The Half Decent Pharmaceutical Chemistry Blog

Today we start with a raw number: 171,000,000. This is the estimated amount of people suffering from diabetes, according to the WHO.

Thing is, though, I have never covered the subject. Ever! So, this week I talk about a pretty heterogeneous family of drugs which all, through different mechanisms, could improve the life of who suffers from, above all, type 2 diabetes mellitus.

Sulfonylureas are, also chronologically, the first subgroup.

 

Their site of action is located on the inward rectifier ATP-sensitive potassium channel in B cells (those where insulin is produced and secreted). There they inhibit potassium efflux, depolarizing the cell and, thus, allowing insulin to be released.

Moreover, they also inhibit the secretion of glucagon from A cells by increasing the amount of circulating somatostatin, which is a well-known inhibitor of secretions.

Their major toxicity is hypoglycemia: unsurprisingly, if the release of insulin is excessive, dramatic hypoglycemia will result.

Repaglinide (a meglitinides) and Nateglinide (a D-Phenylalanines) have very similar characteristics: both depolarise B cells, both are mainly used to control postprandial glucose levels and both can cause hypoglycemia.



Interestingly, Repaglinide can be useful in case of type 2 diabetes with sulfur and sulfonyureas allergy.

Metformin is my favourite one. This biguanide is a lovely euglycemic agent: it stimulates glycolysis, reduces gluconeogenesis, glucose absorption and glucagon concentration.



Amazingly, it's the only drug, among those effective in type 2 diabetes, which doesn't lead to weight gain or hypoglycemia. Moreover, it may reduce the onset of type 2 diabetes!

Such a fantastic drug isn't, however, free from adverse effects: they are diarrhea, impaired Vit.B12 absorption and, above all, lactic acidosis.

Thiazolidinediones are smart drugs, since modulate gene expression: their target is PPAR-γ (peroxisome proliferator-activated receptor γ), in adipose tissue.
Once bound to PPAR-γ, glucose intake is reduced, as well as the synthesis of lipid hormones and cytokines.



Not only is hypoglycemia a possible side effect, but they also shouldn't be administered in pregnancy. Funnily, Pioglitazone is reported to decrease the bioavailability of oral contraceptives too.

Last but not least, here come the alpha glucosidase inhibitors.



These drugs simply impair the intestinal absorption of starch and disaccharides, reducing glycemic excursion.

Don't think, however, that, although they look rather banal and simple, you can always prescribe them: they're contraindicated, in fact, in the presence of inflammatory bowel disease and renal impairment.

Besides, flatulence and abdominal pain can easily result as natural fermentation of undigested carbohydrates in the colon yield smelly small fatty acids.

 

Honestly, I can't think of any one who would say: "My life will be complete once I'll graduate and start my research project about gout!"

That's why gouty is considered an incredibly uncool subject: everybody wants to study neurodegenerative diseases, nowadays. So, who cares about that annoying pathology.

However, because I hate (scientific) fashions and people with no imagination, who always opt for the currently hottest theme, this week's DotW wants to say: "Hold on: gouty can be thrilling too."

In a nutshell, this week, Allopurinol is my "drug of choice". Here it's and doesn't it look proud?

Its target is xanthine oxidase, the enzyme which converts those purine nucleotides that aren't incorporated in nucleic acids into uric acid.

I must now take a minute to describe what gouty is: in the past (until the end of the middle age), this was a distinctive feature of nobles (and rich people in general).
They were the only ones who could afford to eat an (awful) lot of meat.

This led to a typical symptomatology characterised by acute arthritis and the formation of uric acid calculi in the kidneys.

Now we know the former is due to deposit of urate in joints and the latter is a consequence of massive concentration of uric acid in the urine.

NSAIDs can be used to treat gout: in fact, arthritis results from phagocytation of monosodium urate crystals from synoviocytes, which then release IL-1, prostglandines and other inflammatory modulators.

Once macrophages have arrived, they, too, begin to phagocytate urate crystals and release even more inflammatory mediators.

So, Indomethacin is useful since it inhibits both phagocytosises.

However, in case of chronic gout, recurrent renal stones, renal functions impairment and suspiciously high serum urate levels, Allopurinol is the drug of choice.

Like purines, which always undergo two reactions (both involving the same enzyme: the aforementioned xanthine oxidase), the reaction of this molecule with the said enzyme yield another inhibitor (alloxanthine)!

This means, amazingly, that the drug can be administered just once on a daily basis, because its effect will last 24 hours, although the half life is much shorter.

So, this antagonist has undoubtedly fantastic pharmacokinetics.

Speaking of which, I must underline its interactions: it dramatically increases the effectiveness of those purines antagonists used in cancer chemotherapy (6-MG and 6-TG) as well as cyclophosphamide (the smartest of the alkylating drugs). On the other hand, anticoagulants and uricosuric agents (i.e. probenecid) end up having less power.

Uricosuric agents are, briefly, another class of molecules used in this context: they decrease uric acid reabsorption at the proximal tubule. They are likely to yield calculi, but avoid arthritis.

Finally, the adverse effects. Allopurinol, as a purine derivative, is capable of depressing bone marrow elements.

At the beginning of the therapy, an NSAID is needed since allopurinol precipitates gouty attacks (urate crystals are withdrawn).

Necrotizing vasculitis, dermatitis, pruritic maculopapular lesions and peripheral neuritis are other common side effects.

So, is gout all that boring?

This is the present I received last Christmas from my Grandma: Gioacchino Rossini's "Il Turco in Italy" (The Turk in Italy) featuring Maria Callas, the "divina" (divine).

Even if you only know few things about her, you'll probably be aware of the rumours surrounding her terrific weight loss. It's not unusual for opera singers to be, well, rather fat or, more than that, they never get any thinner throughout their career.

I think their major concern regards the power of the voice: maybe such a therapy would leave them without the source of their fortunes. Frankly, I've no idea whether this is true or not.

However, Maria Callas lost an astonishing 120 pounds, suspiciously quickly, that's for sure.

Now, rumour has it that she swallowed a living tapeworm with a glass of champagne. This wasn't a new approach: since the beginning of the 1900s, tapeworms have been considered to be a way to lose weight and keep yourself thin.

There is no proof cestoda are any good at it, but some people have undoubtedly tried them.

Whether worms are a reliable treatment or not, I hope you'll agree with me that the idea of introducing a living being in your body in order to lose weight is appalling.

Cystercosis is, besides, an infection caused by cestoda, which can worsen, in a nutshell, become a systemic rather than a local one.

Fortunately, there is Niclosamide, which kills tapeworms by inhibiting oxidative phosphorilation and stimulating ATPase activity.



Or you can opt for Praziquantel, especially whenever tenia solium (also known aa tapeworm)   manages to penetrate the intestinal wall and cause (neuro)cystercosis.



Praziquantel is also the drug of choice for Schistosomiasis.

Its mechanism is pretty simple: it increases the permeability to calcium of the cell membranes of the worm. As happens in our cells, this leads to increased contractility: the worm, though, is paralysed, dislodged and, in the end, killed.

This drug, unfortunately, is more toxic than Niclosamide: fever, pruritus, myalgia and urticaria are frequently reported. Moreover, in case of neurocystercosis, meningismus, headache, seizures and intracranial hypertension can occur.

Interestingly, there is a drug which is almost free from adverse effects, Mebendazole, which has some potential in this context too, since it inhibits microtubule synthesis in a wide range of helmintics (ascariasis, hook-, pin- and, also, tape-worms).



Another broad spectrum antihelmintic, Albendazole, could be an option. The mechanism is, again, the inhibition of the synthesis of microtubules.



It's larvicidal in the presence of cystercosis and ascariasis, ovicidal in ascariasis, ancylostomiasis and trichuriasis.

Funnily (considering Maria Callas' story), the drug is more effective if taken with fatty meals, providing a perfect carrier for the drug in order to reach tissue parassites. Otherwise, empty stomach is needed.

Albendazole, for what concerns the side effects, can cause abdominal distress, alopecia and pancytopenia.

So, all things considered, don't you think physical activity plus a balanced diet to be a much safer way to lose weight, Maria?

This week I want to talk about one of my favourite classes of drugs. Anthracyclines are the major sub-type, but other antibiotics have similar function.

Moreover, they are antibiotics: this means they are produced by a microorganism. In this case, Streptomyces is the common "father" of all of them.
Look at how beautiful their patriarch is.

So, we begin with Anthracyclines, which are the most used antitumor antibiotics. They can be used for a huge number of different solid tumors: breast, endometrium, ovary, testicles, bladder, liver, stomach, thyroid and lungs.

Moreover, they play a key role in a variety of childhood neoplasiae (yes, I think that this should be the plural of neoplasia, since it's Latin): osteosarcoma and rhabdoblastoma, for example.



Amazingly, these drugs have more than a mechanism to exert citotoxicity: the major activity is the inhibition of topoisomerase II.
However, their structure allows them to block transcription and translation by intercalating DNA too.
Last but not least, they can impair several ion transports.

Apparently, there is even a fourth one: an adverse effect is cardiotoxicity, which is likely to be linked to the reduction of these antibiotics to semiquinone radicals. I'm sure you can imagine this just by looking at the structures, eh?

These magnificent drugs have cool adverse effects too: the cardiotoxicity, for instance, could be either acute or chronic. The former in the form of arrhythmias, the latter of heart failure.

While myelosuppression is annoyingly usual with cancer chemotherapy, the so-called radiation recall skin reaction isn't.

The other members of the family are pretty "funky" as well.

Bleomycin, for instance, is cell-cycle specific drug: it forces the tumor cell to stop in the G2 phase.



Moreover, the best feature of the molecule is the iron binding function. Iron(II) ions allow the breakage of DNA, once Bleomycin has bound to it, through an oxidative process which yields free radicals.

There is a price, though, to pay for all this amazingness: catastrophic pulmonary toxicity (pneumonia, cough, dyspnea).

No matter, this drug can treat Hodgkin's and non-Hodgkin's lymphomas, germ cell tumor, head cancer and squamous cell cancer.

Another great molecule is Mitomycin: this is an alkylating agent, which is citotoxic through cross-linkage in the DNA.



Squamous cell cancer and superficial bladder cancer are situations where it is often used, although it can cause hemolitic-uremic syndrome (characterised by thrombocytopenia, renal failure and microangiopathic hemolytic anemia) and pneumonia.

The party piece, here, is the selective activation mechanism, which takes place in the stem cells of hypoxic tumors and explains why this is a n alkylating agent (maybe you were wondering how this could be possible...).



Isn't it beautiful?

Mitoxantrone and Dactinomycin are other children of Streptomyces: the former breaks DNA, binding to it, and inhibits transcription and replication; the latter seems to like the G-C base pairs in particular, where it intercalates, inhibiting RNA synthesis.



Mitoxantrone is often used when prostate cancer proves to be refractory to hormone therapy. Dactinomycin is, on the other hand, commonly prescribed with Wilm's tumor, rhabdosarcoma and Ewing's sarcoma. (Mind you, isn't it an impossibly beautiful molecule, too?).

What a superb family!

If you think Aspirin has the broadest spectrum of therapeutic uses, you'll be taken aback by this: Methotrexate, the most multi-purpose, multi-purpose drug, ever!

I bet you already know everything about its use as an anticancer agent: binding to dihydrofolate reductase (check out the similarities with dihydropholic acid) results in sudden lack of thymidylate, purine nucleotides, serine and methionine.



Its effectiveness, however, can be dramatically reduced through four different mechanisms: decreased drug transport, decreased polyglutamate formation (which takes place once the drug is inside the cell and is generally thought to have therapeutic importance), increased dihydrofolate reductase synthesis or expression of an altered form of the enzyme, with less affinity for methotrexate.

Like many anticancer drugs, the most usual toxicities are myelosuppression, leukopenia and thrombocytopenia.

Now, that would be fine, but this amazing drug has two additional applications.

First there is the treatment of arthritis. Actually, methotrexate is the drug of choice for rheumatoid arthritis, since it remarkably decreases the rate of new erosions.

This is due the inhibition of either aminoimidazolecarboxamide (AICAR) transformylase and thymidylate synthetase.

In this case, dosage varies and so does toxicity: hypersensitivity (severe shortness of breath), pseudolymphomatous reactions and mucosal ulcers.

However, the risk/benefit ratio makes it an excellent choice in other rheumatic conditions such as juvenile (chronic) arthritis or subacute lupus erythematosus.

Finally, methotretaxate is effective whenever, in the presence of ulcerative colitis or Crohn's disease, inflammatory bowel disease occurs.

Here, our mighty molecule interferes with IL-1-mediated inflammatory response and, at the same time, is thought to promote the release of adenosine.

I'm sorry for you, Aspirin.