The Half Decent Pharmaceutical Chemistry Blog

Since yesterday I talked about a contraceptive, I've decided to discuss an ovulation inducer today.

Interestingly, also Clomiphene is orally administered as a tablet, but because it's a partial estrogen agonist, it actually increases the secretion of gonadotropines, which results in higher estrogens levels.

With a partial agonist, in fact, the negative feedback utilized by contraceptives (agonists) doesn't occur. On the contrary, as previously highlighted, the pituitary responds by increasing the production of both gonadotropins by the gonadotroph cells.



But there's more.

Estrogens regulate the action of hypothalamus too, which is responsable for the synthesis of gonatropins, secreting the hormone (GnRH) that stimulates gonadotroph cells.
In the presence of clormiphene, however, hypothalamus is unable to exert any effect on the secretions of gonadotropins and what we have is only the strong stimulation caused by the drug, which will eventually end up in proper ovulation.

Ovulation is therefore stimulated and this has dramatic effects in those women with polycystic ovary syndrome, a disease affecting 7% of women of fertile age, whose infertility is the inevitable consequence of oligo or anovulation.

The drug is not potent enough to induce, successfully, pregnancy at first go, and the patient has to be treated until she becomes pregnant.

There are drawbacks, as you may have guessed. Hot flushes are, obviously, the most common.

Visual disturbances (so don't drive and try to get pregnant), headaches, skin reactions, reversible alopecia, breast soreness, weight gain, depression and fatigue are among the others, but most of them are physiologic consequences of an ovulatory menstrual cycle.

Multiple pregnancy occurs in 1 out of 10 cases.

Periodically, newspapers deal with a certain drug. However, it's not its interesting pharmacology that they are interested in.

Few drugs have had so many different trails. In fact I'm just thinking: given that it's a relatively young molecule, the ratio trials:age is probably the highest, ever
.
Almost every country has carried out a series of clinical trials (or is thinking about it) to get sorted, at least clinically, whether the drug is safe enough to provide a strong basis for convincing physicians.
More problems come once you have to convince the whole population (not to mention your political allies). Especially when religion comes into the equation.

At this point you're probably wondering what the hell I'm talking about today. I'm not trying to convince any one of anything: I've already an opinion and I don't want to express it, since this is, fortunately, a scientific blog and not a Sunday tabloid.



This drug is even still called with its acronym used during its development: this underlines, once more, how different this drug is from all the others.

Besides: the most important thing about it, for most of the people, isn't, say, its half-life, but which government has and which hasn't allowed its prescription.
And, because you might be curious at this point, Italy, Ireland, Poland, almost all African and South American countries are in the latter group.

Can you see any similarity among them?



Thing is, though, whatever your opinion on this issue is, you can't deny Mifepristone is, pharmacologically, amazing.



Although RU 486 is a progesterone receptor antagonist, it even shows luteolytic properties, like the other, rather banal, hormonal contraceptives, which are progestins and/or estrogens and, consistently, inhibit pituitary secretions through negative feedback.

This may prove clinical usefullness of Mifepristone as contraceptive, plus its abortifacient use, for which it's usually prescribed. However, because of the peculiar nature of the (many) trials, the rationale explaining this feature is still unknown. And that's pity.

In addition, a single 600mg dose provides reliable postcoital contraceptive effect.



The molecule can antagonize glucocorticoids as well.

So, it seems that mifepristone has potentials in treating endometriosis, breast cancer and meningiomas (whether this neoplasia presents glucocorticoid or progesterone receptors).

But data are still lacking. Studies are much more interested in assaying the frequency and severity of abdominal and pelvic pain and bleeding, which are the only adverse effect on humans that can actually force a woman to stop the therapy.

Well, I do apologize for yesterday's post, which was bearable as a lecture you attend after you came by bike, under heavy rain, when you have the flu: it's always going to be endless.

Today we have something quick and very useful, in particular if you (plan to) have children. We take about asthma, first of all, the most common chronic disease during childhood.

This pathology is characterized by increased secretion of mucus in the bronchi, airway smooth muscles contraction and mucosal thickening.
The results are recurrent bouts of coughing, respiratory problems and chest tightness.

A possible strategy is to target leucotrienes: these molecules are involved in inflammatory disease and are produced (from arachidonic acid) by many cells which are also present in the airways (mast cells, macrophages, etc.).

LTC4 and LTD4, above all, are involved in some of those typical disturbances commonly experienced by asthmatics: bronchoconstriction, mucosal edema and mucus hypersecretion.

Two approaches can be tried: the former is to selectively inhibit the enzyme that produces leukotrienes (5-lipooxygenase) and is achieved by zileuton. The latter is based on molecules, such as zafirlukast and montelukast, which block leukotriene receptors on target cells.



A great advantage of these drugs over, say, corticosteroids is that, while the latter have to be inhaled, the former group consists of drugs orally administered.

Now, if you have kids, you'll probably already know what I'm about to say: compliance towards inhaled therapies is very poor, while pills are easily swallowed. Mmm, relatively...



So, although they are less effective for what concerns airway caliber and the other conditions, they are better tolerated. And both dramatically reduce the frequency of attacks.



Montelukast is the most tolerable and used leukotriene pathway inhibitor among children with asthma (as a long-term therapy).

More than that: these agents have proved, once again, that aspirin induces asthma through inhibition of prostglandin synthesis, which results in increasing concentrations of arachidonic acid (substrate for both classes) available for leukotrienes production.

Last but not least, these antagonists are incredibly free from adverse effects.

Yes, Christmas is over and we are back! The incredibly evil-minded, vicious and unfriendly pharmaceutical chemists who still unaccountably write scientific blogs!
We are back because it's not necessary to pretend to be good, given that a Coke-branded old man has already dropped his stuff and, if he tries to take it back, we'll shoot him.

I'd like to talk about a pretty common condition affecting lots of people: Arrhythmia. You see, 50% of anesthetized patients will suffer from arrhythmia as a side effect, just to show how often such a banal procedure can cause this problem.

This disease is, basically, the result of a series of circumstances which can increase, reduce or disturb the physiologic rhythm of heart contraction and, by doing this, dramatically reduce cardiac output.

Interestingly, many of the drugs used in this context are actually capable of inducing lethal arrhythmia in particular situations.
Thus, drugs are generally used solely when we deal with severe attacks which may lead to life-threatening complications. Otherwise, asymptomatic arrhythmia is not treated.

A nonpharmacologic approach consists of implant of  pacemakers or surgery.

Pacemaker is the key word to explain, briefly, what cardiac arrhythmias are. You see, there are physiologic pacemakers in our heart, where electrical impulses originate. These stimuli have a certain range of normal frequencies and result in cardiac contractions, once the input has been delivered to the different points at a certain rate. The propagation of impulses follows a pattern which optimizes contractions (so, propulsion) and relaxation (filling) of atria and ventricles.

Unsurprisingly, ions (sodium, potassium and calcium) play a central role in these mechanisms. In particular, their diffusion through membranes can trigger (and regulate the frequency of) cardiac action potentials and it is controlled by specific channels.



Action potential and resting potential are tightly bound to each other: the higher (more depolarized) the latter, the less sodium voltage-dependent channels will open, the slower the conduction, the smaller the amplitude of the action potential.

Other key factor is the refractory period, which is that range of time while the cell is unable to evoke any action potential since sodium channels are 'recovering'. Alterations in the normal refractory periods often result in arrhythmias.

As shown above, in pacemaker cells, instead of a relatively long resting potential, depolarization takes place spontaneously due to hyperpolarization-dependent ion channels and their short action potentials don't like like those of cardiac cells at all.

Now, let's point out how some alterations result in arrhythmia.

First of all, there are many possible factors which can induce arrhythmias: ischemia, electrolytes abnormalities, acidosis, alkalosis, excessive cathecolamine exposure, some drugs (such as digitalis), etc.

Arrhythmia may result from problems with the (impulse formation at the) pacemaker (hence, a possible approach is the implant of an artificial pacemaker) or problems with the electrical conduction.

During diastole, spontaneous depolarization in the pacemaker cells takes place. The shorter the diastolic interval, the steeper the slope representing the spontaneous depolarization, the higher the pacemaker rate.
Consistently, beta-blockers slow pacemakers, hypokalemia (because pacemakers are particularly sensitive to hypo as well as hyperkalemia), positive chronotropic drugs and acidosis accelerate the rate.

Re-entry is a very interesting condition which often causes arrhythmia. In a nutshell, a stimulus actually reenters and produces an additional stimulation. A circuit results in which our mighty impulse may like to lap many times: this will cause from a couple of extra beats to tachycardia.

 

This situation is a consequence of some sort of obstruction of physiologic conduction, which creates the circuit with a unidirectional block.
This generates a retrograde input which might stimulate tissues. It MIGHT if the conduction-time is long enough that the input reaches the tissue while still in its refractory period.

However, some drugs slow down the conduction velocity, so that bidirectional block results, instead of a unidirectional. Theoretically, accelerating conduction could be usefull too.

Moreover, a longer refractory period increases the chances of reentry to find a refractory tissue.
This can be achieved by blocking sodium or calcium currents.

To sum up, drugs try either to normalize pacemaker activity or to disable the reentry circuit.

Blocking sodium or calcium channels, sympathetic autonomic effects on the heart or increasing the refractory period, are all possible mechanisms of antiarrhythmic drugs.

Channel-blocking agents have high affinity for activated or inactivated channels, so they are effective in case of tachycardia

Other drugs are those which either reduce the steady-state potential (hyperpolarization) in those cells where channels could be used to propagate stimuli that would result in extra beats, or increase the refractory period of the said cells, by increasing recovery time (from inactive to close).

To sum up, drugs can selectively shunt automaticity and abnormal conduction in depolarized cells, but not in normally (steady-state) polarized cells.

None the less, it's more useful to classify all antiarrhythmic preparations in a different way.
Quinidine, Procainamide and Disopyramide prolong the duration of action potentials and block sodium channels.

Lidocaine and Mexiletine don't alter action potentials but rapidly dissociate from sodium channels.

Flecainide slowly dissociate from sodium channels.

Beta-blockers, such as Propranolol, are useful because of their action on beta cardiac receptors and sympathomimetic activity.



Action potentials may be prolonged and, therefore, refractory periods lengthened by amiodarone (although it has many adverse effects affecting vision), brethlium and dofetilide.

Verapamil is most effective calcium channel-blocker, so antihypertensive, in treating arrhythmias.

Unfortunately, too high dosages of almost all these drugs will result in loss of this amazing specificity and, thus, arrhythmias. Not to mention their own, peculiar, extracardiac, adverse effects.
Moreover, at the very beginning of the therapy, tachycardia can produce arrhythmia, since more cells will be blocked. Other situations when these antiarrythmic agents turn into vicious arrhythmogenic agents includeacidosis, hyperkalemia and ischemia.

Interestingly, adenosine (due to increased potassium and decreased calcium currents), magnesium (because it may influence all three types of channels and the sodium pump) and potassium (because it will stabilize membrane potentials) are theoretically useful, but seldom prescribed.

 

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.