Let’s get on to Macrolides, Lincosamides.
A little bit of stuff on protein biosynthesis won’t hurt to help us understand the pharmacology of these class of drugs, macrolides and Lincosamides.
Bacterial protein synthesis involves proteins required for reproduction, and is made possible by ribosomal RNA, mRNA and tRNA. To begin, the double stranded DNA first unwinds in an untwisting motion in the region which codes for the specific protein to be made and only that one strand of the DNA serves as a template for what is known as transcription.
RNA polymerase makes a copy of this segment, which now stands as what is called mRNA. Once the strand of mRNA is complete, it detaches from that segment, and in turn become attached to ribosomes.
Now it gets interesting.
Bacterial ribosomes are made of two subunits, the small 30s and a bigger 50s ribosomal subunits, together makes up 70s ribosomal unit. The numbers don’t add up right? Yes 30+50 is not 70. If you want to know why, download the Podroom app and join the discussion, there you can ask me and I’ll explain. For now, we move.
The ribosomal subunits attach to the mRNA strand like a zipper and begin the synthesis of the polypeptide chain, along that strand.
Now the amino acids needed for this synthesis, is bound to tRNA, so tRNA + amino acids bind to the ribosome which is on the mRNA strand and begins to work its way from one end of the strand to the other, making the polypeptide chain in the process, until it hits a stop codon which makes it stop and release the full polypeptide chain it has been making. The 70s ribosome couples itself back and awaits further instruction.
It’s very easy, see, these are the steps
1. Bacterial DNA unwinds to reveal a segment to be copied
2. RNA polymerase makes a copy of this segment, a complete mirror image of the segment, detaches this new copy, which now stands alone as mRNA
3. This mRNA attaches to 70s ribosome, which clasps the strands above and below with its two subunits 50s and 30s
4. tRNA which contains amino acids is then bound to the ribosome and this moves along the mRNA strand to synthesize the polypeptide chain.
5. Macrolides and Lincosamides inhibit this ribosome and do not allow it to move. If it cannot move, polypeptide and hence protein synthesis stops, and bacteria cannot grow, everything becomes static, that is why they say these drugs are bacteriostatic.
So now, drugs that affect ribosomes in protein synthesis either affect the 50s or 30s subunits of the 70s ribosome.
Don’t worry, there is a mnemonic for that.
Buy AT 30 and CELL @50
Aminoglycosides and tetracyclines inhibit protein synthesis by inhibiting the 30s ribosomal subunit.
Chloramphenicol, Erythromycin (macrolides), Lincosamides and Linezolid all inhibit 50s ribosomal subunit.
So macrolides – are a class of antibiotics that contain the following drugs
1. Erythromycin – the oldest, strep, staph, pertusis, diphtheria, M. pnemonia
2. Clarithromycin- strongly g +ve, used in eradication of H. pylori, renal toxicity
3. Azithromycin – strong G -ve, RTI mainly
As you go from erythromycin to azithromycin, you go from old to new, and also their half lives increases in that fashion, and hence their frequency of dosing reduces.
MOA– just like I said, inhibits 50s, along with other counterparts in the mnemonic CELL @50
Spectrum of activity – G -ve and +ve, anaerobes (upper airway), atypical bacteria (legionella, chlamydia, mycoplasma etc), others like mycobacterium avium complex, campylobacter, treponema pallidum etc
Absorption– food decreases it, why enteric coated ones are made. Clarithromycin is well absorbed irrespective of food.
Distribution- all body fluids and placenta except CSF and Elimination– Hepatic: ALL, only clarithromycin is partially excreted by renals, why it needs renal adjustment at times. Cannot dialyze.
Erythro t1/2- 1.5hrs, clarithromycin about 6hrs, Azithro – 68hrs
Resistance– 80% is through the active efflux mechanism in which the mef gene encodes for an efflux pump that actively pumps macrolide out of the cell, away from the ribosome it is supposed to inhibit.
Another mechanism is one in which a gene alters the binding site of the macrolide on the ribosome.
Lastly, there is cross resistance which occurs between all macrolides.
A: Arrythmias (prolonged qt interval)
C: Cholestatic Hepatitis
Drug interaction: it inhibits CYP3A4 enzyme leading to increased effects of carbamazepine, theophylline, warfarin, valproate.
Enough of Macrolides. Let’s talk about a close relative in mechanism of action.
The Lincosamides Briefly!
In this class is Clindamycin and Lincomycin
They are active against staph, gram +ve and -ve anaerobes. Also against Bacteroides.
Mechanism of action – You know this already, yes say it, of course if you [email protected] 50 you will know it binds to 50s ribosome and hence inhibits protein synthesis.
It is absorbed well, penetrates well into most tissues including bone, but not CSF
Excreted via the liver, bile and Urine.
Resistance: mechanisms via drug inactivation, alteration of 50s ribosomal subunit by adenine methylation and mutation of the 50s ribosomal protein.
1. Anaerobic infections
2. Osteomyelitis, arthritis
3. AIDS related toxoplasmosis (combined with pyrimethamine)
4. AIDS related pneumocystis carinii pneumonia.
1. Severe diarrhea- pseudomembranous enterocolitis caused by clostridium deficille
2. High IV dose – neuromuscular blockade
4. Impaired liver function
And that’s all fellas. Next, we talk about Sulphonamides in the next episode.
This content is made for medical students, all pharmacology enthusiasts and medical practitioners who want to refresh their memory within the shortest possible time. This is meant to be used in conjunction with detailed pharmacology notes or texts, not sufficient as a standalone.