Macrolides Pharmacology!

Macrolides Pharmacology

Macrolides are among the most widely prescribed antibacterial drug classes; an effective drug class with activity against a broad range of bacteria.

Macrolide antibacterial drugs have been around since the 1950s and have, in that time, proved enormously successful at treating both minor and serious bacterial infections.

Erythromycin was the first macrolide, approved in 1952. Other macrolides include:

• Clarithromycin
• Azithromycin
• Fidaxomicin
• Telithromycin (a ketolide related to macrolide drugs)

Macrolides are predominantly used to treat Gram-positive infections and remain a popular alternative for patients with penicillin allergy. They are active against a limited range of Gram-negative organisms (B. pertussis, H. influenzae etc.).

Macrolides are used in the treatment of infections such as:

• Respiratory tract infections
• Skin and soft tissue infections
• Pneumonia – often added to a penicillin drug to cover atypical organisms such as L. pneumophila and M. pneumoniae.
• Peptic ulcer disease – used in combination with a PPI and a penicillin to eliminate Helicobacter pylori infection

Mechanism of action

Macrolide antibacterial drugs are protein synthesis inhibitors.

More specifically, macrolides prevent elongation of the polypeptide chain – an effect achieved through their reversible binding to the P site of the 50S ribosomal subunit.

Their mechanism of action has a bacteriostatic effect – that is to say, they prevent bacterial growth, allowing the body to take over and eliminate the bacterial infection.

Erythromycin was the first macrolide and is associated with less activity against Gram-negative organisms compared to later, synthetic macrolides – such as azithromycin and clarithromycin.

Side effects

Side effects with macrolides include:

• GI effects – nausea, vomiting, abdominal pain, diarrhea
• Antibiotic-associated colitis
• Cholestatic jaundice
• QT interval prolongation – predisposing patients to arrhythmias

Gastrointestinal effects are more pronounced with erythromycin because the drug also acts as a motilin agonist.

At high doses, macrolides can cause ototoxicity.

Clinical Pharmacology

When we talk about the clinical pharmacology of macrolides, we must consider the following factors:

• Macrolides interact with statins to increase the risk of myopathies.
• Macrolides should be used with caution in patients taking other medicines that prolong the QT interval – fluoroquinolones, antipsychotics, SSRIs, quinine, and amiodarone, for example.
• Macrolides increase the risk of bleeding in patients taking warfarin.
• That later macrolides, such as clarithromycin, are associated with fewer adverse effects compared to earlier macrolides, such as erythromycin.
• Macrolides are often given alongside penicillins to treat pneumonia. Macrolides cover atypical organisms – such as Legionella and Mycoplasma – that penicillins do not cover.
• Macrolides are often given alongside other antibacterial agents – such as amoxicillin and omeprazole – in the treatment of H. pylori infection.
• Macrolides should not be prescribed to patients who have a positive history of hypersensitivity to macrolide antibacterial agents. They are often used as an alternative where patients are allergic to penicillins.
• Erythromycin has gastroprokinetic effects – part of the reason why its gastrointestinal side effect profile is more pronounced.
• Macrolides are mostly eliminated via the hepatic route. Caution is needed in patients with severe hepatic impairment. A dose reduction may be required in patients with renal impairment because a small amount of macrolide is eliminated by this route.
• Both erythromycin and clarithromycin, but not azithromycin, inhibit CYP3A4 and consequently impact the metabolism of a wide range of medicines. Their effect on CYP3A4 is responsible for the effects on warfarin and statins mentioned above.
• Macrolides, such as erythromycin, are inactivated by gastric acid – meaning their oral formulation is given as an enteric-coated agent or as a more stable ester.

That concludes our rapid review of macrolides pharmacology. Check back to our pharmacy blog soon for more exclusive content to help you master the science of medicines!