Ethambutol is included in first-line tuberculosis therapy due to its efficacy and fewer adverse effects. It has synergistic effects with other anti-tuberculosis drugs and contains two asymmetric carbon atoms, with the D-form being 16 times more active. Ethambutol inhibits the formation of mycolic acid in the cell wall, particularly through inhibiting arabinosyl transferase and preventing polymerization of D-arabinofuranose. Common adverse effects include optic neuritis and color blindness.

1. Ethambutol
• Due to its efficacy and less adverse effects it is
included in first-line therapy of Tuberculosis
• It has synergistic action with other anti-Tb drugs
• It contains 2 asymmetric carbon atoms
• It is stereo-specific and d-ethambutol (hydroxy
methyl groups are in front and H is at back) is 16
times more active than the levo form

2. • It is more active on dividing cells, whereas, low or
inactive on non-dividing cells. It inhibits the
formation of cell wall.

3. Ethambutol: Chemistry
Ethane
Butanol
Amino

4. Mechanism of action
• Mechanism of EMB remains unknown though
there was mounting evidence that it inhibits
synthesis of cell wall
• But due to complex structure of the cell wall
it was difficult to know the mechanism

5. Mechanism of action
• Peptidoglycan of the cell wall is covered by an
envelop of arabinofuranose and galactose
(AG) which is covalently attached with
peptidoglycan and intercalated network of
lipoarabinomannan (LAM). AG portion is
highly branched and has distinct segments of
galactan and distinct segments of arabinan.
Mycolic acid is attached at C5 of the arabinan,
usually penultimate unit

6. • Initially, it was thought that EMB inhibits the
synthesis of AG part of the cell wall
• Now, it is found that it inhibits arabinosyl
transferase that catalyzes the polymerization
of D-arabinofuranose leading to the formation
of AG and LAM
• As a result the accumulation of alpha D-
arabinosyl-1 monophosphoryl decaprenol that
leads to the over expression of the enzyme
results in resistance
• Hence, the inhibition of the formation of these
complexes increases permeability of the cell
wall

7. Structure activity relationship
• OH groups at CH2
• Aliphatic chain
• NH groups Amino

8. Structure activity relationship
• If OH groups are replaced by OCH3 or OC2H5, the
compound remains active, and if replaced by
aromatic system (phenyl or pyridine) the
compound became inactive
• By removing OH groups activity is lost

9. • Extension of ethane diamine results in loss of
activity
• Removal of either of the amino groups activity
is lost
• Increase in size of N-substituent activity is lost

10. Chemical Synthesis
2-amino butanol reacts with 1, 2 dichloro ethane to
produce ethambutol

11. Antibacterial spectrum
• Bacteriostatic
• Specific for most of the strains like MT and M.
kansasii
• Absorption
– Well absorbed after oral absorption
• Distribution
– Well distributed in all body fluids and tissues
including CNS

12. Metabolism
• 73% of the drug is excreted in urine as
unchanged,15% is metabolized into metabolite
A and B, both of them are inactive

13. Therapeutic uses
• Used in combination with INH, PZA and
Rifampicin
• Its action is synergistic with other drugs
because it disrupts cell wall and facilitates the
penetration of other drugs

14. • Adverse reactions
– Optic neuritis
– Red green color blindness
– Arthralgia (due to decreased urate excretion)
– Vertical nystagmus (movement of eye ball)
– Milk skin reaction

15. Para-aminosalisylic acid
• It is a synthetic 2nd line agent, used in case
of resistance, re-treatment and
intolerance to first line therapy, used in
treatment of Tuberculosis
• It is used in combination with
streptomycin and INH and in long term
treatment (6-9 months) causes toxic
effects on GIT and shows
allergic reactions

16. • GIT: nausea, vomiting, diarrhoea, abdominal
pain, un-dissolved granule coatings in stools
• Allergic reaction: difficulty in breathing,
closing of throat and swelling of lips, tongue
or face

17. • For maximum activity COOH and NH2 groups
should be at para-position to each other
• OH group may be at ortho or meta position,
but max activity when at ortho
• NH2 group if replaced with Cl
or alkyl activity is reduced
• COOH if converted into amide or
ester compound became less active

18. Mechanism of action
• It acts as an anti-metabolite interfering with
incorporation of PABA into folic acid
• It is a structural analogue of PABA, hence inhibits
the synthesis of folates in MT
• MT can distinguish between PABA and
sulfonamides but not between PABA and PASA
• When co-administered with INH, prevents the
acetylation of INH, being a substrate, results in
increase in INH concentration in plasma

19. Mechanism of action continued
• There are two mechanisms responsible for
bacteriostatic action against Mycobacterium
tuberculosis.
– Firstly, p-aminosalicylic acid inhibits folic acid
synthesis. It binds to pteridine synthetase with
greater affinity than PABA, effectively inhibiting
the synthesis of folic acid.
– Secondly, p-aminosalicylic acid may inhibit the
synthesis of the cell wall component, mycobactin,
thus reducing iron uptake by M. tuberculosis.

20. Metabolism
• It is extensively acetylated at amino group
• It is conjugated with glucuronic acid and
glycine at the carboxylic group

21. Synthesis

22. • Step 1
2-amino benzoic acid (anthranilic acid)
undergoes nitration to produce 2-amino, 4-nitro
benzoic acid
• Step 2
Diazotization
• Step 3
Diazonium salt undergoes hydrolysis to produce
p-nitro salicylic acid
• Step 4
reduction of nitro group to amino group

23. 2-amino benzoic acid
Synthesis
2-amino, 4-nitro benzoic acid
p-nitro salicylic acid

24. Ethionamide
• A 2nd line anti TB agent, analogue of
isonicotinamide but it is di-substituted
and contains S in place of O
• It contains ethyl group at position 2

25. • In vitro it is less active but in vivo more active
because of increased lipocity due to C2H5
• Mechanism of action is similar to INH
• Its active metabolite is ethionamide sulfoxide

26. Mechanism of action
• Ethionamide upon oxidation with catalase-
peroxidase is converted to an active acylating
agent, ethionamide sulfoxide, which inturn
inactivate inhA enoyal reductase. It acylates
cystine No. 243 in inhA protein

27. Mechanism of action
Ethionamide sulfoxide
Ethionamide

28. Metabolism
• Less than 1% of the drug is excreted unchanged
in urine. Rest of the drug is excreted as one of the
following metabolites, which are given as follows:

29. Cycloserine
• Analogue of amino acid serine
and it exists in cyclic form- a five
member ring containing O and N at
an adjacent positions
• Also called Isoxazolidine or oxazolidine
• Obtained naturally as d-isomer
• Contains Keto group at position 3 and NH2 at
position 4, which is in front
• d-isomer is more active

30. • It was first isolated from Streptomyces
orchidaceous, but now being synthesized in
laboratory
• It causes CNS toxicity
• Bacteria become resistant after sometime
• It acts on cell wall of bacteria and is not
selective against MT because all bacteria
contain peptidoglycan

31. • It acts on normal peptidoglycan portion of cell
wall rather than acting on outer layer of
mycolic acid
• It inhibits alanine resemase and alanine ligase
• Alanine resemase converts L-isomer of alanine
to d-isomer. Because only d-form can be
incorporated into cell wall. Alanine is present
in levo form, hence need to be converted to d-
form
• alanine ligase is necessary for attachment of
two alanine units

33. Synthesis

34. • Readily absorbed after oral administration and
is widely distributed including CNS
• It binds to neuronal N-methyl, d-aspartate
receptor and effects the synthesis and
metabolism of aminobutyric acid leading to
serious CNS effects