Living Textbook MC610

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Macrolides

They were first isolated in the 1950s from Streptomyces sp. Chemically they contain a large lactone ring (12, 14 or 16-membered) attached to one or two sugar molecules by a glycosidic linkage.

They are more active against Gram positive but have some activity against Gram negative as well. They are used in place of Penicillins in many cases, mostly for lower and upper RTI and sexually transmitted diseases.

Mechanism of Action:

They bind to the 50S subunit and prevent translocation of the peptidyl-tRNA from the A-site to the P-site and releasing an incomplete peptide. They have no effect on the 80S ribosomes. They are bacteriostatic agents.

They are bases with pKa around 8 and are inactivated in acids due to formation of an internal ketal between the 6 and/or 12-hydroxyl group and the 9-ketone. These products may lead to gastric upset and cramps.

Dosage Forms:

To improve oral use, several alternatives are available:

  1. Use the basic drug as an enteric coated pill. This will mask the bitter test and improve acid stability to a certain degree, leading to better oral bioavailability and lower incidences of GIT cramps.
  2. Use as a salt with the sugar amine as the insoluble Stearate or the soluble Lactobionic and Glucoheptonic salts. They release the base in the intestine and show better oral absorption. The soluble salts are also used parenterally.
  3. Use as an ester prodrugs with the sugar hydroxyl group as Erythromycin Ethyl Succinate (EES), which is tasteless and suitable for pediatric preparations or Erythromycin Estolate that is insoluble and shows better acid stability and oral absorption.

Structure Activity Relationship:

Has not been extensively studied. The only modification that seems to improve drug characteristics is removal of the 9-ketone group to improve potency and oral activity.

Resistance:

  1. By efflux of the drug to the outside of the cells.
  2. Methylation of a Purine (usually a Guanine) or mutation of nucleotides (such as replacing an Adenine with a Guanine on the 50S subunit. These modified ribosomes become less efficient as protein manufacturers but reduce Macrolides' binding. It is also known as MLS resistance as there is cross-resistance with Lincomycins and Streptogramins.

Toxicity:

Low, mostly GIT disturbances due to an increase in bowel movement causing cramps and diarrhea. Liver toxicity and cholestatic jaundice have been reported in rare cases, and the patient should be switched to a non-macrolide agent.

Notes:

  1. Many macrolides are metabolized by oxidative demethylation (of the amine) by Cytochrome P450, and will thus compete with other drugs such as Warfarin, Theophylline or Carbamazepine for the enzyme. Their interaction with Astemizole and Terfenadine can lead to very serious cardiovascular effects (these antihistamines were withdrawn from the market due to these drug-drug interactions).
  2. Absorption is generally erratic and affected by food.

Individual Agents:

Erythromycin is the prototype of this class. The discussion so far has been based on this drug.

Clarithomycin is more stable with better oral bioavailability and less GIT effects (6-methoxy group), due to the higher lipophilicity of the agent and its stability in acidic medium. It is effective against Helicobacter pylori. It is metabolized through first pass effect to the 14-hydroxy compound, which is more active especially against Hemophilus Influenzae.

Dirithromycin is readily absorbed following oral administration and undergoes rapid non-enzymatic hydrolysis to Erythromycylamine. Absorption is enhanced by food. It is used in respiratory-tract, skin, and soft tissue infections caused by susceptible organisms, given orally as enteric-coated tablets once daily. It is not a substrate for Cytochrome P450, thus the aforementioned drug-drug interactions are not observed with this agent.

Azithromycin , an azalide is more effective against Gram negative, not affected by Cytochrome P450 and distributed to tissues very efficiently. It is slowly released from the tissues and thus has a longer half-life. It is usually given as two tablets the first day then once a day for 5 days. It should be given on an empty stomach and avoid using it with antacids. No possibility for formation of an internal ketals due to the absence of the 9-keto group.

Telithromycin, a ketolide is related to Macrolides, but does no share or induce the MLS resistance and does bind to the methylated ribosome in these species. Formation of the ketal is not possible due to the absence of a hydroxyl group at the 6 or 12-positions. Much of the interest in new Macrolides is related to developing new ketolides.