Cotrimoxazole: An introduction, classification, mechanism, synthesis with its effect.

Cotrimoxazole

The combination of trimethoprim and sulfamethoxazole within a fixed-dose in the ratio of 5:1 is called cotrimoxazole. It is a drug combination with broad-spectrum antibacterial activity against both gram-positive and gram-negative organisms with their action. Trimethoprim is a diaminopyrimidine related to the antimalarial drugs pyrimethamine which selectively inhibits bacterial dihydrofolate reductase (DHFRase).

Structure-of-Trimethoprim-and-Sulfamethoxazole
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Sulfamethoxazole with trimethoprim is a fixed combination of antibiotics that are widely used for mild to moderate bacterial infections and as prophylaxis against opportunistic infections.

Cotrimoxazole is introduced in 1969, which causes the sequential block of folate metabolism. Trimethoprim is more than 50,000 times more active against bacterial DHFRase than against the mammalian enzyme. Thus, human folate metabolism does not interfere with antibacterial concentrations of trimethoprim. Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same t1/2 of 10 hours.

Molecular formula- C24H29O6S

Molecular weight- 543.6 g/mol

IUPAC Name- 4-amino-N-(5-methyl-1,2-oxazol-3-yl) benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl) methyl] pyrimidine-2,4-diamine

Mechanism of action of cotrimoxazole-

Cotrimoxazole inhibits sequential steps in the synthesis of tetrahydro folic acid (THFA), an essential metabolic cofactor in the bacterial synthesis of purines, thymidine, glycine, and methionine. Sulfonamides, including sulfamethoxazole, are structural analogs of para-aminobenzoic acid (PABA) and block the synthesis of di-hydropteroic acid (DHA), the immediate precursor of dihydro folic acid (DHFA), from para-aminobenzoic acid and peridine.

Mechanism-of-Action-of-Cotrimoxazole
Source-internet

In cotrimoxazole, trimethoprim subsequently acts to inhibit the reduction of di hydrofolic acid (DHFA) to the metabolically active tetrahydro folic acid (THFA) by the enzyme, dihydrofolate reductase (DHFR). The most important consequence of this sequential enzymatic inhibition appears to be the interruption of thymidine synthesis.

Spectrum activity of cotrimoxazole-

It is a drug combination with broad-spectrum antibacterial activity against both gram-positive and gram-negative organisms with their action. It has a border spectrum of antibacterial action then sulfonamides drugs alone. It is effective in treating UTIs and respiratory tract infection, as well as Pneumocystis jirovecii pneumonia (PCP), toxoplasmosis, and ampicillin- or chloramphenicol- resistant salmonella infections.

Cotrimoxazole has the activity against MRSA that can be particularly useful for community acquired skin and soft tissue infections caused by this organism.  It is the drug of choice for infection caused by susceptible Nocardia species and stenotrophomonas macrophilia. The antibacterial spectrum of trimethoprim and sulfonamides overlap considerably. Additional organisms covered by the combination are- salmonella typhi, Serratia, Klebsiella, pneumocystis jiroveci and many sulfonamides resistant strains of staph. Aureus, strep. Pyogenes, Shigella, enteropathogenic E. coli, H. influenzae, gonococci, and meningococci.

Resistance of cotrimoxazole-

Bacteria are capable of acquiring resistance to trimethoprim mostly through plasmid-mediated acquisition of a DHFrase having a lower affinity for the inhibitor.

The resistance of the combination is slow to develop as compared to either drug alone, but the wide-spread use of the combination over a long period has resulted in related responsiveness of over 30% originally sensitive strains. Significant resistance has been documented in a number of clinically relevant organisms, including E. coli and MRSA.

The resistance of co-trimoxazole is a smaller amount frequently encountered than resistance to either of the drugs alone because it requires that the bacterium have simultaneous resistance to the mixture of a combination of trimethoprim-sulfamethoxazole.

The spectrum of activity of trimethoprim is similar to sulfamethoxazole, although the former drug generally is 20-100 times more potent than the latter. Most gram-negative and gram-positive microorganisms are sensitive to trimethoprim, but resistance can develop when the drug is used alone.

You may read- anti microbial agents.

Pharmacology of cotrimoxazole-

Pharmacokinetics-

Cotrimoxazole is generally administered orally. Intravenous administration may be utilized in patients with severe pneumonia caused by PCP. Both agents are distributed throughout the body. Trimethoprim concentrates in the relatively acidic milieu of prostatic fluids, and this accounts for the treatment of prostatitis. Cotrimoxazole readily crosses the blood-brain barrier. Both patent drugs and their metabolites are excreted in the urine.

Absorption-

Cotrimoxazole is well absorbed from the GI tract after oral administration.

Distribution-

It is distributed widely into body tissues and fluids, including middle ear fluid, prostatic fluid, bile, aqueous humor, and CSF. Trimethoprim has a 44% of protein binding, and sulfamethoxazole has 70%. The drug crosses the placental barrier.

Metabolism-

It is metabolized by the liver.

Excretion-

In cotrimoxazole, both components are excreted primarily in urine by glomerular filtration and renal tubular secretion and some are from breast milk. Trimethoprim having a plasma half-life in patients with normal renal function is 8 to 11 hours and extended in patients with severe renal dysfunction is 26 hours. Sulfamethoxazole having plasma half-life is 10 to 13 hours and extended in patients with severe renal dysfunction is 30 to 40 hours.

Structure of cotrimoxazole-

Structure-of-Trimethoprim-and-Sulfamethoxazole
Source-internet

Uses of cotrimoxazole-

-Urinary tract infection

-Respiratory tract infection

-Bacterial diarrheas and dysentery

-Pneumocystis jiroveci

-Chancroid

-Typhoid

Method of manufacturing of cotrimoxazole-

It is prepared from the mixture of trimethoprim and sulfamethoxazole in ratio of 5:1.

Storage condition of cotrimoxazole-

Cotrimoxazole concentrate for injection should be stored at 15-30 °C and should not be refrigerated. Oral suspensions of the drug should be stored in tight, light-resistant containers at 15-25 or 15-30 °C, depending on the formulation (the manufacturer’s recommendations should be followed). The tablets should be stored in well-closed, light-resistant containers at 15-30 °C.

Adverse effects of cotrimoxazole-

Cotrimoxazole can produce as same all the adverse effects that seen in sulfonamides, like-

-Nausea, vomiting, stomatitis, headache, and rashes are the usual manifestations.

-Folate deficiency (megaloblastic anemia) is infrequent, occurs only in patients with marginal folate levels.

– Blood dyscrasias occur rarely.

Cotrimoxazole should not be given during pregnancy. Trimethoprim being an antifolate, there is a theoretical teratogenic risk. Neonatal hemolysis and methemoglobinemia can occur if it is given near term.

-Patients with renal disease may develop uremia. The dose should be reduced in moderately severe renal impairment.

-A high incidence (up to 50%) of fever, rash and bone marrow hypoplasia has been reported among AIDS patients with pneumocystis jiroveci infection when treated with high dose cotrimoxazole.

– In the elderly aged person’s that also at greater risk of bone marrow toxicity from cotrimoxazole.

-A combination of co-trimoxazole with diuretics is produced a higher incidence of thrombocytopenia.

Trimethoprim-

Trimethoprim is a dominant inhibitor of bacterial dihydrofolate reductase that exhibits an antibacterial spectrum similar to that of the sulfonamides. Trimethoprim is most often compounded with sulfamethoxazole, producing a combination called cotrimoxazole.

It is structurally and chemically related to pyrimethamine, another antifolate antimicrobial used in the treatment of plasmodial infections.

Structure-of-Trimethoprim
Source-internet

Trimethoprim is a synthetic derivative of trimethoxy benzyl-pyrimidine with antibacterial and antiprotozoal properties. As a pyrimidine inhibitor of bacterial dihydrofolate reductase (DHFR), trimethoprim binds tightly to the bacterial enzyme, blocking the production of tetrahydro folic acid (THF)from dihydro folic acid (DHA). The antibacterial activity of this agent is potentiated by sulfonamides.

Molecular formula– C14H18N4O3

Molecular weight- 290.32 g/mol

IPUAC Name- 5-[(2,3,4-trimethoxyphenyl) methyl] pyrimidine-2,4-diamine

Mechanism of action of trimethoprim-

In trimethoprim, the active form of folate is the tetrahydro derivative (THD) that is formed through the reduction of dihydrofolic acid (DHFA) by dihydrofolate reductase (DHFR).

This enzyme reaction is inhibited by it, leading to a decreased availability of the tetrahydrofolate cofactor required for purine, pyrimidine, and amino acid synthesis.

Mechanism-of-Action-of-Trimethoprim

In trimethoprim, bacterial reductase has a stronger affinity for trimethoprim than does the mammalian enzyme, which accounts for the selective toxicity of the drug.

Spectrum activity of trimethoprim-

The spectrum of activity of trimethoprim is similar to that of sulfamethoxazole. However, the trimethoprim is consisting of 20 to 50-fold more potent than the sulfonamides. Trimethoprim may be used alone in the treatment of UTIs and the treatment of bacterial prostatitis.

Resistance of trimethoprim-

Resistance for trimethoprim in gram-negative bacteria is due to the presence of an altered dihydrofolate reductase that has a lower affinity.

Efflux pumps and decreased permeability to the drug may play a role.

Pharmacology of trimethoprim-

Pharmacokinetics-

It is rapidly absorbed following oral administration.

Because the drug base is a weak base, a higher concentration of trimethoprim is achieved in the relatively acidic prostatic and vaginal fluids.

The drugs are widely distributed into body tissues and fluids, including penetration into the cerebrospinal fluid. Trimethoprim undergoes some O-demethylation, but 60% to 80% is really excreted unchanged.

Structure of trimethoprim-

Structure-of-Trimethoprim

Synthesis of trimethoprim-

Synthesis-of-Trimethoprim

Properties and use-

-Trimethoprim is a white or yellowish-white powder, very slightly soluble in water and slightly soluble in ethanol.

-It is used as a dihydrofolate reductase inhibitor, effective against chloroquine and pyrimethamine resistant strains of Plasmodium falciparum.

Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid.

Determine the end-point potentiometrically.

Physical properties of trimethoprim-

– Trimethoprim is an odorless white powder in crystalline form.

-It has a bitter taste.

-The melting point for it is 199-203˚C.

-It is slightly soluble in water and slightly soluble in alcohol. Soluble in N, N-dimethylacetamide, benzyl alcohol, propylene glycol, chloroform, menthol, ether, and benzene.

-Stability-The solubility in aqueous solution is partially dependent on the pH of the solution.

-It is a weak base, and solubility is lower in solution with a more alkaline pH.

-When heated to decomposition it emits toxic fumes of/ nitrogen oxide.

Method of manufacturing of trimethoprim-

 It is Prepared from guanidine and beta-ethoxy-3,4,5-trimethoxybenzylbenzalnitrile.

Storage condition of trimethoprim-

Trimethoprim tablets should be stored in tight, light-resistant containers at 15-30 °C in a dry place. Trimethoprim should be stored at room temp & not refrigerated. The multiple-dose vials should be used within 48 hours of initial entry.

Adverse effects of trimethoprim-

Headache

Itching and rash

-nausea, vomiting

-stomach upset

-loss of appetite

-Change in taste

-skin sensitivity to sunlight

-swollen tongue and fever

It can produce the effects of folic acid deficiency, includes megaloblastic anemia, leukopenia, and granulocytopenia, especially in pregnant patients and those having poor diet.

 -These blood disorder may be reserved by the simultaneous administration of folinic acid, which does not enter bacteria.

Sulfamethoxazole

It is in the class of sulfonamide bacteriostatic antibiotic that is commonly used in combination with trimethoprim as Bactrim drug. It is competitively inhibiting dihydropteroate synthase (DHPS) that preventing the formulation of di hydropteroic acid (DHPA), a precursor of folic acid which is required for bacterial growth.

Structure-of-Sulfamethoxazole
Source-internet

Molecular formula– C10H11N3O3S

Molecular weight– 253.28

IUPAC Name- 4-amino-N-(5-methyl-1,2-oxazol-3-yl) benzene sulfonamide

You may read- sulfonamides.

Mechanism of sulfamethoxazole-

Sulfamethoxazole prevents the formation of dihydro folic acid and synthesis due to its structural analog to an endogenous substrate of para-aminobenzoic acid (PABA). There is most of the bacteria meet their need for folic acid by synthesizing it from PABA.

Mechanism-of-Sulfamethoxazole

IT is competitively inhibiting dihydropteroate synthase (DHPS), the enzyme that responsible for bacterial conversion of PABA to dihydrofolic acid. The inhibition of this pathway prevents the synthesis of tetrahydrofolate and finely the synthesis of bacterial purines and DNA, resulting in a bacteriostatic effect.

Pharmacology of sulfamethoxazole-

Pharmacokinetics-

Absorption

It is well absorbed when administered topically and is rapidly absorbed by this route.

Distribution-

It is distributing generally into most body tissues as well as sputum vaginal fluid, and in middle ear fluid also. In an approx.70% of the drug is bound to plasma protein. The half-life of sulfamethoxazole is 10 hours.

Metabolism-

It is metabolized in the liver.

Excretion

It is primarily excreted via glomerular filtration and tubular secretion in renal. In an approx. 20% of it is via urine in uncharged form, 15-20% of it is via N-glucuronide conjugate and the other 70% is via acetylated metabolites. It is also excreted via breast milk.

Structure of sulfamethoxazole-

Structure-of-Sulfamethoxazole

Synthesis of Sulfamethoxazole-

Synthesis-of-Sulfamethoxazole

Properties and uses- It is a white or almost white crystalline powder, which is practically insoluble in water, soluble in acetone, sparingly soluble in ethanol, dissolves in dilute solutions of sodium hydroxide and in dilute acids. Used in the treatment of bacterial infections.
Dissolve the sample in dilute hydrochloric acid and add potassium bromide. Cool in ice and titrate against 0.1N Sodium nitrate. Determine the end-point electrometrically.
Dose- Orally 2 g followed by 1 g every 8 h.

Physical properties of sulfamethoxazole-

-It is found in crystal form with yellow-white powder.

-It is practically odorless in nature.

-It is bitter in taste.

-The melting point is 167˚C.

-It is practically insoluble in water, ether, and chloroform, and dissolve in hydrogen chloride (HCL).

Method of manufacturing of sulfamethoxazole-

It is prepared from ethyl 5-methylisoxazole-3-carbamate

Adverse effect of sulfamethoxazole-

-Headache

-dizziness

-Lethargy

-Diarrhea

-Anorexia

-Nausea, vomiting

-Rashes

-Liver damage

-Low white blood cells (WBC) count

-Low platelet count (Thrombocytopenia)


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