The Half Decent Pharmaceutical Chemistry Blog

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.

 

It is not unusual for an important man to have (many) sons and daughters, but only one who is able to follow his steps. A bright example are the Coumarins and the virtuous heir is Warfarin.

Dicumarol is a natural substance which was discovered as a rodenticides and, from observations on hemorrhages induced in cattle, anticoagulant.
Dicumarol, however, is not used any more because it's as unreliable as its derivatives (severe gastrointestinal effects), but, nevertheless, it has, in my opinion, to be regarded as a brilliant natural drug which leaded to the most used anticoagulant, Warfarin.
Clinical use of phenindione can result in many side effects in liver and kidney. Phenprocoumon is highly toxic too.

Warfarin, as sodium salt, is an orally administered drug with terrific 100% bioavailability. Not only does it prevent the carboxylation of prothrombin, but also several clotting factors are inactivated. This multiple activity is achieved thanks to the common biochemical pathway normally involved, the so-called vitamin K cycle, or, basically, the oxidation of vitamin K epoxide, blocked by this substance.



Although these drugs cause adverse effects, the most interesting feature are the huge number of interactions, pharmacokinetic and dynamic.

Adverse effects may be due to an overdose, which results in uncontrolled hemorrhages, cutaneous necrosis, infraction of breast or intestine and venous thrombosis because of a reduced activity of protein C.

Pharmacokinetic interactions with other drugs are mainly caused either by induction or inhibition of cit. P450 isoforms. Cimetidine, disulfiram, metronidazole, fluconazole, sulfamethoxazole and trimethoprim augment hypoprothrombinemia.
On the contrary, barbiturates and rifampin, inducing hepatic enzymes, partly reduce the effectiveness of coumarin anticoagulants.

The way other drugs may alter the outcome of an anticoagulant therapy, pharmacodynamically, are many and different. Aspirin dangerously increases the effects of warfarin due to its action on platelet metabolism; heparin inhibits many clotting factors as well as warfarin; interestingly, even cephalosporins, albeit solely those belonging to the third generation, do the same since they tend to kill some intestinal bacteria which generally yield vitamin K.
Inhibition might be achieved with some diuretics, such as spironolactone, but it's mainly due to genetic hereditary mutations of vitamin K cycle molecules.

Fortunately, many important drugs can be taken (relatively!) light-heartedly: benzodiazepines and opioids (both future protagonists in the Psycho Week), indomethacin (check out an article next week) and most antibiotics don't alter the effects of these anticoagulants.

Although four years ago I was still at high school, since university began, there has been a bit of tradition going on among us, former classmates: the annual pre-Christmas reunion.

Every year, the week before December 25 (so, the next one), we meet in some place to have dinner together and talk about what we have been doing that year.

 

 

Two hours ago, I was texted by a friend who told where and when we are going to have this meeting.
That made me remember of last year's dinner, when one of the lads, not a particular friend of mine, annoyed me with his boring questions about beta-blockers all the time.

Let me explain: he is a pretty successful violinist, who, with a surprisingly smart decision, decided to not go to university and went on playing his instrument. That's fair.
He plays in important orchestras all over the world with his mates, wh are, apparently, anxious, insecure, middle-aged people.

He asked me about beta-blockers for a variety of reasons: he can't use internet (he likes to act like a middle-aged man, what a d***), he thought it was my turn to have the pleasure of a chat with him or he was just pathetically looking for human compasion, sharing a view of his life. Well, you looked in the wrong place, dear.

However, beta-blockers are widely misused by a lot of people, even scientists (chemists included). There's something which all these people has in common: very, very insecure as they are, they even have to perform in front of (relatively) huge crowds.

 

 

While in the Seventies musicians playing in front of massive crowds would have opted for cocaine or other drugs (depending on the attitude), we live in a dark age, where antihypentensive drugs rock.

Anxious performers (even a scientist who speaks at a conference) find these drugs really effective, although they fortunately use them a lower dosage than those who take them for, say, hypertension.

A healthy person won't sense any change for what concerns his/her blood pressure, but a remarkable difference is the negative inotropic and chronotropic effect: atrioventricular conduction is slowed even at low dose, for example.

Adverse effects, such as bronchoconstriciton, may appear, but likely to be very moderate and overwhelmed by the feel-good mood.

However, if I were an asthmatic and a musician, I wouldn't try them. Same story with diabetes: they are reported to be capable of impairing recovery from hypoglycemic crisis.
Not to mention, the effectiveness of, for example, a chronic use of propranolol (the most used for this non-therapeutic purpose) in terms of increasing the concentration of VLDL, with long-term consequences such as atherosclerosis.

Generally, I believe, beta-blockers calm anxious performers mainly because of their placebo effect: it's not important what I actually swallow, if I firmly believe it will help me as usual.

 

I haven't yet decided if I'll go this year.