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.
