The Half Decent Pharmaceutical Chemistry Blog

Quite a dull day: bought some food in the morning, studied laxatives in the afternoon. And, in all this dullness, I suddenly remembered one of the last posts on Tenderbutton, where Dylan talked about levodopa. I was still in Amsterdam...
That was a great blog, by the way.

Unfortunately, I must admit I can't remember what he said about it: there was that movie (because it's American) with De Niro and Robin Williams, a photograph of a preparation of the drug, something concerning drug holidays...and that's it. I mean there was the iPod thing going on and people posting comments on that rather than discussing the article. At least those I read.
I sensed the same atmosphere you feel on the last day of school, before the exams.

Levodopa is a very interesting drug, however. Very usually prescribed to parkinsonians, so, since parkinsonism is a glamorous disease which everyone wants to study nowadays, this has to be considered a fashionable drug.

Now, we all know this worryingly common disease is likely to result from degeneration of dopaminergic neurons in the substantia nigra, lowering the concentration of dopamine in the basal ganglia, where this neurotransmitter normally inhibits GABAergic transmission (balancing the effect of cholinergic neurons).
What starts the degenerative process is still partly unclear.

No matter, one of the first, successful approaches was to re-establish the normal equilibrium by administering, basically, dopamine. Actually, what levodopa does is to increase the production of dopamine in the remaining dopaminergic neurons.
Dopamine itself, in fact, as well as any other neurotransmitter, would be too hydrophilic to cross the blood-brain barrier.

Levodopa is the direct precursor of dopamine: the substrate (levo stands for levorotatory isomer, since the active site is stereoselective) of DOPA decarboxylase.

I sincerely doubt Dylan described the breathtaking pharmacokinetics. Now, the drug is orally administered but, once absorbed, it is activated in situ by local DOPA decarboxylases, which explains some of its adverse effects.

So, nowadays, levodopa is prescribed either in a combined regimen or as single tablet with two molecules. Either case levodopa needs a decarboxylase inhibitor (i.e. carbidopa) in order to reduce this peripheral metabolism and allow a high cerebral concentration.

Now, as it was probably written on Tenderbutton, the terrific efficacy of the treatment is most appreciable right at the beginning: then, year after year, it tends to decline, even due to the necessary dose reductions, which can't be avoided because of the neurologic adverse effects.
This is also caused by supersensitivity, which after 4 years is almost always detected, a possible consequence of the drug itself: the receptors become much more sensitive to dopamine, so, theoretically, the dosage should be constantly increased.

Nevertheless, drug holidays aren't any more the best choice, since, balancing the pros and cons, changing the drug is definitely a better option.

Levodopa doesn't obviously cure parkinsonism: it solely improve the life of the patient. In particular for what concerns bradykinesia (much slower movements, in a nutshell).

Some of the drawbacks avoided by using a DOPA carboxylase inhibitor are tachycardia and atrial fibrillation: they would be the outcome of a high concentration of catecholamine extracerebrally. Life-threatening hypertension can result if the patient is also taking anti-MAOs.

However, although bradykinesia is remarkably improved, dyskinesia is a common side effect, even when the drug is correctly administered.

More important are depression, anxiety, insomnia, somnolence, hallucinations and euphoria: these contradictory adverse effects result from the concentration of dopamine in the brain, thus, they are even worsened by the use of a decarboxylase inhibitor at the same time. Instead of opting for drug holiday (this was the reason), antipsychotics such as clozapine are often prescribed.
However, levodopa shouldn't be prescribed if the patient has a (family) history of psycosis.

The effect of levodopa itself can vary throughout the therapy: on-off phenomenon is a distinctive feature of this molecule and consists of akinesia followed, after few hours, by relatively normal mobility (with dyskinesia, though).

Finally, mydriasis, gout, abnormalities of smell and taste, elevations of transaminases, alkaline phosphatase and bilirubin, brown saliva, urine and vaginal secretions and priapism (STOP LAUGHING!) can happen as well.

Mind you, does anyone know how I can get a password for Tenderbutton?

No serious stuff today: just a little bit of self-promotion (or advertising, perhaps).

From January 1 to 7, we will focus only on drugs acting in the central nervous system.

That's why it is the Psycho Week!

Can you think of better way to kick off a new year?

Today's family is composed by four drugs only. They can be therefore divided into two groups according to structure and function. Moreover, these drugs don't derive from the same pharmacophore (or lead), but have common mechanism to trigger their diuretic effects.

Aldosterone is a hormone which regulates sodium reabsorption and potassium secretion at the collecting tubule.

Because it's a hormone, its action basically consists of a regulation of gene expression: in particular, it increases the activity of apical membrane channels and basolateral sodium/potassium ATPase.

Now, the first two drugs, at the top of the picture, are clearly synthetic hormones, antagonists of aldosterone receptors, while amiloride and triamterene block the influx of sodium and, by doing this, greatly reduce potassium secretions.



Spironolactone is the oldest: a synthetic hormone, which exhibits competitive antagonism to aldosterone. Eplerenone is newer and bares a remarkable much lower onset (spironolactone requires days to exhibit a decent effect).

Amiloride and triamterene block sodium absorption, affecting those sodium channels (ENaC) in the apical membrane at the collecting tubule.

PSDs are used in the treatment of pathologies where overproduction of mineralcorticoids is a distinctive feature: Cohn's syndrome, heart failure, hepatic cirrhosis, nephrotic syndrome, everytime there's a strong decrease of the intravascular volume.

Unsurprisingly, severe hyperkalemia is a typical, and life-threatening, side effect cause by these substances, especially when the patient is taking NSAIDs or any other drug that reduces renin activity.
However, the combined effect of other diuretics (such as thiazides), which induce hypokalemia, in the same regimen, can compensate these dangerous dysregualations of potassium levels.

Other interesting adverse effects include: acidosis, kidney stones, renal failure (with triamterene only), gynecomastia and benign prostate cancer. These last, eerie phenomena are due to the effects of synthetic steroids in the bloodstream.

Good evening and welcome! Tonight we have a very smart drug with a pretty mysterious synthesis (you'll understand soon).

Fluphenazine is an antipsychotic phenothiazine, one of the safest, actually. Still, those phenothiazines with piperidine in their side chain are less potent than aliphatic derivatives, but they are also more selective and have less adverse effects.

Phenotiazines are the first drugs designed for the treatment of schizophrenia. The dopamine hypothesis, now proved partly wrong and simplistic, clarified the paramount importance dopamine antagonists can have in this disorder. Consistently, phenotihiazine are all dopaminergic antagonists.

Fluphenazine is no exception, but it has an additional feature. I circled the very last part of the side chain because the hydroxyl group is very useful: pharmacokinetics has been dramatically improved by pharmaceutical industries which launched esters of fluphenazine (decanoate and enanthate, namely) with remarkable retard-effect.
That was why a common problem with neuroleptic lies in their dosage: the patient often refuses to take medications or is unable to take them regularly.

To sum up, a very smart drug: selective, less dangerous and with long-lasting effects. And here is its synthesis.

We start with an Ullmann reaction: the carboxyl group provides a lovely activating function since this is basically a particular SNA.
The aforementioned group is then removed without the use of any chemical: heat is sufficient with benzoic acid derivatives. How smart, isn't it?

Now, here is the mysterious step. My professor of pharmaceutical chemistry admitted he had no clue, so, I expect you, proper organic chemists, to come up with a brilliant explanations: how can sulfur (at high temperature) promote this cyclization?

Having pointed this out, let's move on. What we have described so far is a standard procedure to yield the common backbone: phenothiazine.
We must now deprotonate phenothiazine and add the first part of the side chain.

For what concerns the second half, before the retrosynthesis could occur, we have to carry out a reaction between piperazine and ethyl chloroformate, at pH 5.5, as we did for Prazosin, to 'protect' a nitrogen.
Then, this amazing prep ends with a reaction between the two by-products, which, I think, is performed in mild basic conditions.

Last week's post about Eflornithine was, in my opinion, rather interesting: it described how a drug could be equally effective in two completely different situations.

The same thing could be said about another drug, although without the dramatic connotation provided by the potential, massive life-saving role among African populations of eflornithine: Minoxidil.

This time both pathologies are very common in Western countries, but, amazingly, affecting much more people than trypanosomiasis and female facial hair: we are going to talk about hypertension and baldness.

 

Actually, hypertension is at the top of chart of cardiovascular diseases, which are, as everybody knows, leading cause of death in the Western World. In fact, arterial hypertension can lead to renal and cardiac failure, stroke and many coronary diseases.

Generally speaking, this disorder results from too high resistances to the normal blood flow.
This might be due to genetic abnormalities, stress, smoking, diabetes and hyperlipidemia: however, these are risk factors, which cooperate to the final effect.

Since blood pressure is the product of cardiac output and vascular resistance, it has to be said that the former often remains constant, while the latter increases here. The normal mechanisms of modulation of blood pressure fail: either the baroreceptors, responsible for detecting stretches of the vessel walls and, consequently, regulating the central sympathetic discharge, or the long-term renin-angiotensin system, which is activated by decreased blood pressure in renalarterioles and triggers vasoconstriction and aldosterone synthesis (excellent for increasing intravascular blood pressure).

By the way, these days, anyone knows someone who suffers from hypertension. A pretty vicious disease, because often detectable only in the presence of a damage to an organ.
So, much should be done in order to prevent it, paying attention at the risk factors. (Yes, you can't do anything against genetic causes...).

Fortunately, because this is a very 'American' disease, lots of research is going on and many drugs are on the market.
There are, interestingly, many different approaches available to cure hypertension and a monotherapy is often useless (at least, you have to vary drugs through the stages -either improvement or worsening-).

Maybe the most obvious pharmacological action is inducing vasodilatation, thus reducing peripheral resistance. Compensatory responses, given that sympathetic reflexes are not damaged at all, don't allow monotherapy, and beta-blockers are generally associated.

These substances are cheap and relatively harmless, so they are still popular. One of cheapest, actually, is minoxidil. And here it is.

 

Although the drug is quite old, it is thought to act on potassium channels, present on smooth muscle membranes, opening and, thus, stabilizing them at such a resting potential that they will be unable to induce vasoconstriction.
The drug must be prescribed together with a beta-blocker, or a loop diuretic: otherwise, among the side effects (but, in this case, simply a terrible mistake for which the doctor has to be blamed) tachycardia, angina pectoris and edema are inevitable result of compensatory reflexes.

Well, an adverse effect, seen even when the drug has been put in the proper regimen, is hirsutism.
Now, if you type 'minoxidil' on Google, apart from boring wikipedia, you'll suddenly realise how this is far from being a problem.
In fact, minoxidil is now present in two different products, both also available as generic: tablets for your hypertension, lotion for your baldness.

 

What I find disgusting, anyhow, is the shocking prevalence of the anti-hair loss effect, which makes me think: do people care more about hair rather than blood pressure?