The Half Decent Pharmaceutical Chemistry Blog

Depression is a disease, that's (now) for sure. It hasn't always been considered a pathology: in the past, there was the same attitude towards it we may have for laziness or bad temper.

Even the term "depression" is a little bit too vague: the most common form of depression is classified as reactive depression.
This is the most misleading type: it's thought to be caused by a particular stimulus (such as the death of someone we love, a terrible disease, etc.).
In these cases, it's not uncommon to hear (or say) things like: "S/He is depressed, but time will help."

Time is often of no help in this case: drugs are often the only solution, if a (specific) doctor chooses the right one or the perfect regimen.

Then there is also the so-called endogenous depression, which is almost always genetically caused. Still, there's frequently some tragic event which starts the process.

The third, and most severe, is, basically, the depression experienced by who suffers from bipolar disorder: as outlined, the ups are the periods of mania, but the downs (which outnumber the periods of maniac behaviour) can be described as severe depression.

Although scientists could point out these three types of depression, and characterize them, they only GUESS that the cause lies in problems with the amine-dependent synaptic transmission.

The amine hypothesis (this underlines how far we are from the end of the tunnel) describes serotonin and norepinephrine as the sole neurotransmitters involved.
Despite a great number of other suppositions and studies (it's one the most studied diseases ever), all the important classes of antidepressives, so far, have been designed bearing in mind the principles of the amine theory.



Tricyclic antidepressants are the best known, most commonly prescribed and cheapest.

Look at them, aren't they beautiful?



Their action is simple and smart: they block the re-uptake of norepinephrine and serotonin (although not all have the same affinity for both systems). This prolongs the action of these neurotransmitters.

Later, a second group of antidepressants was launched on the marked: the so-called Heterocyclics.



Albeit members of the same group, they have different mechanisms. Yes, re-uptake impairment is still the major role played by some of them, but there are interesting exceptions.
Many of them, in fact, partly antagonize dopamine re-uptake pumps in the brain too.

Amoxapine, for example, is the derivative of a neuroleptic (loxapine), so it acts as a proper dopamine antagonist.

Mirtazapine is a powerful antihistaminic and is the most sedating of all the heterocyclics., but it's also the most likely to cause weight gain (which can induce depression in some people, I guess).

Considering the adverse effects of the tricyclic antidepressants, scientists realised they were all caused by their antimuscarinic, antihistaminic and alpha adrenoceptor-blocking actions.
Only serotonin remains a useful target, theoretically free from adverse effects: so, pharmaceutical firms designed the selective serotonin re-uptake inhibitors (SSRIs) and thought they managed perfectly.



In theory they were perfect, but soon important drawbacks were reported: decreased sexual function and libido, interactions with other types of antidepressants (anti-MAO) and serotonin syndrome, a condition characterized by hyperthermia, muscle rigidity, rapid changes in mental status and vital signs.

How sad...

Monoamine oxidases are a group of enzymes which oxidize monoamines, so, neurotransmitters such as norepinephrine. The inhibition of the catabolic pathway leads to an increased number of amines released by the presynaptic cell.
Also dopamine is metabolized by MAOs: this means the same effects on dopaminergic transmission seen with the heterocycles might be found with anti-MAO too.



Serotonin and norepinephrine are both metabolized by the MAO-A enzyme, while MAO-B are involved in the metabolism of dopamine.
Irreversible MAO inhibitors lead to tyramine accumulation. This explains why people taking anti-MAOs can't assume foods (cheese) or drinks (red wine) with high levels of tyramine: a fatal hypertensive crisis may occur.

All these drugs, however, in the end, increase the serotonergic transmission, although to different extents.

It has to be said, on the other hand, that a chronic use eventually results in down-regulation of the receptors.

So, here you are: four different classes of drugs. Amazingly, they are not only effective in the treatment of depression: panic attacks can be contrasted by anti-MAOs and SSRIs (although benzodiazepines remain the best option, due to the quickest onset of the anxiolytic effect), Fluvoxamine, an SSRI, is used to treat obsessive-compulsive disorder; eating disorders (bulimia), attention deficit hyperactivity disorder and enuresis are often tackled with these molecules.



These drugs are never drugs of abuse: a normal patient would experience unbearable phenomena such as sedation, tremor, insomnia, constipation, confusion, orthostatic hypotension, arrhythmias, seizures, weight gain, sexual disturbances, etc.

These symptoms are best tolerated, or not experienced at all, by depressed patients, where those pathways involved are not working as they should.

Sadly, these are very often chosen in order to commit suicide: tricyclines, in particular, are the "best" choice for these purpose.  And depressed people are so likely to be suiciders that the drug itself is often given to friend or relatives of the patient, so that THEY take care of schedules and doses.

I came across, accidentally, my old book of Greek literature , which I used at the high school.



I really enjoyed studying the development of literature in ancient Greece and that book is just uncanny: you get the impression it's a book designed for university rather than high school.

While I was happily leafing through the pages my eyes were caught by a passage where the plot of Aeschylus's "Oresteia" was outlined.

This is actually a trilogy, composed by: Agamemnon, The Libation Bearers and The Eumenides.
If I were you, I would go and get a copy of it because it's simply amazing. And it's the only trilogy left to us.

By the way, in the Agamemnon a well-known character, the prophetess Cassandra, has a vision of the murder of Agamemnon. Sadly, she will be killed too, soon after.

The description of Cassandra's behaviour resembles a typical case of grand mal or epilepsy, the most interesting of the neurological disorders.

This disease is thought to result from a wide spectrum of causes: genetic or developmental defects, injuries, neurodegenerative pathologies.
All these lead to seizures, that are the result of abnormal discharge of cerebral neurons.

So, while in the ancient past you were considered a prophet and Apollo was responsible for your gift (which Cassandra considered a cursed gift: how could you blame her?), now you're just ill and treated with different approaches (including electroshock therapy or neurosurgery).

There's a pharmacological way too. A lot of drugs have been developed or just tested for this purpose.

Phenytoin is the oldest nonsedative antiseizure agent.

It binds to sodium channels, stabilizing them in the inactive state. Inhibition of calcium influx across membranes leads to the inhibition of calcium-induced secretions of hormones and neurotransmitters.
At high doses, this drug also inhibits release of serotonin and norepinephrine and increases the re-uptake of dopamine.

This leads to a selective reduction of high-frequency firing action potentials neurons.
For this purpose, this is considered the most potent drug.

Unfortunately, there are frequent and eerie adverse effects: nystagmus, which means the patient loses smooth extraocular pursuit movements, diplopia, ataxia, gingival hyperplasia, hirsutism, coarsening of facial features and peripheral neuropathy.

Moreover, the drugs leads to incorrect thyroid function tests, binding very well to thyroid-binding globulin.
Phenytoin is a cit. P450 inducer, but also a substrate: barbiturates and isoniazid, for instance, interact with it.
Sulfonamides interfere pharmacokinetically because they are hugely bound to plasma proteins too.

A second option, for partial seizures, in particular, is carbamazepine, which is another nonsedative agent and is used for trigeminal neuralgia and bipolar disorder too.



Like phenytoin, sodium channels are blocked and this accounts for the inhibition of high-frequency firing neurons.

Barbiturates reduce its effectiveness through cit. P450 induction.

Adverse effects are diplopia and ataxia and idiosyncratic reactions, including aplastic anemia and agranulocytosis.

Phenobarbital has been used in this context too.



Especially for children, this is a remarkably useful drug. It significantly reduces sodium and calcium flows, but, due to its action on GABA receptors, it is excellent at suppressing firing at epileptic foci as well.

Primidone is a prodrug of phenobarbital and it is even more potent, thanks to its improved pharmacokinetics.



Vigabatrin acts only at the GABA receptor, inhibiting GABA-T, the enzyme that degradates GABA.
The drug, though, can cause agitation, confusion and psychosis rather frequently.

Gabapentin alters GABA metabolism and its re-uptake.



This relatively new drug is under investigation: it may have even usefullness as sole drug in the management of epilepsy.

Topiramide blocks sodium conductance, but it also potentiate GABA-induced inhibition, acting at  sites other than benzodiazepines or barbiturates sites.
It guarantees the widest spectrum of seizures-related pathologies, but it can cause somnolence, cognitive slowing, paresthesia, nervousness and confusion.
Besides, it reduces the effectiveness of contraceptives.

Tiagabine is a GABA uptake inhibitor, increasing the concentration of GABA in the forebrain and hippocampus (common focus).
Excessive GABAergic response, however, may result in depression, somnolence, ataxia and tremor.

Levetiracetam interferes with the whole allosteric modulation of GABA receptors, voltage-dependent calcium channels and potassium channels.

Lamotrigine inactivates sodium channels too, and presents, surprisingly, few, mild, side effects: headache, somnolence, skin rashes the most commonly reported.

Also ethosuximide is a relatively safe. It can be considered an potent and selective inhibitor of calcium currents (in the thalamus). Its adverse effects include gastric distress, lethargy, headache, hiccup and euphoria. But they are only transient.

Valprioc acid and its salts block the excitatory receptor NMDA and increase levels of GABA, increasing its synthesis through glutamic acid decarboxylase (GAD), which it seems to stimulate. Somehow...



It inhibits the metabolism of barbiturates, phenytoin and carbamazepine.

For what concerns its side effects, it causes weight gain, hair loss and idiosyncratic reactions (hepatotoxicity, above all).

Felbamate blocks the NMDA receptor, but induces aplastic anemia and severe hepatitis. Still, it's superb in the treatment of Lennox-Gastaut syndrome.

Trimethadione reduces calcium currents, greatly reducing the pacemaker role of thalamic neurons.
Its major drawbacks are sedation and visual disturbances.

Clonazepam, a benzodiazepine, is one of the most effective treatments of the so-called absence seizures. Since it's a benzodiazepine, it'll induce sedation, of course.
Moreover, tolerance develops rapidly, so, this is certainly not the drug of choice for the grand mal.

Last but not least, there is, oddly, a diuretic: acetazolamide.
Since it can induce mild metabolic acidosis, due to the inhibition of carbonic anhydrase, and a lower pH may reduce the frequency of seizures attacks, it's a possible choice.

Moreover, bicarbonate ions are rumoured to trigger depolarization through GABAergic ion channels: reducing their concentration (with a carbonic anhydrase inhibitor) will avoid this depolarization.

This drug has found itself a small niece: in fact, it's the best one for treating seizures during menses, when women experience an increased number of epileptic events.

As you can see there are lots of substances: which one do you think Cassandra should opt for?

Maybe, you don't, I'm afraid. But, to tell you the truth, you're in good company. Some books, for instance, still talk about a benzodiazepine receptor, for which they claim that agonist, antagonist and even inverse agonist were found.

But they are wrong or, at least, partly wrong.
Oddly, though, you can't blame them too much for this: their problem is that they are not pharmaceutical chemists or biologists or biochemists.

Otherwise they would perfectly know that there is NOT a receptor full-stop, but an ALLOSTERIC receptor. And that makes a difference.

You cannot have agonists or antagonists, but activators, inhibitors (beta-CCE) and, in this particular context, a sort of neutralizer, which should inhibits the activity of OTHER allosteric modulators.

This last class is tricky to understand and may have caused the misunderstanding.
Oh, and now you're probably thinking it doesn't exist, but, I'm afraid, you're wrong again: Flumazenil is that neutralizer, although it antagonizes the activity of benzodiazepines only. The other modulators (barbiturates, ethanol, opioids and general anesthetics) are unaltered in their activity.

However, the drug has dramatic importance for treating benzodiazepine overdoses and improve the conditions of people suffering from hepatic encephalopathy. On the other hand, in the presence of high concentrations of tricyclic antidepressants, seizures and arrhythmias will precipitate.

Of course, the difference has no clinical, practical utility, but, still, it's something it be considered, in my opinion.

The benzodiazepine receptor was discovered after barbiturates, however.  These drugs were, thus, the first class of sedatives launched on the market.
Like most of the old drugs, barbiturates have a worse toxicological profile than benzodiazepine, but they are still available, especially due to their low cost.

Moreover, there's one thing where old barbiturates beat newer benzodiazepine: anesthesia.
Thiopental and methohexial penetrate brain tissue (better than benzodiazepines) but their remarkable tissue redistribution and the relative absence of respiratory depression make them the better option.

Both drugs are able to induce sedation, anxiolysis, drowsiness, induce or just facilitate sleep. The major difference between barbiturates and benzodiazepines lies in the therapeutic index: benzodiazepines induce anesthesia at much higher dose than barbiturates. Not to mention coma and death: both can kill you, if the dose is so high that the drug depresses either the respiratory and vasomotor centre in the medulla; but the amount of pentobarbital (now used solely as anesthetic) Marilyn Monroe took was less than that she should have swallowed of any benzodiazepine.



Barbiturates are less selective and can depress the action of glutamic acid too. And even nonsynaptic membrane effects.
To sum up, they are stronger but more furious.

So, benzodiazepines: here they come and don't they look proud?

Some of the changes have dramatically improved pharmacokinetics: oxazepam, for instance, reacts with succinic acid and, in the end, we yield its sodium emisuccinate, water soluble.

However, as you can see some things are paramount: benzene and carbonyl must be co-planar, a substituent on the benzene (position 7) increases affinity, the benzene binding to the central structure increases the activity.

Benzodiazepines (and functional congeners) bind to the said site, which is only in type A GABA receptor (the most common). These receptors are in the central nervous system and, once GABA binds to its own site, these chloride channels open, chloride ions cause hyperpolarization:  this results in inhibition.



Another difference between a benzodiazepine and a barbiturate: while the former increases the frequency of the opening of the channel (ONLY IF GABA IS PRESENT), the latter lengthens the opening period.

Clinical use and adverse effect are linked: higher doses exacerbate every therapeutic usefullness (even respiratory depression follows the same pattern). Although they are very often taken to commit suicide (with alcohol), there is tolerance, which occurs frequently.

You see, old people take benzodiazepines to sleep. These drugs decrease the time needed to fall asleep, prolong stage 2 NREM, reduce REM sleep and stage 4 NREM.
They take the same substance regularly, forever. After some time, there are metabolic or pharmacodynamic tolerances (or both) reducing the effectiveness.

The dose is self-adjusted by the patient who increases the number of administrations, even because it's experiencing physiologic (anxiety, insomnia, excitability and even convulsions) and phychologic dependence.

Sedation is another effect of both types of drugs. However, in this case, anxiolysis, even at therapeutic dose, is associated with impaired cognitive functions and problems with normal motor activities such as driving.

Only barbiturates are reported to cause adverse effects not related to their clinical use (namely, porphyria).

This is the scariest drug in the world. Look at it: you may be tempted to say, with a funny voice, "Mmm, it's just a salt: it doesn't look any frightening." Well, dear, things are pretty much the opposite.

This summer I remember a great series on the good, old BBC: "Stephen Fry: The Secret Life of the Manic Depressive". Now, if you don't know him, go get some information on this terrific actor, as soon as possible.
Anyhow, in this series, he met people who, like him, suffer from bipolar disorder (also known as manic-depressive disorder).



This disease is a particular form of psychosis characterized by an alternation of periods of depression, followed by shorter periods of mania.
The latter is often referred to as a form of paranoid schizophrenia, with grandiosity, aggressivity, overactivity and paranoid behaviour.

There are, though, many different degrees of bipolar syndrome and the pathology has certainly a genetic component, although we still do not know much about it and many studies are under way (particularly due to a worryingly increasing number of cases).

It's been noticed,  however, that cathecolamines (norepinephrine and epinephrine) play a key role. But, still, why a person's behaviour switches from depression to mania remains (partly) unknown.

So, lithium carbonate is this week's Drug of the Week because it is a very, very interesting drug. Its importance in the treatment of bipolar disorder is due to its mood-stabilizing properties.



Amazingly, how it really works is partly a guess. Some think it enhances the activity of serotonin. What's for sure is its blockade of that phenomenon called supersensitivity, which affects dopamine receptors during treatments with antipsychotics (dopamine antagonists), as well as with levodopa (dopamine agonist!).
Probably it reduces norepinephrine and dopamine turnover too.
Last but not least, some believe lithium to increase acetylcholine synthesis: this neurotransmitter could be dramatically important for avoiding mania through cholinergic activity.

A second type of activity is that, which lithium exerts on inositol phosphates.



As shown above, this drug blocks either the conversion of IP2 to IP1 and that of IP to inositol. The whole pathway is therefore depressed and, because it's been proved a link between its overactivity and mania, the inhibition is rather selective.

Moreover, lithium may be involved in G-protein-related transmissions: it has been proposed that the drug uncouples receptor and its G protein.

Fortunately, the drug is losing its previous status of drug of choice for the treatment of bipolar disorder: valproic acid (antiseizures agent) and olanzapine (new antipsychotic) are now considered the better option.

In fact, a common problem with lithium is that it's terrific against mania, but it needs antidepressants to treat the exacerbated subsequent depression. And traditional tricyclic antidepressant make the switches mania-depression quicker, serotonin re-uptake inhibitors are less potent and anti-MAO have lots of side effects

Nevertheless, prophylactic use of lithium has been of paramount importance to control (and reduce the frequency of) mood changes.

Besides, when taken with other antipsycotics, lithium can have potential in the treatment of schizoaffective disorders. It must be said, though, that severe extrapyramidal syndromes very often result from interaction between lithium and antipsychotics.

Those few people who are still under lithium-based therapies need to carry out a maintenace treatment, if they suffer from more than a episode of mania per year.



Such a thrilling drug couldn't be without mind-blowing adverse effects.
Tremor is undoubtedly the most frequently observed and often requires co-administration of beta-1 selective antagonists. Hyperactivity, ataxia, dysarthria, aphasia are the other neurologic side effects.

Mental confusion and lack of motor coordination often lead to a temporary stop of the therapy.

Lithium can impair thyroid functions. Polydipsia and polyuria are renal and reversible complications; nephrogenic diabetes insipidus (due to inability to retain water at the collecting tubule), glomerulopathy, chronic interstitial nephritis, are reported too.

Not only does it cause water retention, but also lithium and sodium are affected, leading to edema, which can eventually provoke weight gain.

Acne and leukocitosis are among the main side effects as well.

Lastly, lithium is easily transferred through breast milk: babies accidentally assuming lithium this way show lethargy, cyanosis and hepatomegaly.

This is not a family, you're right. Actually they are two different families, with a common patriarch: acetylcholine. But unlike what happens in the real world, they live in harmony and work together in the name of, well, parasympathetic effect.

These families are among the noblest ones, deriving from a neurotransmitter.

Although they have different targets and mechanisms, both aim to modulate the physiological effects of parasympathetic and sympathetic nervous system.

Those which directly stimulate the receptors are to be further divided into muscarinic and nicotinic agonists, since they stimulate one of this two types of receptor (subsequently divided into subtypes). Moreover, the two classes are named after their own "father".



Because nicotinic and muscarinic receptors are very often at different sites and are rather different from each other, thus, selectivity is not a problem. Muscarinic receptors are coupled to G-proteins, whereas nicotinc receptors are ion channels.

Generally speaking, these drugs have effects on many organs (all those controlled by acetylcholine): so, the way they are administered, the dosage and the choice of a particular drug are all due to a need for selectivity.

For what concerns your eyes, parasympathetic stimulation causes miosis.

They reduce peripheral vascular resistance, probably through the production of nitric oxide which induces vasodilatation, lowering blood pressure; a compensatory reflex, for which the sympathetic system is responsable, increases heart rate.
Sometimes, the latter overwhelms the former and hypertension occurs (pilocarpine, in particular, has too mild negative chronotropic effect, so, causes hypertension).

Moreover, these drugs can be used for their ability to induce contraction of smooth muscles of the bronchial tree, increase secretory and motor activity of the gut and voiding of the bladder.

Rarely, due to nicotinic receptors in the nervous system, parental nicotine causes convulsions, dramatic hypertension and (sympathetic) tachycardia.
These channels are, however, at neuromuscular junctions too: so, disorganized fasciculation of independent motor units as well as strong contraction of entire muscles may occur. Flaccid paralysis can be the result of exogenous nicotine on skeletal muscles.

Cholinesterase is the enzyme which degradates acetylcholine: to inhibit it means we'll have a prolonged action of the neurotransmitter.
Three subgroups of drugs here: those which reversibly bind to the enzyme and prevent access of acetylcholine (i.e. tacrine), carbamoylating agents (i.e. physostigmine) and irreversible phosphorilating agents (chemical weapons, like parathion, which I won't describe).



A modest bradycardia is their usual effect on the heart: this results from negative inotropic, chronotopic and dromotropic effects (reducing the output) and sympathetic activation, at the ganglia, (increasing vascular resistance).

Besides, they can increased the strength of contraction in weak muscles.



To sum up, the members of this large, double family can be used to treat glaucoma or accommodative esotropia, postoperative intestinal atony, urinary retention, myasthenia gravis (only the cholinesterase inhibitors), atropine intoxication or tricyclic anti-depressant overdose in suicide attempts.

Newest cholinesterase inhibitors Donepezil, Galantamine and Rivastigmine have now replaced older tacrine in the treatment of Alzheimer's disease.



The adverse effects are basically due to excessive parasympathetic stimulation: sweating, bronchoconstriction and acute nicotine toxicity (convulsions, respiratoryparalysis, hypertension and arrhythmia).

That's it for this week. Last week it'll be the Psycho Week, so, no family reunion but 7-days long therapy! The series will be back on Sunday 14.

See you tomorrow for the beginning of the Psycho Week.

Until then, Happy New Year's Party!