The Half Decent Pharmaceutical Chemistry Blog

Good evening and welcome to the Christmas's special of S.N.S. Now, the main feature of this special is that there is nothing which may even remotely remind you that Christmas is coming.

What we have, instead, is the nice synthesis of chlordiazepoxide. This is obviously a benzodiazepine, so, it has sedative properties. Because benzodiazepines will be featured in the Psycho Week, I'm not to describe their pharmacology.

For what concerns this particular drug, interestingly, it was the first benzodiazepine to be launched on the market and the biotransformations it undergoes, once absorbed, lead to remarkably active metabolites.

Now, let's take a look at this accidentally discovered synthesis.



We begin with a Friedel-Craft acylation, which requires zinc chloride, instead of traditional aluminum trichloride. However, because of the nature of the two molecules, the very first reaction taking place is between the amino group and the acyl chloride, yielding an amide. Then, the acylation occurs, but, because the solution will contains unreacted amines, these can attack the carbonyl.

Actually, this amino group will therefore yield an imine: the pH of the solution has been properly adjusted, I guess.
No matter, we end up with a very unstable adduct: that Schiff base easily reacts with water and this is very nice, since we finally have what we were looking for.

We add hydroxylamine and, then, that particular acyl chloride. And here comes the tricky question: which group will react with the carbonyl?

Now, this whole first part of the synthesis, so far, was designed so that the hydroxyl would  attack the carbonyl, but, surprisingly, it doesn't, whereas that nitrogen succeeds.

We've got now another adduct which is likely to lead to a much thermodynamically stabler molecule, the final product, luckily.
Methylamine sort of ignites this 'rearrangement' or intramolecular series of reactions, if you prefer.
Please forgive me if the arrows don't perfectly point towards the atom but they seem to indicate bonds: I'm still learning how to use that programme.

What I hope you to check is if I've correctly drawn what reacts with what.

To sum up, by the way, a pretty successful mistake, eh?

The title of this episode could have been "The drug who lived twice", from that Harry Latchman's film. Amantatine has two, completely different, clinical uses. It is either effective against virus influenza A (but not B) and, being a dopamine agonist, it is used to treat parkinsonism

When this aminoadamantate was launched, it was thought solely to be a useful agent to tackle viruses. It's action can be briefly described as a selective inhibition of uncoating of viral RNA inside the host cell. Not all viruses, though, are sensitive: actually only virus influenza A is so badly struck that won't be able to replicate itself.

The way this orally administered drug blocks viral cycle has to be found on the viral membrane and, in particular, in the M2 proteins. This protein is, unfortunately, likely to mutate and that explains for half of the patients amantadine is useless against this very virus.



This, frankly, unreliable antiviral has even important adverse effects: nervousness, difficulty in concentrating, birth defects if taken during pregnancy and fatal neurologic toxicities.

Maybe at this point some people might have thought of getting rid of poor amantadine: a less toxic derivative (rimantadine) was later developed and other anti-influenza agents such as zanamivir and oseltamivir, with wider spectrum and incredibly few drawbacks, were launched as well.

Accidentally, though, the drug was found to have antiparkinsonism properties, although, to date, it's not completely clear how this is possible. What we know for sure is that, like levodopa, its action is indirect, on the synthesis or release or, maybe, re-uptake of dopamine.

Still, compared to levodopa, it's less potent and its action is shorter. None the less, during that short period, bradykinesia, rigidity and tremor, all are dramatically improved, with better results than those seen with levodopa.
And we still don't know everything about the way anantadine works.

Anyhow, this molecule should never be prescribed to people likely to develop seizures or with some genetic predisposition for heart failures. In fact, all the central effects remain and there are even some added to the list: restlessness, depression, agitation, excitement, hallucinations, confusion and acute toxic psychosis.

Livedo reticularis (very unpleasant), edema, postural hypertension and urinary retention are, among other common (especially the first one) adverse effects, the nastiest.

Yesterday I saw an ER advert on the telly. This means, within a month three or four TV series will be on the Italian television: we've got ER, House, Grey's Anatomy and that one on MTV (I think it's the funny one, which doesn't want to be taken seriously). How boring is that?!

Honestly, I've never liked any of them and, frankly, I could bare only some ER episodes, before turning to something more interesting. However, there are lots of fans in this country of those dramas, as in the rest of the World.
Mind you, I think I've never watched a single C.S.I. episode from the beginning to the end, either. Perhaps I've got a problem with TV series as a whole.

There is one thing, however, I clearly remember: some doctor oddly yelling lidocaine dosages at the nurses, possibly meaning that American doctors are either bossy or lacking in self-control every time they deal with emergencies. Or maybe nurses are all deaf there.

Although this drug is a terrific local anesthetic, it's a much cooler drug if taken for arrhythmias, in my opinion.

Intravenously administered, lidocaine causes dramatic improvements and few drawbacks to people suffering from arrhythmias, especially whenever acute myocardial infarction is a consequence.

Even though it quickly binds to activated and inactivated sodium channels, the latter effect gives them the opportunity to block Purkinje and ventricular cells, whose action potentials are the longest.



Massive and longer inactivation results in a selective depression of depolarized cells.

Because of its remarkable ability to inactivate ventral cells, this is the drug of choice for ventricular tachycardia and it can prevent ventricular fibrillation which comes with acute ischemic attacks.

As I said, it is phenomenally safe. It's the least cardiotoxic among those which act as sodium channel blockers and hypotension occurs only at high doses and in people with pre-existing heart failure. Moreover, the prophylactic use of lidocaine for the aforementioned fibrillation may increase asystole and, thus, being potentially lethal. But this are well-known facts.

Oddly, the major drawbacks come when it's used as an anesthetic.



These effects include paresthesias, tremor, hearing disturbances, slurred speech and convulsion. This is often caused by a too rapid injection, so, you'll never see it on TV, I guess.

To sum up, a pretty smart drug, with additional potentials in the world of serials.

Yeah, it's Christmas time, which means I should relax, enjoy the atmosphere and work less, right? Well, I think I'm doing the opposite: I mean, I've managed to do both, to date.
This requires some sort of backup, I've used as stimulants coffee and tea only, which I generally consume in other periods of the year too, but, perhaps, at a lower dosage.

Moreover, Christmas is when even the least glamorous café increases the variety of coffees, teas and other sweet, tasteful, hot beverages, so, you are also much more tempted than before.

Tea, Coffee, Chocolate: they are all more or less energetic, they can all warm and, maybe, wake you, they are all associated with the idea of having a break or breakfast.

Predictably, they all contain molecules from the same class: the Xanthines.

Tea is rich in theophlline (and caffeine), the most drug-like of them. It has been the first drug used to treat asthma and, odd as it may sound, its low cost makes it an important treatment even nowadays, although more potent therapies are available.

Oh, a lovely cup of tea! Theophylline induces bronchodilatation and has some anti-inflammatory properties. It can inhibit many phosphodiesterases, which will result in higher cAMP concentrations and, predictably, cardiac stimulation and reduced resistance.
At the same time, theophylline, that clearly resembles adenosine, acts as competitive antagonist of adenosine on surface receptors on either smooth muscle and mast cells. The latter results in less histamine released in the airway.

Although they all are able to cross the blood-brain barrier, only at very high doses theophylline would trigger seizures and lead to death. Some people has committed suicide with an overdose of theophylline.

All xanthines have inotropic and chronotropic effect on the heart. This is primarily due to inhibition of presynaptic adenosine receptors on adrenergic neurons and, with higher concentrations, the said inhibition of phosphodiesterases.
A benefit might be achieve thanks to their ability to reduce blood viscosity.

Tea is a diuretic, as we all know, because more glomerular filtration and less sodium reabsorption occur.

Theophylline is a reliable long-term treatment for asthma, especially when also inhaled corticosteroids are administered.

Now, when I'm abroad the only thing I really miss is a proper coffee, like this.

 

I can't stand those long, brownish, tasteless, aqueous liquids you are used to call coffee. A real (Italian) coffee has nice quantities of caffeine and IT could wake you up.

Caffeine has less effectiveness on smooth muscle cells, but, predictably, cross the blood-brain barrier more easily than the others. Here xanthines trigger vasoconstriction, so, and I'm giving you first-hand information now, will make you feel better if you have headache.
Sensitive people may show nervousness and find difficult to fall asleep.

From a cardiovascular point of view, blood pressure is likely to be raised, because it is a more potent antagonist of adenosine at its presynaptic adrenergic receptors.

A typical adverse effect experienced by usual coffee consumers is the increase of acid secretions in the stomach, but this is likely to be due to a component of coffee other than caffeine.

I can't think of anything more Christmas-ish than a cup of hot chocolate. Maybe with cream on top. Mmm...

Cocoa, as well as chocolate, contains theobromine, or 3,7-dimethylxanthine. Actually, there's not very much to say about this xanthine, since it has no particular features.
None the less, it's thought to be the strongest stimulant of the centre of pleasure (probably located in the hypothalamus) of them all. How can you deny this? Mmm...

Of these three beautiful xanthines, my favourite remains theophylline, but, the real reason is because I like tea very much.

 

 

 

 

Now, this is Aspirin but don't turn over, because I think it's still a very cool drug.

 

It might be a familiar shape, but if you stop and think, you'll realise it remains a brilliant molecule. A very simple anti-inflammatory drug and an analgesic, quickly absorbed from the intestine.

Aspirin is THE non selective COX inhibitor, but its anti-inflammatory effect is also the result of its interference with granulocyte adherence, stabilization of lysosomes and inhibition of macrophages and leukocytes.

Nowadays, aspirin is more likely to be prescribed because of its analgesic potential: a possible explanation is its inhibitory role at some subcortical sites.
You can even treat with it someone with pain caused by a cancer, as well as subjects suffering from rheumatic fever or rheumatoid arthritis.

We can't, however, forget about the remarkable reduction of high temperature aspirin can trigger by inhibiting not only the COXs, but also IL-1.

A still popular use of this triumph of German chemistry is the one that people fearing myocardial infarction, thrombosis or ischemic attacks will always say to be the most important one: due to irreversible inhibition of COX isoforms in the platelets, aspirin dramatically reduces platelet aggregation.
Oh, old Americans are so fond of it!

While 0.6 grams of aspirin are the typical dose for achieving the antipyretic effect, 50 to 75 mg/kg on a daily basis should be the range for an anti-inflammatory effect.

Sure, we all know about its nasty gastric adverse effects (from intolerance to gastric ulcer and erosive gastritis) and you might have experienced asthma, hyperpnea, rashes or some degree of hepatic or renal toxicity.

What you probably haven't tried yet is salicylism: high doses result in vomiting, tinnitus, vertigo.

Even more uncommon are the effects produced by a toxic dose of this NSAID: high quantities of salicylates tend to cause metabolic acidosis, respiratory depression and cardiotoxicity. In this case, sodium bicarbonate is parentally administered and, through increasing the pH of urine, increases the excretion of salicylate.

If you're looking for less gastrointestinal problems, though, you should consider this.

A derivative of phenylpropionic acid called Ibuprofen, which is often administered orally to achieve a great analgesic function.
In fact, you'll rarely use this as anti-inflammatory. Actually, if administered with aspirin, you'll end up with less anti-inflammatory effectiveness. Even the very popular antiplatelet effect will be lost.

Still, when it comes to analgesic action, this is a class of its own: creams are often use to treat osteoarthritis and gels will help you dealing with postsurgical dental sorrow.

Although you get slightly less pain in your stomach, prepare yourself for rash, pruritus, headache, aseptic meningitis and fluid retention.

And, if you are really unlucky, agranulocytosis and aplastic anemia.

At this point you may be tempted by choosing one of these, according to your prevalent issues, but hold on!, because there's a third option.



Yes, Indomethacin, one of the most powerful non selective COX inhibitors. So potent, it can inhibit phospholipases and reduce the number of Tand B cells too.

This drug has paramount importance in the treatment of gout and ankylosing spondylitis and, maybe, it might have a potential for rheumatoid arthritis, nephrotic syndrome, diabetes insipidus and many more.
Conjunctival inflammations can be tackled with a proper ophthalmic preparation containing this drug.

However, there is a price to pay for all this effectiveness: severe abdominal pain (including hemorrhages and pancreatitis), psychosis, thrombocytopenia, aplastic anemia, hyperkalemia and, for a grand finale, renal papillary necrosis can all occur, although with different frequencies.