – malformations were noted among newborns
- Phocomelia – seal limbs in 10,000 children born
- Can also be used in the treatment of leprosy
-Must get special permission to use it
- Are seeing a reemergence of the defects associated with its use in 3rd world countries. Female pts must not be pregnant!
Clinical problems of Tuberculosis and Leprosy drugs
- Isoniazid – peripheral neuritis, Vitamin B6 deficiency, liver toxicity (note serum enzymes)
- Rifampicin – hepatitis and inhibits metabolism of certain drugs
- Ethambutol – color blindness, retro bulbar neuritis, acuity and color vision problems and some GI disturbances
- Pyrazinamide – Hepatotoxicity
- Dapsone – anemia and methemoglobinemia
- Clofazimine – discoloration of the skin
- Bacterial resistance to leprosy is developing and drug therapy for it may be life long
Mycobacterium Avium Complex
- Usually seen with AIDS, in advanced stages
- Drug Choices:
- Rifabutin – a derivative of Rifampin
- Macrolides
- Quinolones – ‘floxins
- Clofazamine
- Amikacin
*point -multiple drugs used, consider drug-drug interactions
-Side notes:
-from the Avalanche Journal – article worries about “new penicillin resistant TB strains, and how MDs aren’t taught about the disease in med school anymore” point – don’t trust AJ for medical reports.
-1.7 billion cases of TB worldwide, 3 million deaths annually