Antifolate drugs (sulphonamides and trimethoptim)

Antifolate Drugs
(Sulphonamides and Trimethoprim)

Classification of Sulphonamides

>Short-acting, well absorbed in the gastrointestinal tract such as sulphamethoxazole and
Co-trimoxazole (the combination of sulphamethoxazole with trimethoprim).
> Long-acting, well absorbed in the gastrointestinal tract such as sulphametopyrazine.
>Poorly absorbed in the gastrointestinal tract such as sulphasalazine. This medicine is used for topical application.
>Sulphasalazine is used for inflammatory bowel disease.

Mechanism of Action of Sulphonamides and Trimethoprim
>Folic acid is essential in the bacterial growth and the only source of folic acid to bacteria is by synthesis.
>These medicines block the synthesis through the following mechanisms of action.
       Sulphonamides
>The medicine is a synthetic chemical compound of structural analogues of Para-Amino Benzoic Acid (PABA).
>They compete with PABA in the folic acid synthesis pathway.
>Pathway produces purines and pyrimidines - building blocks of nucleic acids (Nucleic acid synthesis inhibitors).
>The medicine does so only to bacteria and not to human cell because humans cannot synthesize folic acid they only receive it through diet. That is why this mechanism is called selective toxicity.
>The action of a sulphonamide is to inhibit growth of the bacteria, not to kill them. It is bacteriostatic rather than bactericidal.

>The action is negated by the presence of pus and the products of tissue breakdown since these contain thymidine and purines, which bacteria use to bypass the need for folic acid.
Note
Target both gram negative and gram positive bacteria) but does not function well if there pus formation
         Trimethoprim /septrin/bactriam
>Trimethoprim is a diaminopyrimidine/ pyrimidine analogue.
> It inhibits bacterial dihydrofolate reductase by combining with the enzyme Dehydrofolate reductase (DHF).

> The enzyme is present in human cells but trimethoprim binds more to the bacterial enzyme than human cell
enzyme. This is what is called selective toxicity based on differential affinity for DHF from different sources (e.g. mammalian versus bacterial).

>Trimethoprim-sulphonamide combination has broad range of activity.
      Displays synergism when used in combination with sulphonamides (co-trimoxazole).
o Remains the treatment of choice for some infections:
Pneumocystis infections in HIV&AIDS or any immunocompromized patients.
Salmonella typhi
>Sulfamethoxazole inhibits dihydropteroate synthase.
>Trimethoprim inhibits dihydrofolate reductase.
Mechanism of Action, Inhibitory Effects of Sulphonamides and Trimethoprim on Folic Acid Synthesis

>Pharmacokinetics of Sulphonamides and Trimethoprim.

Sulphonamides
>Sulphonamides are broad spectrum bacteriostatic agents effective against Gram-positive & Gram-negative bacteria.
>Most sulphonamides are readily absorbed in the gastrointestinal tract and reach maximum concentrations in the plasma in 4-6 hours.
> They are usually not given topically, mainly because of the risk of sensitisation and allergic reactions. An exception is silver sulphadiazine which is used topically in the treatment of infected burns.
>The drugs pass into inflammatory exudates, and cross the placental barrier; most reach an effective concentration in the cerebro-spinal fluid (CSF), but they are no longer used to treat most of the central nervous system (CNS) infections except for the trimethoprim which is used to treat CNS toxoplasmosis.
> They are metabolised mainly in the liver, the major product being an acetylated derivative which lacks antibacterial action. They are excreted in the urine.
>Resistance, due to the synthesis of an enzyme insensitive to the drug.

Trimethoprim
      >Given orally, is fully absorbed in the GIT.
     >It reaches high concentrations in the lungs and the kidneys and fairly high concentrations
in the CSF.
      >Since trimethoprim is a weak base, its elimination by the kidney increases with decreasing urinary pH.

Principles for Use of Combinations of Sulphonamides
√Combination of sulphonamides must include two drugs with a synergistic action i.e. One inhibiting dihydropteroate synthase (Sulphamethoxazole) and the other inhibiting dihydrofolate reductase (Trimethoprim).
√Inhibition of these two enzymes interferes with two serial steps in folic acid synthesis, and thereby inhibits synthesis of nucleic acids and proteins.

Clinical Uses of Sulphonamides and Trimethoprim
√Absolute indications are very few, but sulphonamides may be used as follows:
√ Combined with trimethoprim (co-trimoxazole) for Pneumocystis jiroveci (also known asP.carinii). Pneumocystis jiroveci pneumonia (PCP) almost always occurs when the CD4<200.
√Combined with pyrimethamine for drug-resistant malaria and for toxoplasmosis.
√ In inflammatory bowel disease: sulfasalazine.
√For infected burns: silver sulfadiazine given topically and for some sexually transmitted infections (e.g. trachoma, chlamydia, and chancroid).

Clinical Uses of Trimethoprim
√For urinary tract and respiratory infections: trimethoprim, used on its own, is usually preferred.
√For infection with Pneumocystis jiroveci, which causes pneumonia in patients with AIDS
co-trimoxazole is used in high dose.
Unwanted Effects of Sulphonamides and Trimethoprim

Adverse Effects of Sulphonamides
a/Mild to moderate side-effects are nausea and vomiting, headache, and mental depression.
b/Crystalluria, due to precipitation of acetylated metabolites in the urine.
√It can be prevented by giving plenty of fluids and keeping the urine alkaline, and is less likely to occur with the more water-soluble drugs.
c/Hypersensitivity reactions (allergies)
d/Haemolytic anaemia
e/Drug interaction: Due to the high affinity to plasma proteins, some of the newer products may free other drugs from their binding proteins, thereby may potentiate activities of the freed drugs.These include anticoagulants, and hypoglycaemic agents of sulfonylurea group. (Antidiabete)

Unwanted Effects of Trimethoprim
√Nausea, vomiting, blood disorders and skin rashes.
√Folate deficiency, with resultant megaloblastic anaemia a toxic effect related to the pharmacological action of trimethoprim can be prevented by giving folinic acid.

Antimetobolite antibiotic
Drug interaction

Antimetabolites

A drug may be classified by the chemical type of the active ingredient or by the way it is used to treat a particular condition. Each drug can be classified into one or more drug classes.

Antimetabolites are drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis. They affect DNA synthesis by acting as a substitute to the actual metabolites that would be used in the normal metabolism (for example antifolates interfere with the use of folic acid).

Antimetabolites are drugs used in cancer chemotherapy. Cancer cells divide more rapidly compared to normal cells so antimetabolites affect cancer cell replication more than they affect normal cell replication.

Posted by 
   Welfare Jambo
You can follow me on
Blog
  Welfarejambo.blogspot.com
contacts
      Whatsapp
    0765896355.0684127127
Facebook
     Well Jambo
Instagram
     Mr. Welfare Jambo