Generality
The term " anesthetic drugs " is used to indicate a heterogeneous group of active ingredients which - by acting at different sites and with different mechanisms of action - induce anesthesia .
However, it should be pointed out that anesthetics do not induce analgesia, since - contrary to what happens to painkillers - they are not able to inhibit the synthesis and release of pain mediators, nor do they interact with pain receptors .
However, based on the above, anesthetic drugs can be divided into two macro-groups:
- general anesthetics (which induce loss of sensitivity associated with loss of consciousness)
- local anesthetics (which perform a local action, precisely, without loss of consciousness).
General Anesthetics
As mentioned, general anesthetic drugs induce anesthesia with loss of consciousness .
The state of ideal general anesthesia should be characterized by a total loss of all sensations and should also be associated with analgesia and muscle relaxation. These aims are mainly achieved through the depression of neurons in specific areas of the central nervous system, such as the cortical regions, within which the anesthetic interacts with the stellate cells and with the pyramidal cells.
In order to reach the aforementioned state of anesthesia, it is necessary to resort to the use of ideal anesthetic drugs, which should:
- Induce a rapid state of surgical anesthesia (characterized by unconsciousness, regular breathing, loss of spinal reflexes and loss of muscle tone);
- Induce adequate skeletal muscle relaxation;
- Be free of toxicity and side effects;
- Have a large safety margin;
- Allow a quick and pleasant awakening from the state of anesthesia;
- Be inert from the chemical point of view;
- Have a low cost.
As one can well imagine, the ideal anesthetic has unfortunately not yet been identified. Nevertheless, since the discovery of the first anesthetic to date, research in this field has made great strides, making it possible to synthesise increasingly safe and effective anesthetic drugs.
Currently, general anesthetics can be divided into two categories:
- general inhalation anesthetics
- general intravenous anesthetics.
Below, these categories will be briefly illustrated, but first it is useful to understand with which mechanism of action these drugs act.
Mechanism of action of general anesthetics
In truth, the exact mechanism by which the general anesthetics perform their action has not yet been fully identified and still remains the object of study.
Over the years various hypotheses have been made in the attempt to define the mechanism by which these drugs generate the state of general anesthesia, reaching the conclusion that every active principle can act with different mechanisms of action by virtue of its characteristics.
However, at present, the most accredited hypothesis is that of the ion channel and the protein receptor. According to this hypothesis, the mechanism of action with which the anesthetic exercises its activity is related to the direct interaction with ion channels present on the membrane of nerve cells, and to the interaction with receptors able to modulate ion channels ionically.
In particular, following several studies conducted in this regard, it emerged that general anesthetics mainly affect the cellular flow of calcium ions and sodium ions.
More in detail, various active ingredients have been shown to possess affinity for the gamma-aminobutyric acid receptor type A (GABAA receptor). This receptor is an ionic channel that - once activated by its ligand (gamma-aminobutyric acid, or GABA, in fact) - opens up, allowing the entry of chloride ions into the neuron and causing hyperpolarization, with resulting inhibitory effect. Not surprisingly, GABA is the most important inhibitory neurotransmitter of our central nervous system.
General anesthetics act in a similar way to GABA, ie they bind to a specific site present in the above mentioned receptors, activating them and thus generating an inhibitory effect on nerve cells.
Furthermore, general anesthetics have also been shown to be able to antagonize the NMDA receptor . The latter is a channel receptor that - when activated by its glutamate ligand (the most important excitatory neurotransmitter in our body) - favors the entry of sodium ions into the neuron, promoting excitability.
With the antagonization of the aforementioned receptor, therefore, an opposite effect is obtained, therefore an inhibitory effect that favors the appearance of anesthesia.
General inhalation anesthetics
The general inhalation anesthetics, generally, are drugs available in the form of volatile liquids that are administered, mixed with other gases, to the patient who must be anesthetized.
Of course, the degree of anesthesia that can be achieved depends on the type of anesthetic that is used and its concentration in the gaseous mixture.
Once inhaled, the anesthetic reaches the lungs and alveoli, at the level of which is solubilized in the blood. Then, through the bloodstream, the active principle reaches the central nervous system, where it performs its action.
Among the general inhalation anesthetics most commonly used in therapy, we mention isoflurane, desflurane, sevoflurane and methoxyflurane . These active ingredients are fluorinated hydrocarbons which can cause - though rarely - hepatotoxicity, nephrotoxicity and malignant hyperthermia.
Finally, also nitrous oxide (commonly called hilarious gas) falls into the category of general inhalation anesthetics mostly used in clinical practice.
General intravenous anesthetics
The most commonly used intravenous general anesthetics are propofol, ketamine (or ketamine, if you prefer) and ultra-short acting barbiturates such as thiopental .
Once injected, these active ingredients immediately reach the central nervous system through the bloodstream, exercising a very rapid anesthetic activity. However, their duration of action is quite short.
For this reason, in most cases, these drugs are used for induction of anesthesia which will then be maintained by the subsequent administration of general inhalation anesthetics.
Local anesthetics
Local anesthetics - as one can easily guess from their own name - are drugs that, if administered topically or parenterally in a localized area, are able to induce a limited anesthesia to the area of application / injection of the drug itself .
Among the main local anesthetics used in therapy, we mention benzocaine, lidocaine, articaine, chloroprocaine, mepivacaine, bupivacaine, levobupivacaine and ropivacaine .
Mechanism of action of local anesthetics
Local anesthetics, similar to what happens for general anesthetics, exert their action by acting on the ion channels present in the membranes of nerve cells.
More in detail, local anesthetics are able to bind to voltage-dependent sodium channels, preventing this ion from entering the cell, thereby preventing excitation and thus inducing local anesthesia status.
However, the exact receptor site to which local anesthetics bind has not yet been identified.
Side effects of local anesthetics
The undesirable effects that may occur following the administration of local anesthetic drugs seem to be due to the interaction of these same drugs with other receptors and ion channels present on the excitable membranes, such as, for example, the sodium and calcium channels present at level cardiac and nicotinic type cholinergic receptors present in the neuromuscular junctions and in the central nervous system.
Furthermore, although rarely, local anesthetics - as well as general anesthetic drugs and any other active ingredient - can give rise to allergic reactions in sensitive individuals.
