I recettori: tipologie, funzioni e classificazione.

Prima di iniziare a parlare dei recettori dobbiamo fare una piccola premessa sulla farmacologia, in particolare sulla farmacodinamica.

La farmacodinamica è la parte della farmacologia che studia ciò che il farmaco fa all’organismo. A differenza della farmacocinetica che, viceversa, studia ciò che l’organismo fa al farmaco.

Il farmaco assunto dall’organismo può agire localmente (Azione locale) o sistemicamente (Azione sistemica). L’azione locale si esplica nella sede di applicazione del farmaco. Non è quindi necessario che il farmaco venga assorbito. L’azione sistemica, invece, è quella in cui il farmaco viene assorbito ed esplica la propria funzione in una sede distante dal luogo di applicazione.

C’è da sottolineare, però, che il farmaco non crea l’effetto ma modula una funzione preesistente. Questa modulazione genera diverse funzioni. Ad esempio, può generare una funzione stimolatoria (come quella della digitale che aumenta la forza di contrazione del miocardio), una funzione depressoria (come quella degli anestetici che deprimono le funzioni del sistema nervoso centrale), una funzione sostitutoria (cioè che va a sostituire un’attività funzionale mancante o carente, come ad esempio l’insulina nel diabete o la tiroxina nell’ipotiroidismo) ed una funzione eliminatoria (ossia l’eliminazione degli agenti infettivi, come l’azione degli antibiotici o antimicotici).

I recettori

Il farmaco, per poter espletare la sua funzione biologica, deve interagire con una parte dell’organismo. Qui entrano in gioco i recettori. Essi rappresentano la porta d’ingresso di tutte le funzioni farmacologiche.

Il recettore può essere definito come una macromolecola a cui si lega una sostanza endogena (ad esempio un neurotrasmettitore come l’adrenalina, l’acetilcolina ecc..) per modificare la funzione della cellula e generare così una risposta biologica.

Esistono diverse tipologie di recettori. Ci sono recettori classici (come le benzodiazepine), gli enzimi (come l’aspirina), i canali ionici (come quelli calcio-antagonisti) e gli acidi nucleici (come il cisplatino, un chemioterapico antineoplastico in grado di interferire con tutte le fasi del ciclo cellulare legandosi al DNA attraverso la formazione di legami crociati tra filamenti complementari).

In piccola parte, poi, esistono farmaci che non hanno un recettore “bersaglio” come il bicarbonato, i disinfettanti e il manitolo.

Il legame farmaco-recettore

Nell’interazione farmaco-recettore è importante tenere a mente due caratteristiche fondamentali quali l’efficienza e la stabilità di interazione. Queste due caratteristiche dipendono soprattutto dal tipo di legame che si forma tra il recettore ed il farmaco/neurotrasmettitore (covalenti, ionici ecc.). Inoltre, nell’interazione tra il farmaco e il recettore è importante prendere in considerazione anche l’affinità che c’è tra i due. Da essa dipende la velocità di associazione e quella di dissociazione del farmaco al recettore.

La costante di dissociazione (Kd), che si calcola tramite la formula matematica Kd = [F][R]/[FR], ci permette di capire il grado di affinità di un farmaco ad un suo recettore. Quanto più è elevata l’affinità tanto meno farmaco avremo bisogno per attivare il recettore. Se si somministra un farmaco più volte ma con dosaggio sempre differente, ci si rende conto che anche il grado di affinità ad un determinato recettore cambia. Per questo motivo, a seconda del dosaggio del farmaco, l’effetto sul nostro organismo può essere differente.

A seconda del tipo e del numero di legami chimici coinvolti, l’interazione farmaco-recettore può essere reversibile o irreversibile.

Illustrazione dell'interazione del farmaco (chiave) con il recettore (serratura).
Illustrazione dell’interazione del farmaco (chiave) con il recettore (serratura).

Farmaci agonisti ed antagonisti

Si definisce “agonista” un farmaco che, legandosi ad un recettore, provoca una risposta biologica. L’antagonista, invece, è un farmaco che NON provoca una risposta biologica. Può, tuttavia, avere la funzione di “blocco” per il recettore bersaglio, impedendo il legame di quest’ultimo con una sostanza endogena (con un agonista).

Semplifichiamo il concetto con un esempio.

Una automobile, per accendersi, necessita di una chiave. In questo caso, la chiave “agonista” permette l’accensione della macchina. Quella “antagonista” invece NON accende la macchina e, se inserita nella fessura per l’accensione del motore, impedisce a quella agonista di esercitare la propria funzione.

L’agonista può essere puro o parziale.

L’agonista puro attiva totalmente il suo recettore. L’agonista parziale è un farmaco che attiva non totalmente il suo recettore.

Esiste poi un tipo di agonista chiamato “Agonista inverso” che si lega allo stesso recettore dell’agonista puro ma produce effetti diametralmente opposti e la sua azione è bloccata dagli stessi antagonisti che bloccano quella degli agonisti, ad esempio il GABA che presenta oltre al sito di legame del neurotrasmettitore, anche siti di riconoscimento di agonisti allosterici.

In base alla sua natura, possiamo trovare tre tipologie di antagonista: farmacologico, funzionale e chimico.

L’antagonista recettoriale/farmacologico è quel farmaco che blocca il recettore impedendo il legame di un agonista (sia esso esogeno o endogeno).

L’antagonista funzionale è un farmaco che agendo su un recettore diverso da quello dell’agonista hanno effetti opposti rispetto a quest’ultimo.

Per semplificare il concetto, prendiamo come esempio i farmaci anti-staminici che si utilizzano prevalentemente in primavera per l’aumento della presenza dei pollini e dei “raffreddori da fieno”. L’anti-staminico agisce sull’istamina ed ha un’azione broncocostrittrice. Per annullare questo effetto necessitiamo di un’antagonista. Se decidiamo di utilizzare un’antagonista funzionale, somministriamo un farmaco beta-agonista che rilascia la muscolatura bronchiale. Esso lo fa legandosi al recettore beta2-adrenergico e NON al recettore dell’istamina. Dunque agisce sulla funzione.

L’antagonista chimico, riguarda sostanze che reagiscono chimicamente con un agonista bloccandone l’azione o favorendone l’eliminazione. È dunque quel farmaco che si lega all’agonista e lo blocca (o lo rimuove), impedendone gli effetti indesiderati causati, ad esempio, da iperdosaggio assoluto o relativo oppure per neutralizzare gli effetti di sostanze tossiche (antidotismo).

ANTAGONISMO ANTAGONISTA AGONISTA
Farmacologico Naloxone Morfina
Funzionale Adrenalina Istamina
Chimico Protamina Eparina

 

Classificazione funzionale dei recettori

Funzionalmente, possiamo distinguere i recettori in due grandi classi: i recettori metabotropici e i recettori ionotropici.

I primi, una volta raggiunti dal ligando, attivano una serie di reazioni intracellulari a cascata mediata da un secondo messaggero e sono localizzati sulla membrana citoplasmatica (sono recettori transmembrana).

Fanno parte di questa classe i recettori accoppiati alle proteine G (recettori colinergico.muscarinico, adrenergico, dopaminergico, serotoninergico, cannabinoidi, oppiacei e purine), i recettori tirosin-chinasici, i recettori per le citochine e per le guanil-ciclasi.

I recettori ioinotropici, invece, causano l’apertura di un canale di membrana racchiuso dal recettore stesso. Anche questi sono recettori transmembrana. Tra questi, ricordiamo i recettori colinergico-nicotinici, quelli 5HT-3, NMDA, GABA e quelli per la glicina.

Classificazione per localizzazione dei recettori

Per localizzazione, possiamo distinguere i recettori in due grandi classi: i recettori di membrana e i recettori intracellulari.

I primi trasducono il segnale portato da mediatori idrofilici che difficilmente passano la membrana cellulare (citochine, neurotrasmettitori classici, peptidici, fattori di crescita ecc.)

Trasducono il segnale generando delle modificazioni intracellulari, generando di secondi messaggeri oppure stimolando la formazione di macrocomplessi molecolari biologicamente attivi.

I recettori intracellulari invece trasducono il segnale portato da ormoni e altri mediatori lipofilici che diffondono facilmente attraverso le membrane cellulari. (Ormoni steroidei e tiroidei, Vit. D, ac. retinoico ecc.)

Nel prossimo articolo entriamo nel dettaglio di queste due grandi classi, andando ad analizzare i vari tipi di recettori di membrana e dando uno sguardo ai recettori intracellulari.

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