EXPERIMENT NO.

: DATE:

AIM: To study fixed dose drug combination (FDC) of marketed preparation ‘Tablet Nor-
Metrogyl’ with respect to comments on active ingredients, mechanism of action and justification
of inclusion of each ingredient, possible indications, dose, route of drug administration, adverse
reactions, contraindications, precautions and special instruction to patients. Evaluate the
rationality of this FDC for treatment of acute dysentery.

REFERENCES:
 Principles of pharmacology, David E. Golan, Armen H. Tashjian, Armstrong, third edition
Pg. no.596, 638-639
 Essentials of medical pharmacology, K. D. Tripathi, seventh edition, Pg.no.837-839, 709-
713.

THEORY:
1. Active ingredients:

1. Metronidazole
2. Norfloxacin

2. Mechanism of action of each ingredient:

1. Metronidazole
 It is a broad-spectrum highly active against protozoa (amoebicidical). It is
selectively toxic to anaerobic and microaerophilic microorganisms.
 When it enters the cell by diffusion, nitro group present in it is reduced by certain
redox proteins to substances which are active only in anaerobic environment.
Hence it is toxic to the anaerobic bacteria.
 The nitro radical competes with the enzyme ferredoxin oxidoreductase (PFOR)
and interferes with a DNA formation.
 The energy metabolism of anaerobes that have no mitochondria is thus, disrupted.
 Anaerobes which develops metronidazole resistance and become deficient in
PFOR.
 Aerobic environment reduces cytotoxicity of metronidazole by inhibiting its
reductive activation. Hence it has least activity against aerobic bacteria.
 METRONIDAZOLE

METRONIDAZOLE

FERREDOXIN (REDUCED)

FERREDOXIN (OXIDIZED) METABOLITES

BACTERIUM

DNA

DNA FRAGMENTED

2. Norfloxacin

 Norfloxacin is a broad-spectrum antibiotic. It is active no only against gram

positive but also against gram negative bacteria.
 It functions by inhibiting DNA gyrase, which is a type of topoisomerase II, and
topoisomerase IV, enzymes necessary to separate bacterial DNA, thereby
inhibiting cell division.
 Norfloxacin does not directly bind to DNA gyrase but does bind to the substrate
DNA.

3. Justification of inclusion of each ingredient:

 Metronidazole is used as ant amoebic which is bactericidal and is used to treat

diarrhea caused by amoeba.
 Norfloxacin is used as antimicrobial which is bacteriostatic and is used to treat
bacterial infections.
  Most of the times the diarrhea is caused by one type of amoeba or bacteria and hence
norfloxacin is not required to be given in combination as such combination may only
add to the cost, adverse effects, and may encourage resistance.
 Norfloxacin is still the most cost-effective choice for bacterial diarrhea and urinary
tract infections in adults. But it shows trends of increasing resistance.
 This could be a consequence of using these molecules in FDCs. As this resistance
grows, the next generation of antimicrobials will replace the existing ones in FDCs.
Hence this FDCs is irrational and banned as there is no requirement of norfloxacin to
treat diarrhea.

4. Possible indications:

 Pneumonia
 Bronchitis
 Pyelonephritis (inflammation of kidney due to bacterial infection)
 Cystitis (inflammation of bladder due to bacterial infection )
 Prostatitis
 Gonococcal infection
 Joint infection
 Pneumonia with cystic fibrosis

5. Dose:

 For adult and children over 12 yrs Nor metrogyl 500mg /400mg per day

6. Route of drug administration:

 Oral
 Parenteral

7. Adverse reactions:

 Cartilage damage
 Sever hypersensitivity reactions: skin rash
 Seizures
  GIT disturbance
 Leukopenia, thrombocytopenia
 Ototoxocity
 Common adverse effect: headache, nausea, vomiting, dizziness

8. Contraindications:

 First trimester of pregnancy

 Contraindicated with alcohol shows disulfiram-like reaction
 Contraindicated in kidney disease
 Contraindicated in patients with liver disease
 Contraindicated in lactating women
 Do not drive after administration

9. Precautions and special instruction to patients:

 Do not take if allergic reaction are observed

 People with genetic disorder may have a risk of liver disease
 Do not use if under vaccination
 As this medication passes into breast milk, hence should be avoided with pregnant
women.

10. Evaluation the rationality of the FDC of ‘Tablet Nor-Metrogyl’ for acute dysentery:
a) Efficacy:

FDCs should be avoided when one drug is adequate for the treatment of said condition.
Metronidazole is effective in acute amoebic dysentery and hence there is no need to give norfloxacin.
Therefore, metronidazole followed by diloxanide furoate to get rid of the cysts that may remain after
the metronidazole therapy is the treatment for amoebic diarrhea.

b) Safety:

By using norfloxacin + metronidazole combination, adverse effects commonly associated with

norfloxacin (fluoroquinolone) such as mild nausea, vomiting, and abdominal discomfort would be
added to adverse effects of metronidazole. Hence norfloxacin in combination with metronidazole
 should be avoided to prevent unnecessary adverse effect and make the treatment more safe and
effective.

c) Cost-effectiveness:

Rational therapy calls for the prescription of less-costly single ingredient drugs more often than
costlier combination agents. Metronidazole is to be administered as 750 mg three times a day for 5
days while the combination of norfloxacin 400 mg + metronidazole 500 mg is given twice daily for 5
days in acute amoebic dysentery. Average minimum cost for 10 tablets of metronidazole 400 mg is
Rs. 03.10 and so the cost of 30 tablets of the same strength would be about Rs. 10.00. On the other
hand, average minimum cost for 10 tablets of combination of norfloxacin 400 mg + metronidazole
500 mg is Rs. 45.00. Thus, the average minimal cost of therapy of acute amoebic dysentery with
metronidazole and with combination of norfloxacin + metronidazole would be Rs. 10.00 and Rs.
45.00, respectively. This shows difference of Rs. 35.00 which clearly indicates that the combination
of norfloxacin + metronidazole is more expensive than metronidazole.

Conclusion:

From above discussions it indicates that the use of irrational FDCs adds unnecessary cost and adverse
effects to the therapy. In addition, injudicious use of antimicrobial agents may lead to the development of
resistant organisms too. Hence it is clear that the use of FDC Metronidazole and Norfloxacin should be
avoided as it is irrational FDC.