The Half Decent Pharmaceutical Chemistry Blog

Tonight, however, we've managed to restore the normal service and here we are, talking about a well-known class of drugs: tetracyclines.



Basically, they are broad-spectrum antibiotic with bacteriostatic activity against anaerobes, rickettsiae, chlamydiae and mycoplasmas, above all. In clinical use, tetracyclines are prescribed in the treatment of infections with Mycoplasma pneumoniae, in combined regimens to wipe out Helicobacter pylori and in some unpleasant sexually transmitted diseases. Besides, they can be used to cure community-acquired pneumonia, acne and leptospirosis.

Tetracyclines bind to the 30S subunit, which is present in bacteria only, leaving human ribosomes (and, consequently, our protein synthesis) unaltered. By the way, our mighty tetracycline blocks the aminoacyl-tRNA, which, in a nutshell, can't bind to m-RNA any more.
Sure, there is resistance. In particular, bacteria can produce an efflux pump, whose genes are encoded on a horizontally transmittable plasmid.

Looking at the basic structure, you'll easily recognise the chelating potential of the molecule. Such a reactivity means there are many interactions with food: milk, for instance, due to calcium ions, impairs the absorption of these drugs.
On the other hand, tetracyclines cause huge issues, especially in babies, reacting with calcium deposited in bones and teeth (they can even produce a pretty eerie fluorescence).

Other intersting drawbacks include a modification of normal intestinal flora: so, candidiasis and enterocolitis could be a consequence, because the physiological balance of intestinal bacteria is dramatically altered.
Another phenomenon I'd like to highlight is photosensitization (quite common, especially if, like me, you're skin is fair) and nitrogen retention, due to their moderate kidney toxicity.

There is an interesting story behind this molecule: as you can see, flucytosine bears a close resemblance to fluorouracil, a cancer chemotherapeutic drug. It was first synthesized in 1957 but, soon, it became clear it had no anticancer activity. In 1963, however, a study proved it had antifungal activity. And the story began...

Nowadays, in fact, flucytosine is prescribed for systemic fungal infections.



Yes, it has a narrower spectrum than amphotericin B, but, in my opinion, it has more brilliant mechanism. Orally administered, the drug is well absorbed and reaches all fluid compartments.
Fungal cells introduce thanks to their cytosine permease and, then, activate the drug by converting it to 5-flurouracil and, subsequently, 5-fluorodeoxyuridine monophosphate and fluorouridine triphosphate: the former inhibiting DNA, the latter RNA.
This mechanism is impossible for our cells, but this doesn't mean there aren't adverse effects: fluorouracil is still produced and this can result in anemia, leukopenia and thrombocytopenia, in particular.

Although it has a less broad spectrum than amphotericin B, some candidiasis and vicious Cryptococcus neoformans can be treated either on asinlge drug therapy or, more commonly, in association with amphotericin B, which may help flucytosine to enter the fungal cell.

Welcome to a new weekly series. I chose this title because, generally, families gather on Sundays to have lunch together. The families I will talk about here, in particular, are classes of molecules.

Molecules will be described only from a pharmacological point of view. Nevertheless, chemistry may "drop in" every so often, in particular, to explain awesome mechanisms.

Moreover, I hope usual readers of KinasePro will find this interesting, even if new drugs won't be very common.

Today, we start with an old and quite small class: H2-antagonists. I said old and small, but this doesn't mean unimportant by any means.

Before the introduction of PPIs (proton pump inhibitors), these drugs were of paramount important. Nowadays, due to their cost, they are still prescribed for treating gastroesophageal reflux, peptic ulcer and stress-related gastritis (we don't live peaceful lives, do we?).

Four drugs are currently in clinical use: cimetidine, ranitidine, famotidine and nizatidine. They are amazingly selective for histamine type 2 receptors.

H2 receptors are situated on parietal cells of the stomach, those which secrete HCl in the lumen. The interaction between histamine and said receptor activates adenylyl cyclase. This inceases the intracellular level of c-AMP, which stimulates the pump regulating the secretion of H+ ions.

Basically these antagonists reduce by 60-70% the daily secretion of hydrochloric acid. In particular, these drugs have terrific efficiency on nocturnal secretion (better than newer PPIs).

Still, there are more drawbacks here than with PPIs, which have almost no adverse effect. However, considering the average number and frequency, these drugs are extremely safe. Sure, they might induce diarrhea, myalgias and constipation, but these are annoyingly common.
More interestingly, when administered intravenously, confusion may occur.

Cimetidine, the oldest, is also the least selective, messing up the metabolism of androgens, estradiol and prolactin. So, long therapies at quite high doses can end up with pretty nasty stuff such as gynecomastia in men and galactorrhea in women.

Cimetidine triggers metabolic inhibition of c-P450s too.

Generally speaking, drugs are divided in agonist and antagonist molecules. Basically, the agonist triggers a biological response, while the antagonist doesn't.

Pharmacologists have always tried to explain how the biological effect is correlated with the binding of the molecule to its target. During their studies, scientists have pointed out differences among the agonists and, therefore, two subtypes of agonists were defined: partial and inverse agonists. Antagonists were subclassified too.
Partial agonists are unable to trigger the maximum response; inverse agonists, on the other hand, reduce the baseline activity of the target.

Clark was one of the first to formulate a theory that explained the aforementioned relationship: he said there is a linear dependence between responce and number of receptors occupied by the molecule (or, in other words, its concentration).
Clark's theory has been corrected, as time passed:new discoveries showed, in particular, that proteins are actually in a dynamic equilibrium between an active and an inactive form.
Consistently, an agonist(A) will bind to the active form of the receptor R (R*), while an antagonist will form an adduct with the inactive form.

Basal activity will be due to the number of receptors normally in the active form.

Let's go back to the definition of inverse agonist, now. We said these molecules bind to the receptor and REDUCE its basal activity.
Since the chances of a response are tightly linked to the active form, inverse agonists have an extremely higher affinity for the inactive form R, rather than R*.
Inverse agonists will bind to R, reducing the number of active receptor.
To sum up, agonists move the equilibrium to R*, inverse agonists to R.

According to its definition, an antagonist will not reduce the basal activity: it'll solely NOT trigger any additional biological effect, but it will leave unaltered the basal activity of the protein.
We should therefore consider our antagonist as the fulcrum of a balance, on whose  plates agonism (hence, R*, in order to trigger the biological respose) and inverse agonism (hence, R, in order to decrease the baseline response) were placed.

This can lead to the conclusion that antagonism doesn't REALLY exist, but is a mere pharmacologic, theoretical artifact, with no correspondence in a real biological system.