Pharmacology

1. Antimycobacterial Drugs
The chemotherapy of infections caused by Mycobacterium tuberculosis,
M leprae, and M avium-intracellulare is complicated by numerous factors,
including:
 (1) Limited information about the mechanisms of antimycobacterial drug
actions;
(2) The development of resistance;
(3) The intracellular location of mycobacteria;
(4) The chronic nature of mycobacterial disease, which requires
protracted drug treatment and is associated with drug toxicities;
(5) And Patient compliance.
Chemotherapy of mycobacterial infections almost always involves the use of
drug combinations to delay the emergence of resistance and to enhance
antimycobacterial efficacy.

3. Antimycobacterial Drugs
DRUGS FOR TUBERCULOSIS:
The major drugs used in tuberculosis are isoniazid (INH), rifampin,
ethambutol, pyrazinamide, and streptomycin.
Actions of these agents on M tuberculosis are bactericidal or bacteriostatic
depending on drug concentration and strain susceptibility.
Appropriate drug treatment involves antibiotic susceptibility testing of
mycobacterial isolates from that patient.
Initiation of treatment of pulmonary tuberculosis usually involves a 3- or 4-
drug combination regimen depending on the known or anticipated resistance to
isoniazid (INH).
Directly observed therapy (DOT) regimens are recommended in noncompliant
patients and in drug-resistant tuberculosis.

4. DRUGS FOR TUBERCULOSIS
Isoniazid:
Mechanisms of action:
Isoniazid (INH) is a structural congener of pyridoxine.
Isoniazid (INH) mechanism of action involves inhibition of the synthesis of
mycolic acids, essential components of mycobacterial cell walls.
Resistance can emerge rapidly if the Isoniazid (INH) is used alone.
High-level resistance is associated with deletion in the katG gene that codes
for a catalase-peroxidase involved in the bioactivation
of Isoniazid (INH).
Low-level resistance occurs via deletions in the inhA gene that encodes the
target enzyme, an acyl carrier protein reductase.
Isoniazid (INH) is bactericidal for actively growing tubercle bacilli, but is less
effective against dormant organisms.

5. DRUGS FOR TUBERCULOSIS
Isoniazid:
Pharmacokinetics:
 Isoniazid (INH) is well absorbed orally and penetrates cells to act on
intracellular mycobacteria.
The liver metabolism of Isoniazid (INH) is by acetylation and is under genetic
control.
Patients may be fast or slow inactivates of the Isoniazid (INH) .
Isoniazid (INH) half life in fast acetylators is 60–90 min; in slow acetylators it
may be 3–4 h.
The proportion of fast acetylators is higher among people of Asian origin (and
Native Americans) than those of European or African origin.
Fast acetylators may require higher dosage than slow acetylators for
equivalent therapeutic effects.

6. DRUGS FOR TUBERCULOSIS
Isoniazid:
Clinical use:
Isoniazid (INH) is the single most important drug used in tuberculosis and is a
component of most drug combination regimens.
In the treatment of latent infection (formerly known as prophylaxis) including
skin test converters and for close contacts of patients with active disease,
Isoniazid (INH) is given as the sole drug.

7. DRUGS FOR TUBERCULOSIS
Isoniazid:
Toxicity and interactions:
Neurotoxic effects are common and include peripheral neuritis, restlessness,
muscle twitching, and insomnia.
These effects can be alleviated by administration of pyridoxine (25–50 mg/d
orally).
Isoniazid (INH) is hepatotoxic and may cause abnormal liver function tests,
jaundice, and hepatitis.
Fortunately, hepatotoxicity is rare in children.
Isoniazid (INH) may inhibit the hepatic metabolism of drugs
(eg,carbamazepine, phenytoin, warfarin).
Hemolysis has occurred in patients with glucose-6-phosphate dehydrogenase
(G6PDH) deficiency.
A lupus-like syndrome has also been reported.

8. DRUGS FOR TUBERCULOSIS
Rifampin:
Mechanisms:
Rifampin, a derivative of rifamycin, is bactericidal against M tuberculosis.
Rifampin inhibits DNA-dependent RNA polymerase (encoded by the rpo gene)
in M tuberculosis and many other microorganisms.
Resistance via changes in drug sensitivity of the polymerase often emerges
rapidly if the Rifampin is used alone.

9. DRUGS FOR TUBERCULOSIS
Rifampin:
Pharmacokinetics:
When given orally, rifampin is well absorbed and is distributed to most
body tissues, including the central nervous system (CNS).
Rifampin undergoes enterohepatic cycling and is partially
metabolized in the liver.
Both free drug and metabolites, which are orange-colored, are
eliminated mainly in the feces.

10. DRUGS FOR TUBERCULOSIS
Rifampin:
Clinical uses:
In the treatment of tuberculosis, rifampin is almost always used in combination
with other drugs.
However, rifampin can be used as the sole drug in treatment of latent
tuberculosis in Isoniazid (INH)-intolerant patients or in close contacts of
patients with Isoniazid (INH)-resistant strains of the organism.
In leprosy, rifampin given monthly delays the emergence of resistance to
dapsone.
Rifampin may be used with vancomycin for infections due to resistant
staphylococci (methicillin-resistant Staphylococcus aureus [MRSA] strains) or
pneumococci (penicillin-resistant Streptococcus pneumoniae [PRSP] strains).
Other uses of rifampin include the meningococcal and staphylococcal carrier
states.

11. DRUGS FOR TUBERCULOSIS
Rifampin:
Toxicity and interactions:
Rifampin commonly causes light-chain proteinuria and may impair antibody
responses.
Occasional adverse effects include skin rashes, thrombocytopenia, nephritis,
and liver dysfunction.
If given less often than twice weekly, rifampin may cause a flu-like syndrome
and anemia.
Rifampin strongly induces liver drug-metabolizing enzymes and enhances the
elimination rate of many drugs, including anticonvulsants, contraceptive
steroids, cyclosporine, ketoconazole, methadone, terbinafine, and warfarin.

12. DRUGS FOR TUBERCULOSIS
Other rifamycins:
Rifabutin is equally effective as an antimycobacterial agent and is less likely to
cause drug interactions than rifampin.
It is usually preferred over rifampin in the treatment of tuberculosis or other
mycobacterial infections in AIDS patients, especially those treated with
cytochrome P450 substrates including protease inhibitors or efavirenz.
Rifaximin, a rifampin derivative that is not absorbed from the gastrointestinal
tract, has been used in traveler’s diarrhea.

13. DRUGS FOR TUBERCULOSIS
Ethambutol:
Mechanisms of action:
Ethambutol (ETB) inhibits arabinosyltransferases (encoded by the embCAB
operon) involved in the synthesis of arabinogalactan, a component of
mycobacterial cell walls.
Resistance occurs rapidly via mutations in the emb gene if the drug is used
alone.

14. DRUGS FOR TUBERCULOSIS
Ethambutol:
Pharmacokinetics:
The drug is well absorbed orally and distributed to most tissues, including the
CNS.
A large fraction is eliminated unchanged in the urine.
Dose reduction is necessary in renal impairment.
Ethambutol:
Clinical use:
Clinical use—The main use of ethambutol is in tuberculosis, and it is always
given in combination with other drugs.

15. DRUGS FOR TUBERCULOSIS
Ethambutol:
Toxicity:
The most common adverse effects are dose-dependent visual disturbances,
including decreased visual acuity, red-green color blindness, optic neuritis,
and possible retinal damage (from prolonged use at high doses).
Most of these effects regress when the drug is stopped.
Other adverse effects include headache, confusion, hyperuricemia and
peripheral neuritis.

16. DRUGS FOR TUBERCULOSIS
Pyrazinamide:
Mechanisms:
The mechanism of action of pyrazinamide is not known;
However, its bacteriostatic action appears to require metabolic conversion via
pyrazinamidases (encoded by the pncA gene) present in M tuberculosis.
Resistance occurs via mutations in the gene that encodes enzymes involved in
the bioactivation of pyrazinamide and by increased expression of drug efflux
systems.
This develops rapidly when the drug is used alone, but there is minimal cross-
resistance with other antimycobacterial drugs.

17. DRUGS FOR TUBERCULOSIS
Pyrazinamide:
Pharmacokinetics:
Pyrazinamide is well absorbed orally and penetrates most body tissues,
including the CNS.
Pyrazinamide is partly metabolized to pyrazinoic acid, and both parent
molecule and metabolite are excreted in the urine.
The plasma half-life of pyrazinamide is increased in hepatic or renal failure.

18. DRUGS FOR TUBERCULOSIS
Pyrazinamide:
Clinical use:
Clinical use—The combined use of pyrazinamide with other antituberculous
drugs is an important factor in the success of short-course treatment
regimens.

19. DRUGS FOR TUBERCULOSIS
Pyrazinamide:
Toxicity:
Approximately 40% of patients develop nongouty polyarthralgia.
Hyperuricemia occurs commonly but is usually asymptomatic.
Other adverse effects are myalgia, gastrointestinal irritation, maculopapular
rash, hepatic dysfunction, porphyria, and photosensitivity reactions.
Pyrazinamide should be avoided in pregnancy.

20. DRUGS FOR TUBERCULOSIS
Streptomycin:
This aminoglycoside is now used more frequently than before because of the
growing prevalence of strains of M tuberculosis resistant to other drugs.
Streptomycin is used principally in drug combinations for the treatment of
life-threatening tuberculous disease, including meningitis, miliary
dissemination, and severe organ tuberculosis.
The pharmacodynamic and pharmacokinetic properties of streptomycin are
similar to those of other aminoglycosides.

21. ALTERNATIVE DRUGS FOR TUBERCULOSIS
Several drugs with antimycobacterial activity are used in cases that are
resistant to first-line agents;
They are considered second-line drugs because they are no more effective,
and their toxicities are often more serious than those of the major drugs.
Amikacin:
Amikacin is indicated for the treatment of tuberculosis suspected to be caused
by streptomycin-resistant or multidrug-resistant mycobacterial strains.
To avoid emergence of resistance, amikacin should always be used in
combination drug regimens.

22. ALTERNATIVE DRUGS FOR TUBERCULOSIS
Ciprofloxacin and ofloxacin:
Ciprofloxacin and ofloxacin are often active against strains of M tuberculosis
resistant to first-line agents.
The fluoroquinolones should always be used in combination regimens with
two or more other active agents.

23. ALTERNATIVE DRUGS FOR TUBERCULOSIS
Ethionamide:
Ethionamide is a congener of Isoniazid (INH), but cross-resistance does not
occur.
The major disadvantage of ethionamide is severe gastrointestinal irritation
and adverse neurologic effects at doses needed to achieve effective plasma
levels.

24. ALTERNATIVE DRUGS FOR TUBERCULOSIS
P-aminosalicylic Acid (PAS):
P-aminosalicylic acid (PAS) is rarely used because primary resistance is
common.
In addition, P-aminosalicylic Acid (PAS) toxicity includes gastrointestinal
irritation, peptic ulceration, hypersensitivity reactions, and effects on kidney,
liver, and thyroid function.
Other drugs:
Other drugs of limited use because of their toxicity include capreomycin
(ototoxicity, renal dysfunction) and cycloserine (peripheral neuropathy, CNS
dysfunction).

25. Antitubercular Drug Regimens
Standard regimens:
Standard regimens—For empiric treatment of pulmonary TB (in most areas of
<4% Isoniazid (INH) resistance), an initial 3-drug regimen of Isoniazid (INH),
rifampin, and pyrazinamide is recommended.
If the organisms are fully susceptible (and the patient is HIV-negative),
pyrazinamide can be discontinued after 2 month and treatment continued for a
further 4 month with a 2-drug regimen.

26. Antitubercular Drug Regimens
Alternative regimens:
Alternative regimens in cases of fully susceptible organisms include Isoniazid
(INH) + rifampin for 9 month, or Isoniazid (INH) + ethambutol for 18 month.
Intermittent (2 or 3 × weekly) high-dose 4-drug regimens are also effective.

27. Antitubercular Drug Regimens
Resistance:
If resistance to Isoniazid (INH) is higher than 4%, the initial drug regimen
should include ethambutol or streptomycin.
Tuberculosis resistant only to Isoniazid (INH) (the most common form of
resistance) can be treated for 6 month with a regimen of rifampin +
pyrazinamide + ethambutol or streptomycin.
Multidrug-resistant organisms (resistant to both Isoniazid (INH) and rifampin)
should be treated with 3 or more drugs to which the organism is susceptible
for a period of more than 18 month, including 12 month after sputum cultures
become negative.

28. DRUGS FOR LEPROSY
Sulfones:
Dapsone (diaminodiphenylsulfone) remains the most active drug against M
leprae.
The mechanism of action of sulfones may involve inhibition of folic acid
synthesis.
Because of increasing reports of resistance, it is recommended that the drug
be used in combinations with rifampin and/or clofazimine (see below).
Dapsone can be given orally, penetrates tissues well, undergoes
enterohepatic cycling, and is eliminated in the urine, partly as acetylated
metabolites.
Common adverse effects include gastrointestinal irritation, fever, skin rashes,
and methemoglobinemia.
Hemolysis may occur, especially in patients with G6PDH deficiency.

29. DRUGS FOR LEPROSY
Sulfones
Acedapsone is a repository form of dapsone that provides inhibitory plasma
concentrations for several months.
In addition to its use in leprosy, dapsone is an alternative drug for the
treatment of Pneumocystis jiroveci pneumonia in AIDS patients.

30. DRUGS FOR LEPROSY
Other Agents:
Drug regimens usually include combinations of dapsone with rifampin (or
rifabutin, see prior discussion) with or without clofazimine.
Clofazimine, a phenazine dye that may interact with DNA, causes
gastrointestinal irritation and skin discoloration ranging from red-brown to
nearly black.

31. DRUGS FOR ATYPICAL MYCOBACTERIAL INFECTIONS
Mycobacterium avium complex (MAC) is a cause of disseminated infections in
AIDS patients.
Currently, clarithromycin or azithromycin with or without rifabutin is
recommended for primary prophylaxis in patients with CD4 counts less than
50/μL.
Treatment of Mycobacterium avium complex (MAC) infections requires a
combination of drugs, one favored regimen consisting of azithromycin or
clarithromycin with ethambutol and rifabutin.
Infections resulting from other atypical mycobacteria (eg, M marinum, M
ulcerans), though sometimes asymptomatic, may be treated with the
described antimycobacterial drugs (eg, ethambutol, Isoniazid (INH), rifampin)
or other antibiotics (eg, amikacin, cephalosporins, fluoroquinolones,
macrolides, or tetracyclines).