Cont. SICILIAN GAMBIT

11. Targets of drug action

Targets of drug action are the sites at which drugs act. It is important to understand that these sites are not uniquely the recipients of drug molecules. They can be affected by neurohumors and neuropeptides and a variety of other endogenous substances.

Moreover, they can interact with one another (for example cytoplasmic regulators may modulate channels).

However, it is these targets, acting individually or in concert, that determine the rhythm of the heart.

		DRUG ACTIONS
	TARGETS
NERVES and HUMORS
A. CHANNELS B. PUMPS C. RECEPTORS D. OTHER
MECHANISMS OF ARRHYTHMIAS
A. CELLULAR B. EXPERIMENTAL C. CLINICAL

12. Use-dependent block

Molecules that are ionized are present in the cytosol and interact with the Na⁺ channel. They gain access to the binding site only when both the "m" and "h" gates are open. The faster the heart is beating and more channel openings there are per unit time, the more rapid will be the binding. This is referred to as rate-or use-dependent block. Drugs which bind and unbind rapidly tend to accumulate minimally and have a short duration of action and a low cardiac toxicity. By contrast, drugs which unbind very slowly tend to accumulate to a more marked extend and have been shown to be far more proarrhythmic.

The pharmacokinetics and dynamics of drugs, which often are solely conceived of in terms of equilibria for absorption, metabolism and excretion, are important at the level of the binding site as well, and characterize how a drug will act. Characteristics such as these, which determine both drug efficacy and drug toxicity, must be taken into account for each drug and each binding site if we are to understand the action of antiarrhythmic compounds.

13. Pharmacological indices associated with the functional definition of drug action

Use dependence as described before is only one example of drug action. In figure there is a list of indices divided in three major groups:

1. the experimental variables used to study pharmacodynamics;
2. pharmacodynamics;
3. pharmacokinetics.

14. Concept of the vulnerable parameter

Now let us go to what probably is the most critical concept of the Sicilian Gambit: vulnerable parameter. There are two assumptions.

First, we assume that, for each arrhythmogenic mechanism, a specific alteration in one or more of several electrophysiological properties will be sufficient to terminate the arrhythmia or to prevent its initiation.

Second, we assume that, among the several possible effective changes in electrophysiological properties, usually one is most susceptible to alterations while manifesting a minimum of undesirable effects on the heart. That property which, if appropriately altered, is most likely to prevent or terminate an arrhythmia with the least negative effects is called the "vulnerable parameter".

Reentry is an arrhythmogenic mechanism for which the vulnerable parameter is defined. With a long excitable gap, depressing conduction and excitability should induce conduction block in the segment of slow conduction.

With a short excitable gap, the most likely way to terminate the tachycardia is by prolonging the refractory period, whereby the head of the wave front will encroach upon its refractory tail.

15. Wolff-Parkinson-White syndrome

Let us start with a few examples of specific arrhythmias. During orthodromic circus movement tachycardia, antegrade conduction to the ventricles is through the AV node/His-Purkinje system and retrograde conduction to the atria is through the accessory pathway.

There are two potentially vulnerable segments in this anatomically large circuit: the AV node and the accessory connection. If we choose to impair slow AV nodal conduction, the vulnerable parameter is represented by calcium-dependent conduction and excitability, and they should be depressed. The target ionic current is I_Ca-L, which should be blocked, and the most logical drugs are calcium channel-blocking agents.

WPW Orthodromic Atrioventricular Tachycardia

If we choose to delay the fast conduction through the accessory pathway, the vulnerable parameter is represented by conduction and excitability, which should be depressed. The target ionic current is I_Na, which should be blocked, and the most logical drugs are sodium channel blockers.

WPW Orthodromic Atrioventricular Tachycardia

However, the reentrant circuit may have a short excitable gap. In that case, the vulnerable parameter is the refractory period of the accessory pathway, which should be prolonged. The target current is I_K, and the most logical drugs are potassium channel blockers.

WPW Orthodromic Atrioventricular Tachycardia

16. Ventricular tachycardia

Ventricular tachycardia may occur in different substrates and with different mechanism. Here we will present only the most frequent condition, namely circus movement ventricular tachycardia occurring in patients with chronic ischemic heart disease.

The two main therapeutic options are based on the assumption that sodium channel-dependent reentry occurs over a circuit with either a long or a short excitable gap. This example shows that, in long excitable gap reentry with a segment of impaired conduction, the vulnerable parameter is excitability and conduction, which should be decreased.

The target ionic current is I_Na, which should be blocked. The drugs should be chosen among the sodium channel blockers. Clinically, it is often difficult or impossible to determine if a ventricular tachycardia depends on a short or long excitable gap. If the tachycardia can be readily entrained during electrophysiological testing, then it is likely that the excitable gap is long. In this setting, sodium channel-blocking drugs are usually effective.

Ventricular Tachycardia (with a long excitable gap)