ANTIMYCOBACTERIAL DRUGS
Prof. Dr. Ece Genç
LEARNING OUTCOMES
• Identify the characteristic
pharmacodynamic and pharmacokinetic
properties of izoniazid and rifampin
• List the typical adverse effects of
antituberculosis and antileprosy drugs
ANTIMYCOBACTERIAL
DRUGS
First line of drugs:
• Isoniazid (INH)
• Rifampin
• Ethambutol
• Streptomycin
• Pyrazinamide
Alternative drugs:
Amikacin
Ciprofloxacin
Ethionamide
p-Aminosalicylate
STRUCTURE OF MYCOBACTERIA CELL WALL
>60% of the cell wall is lipid, 2branched, 3-hydroxy fatty acids
with chains made of 76-90 C
atoms. Difficult for drugs to
penetrate. Efflux pumps in the
cell membrane, another defence,
ATP binding casette permeases
comprise a full 2.5% of the
genomeof MT.
NEVER USE A SINGLE DRUG
THERAPY
• Isoniazid –rifampicin combination
administered for 9 months will cure 9598% of cases
• Addition of pyrazinamide for this
combination for the first 2 months allows
total duration to be reduced to 6 months
• Rifampin, ethambutol, pyrazinamide 6 mo
RIFAMPIN
Rifampin is a semisynthetic
derivative of rifamycin B→
streptomyces mediterranei
Active in vitro against gram positive
and gram negative cocci, some
enteric bacteria, mycobacteria
and clamydiae
Resistant mutants are present at ~
1 in 106 organisms
B-esterases and
cholinesterases
remove the
Rifabutin is equally effective as an
antimycobacterial agent
Preferred over rifampin in the treatment of
tuberculosis or other mycobacterial
infections in AIDS patients (cytochrome P450
substrates, protease inhibitors efavirenz)
MECHANISM
Blocks beta unit of DNA dependent RNA
polymerase of mycobacteria and other
microorganisms
Resistance develops rapidly, limits the wider use of
the drug. It is acquired by a one step genetic
mutation of the DNA-dependent RNA
polymerase. One of every 107 to 108 tubercle
bacilli, is resistant to the drug.
PK
After oral administration rifamycins are absorbed to
variable extents
Food ↓ rifampin Cpmax by 1/3
Rifampin should be taken on an empty stomach
Rifabutin absorption is not effected by food
Drug is progressively deacetylated
With repeated administration AUC ↓
Good penetration into many tissues, but not to CNS
(P-glycoprotein)
30% xcreted in urine 60-65% in feces. Adjustment
of dosage is not necessary in patients w impaired
Induces P450 enzymes such as CYP1A2, 2C9,
2C19, 3A4 and decreased half-life is observed
HIV protease and non-nucleoside reverse
transcriptase inhibitors, digitoxin, quinidine,
ketoconazole, propranolol, verapamil,
methadone, oral contraceptives, reduces plasma
levels of phenytoin, warfarin, Thephilline,
halothane, fluconazole, cyclosporin,
corticosteroids, barbiturates and sulfonylureas.
UNDESIRABLE EFFECTS
Generally well tolerated.
Rash 0.8%, fever 0.5%, nausea and vomiting
1.5%
Secretions (urine, sweat) turn orange-red.
Hepatitis rarely is seen (especially in alcoholics
or preexisting disease)
if given < twice weekly flu like (rash, fever,
nausea and vomiting) symptoms in 20% of
patients.
GI disturbances have occasionally required
discontinuation of drug
Strongly induces liver drug-metabolizing enzymes
ISONIAZID
Isonicotinic acid hydrazide is a primary drug
for tuberculosis.
• Is a prodrug activated by catalaseperoxidase (KatG) activity within
susceptible cells
• Inhibits mycolic acid synthesis in wall of
Mycobacterium tuberculosis.
PK
PO. Readily absorbed-reduced w food-, widely
distributed. N-acetylated, thus, slow acetylators
have greater toxicity.
Kidney excretion. 75% - 90% is excreted in the
urine within 24h mostly as a metabolite
Available as a pill elixir and for paranteral
administration
METABOLIC STEPS IN INH
Enoyl acyl carrier
↓ synthesis of
mycolic acid
protein reductase
INH CLEARANCE DUE TO NAT2
POLYMORPHISMS
Fast acetylators are found
in Inuit and Japanese
Slow acetylators most
Scandinavians, Jews, North
African whites
RESISTANCE
The most common mechanism is mutations in
catalase-peroxidase that decrease the drug’s
activity.
Cross-resistance between isoniazid and other
agents (except ethionamide) does not occur.
Approximately one in 106 tubercule bacilli will be
genetically resistant to isoniazid. Tuberculous
cavities may contain as many as 107 to 109
microorganisms.
UNDESIRABLE EFFECTS
Incidence of adverse effects estimated ~ 5.4%.
Rash 2%, fever 1.2%, jaundine 0.6%, peripheral
neuritis 0.2%.
Peripheral neuropathies* (can be prevented by
pretreating with pyridoxine – 15-50 mg per dayin malnourished patients and those predisposed
to neuropathy –elderly, pregnant, HIV infected,
diabetics, alcoholics, uremics-), hepatitis,
hepatotoxicity.
Most commonly paresthesia of feet and hands.
UNDESIRABLE EFFECTS 2
Hypersensitivity to INH may result in fever,
various skin eruptions, hepatitis, and rashes.
Hematological reactions such as
agranulocytosis, eosinophilia, thrombocytopenia,
anemia can happen.
INH may precipitate convulsions in patients w
seizure disorders (if no history, incidence is
rare).
UNDESIRABLE EFFECTS 3
Severe hepatic injury leading to death may occur.
(Acetylhydrazine causes hepatic damage........)
Rare >20 y of age.
0.3% 20-34y 1.2% 35-49y 2.3% >50y
Patients receiving isoniazid should be carefully evaluated
at monthly intervals for symptoms of hepatitis (anorexia,
malaise, fatigue and jaundice
Some prefer aspartate aminotransferase activity
measurement at monthly intervals in high risk individuals
Xs alcohol intake, history of liver disease). Elevation 5X
normal is cause for drug discontinuation.
ETHAMBUTOL
Inhibits mycolic acid
synthesis in bacterial
cell wall
Effective against
mycobacteria, no
activity against any
other genus
PK
PO. 75-80% of an orally administered dose is
absorbed from the GI tract. Wide distribution.
Reaches 50% concentration in CNS
80% of the ingested dose is excreted unchanged
in the urine (in renal failure dose should be
reduced)
The rest is metabolized by alcohol
dehydrogenase→aldehyde and aldehyde
dehydrogenase→dicarboxylic acid
UNDESIRABLE EFFECTS
Very few serious untoward reactions.
Reversible optic neuritis. Initial red/green color
blindness, then loss of central vision. Dose
related and usually reversible. Patients must
have ophthalmologic exam prior to treatment.
PYRAZINAMIDE
• It is converted to pyrazinoic acid ,the
active form (prodrug) pyrazinamidases
• Mechanism is unknown.
• Bactericidal
• Acting on intracellular organisms.
• Well absorbed orally ,metabolized in liver
excreted mainly through kidney
PK
Well absorbed from the GI tract, widely
distributed in body tissues including inmflamed
meninges.
Half life is 8-11 h. It is primarily xcreted by renal
glomerular filtration. Hydrolyzed and
hydroxylated before excretion.
Clinical uses
• Mycobacterial infections (TB) mainly in
multidrug resistance cases.
• It is important in short –course (6 months)
regimens with isoniazid and rifampicin.
• Prophylaxis of TB in combination with
ciprofloxacin.
Adverse effects
•
•
•
•
Hepatotoxic
Hyperuricemia
Nausea & vomiting
Drug fever & skin rash
The multiplication of M.
Tuberculosis is
suppressed by
ethionamide. It is a
prodrog and activated
by a mycobacterial
redux system.
• It is a secondary agent. To be used concurrently
with other drugs only when therapy w primary
agents is ineffective or contraindicated.
• Orally administered
• Anorexia, nausea, vomiting, gastric irritation,
variety of neurologic symptoms. Pyridoxine
relieves the neurologic symptoms.
DOSE REGIMENS
• Mycobacterium tuberculosis readily develops
resistance to single-drug therapy. Three or four
drugs are used in the 'initial phase' for the first 2
months to rapidly reduce the bacterial population
until bacterial sensitivities are known, when
treatment is continued with two drugs for a
further 6 months ('continuation phase') to
achieve a cure. In some cases, more prolonged
treatment may be necessary, especially for
tuberculous meningitis or for resistant
mycobacteria.
• Ethambutol is not used for treatment of
young children because of difficulty in
monitoring for eye toxicity. Streptomycin is
used in some countries in the initial phase
of treatment. In countries that cannot
afford rifampicin, thiacetazone is often
used with isoniazid and initially
streptomycin.
• Compliance can be a major problem in the
treatment of tuberculosis, and combination
tablets are often used to maximise this. In
developed countries, directly observed
treatment (DOT) has been instituted to
improve compliance. This can result in
major improvements in eradication
WHAT IS DOTS
•
•
•
•
Political commitment
Microscopy services
Drug supplies
Surveillance and monitoring systems
DOTS
Once patients with infectious TB (bacilli visible in
sputum smear) have been identified using
microscopy services health and community
workers and trained volunteers observe and
record patients swallowing the full course of the
correct anti TB medicines. Treatment lasts 6-8
months.
DOTS
• DOTS produces cure rates of up to 95 percent even in
the poorest countries.
• DOTS prevents new infections by curing infectious
patients
• DOTS PREVENTS THE DEVELOPMENT OF
MULTIDRUG RESISTANCE TB BY ENSURING THE
FULL COURSE OF TREATMENT IS FOLLOWED.
• A six month of drugs for DOTS costs US 11 dollars per
patients in some parts of the world. The world Bank has
ranked the DOTS strategy as one of the most cost
effective of all health interventions.
Streptomycin
• Life threating forms of TB ( meningitis,
dissiminated disease).
• Resistant cases (Multidrug resistance
tuberculosis at least to INH & rifampicin ) .
• Amikacin can be used as alternative to
streptomycin.
• Both active mainly against extracellular
bacilli.
Ethionamide
•
•
•
•
•
•
•
•
As isoniazid blocks synthesis of mycolic acid .
Available only in oral form.
Metabolized by the liver ,excreted by kidney.
It is poorly tolerated because of :
-intense gastric irritation
-neurologic symptoms
-hepatotoxicity
Used in TB & leprosy.
DRUGS USED IN LEPROSY
DAPSONE
•
•
•
•
Inhibits folate synthesis.
Well absorbed orally,widely distributed
N acetylated, N-oxidation via CYP2E1
Excreted into bile and reabsorbed in the
intestine.
• Excreted in urine as acetylated.
• It is well tolerated.
DAPSON’S MODE OF ACTION
Clinical uses
• Tuberculoid leprosy.
• Lepromatous leprosy in combination with
rifampin & clofazimine.
• To prevent & treat Pneumocystis
pneumonia in AIDS caused by
Pneumocystis jiroveci ( Pneumocystis
carinii).
Adverse effects
•
•
•
•
Haemolytic anaemia
Methemoglobinemia
Gastrointestinal intolerance
Fever, pruritus, rashes.
Clofazimine
• It is a phenazine dye.
• Unknown mechanism of action ,may be DNA
binding.
• Antiinflammatory effect.
• Absorption from the gut is variable.
• Given orally , once daily.
• Excreted mainly in feces.
• Stored mainly in reticuloendothelial tissues and
skin.
• Half-life 2 months.
• Delayed onset of action (6 weeks).