The Half Decent Pharmaceutical Chemistry Blog

The incidence of cardiac pathologies is dramatically increasing everywhere. So, no doubt a class of drugs, with a wide spectrum of use in the many different conditions, generally called cardiovascular diseases, has a huge importance.
Among these multipurpose drugs, calcium channel blockers are probably the best-known.

Although you're not much of a doctor, there is a distinct possibility you'll know the importance calcium ions play in muscle contraction. Cardiac muscle is no exception: there are different types of channels, though, and those blockers currently on sale are more or less all non-selective. But very useful.

Interestingly, there are two groups of CCBDs: dihydropyridines (on top), that resemble a family-like structure, and three molecules with unrelated structures to the former (and all different from each other). Among the latter class, Verapamil was the very first blocker tested. Nifedipine is the father of the dihydropyridines.



Now, both types of drugs reduce the frequency of opening of channels by binding from the inside of (above all) depolarized membranes. So, heart's contractility and conduction velocity are reduced.

So far, T-type channel selective blockers (most common on heart cells) hasn't been found: those currently prescribed are L-type selective. This channel is more present on smooth muscles.
In fact, vascular smooth muscles are relaxed, which results in a reduction of blood pressure through peripheral vasodilatation.

CCBDs also reduce cardiac contractility and output through their action on channels in the sinoatrial and atrioventricular nodes. There are differences in between the two groups of CCBDs with dihydropyridines less effective in reducing cardiac contractility.

An additional minor effect lies, in my opinion, in one of the features of nimodine: this molecule has a remarkable affinity for cerebral blood vessels. This makes of nimodipine an extremely useful drug for hemorrhagic stroke. And, interestingly, some say that any CCBD may play a key role in the aftermath of thromboembolic stroke.

To sum up, these drugs have great importance in the treatment of anigina pectoris, since a decreased cardiac contractility leads to a minor oxygen requirement. The peripheral vasodilation, moreover, explains why they are increasingly prescribed as a prophylactic treatment for angina.
The action on the pacemakers makes these drugs (albeit, not the dihydropyridines) suitable for treating some kinds of tachycardia.

As I said in the beginning, CCBDs have such a variety of actions they have a place in regimens for hypertension and arrhythmia.
For the former, dihydropyridines are stronger than the others when it comes to reduce pressure only. However, since they almost do not alter cardiac contractility, reflex sympathetic activation would trigger tachycardia: so, nifedipine is orally administered in case of emergency hypertension only.

The other CCBDs are more often prescribed in cardiac arrhythmias than nifedipine and its offspring.
Verapamil, in particular, directly acting on sinoatrial node, tends to eliminate afterdepolarizations in supraventricular arrhythmias.

Finally, my favourite part: adverse effects. Here, however, it's just a matter of quantities and there's nothing that might scare you: if doses are excessive, the very therapeutic mechanism can cause cardiac arrest, bradycardia and heart failure.

Digoxin is a very cool drug. If not the coolest, it's one of the most thrilling substances you could come across. Oh, yes, it can save your life, but, through the same mechanism, it can kill you too. Very easily, indeed.
So, here we are: a genuinely thrilling drug.

As you probably know, digoxin is one of the glycosides present in foxglove. Chemically, it's nothing more than a steroid, plus a lactone, plus sugars. Far from being a surprise, the steroid is substituted at the 17 and 3 positions.

Still, you may thing it's a bit obsolete as a drug, but I let you into a little 'secret': in case of emergency, it's always gonna be one of the major options to consider.
Moreover, as you might have already realised, the fact that it's very old makes it extremely cheap (a generic is available), which means it's very used in underdeveloped countries.

To use it correctly, however, cold blood and lots of experience are foundamental, because a match between the likelihood of the pros and of the cons will very often end up in a comprehensive defeat for the former.

Still, this mainly orally administered drug has benefits when it comes to heart failure. This pathology can be described as a situation where the heart can't sufficiently provide oxygen for organs and tissues.

One of the things that controls cardiac contractility is the so-called sodium pump (or Na+/K+ ATPase), which is present almost in every district of our body. Obviously, this already explains how easy it can be for a drug like digoxin to cause lots of side effects.

In fact, digoxin inhibits the sodium pump, which results in marvelous increase in contractility: actin and myosin, in cardiac sarcomeres, interact more intensively, because the concentration of calcium ions is now higher.
The partial blockage of the pump, in fact, triggers a reduction of calcium expulsion, which has a massive impact on contractivity.

A larger amount of calcium in the cells means a higher potassium conductance. So, digoxin produces shorter action potentials. Which is another good thing: shorter atrial and ventricular refractoriness is achieved.

Now, here come the terrible drawbacks. If your doctor is not a good one and gives you a slightly too higher dose, the resting potential of cardiac cells will be significantly reduced and, little by little, delayed afterdepolarizations begin to interfere with the normal resting potentials...until the inevitable happens. Afterpotentials increase until they reach the threshold required in order to evoke action potentials: once there, they will cause a constantly increasing tachycardia, which, eventually, end up in fibrillation. Fatal fibrillation.
Besides, digoxin's sympathetic effects at toxic dose often results in arrhythmia.

Due to its structure, cardiac glycosides cross the blood-brain barrier and reach the nervous system, where they can produce disorientation and hallucinations (do not lick frogs, you know what I mean).

The action towards the chemoreceptor zone results in anorexia and terrible nausea.

A possible antidote to this toxicity is potassium, which competes with glycosides at the sodium pump and slows down cardiac automaticity.
On the opposite side, calcium increases toxicity (hypercalcemia is linked to arrhythmia).

Last "Drug of the Week" was metronidazole, which I chose for two reasons: its adverse effects (dark urine was so amazing, wasn't it?) and importance (it is the drug of choice for the treatment of amebiasis).

One of my usual readers, movies, has expressed bewilderment looking at the list of drawbacks: to sum up, how can a substance with so many frequent and severe side effects be in clinical use?
Well, things can be worse, much worse.
As I said, the aforementioned drug is very cheap, being available as generic, and, believe it or not, is the safest to contrast Entamoeba hystolitica's infections pharmaceutical firms have come up with, so far.

Thing is pathologies caused by protozoans (including malaria) are much more diffused in Africa and Southern Europe than America and Western Europe.
This means that pharmaceutical industry doesn't invest very much in research for this kind of therapies: so, molecules are generally old and seldom improved after their registration.

Now, you can think pharmaceutical companies are the devil or go on hating them. However, if you live in the USA or Europe, where life-attendance is much longer than in Africa, you are more likely to get a cancer or Alzheimer disease, for example. In that case, you'll probably change your mind, considering the huge efforts pharmaceutical industries are constantly putting in development of newer, less toxic, state-of-art treatments for these pathologies.
You're chances of living longer and better than in the past depends on the money invested on some drugs instead of antiprotozoals.

By the way, I believe countries like India, that face these emergencies, with their growing economies and superb scientists, will improve this class of drugs. One day or another.

This said, let's go back to protozoans and remedies used to tackle this issue.
In particular, I would like to tell you a funny story which deals with trypanosomiasis. Well, you will maybe think it's actually very sad: it depends...

Generally speaking, these drugs lack in efficacy and safety, as movies pointed out. More worryingly, they are often quite expensive.
But, at this point, nonprofit foundations come into the equation: most of the time only thanks to their donations, governments can afford to buy these drugs.

Advanced African tryponosomiasis has been treated with melarsoprol since 1949: this arsenical can cross the blood-brain barrier, which is dramatically important here.
This molecule, however, can cause encephalopathy, which leads to edema, seizures and coma. The patients may even die, if not monitored.
Renal and cardiac toxicities are reported too.
As I said, things can be even worse: drug resistance, in fact, is increasing in Africa.

But, hold on, because there is a second way: a depilatory cream called Vaniqa

Eflornithine is molecule designed to inhibit ornithine decarboxylase, an enzyme of paramount importance for the protozoa.
Although its spectrum is limited to T brucei gambiense (which is the major source of African tryponosomiasis) and it presents side effects such as anemia, thrombocytopenia, leukopenia and seizures, toxicity is generally reversible and cross-resistance with melarsoprol hasn't been reported so far.

Scientists registered the molecule and it is still on sale. Anyhow, the price wasn't affordable for governments of those places where it is so badly needed. And, apparently, for nonprofit organizations too.

Some years ago, a lower dosage of eflornithine was found to have efficacy when used as a depilatory cream.

 

 

Actually, it must have been such a success for the company, that eflornithine is now much more available: high profits for the pharmaceutical firm meant it was now possible to donate larger quantities of parental eflornithine.

Funny, isn't it...?

Today's family is one of my favourite ones. I would say that, having a well-known past, we may consider this a royal family: their origin dates back to 1860, although some say they are even older. Not a well-to-do family, though, since the patriarch was sulfur mustard, used in the First World War by the Germans: in a nutshell, the first proper chemical weapon. How sad...

But, still, what amazes me is that chemists could turn such a vicious source of death into the first proper cancer chemotherapeutic drug(s). That's why I like this class of molecules very much.

Looking at the picture below, you'll probably think that I was wrong and forgot about other important alkylating agents such as cisplatin. However, I've considered the issue quite a lot and opted for bisamines and nitrosoureas only, because of the similar mechanism against DNA.
Moreover, bisamines and nitrosoureas have clear similarities solely looking at their structures.
So, if you were looking forward to reading about cisplatin or my beloved thiotepa, well, I guess it'll be the protagonist of an episode of "Drug of Week".



Clockwise from top left, the nitrosoureas (carmustine, lomustine and semustine) and the bis(chloroethyl)amines (chlorambucil, cyclophosphamide and melphalan). In the middle, the patriarch of those sulfur mustards that were designed in order to be drugs: mechlorethamine.
At the bottom, ifosfamide: a derivative of cyclophosphamide.

All these drugs obviously alkylate DNA, triggering cell death either through miscoding or, literally, breaking the strand opening sugar-phosphate bonds.
Both form an ethyleneimonium ion (or a carbonium one), whose main target are the N7 position of guanines. The reaction occurs in such a way that two ethyleneimonium ions are yielded, which results in cross-linking of both DNA strands. It has to be said that monoalkylation is likely to take place too.
How brilliant is that?!

Other, less frequently alkylated positions are the N1 and N3 of adenosines, the N3 of cytosines and the O6 of guanines. Moreover, nitrosoureas carbamoylate lysines through isocyanates as well.

Such a marvelous mechanism, unfortunately, don't take place in neoplastic cells only: all rapidly growing cells are attacked. This means bone marrow, hair, gastrointestinal tissues and the whole reproductive system is likely to be damaged.
Moreover, in the past, bisamines were administered solely parentally: the injection is incredibly painful and very often followed by violent nausea, vomiting and tissue necrosis.
Nowadays, administration is generally oral and much more tolerable.

Going back to the adverse effects, leukopenia is the most common one, with thrombocytopenia at close distance. Bisamines often cause a less dangerous toxicity, which is, however, the most peculiar and common one: alopecia.
Every drug as, in addition, its own particular set of nasty side effects.

The resistance could be a decreased permeability to the drug, an improvement of mechanisms of DNA repair or, the coolest of them all, due to glutathione, which normally inactivates these molecules and can be synthesized at a higher rate.
Cross-resistance is common among bisamines, but some nitrosoureas can be still effective

For what concerns nitrosoureas, they are clearly more lipid-soluble, so, it can be prescribed in the treatment of brain tumors.

Entamoeba histolytica is a pretty vicious protozoan. It can cause asymptomatic intestinal infections, colitis and extraintestinal infections.

Metronidazole is the drug of choice for the treatment of intestinal infections (except for the asymptomatic ones) and all the other infections for which Entamoeba histolytica has to be blamed.
Although the drug doesn't remove cysts and a luminal agent, such as Iodoquinol, has to be added to the regimen to completely get rid off the infection, metronidazole is nicely active against trophozoites.

The nitro group, in fact, is reduced by the protozoan itself, resulting in activation of the drug (although this has not been completely comfirmed yet).

Trichomoniasis is generally treated with metronidazole too, although resistance has been reported.

The reason why I chose this molecule, however, is because of its side effects. Among the most common ones, a metallic taste in your mouth makes it not the best to go with your Thanksgiving turkey (or anything else).

Eerie dark urines may appear, as well as insomnia, vertigo, weakness and paresthesias.
More rarely, people taking metronidazole are subject to severe central nervous system toxicity (including seizures)

More interestingly, metronidazole has disulfiram-like effect: so, you'd better stop drinking while you're taking it, unless you like vomiting very much...

For the grand finale, if you suffer from bipolar disorder and take lithium, its toxicity might be dramatically increased by metronidazole.