Azithromycin

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Azithromycin
Systematic (IUPAC) name
9-deoxy-9a-aza-9a-methyl-9a- homoerythromycin A OR (2R,3S,4R,5R,8R,10R,11R,12S,13S,14S)-11-((2S,3R,4S,6R)-

4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yloxy) -2-ethyl-3,4,10-trihydroxy-13-((2S,4R,5S)-5-hydroxy- 4-methoxy-4-methyltetrahydro-2H-pyran-2-yloxy)- 3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one
Identifiers
CAS number 83905-01-5
ATC code J01FA10
PubChem 55185
DrugBank APRD00397
Chemical data
Formula C38H72N2O12 
Mol. mass 748.88
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 38% for 250 mg capsules
Metabolism hepatic
Half life 68 hours
Excretion biliary, renal (4.5%)
Therapeutic considerations
Pregnancy cat.

B1(AU) B(US)
Legal status
Routes oral (capsule or suspension), intravenous, ophthalmic

Azithromycin is an azalide, a subclass of macrolide antibiotics. Azithromycin (brand names Zithromax in Italy, The United Kingdom, The United States, Australia, Portugal and Belgium; ATM in India, Zithromac in Japan, Vinzam / Zitromax in Spain; Zmax; Sumamed; Aztrin, Zitrocin, Azibiot, Azifine,AziCip) is one of the world's best-selling antibiotics, and is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered. Azithromycin is used to treat certain bacterial infections, most often those causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia and sinusitis. It is also effective against certain sexually transmitted infectious diseases, such as non-gonococcal urethritis and cervicitis. Recent studies have also indicated it to be effective against late-onset asthma, but these findings are controversial and not widely accepted yet. [1] [2]

Contents

[edit] Etymology

Azithromycin's name is derived from the azane-substituent and erythromycin. Its accurate chemical name is

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14S)-11-((2S,3R,4S,6R)- 4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yloxy)- 2-ethyl-3,4,10-trihydroxy-13-((2S,4R,5S)-5-hydroxy- 4-methoxy-4-methyltetrahydro-2H-pyran-2-yloxy)- 3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one

[edit] History

A team of Croatian pharmaceutical company Pliva researchers, Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski and Zrinka Tamburašev led by Dr. Slobodan Đokić, discovered azithromycin in 1980. It was patented in 1981, and was later found by Pfizer's scientists while going through patent documents. In 1986 Pliva and Pfizer signed a licensing agreement which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva brought their azithromycin on the market in Central and Eastern Europe under the brand name of Sumamed in 1988, Pfizer Zithromax in 1991, and Zentiva Azitrox. On April 27, 2007, the US FDA approved AzaSite, an ophthalmic formulation of azithromycin, for the treatment of eye infections. AzaSite is currently marketed in the US by Inspire Pharmaceuticals.

[edit] Available forms

Azithromycin is commonly administered in tablet or oral suspension (a one-dose version was made available in 2005). It is also available for intravenous injection. Tablets come in 250 mg and 500 mg doses. Oral suspension comes in 100 mg/teaspoon and 200 mg/teaspoon strengths. The 250 mg tablets are often dispensed in packages of six and commonly referred to as a "Z-Pak," whereas the 500 mg tablets are commonly available commercially in a pack of three tablets, or "Tri-Pak," intended as a three-day treatment. A common dose of oral azithromycin therapy consists of a "double dose" of medication on the first day of treatment and subsequent treatment for four or five additional days. With the "Z-Pak," this means two 250 mg tablets (a total of 500 mg) on the first day and one 250 mg tablet once daily for the next four days.

Pfizer brand-name (e.g., Zithromax) azithromycin tablets are mottled pink, unscored, film-coated, modified-oval-shaped tablets containing azithromycin monohydrate equivalent to 250 mg or 500 mg azithromycin and the following inactive ingredients: butylated hydroxytoluene, calcium phosphate, carmine, colloidal silicon dioxide, FD&C red # 40 lake, FD&C yellow # 6 lake, hypromellose (2910, 15cP), lactose monohydrate, magnesium stearate, pregelatinized starch, sodium lauryl sulfate, talc, titanium dioxide and triacetin. The 250 mg tablets have the following appearance: They are mottled pink, of a modified-oval-shape, and have "Pfizer" engraved into one side with "306" engraved into the other. The 500 mg tablet is similar in appearance with the exception of its relative size and "ZTM500" engraved onto one side with "Pfizer" on the reverse. As with all medications, generic azithromycin tablets produced by companies other than Pfizer without the Zithromax brand name may have different appearances. For instance, the generic azithromycin sold under the Greenstone brand is pink, with the hexagonal "G" Greenstone, Ltd. logo engraved on one side and the numerals 3060 on the other. Greenstone, Ltd. is a subsidiary of Pfizer.

Brand name Zithromax in Greece and Cyprus is sold in boxes containing a blister of six white 250mg capsules. On the capsules there is printed the "Pfizer" logo and the symbols "ZTM 250".

Azithromycin is now available with microcencapsulated in betacyclodextrin, in India with the brand name of VRENTROX-DS and VENTROX-250. It is also available in India under brand name Azivista-500 in a three dose pack of 500mg each and is manufactured and sold by Cadilla pharmaceuticals.

[edit] Microbiology

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. Azithromycin binds to the 50S subunit of the bacterial ribosome, and thus inhibits translation of mRNA. Nucleic acid synthesis is not affected. Azithromycin has similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Haemophilus influenzae.

Azithromycin resistance has been described and is common in many areas.

Azithromycin has been proven to be most effective against the most isolates of the following microorganisms:

Azithromycin has been shown to be effective against malaria when used in combination with artesunate or quinine; the optimal dose for this is not yet known.[3]

[edit] Pharmacokinetics

Unlike erythromycin, azithromycin is acid-stable and can therefore be taken orally with no need of protection from gastric acids. It is readily absorbed, and diffused into most tissues and phagocytes. Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and 1 to 2 hours for intravenous (IV) forms. Due to the high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of azithromycin are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma. This is due to ion trapping and the high lipid solubility.

Azithromycin's half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days. The new "Zmax" formulation of azithromycin is an enteric-coated suspension that releases the drug in a single 2g dose once it has cleared the stomach, reducing the GI side-effects of high-dose azithromycin.

[edit] Metabolism

Following a single 500 mg dose, plasma concentrations of azithromycin declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and a terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

[edit] Side effects

Most common side effects are gastrointestinal; diarrhea (5%), nausea (3%), abdominal pain (3%) and vomiting. Fewer than 1% of patients stop taking the drug due to side effects. Serious allergic reactions, nervousness, dermatologic reactions, and fatalities have been reported but are extremely rare. Increased appetite may or may not occur in the patient. As with all antimicrobial agents, pseudomembranous colitis can occur during and up to several weeks after azithromycin therapy. This drug may interfere with the effectiveness of birth control pills; other forms of contraception may be required during the treatment period. Although mild diarrhea is normal, if it is moderate to severe, or if it continues or is bothersome, check with your doctor. If you experience vomiting, unable to process food, or hearing loss or ringing in the ears, contact your doctor as soon as possible.

[edit] Allergic reaction

Allergic reaction to this medicine is unlikely, but seek immediate medical attention if it occurs. Patients who suffer from an allergic reaction to Azithromycin can experience blood in the stool 4-10 days after ingestion, although cases of this have been recorded as early as after the first day of ingestion. These allergies are usually non-severe if the treatment is immediately stopped. A severe reaction includes a severe rash, hives, breathing difficulties, or dizziness. If experiencing difficulty breathing; tightness of chest; swelling of eyelids, face, legs, hands, eyes, throat, tongue or lips; or you develop a rash or hives, tell your doctor immediately. If you notice other effects not listed above, contact your doctor, nurse, or pharmacist.

[edit] References

  1. ^ Hahn,D.L. (1995). "Treatment of chlamydia pneumoniae infection in adult asthma: A before -after trial.". J Fam Pract. 41: 345-351. 
  2. ^ JD Klausner, D Passaro, J Rosenberg, WL Thacker, DF Talkington, SB Werner, DJ Vugia (1998). "Enhanced control of an outbreak of Mycoplasma pneumoniae pneumonia with azithromycin prophylaxis". Journal of Infectious Diseases 177: 161-166. 
  3. ^ Noedl H, Krudsood S, Chalermratana K, et al. (2006). "Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomised, phase 2 clinical trial in Thailand" 43 (10): 1264–71. PMID 17051490. 

[edit] External links

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Antibacterials for systemic use: macrolides, lincosamides and streptogramins (J01F)
Macrolides
Lincosamides
Streptogramins