Fixed Dose Combinations

1. Imipenem + cilastatin

Imipenem : It is a beta lactams antibiotic. It binds to bacterial penicillin-binding proteins and

interferes with bacterial cell wall integrity and synthesis. It is a bactericidal agent with wider
antibacterial spectrum whose range of activity includes gram positive and gram negative
aerobes and anaerobes (enterobacteriaceae, pseudomonas, Listeria, bacteroides fragilis,
clostridium difficile). It is resistant to most beta lactamases, inhibits penicillinase producing
staph aureusand some MRSA.

Limiting feature of imipenem is – it is hydrolysed by the enzyme dehydropeptidase I located

in the brush border of renal tubular cells.

Cilastatin: It is a reversible inhibitor of dehydropeptidase I and thereby protects imipenem

from degradation. It has similar pharmacokinetics as imipenem. It has half life of 1 hour.

Dose: 0.5g IV 6hrly `

Maximum dose: 4g/day

Uses

Treatment of severe and complicated skin and skin structure infections, bone and joint
infections, lower respiratory infections, UTI, intraabdominal and urogenital infections

2. Diphenoxylate +atropine
It is an antidiarrhoeal drug.

Diphenoxylate :
It is an opioid agonist with antimotility and antisecretory activity. They reduce propulsive
movement and diminish intestinal secretion by enhancing absorption. This action is
mediated through µ and delta receptors located on enteric neuronal network. It also has
action on intestinal smooth muscle and secretory or absorptive epithelium. It is absorbed
systemically and crosses blood brain barrier producing CNS effects.

Atropine:
It is an anticholinergic, relaxes visceral smooth muscles by causing M3 blockade. Tone
and amplitude of contractions of stomach and intestine are reduced. Passage of chime is
slowed. Constipation may occur. It is also an antispasmodic.
 In this combination atropine is added in subpharmacological doses to discourage abuse
liability. Overdose may produce disturbing side effects of atropine like dry mouth,
weakness, respiratory depression.

Dose: Diphenoxylare 2.5 mg + atropine 0.025mg.

It is given as 5-10 mg tablets followed by 2.5-5mg 6hrly

Uses
Travellers’ diarrhea, nonspecific diarrhea, avoided in patients with acute bacterial
diarrhea associated with high fever or blood in stools. Not to be used in children below 2
years (risk of paralytic ileus). Not to be used in patients of colitis (risk of megacolon).

3. Lignocaine + adrenaline

Lignocaine:
It is a widely used anaesthetic used for surface application, infiltration, nerve block,
epidural, spinal, intravenous and regional anaesthesia. It is also used as an antiarrhythmic.
It blocks nerve conduction by decreasing the entry of Na ions during action potential.

Adrenaline:
Topically 0.5-1% adrenaline can lower intraocular tension. It causes vasoconstriction and
vasodilatation depending on drug dose and vascular bed. Vasoconstriction predominates
in cutaneous mucous membrane.

Lignocaine + adrenaline combination is used in the dose of 1:50000 to 1:200000

Advantages :
Prolongs duration of action of local anaesthetic and enhances intensity of nerve block. It
reduces the systemic toxicity of lignocaine by decreasing its absorption.

4. Cotrimoxazole
It is a fixed dose combination of sulphamethoxazole and trimethoprim. .

Trimethoprim:
It selectively inhibits bacterial dihydrofolate reductase. It is 50000 times more active
against bacterial dihydrofolate reductase than against mammalian enzymes. Hence human
 folate metabolism is not interfered at antibacterial concentration. It is bacteriostatic and
enters many tissues, attains large volume of distribution. It crosses blood bran barrier and
placenta. It is metabolized in liver and excreted in urine

Sulphamethoxazole:
Selected for combining with trimethoprim because both have nearly same half life. It
inhibits folate synthase.

This is effective because:

a) Individually both are bacteriostatic but combination is bactericidal against many
organisms.
b) Maximum synergism is seen when organism is sensitive to both components.
c) Even when the organism is moderately resistant to one component, the action of the
other may be enhanced,
d) Optimal synergism is achieved at a concentration of 20:1 .
e) The minimum inhibitory concentration of each component is reduced by 3-6 times
and plasma conc. of sulphamethoxazole to trimethoprim should be 5:1.
f) Antibacterial spectrum of both drugs overlap considerably. Resistance to the
combination develops slower compared to individual drugs.

Adverse effects:
Nausea, vomiting, stomatitis, headache, rashes, neonatal hemolysis, methemoglobinemia,
rarely megaloblastic anaemia

Uses
UTI, respiratory tract infections, typhoid, bacterial diarrhoeas, pnemocystic jiroveci,
chancroid.

5. Levodopa + carbidopa (Co-careldopa)

It is used in the treatment of Parkinson’s Disease. Levodopa is inactive by itself but is the
immediate precursor of dopamine. More than 95% of the oral dose is decarboxylated in
the peripheral tissues, mainly in the gut and liver. Dopamine thus formed acts on heart,
blood vessels, peripheral organs and on CTZ. About 1-2% of administered L-dopa
crosses BBB and is taken by surviving dopaminergic neuron, converted to dopamine
which is stored and released as the transmitter.
Carbidopa is a peripheral dopa decarboxylase inhibitor, does not cross BBB (does not
inhibit conversion of L-dopa to DA in the brain). Administered along with L-dopa it
increases its t½ in the periphery and makes more of it available to cross BBB to reach its
site of action.
 Benefits of combination:
a) Plasma t½ of L-dopa is prolonged and dose is reduced to approximately 1/4th.
b) Systemic concentration of dopamine is reduced. Nausea, vomiting are not prominent.
c) Therapeutic dose of L-dopa can be attained quickly.
d) Cardiac complications are minimized
e) Pyridoxine reversal of L-dopa effect does not occur.
f) On-off effect is minimized since cerebral levels are more sustained.

Problems not resolved or accentuated by the combination: Involuntary movements,

behavioral abnormality, postural hypotension

Currently L-dopa is always used with the decarboxylase inhibitor except in patients who
develop marked involuntary movements with the combination.

6. Dried aluminium hydroxide gel +Magnesium trisilicate

This FDC is used as a nonsystemic antacid for peptic ulcer. These are basic substances
which neutralize gastric acid and cause rise in gastric pH. Pepsin activity is indirectly
reduced if pH rises above 4 because pepsin is secreted as a complex with an inhibitory
terminal moiety that dissociates below pH 5. Optimum pepsin activity is seen between
pH 2-4.

Aluminium hydroxide gel:

It is a bland slowly reacting antacid. Aluminium relaxes the smooth muscle delaying
gastric emptying. It frequently causes constipation due to action on smooth muscle and
astringent action. Its other side effects are hypophosphatemia as aluminum hydroxide
binds to phosphate ions in intestine and also causes osteomalacia. Hence therapeutically
used in hyperphosphatemia and phosphate stones.

Magnesium trisilicate :
It is a laxative, acts by generating osmotically active magnesium chloride in stomach
through magnesium induced cholecystokinin release.

Uses:
 a) These antacids are now employed for intercurrent pain relief and for acidity in peptic
ulcer.
b) In GERD

7. Amoxycillin + clavulanic acid

Amoxycillin:
It is a beta lactamase sensitive aminopenicillin belonging to the group of extended
spectrum penicillins. It acts by inhibiting bacterial cell wall synthesis. It is acid stable,
hence can be given orally. It is similar to ampicillin in all respects, except that its oral
absorption is better and incidence of diarrhea is less. It penetrates through porin channels
of gram negative bacteria. Primarily excreted unchanged by tubular excretion.

Clavulanic acid:
It is a beta lactamase inhibitor, structurally similar to beta lactams antibiotic, but no
significant antimicrobial action. Binds irreversibly to catalytic site of beta lactamase
enzyme to prevent hydrolysis of amoxicillin and gets inactivated after binding to the
enzyme (suicide inhibitor). Inhibits only plasmid-mediated beta lactamase responsible for
drug resistance. It is eliminated by glomerular filtration.

The combination extends the spectrum of antibacterial spectrum of amoxicillin against

beta lactamase producing bacteria like streptococcus pneumonia, hemophilus infkuenza,
Klebsiella pneumoniae, Neisseria gonorrhoeae, E.coli, Proteus etc.

Uses:
Gonorrhoea
Skin and soft tissue infections
Otitis media, respiratory tract infections
Intraabdominal abscess, gynaecological sepsis, biliary tract infectiob
UTI
Nosocomal pneumonia

Adverse effects
GI intolerance, rashes, stomatitis, rarely cholestatic jaundice, Steven-Jonson syndrome

Dose
Amoxicillin 250/500mg + clavulanic acid 125 mg tablets or acpsules

8. Primethamine + Sulfadoxine
 Pyrimethamine : It is a diamino pyrimidine antiparasitic agent. It selectively inhibits
dihyrofolate reductase enzyme and interferes with tetra hydro folic acid synthesis from
folic acid. Effective against slow acting erythrocytic schizonticide. If used alone
resistance develops rather rapidly by mutation in DHFR enzyme of malarial parasite.
Drug is excreted by the kidney.

Sulfadoxine: It is an ultra long acting sulfonamide. It competitively inhibits

dihydropteroate synthase interfering with folate synthesis. It acts by increasing oxygen in
blood. Effective against asexual forms. The combination is synergistic due to sequential
block in protozoal folic acid synthesis. The combination has least chances developing
resistance. Both the drug have ultra long plasma half life (>95 hrs) but the combination
acts faster.

Uses :

-Clinical cure of falciparum malaria

-As an adjunct with quinine to treat chloroquine resistant falciparum malaria.

-Prophylaxis for travelers diarrhoea where chloroquine resistant falciparum malaria is

endemic.

-First line of therapy for treatment of toxoplasmosis in immune compromised patients.

-Folinic acid is usually co-administered to limit myelosupression.

Adverse effects

Megaloblastic anaemia, granulocytopenic, atrophic glossitis , Steven Johnson syndrome,

allergic alveolitis, blood dyscrasias.

Dosage: sulfodoxine= 500mg + pyrimethamine= 25mg or

Sulfodoxine = 750mg + Pyrimethamine- 37.5mg.

9. OCP’s (Oral Contraceptive Pills)

Both estrogen and progesterone synergise to inhibit ovulation. Progesterone ensures

bleeding at the end of the cycle and block the risk of developing endometrial carcinoma
due to estrogen.
Combined pill

1 tablet taken daily for 21 days starting on the 5th day of menstruation. The next course
started after a gap of 7 days in which bleeding occurs. Thus a cycle of 28days maintained.

Phased Regimun: Estrogen dose is kept constant amount while progesterone is kept low
in first & progressively increased in 2nd and 3rd phase. Is recommended for women of
age above 35yrs.

Progesterone only pill: Efficacy is lowered here (96-98%) lower dose progesterone only
pill is taken continuously.

Post coital & emergency contraceptive pill: 3 Regimen:

Levonorgestrol =0.5mg

Ethinyl estradiol=.01mg

2 tablets taken as early as possible within 2hrs of intercourse and 2 tablets 12hrs later

Levonorgesterol-=0.5mg twice within 12hrs

Mifepristone – is an antiprosterone agent= 600mg single dose within 72hrs of

intercourse. Reserved for unexpected or accidental explosure.

Mechanism of action: Inhibition of gonadotropin release from pituitary gland by

reinforcement of normal feedback inhibition. Progesterone reduces LH surge. Oestrogen
reduces FSH secretion. Both synergise and inhibit mid cycle LH surge. Inhibin &
progesterone also inhibit LH surge . Oral contraceptive pills thickens the cervical mucus
which is hostile to sperm penetration evoked by progesterone action. Even if ovulation
and fertilization has occurred hyper proliferation, hyper secretion, hydrotrophied
endometrium is not suitable for implantation. This action is important for minipill and
postcoital pill. Post vital pill dislodge implanted cyst even after fertilization or they
interfere with fertilization and implantation.

Adverse effects: Nausea, vomiting, breakthrough bleeding , pruritis vulvae, deep vein
thrombosis, pulmonary embolism hypertension, benign hepatoma, gallstone, vaginal
cancer, cervical cancer , breast cancer.

Note: 1. Discontinuation of OCP’s results in full return of fertility within 1-2Months.

2. If a women, on combined OCP’s has missed a tab, is advised to take the missed dose
immediately.

3. If pregnancy occurs, it is terminated by suction and evacuation .

4. If break through bleeding occurs, switch over to pill with high estrogen content.

5. If acne develops, use progesterone content with lacking androgenic effect.

10. Entonox(N2o+ o2)

Nitrous oxide: Also called as laughing gas. It is lighter than air and insoluble in blood. In
practice it is safest anaesthesia. It is sweet smelling and non inflammable. It is a gas of
low potency and poor muscle relaxant property. It has two importnant effects when it is
given at 70=80% concentration: causes diffusion hypoxia and second gas effect. Nitrous
oxide has low blood solubility so after discontinuation it rapidly diffuses from blood into
alveoli and dilutes the alveolar air. This causes excess of nitrous oxide in alveoli and
partial pressure of oxygen in alveoli is reduced. This can be prevented by giving
continuous 100% O2 for few minutes after discontuing N2O anaesthesia.

2nd gas effect: When N2O is given at high concentration(70-80%) with another potent
inhalational agent like halothane it facilitates delivery of latter to blood at higher rate and
helps in achieving faster induction.

Side effects: Diffusion hypoxia, 2nd gas effect, bone marrow depression, megaloblastic
aneima.

Entonox; Mixture of 50% N2O and 50% O2. The ability to combine N2O and O2 at high
pressure.

Uses of Entonox; During labour, emergency medical care.

Routes of administration: Gas is administered through mouth piece or face mask.

Contraindication: N2O should not be used in patients with bowel obstruction,

haemothorax, haemoperitoneum, middle ear infection, sinusitis, haemocephalus, scuba
diving, first 2 trimester of pregnancy, patienst with decreased level of consciousness.