INIBITORI DELLE MONOAMINOOSSIDASI (I) EPATOTOSSICITA’ CRISI IPERTENSIVE EMORRAGIE R.I.P.

Youdim et al. Nature Reviews Neuroscience 7, 295–309 (April 2006) The prevention of tyramine metabolism in the small intestine, liver and endothelium by irreversible monoamine oxidase A and B (MAOA/B) or MAOA inhibitors can lead to its presence in the circulation1, 66, 67. The uptake of tyramine by adrenergic neurons in the ventrolateral medulla, in which MAOA is also inhibited, initiates the release of noradrenaline, a substrate for inhibited MAOA, into the synaptic cleft, with consequent stimulation of cardiovascular sympathetic nervous system activity1. This activity led to hypertensive crises, and, in some cases, death, resulting in the withdrawal of many MAO inhibitors from clinical use. Following reuptake of noradrenaline into the presynaptic terminal, this neurotransmitter can be degraded in the absence of MAOA activity, via an alternative pathway involving catechol-O-methyl transferase (COMT). Because MAOB is not present in adrenergic neurons, the cheese reaction is not seen with irreversible MAOB inhibitors, except at higher doses, which cause the selectivity of these inhibitors to be lost1. The use of reversible MAOA inhibitors avoids this problem, as dietary tyramine is able to displace the inhibitor from peripheral MAOA, allowing its metabolism62, 64, 68, 69. A recently developed brain-selective MAOA/B inhibitor, ladostigil, does not cause the cheese reaction

INIBITORI DELLE MONOAMINOOSSIDASI (II)

INIBITORI DELLE MONOAMINOOSSIDASI(III)

INIBITORI DELLE MONOAMINOOSSIDASI (IV)

1949 Litio 1952 1955 1987 1994 1996 1997 NARI IMAO TCA SSRI SNRI NASSA

ANTIDEPRESSIVI TRICICLICI

TCA 1 H1 M1 Reuptake NA Reuptake 5HT Stabilizzazione delle membrane; disturbi della conduzione cardiaca Effetti complessi (tremori, riduzione soglia convulsiva; viraggio maniacale) Reuptake NA Reuptake 5HT

( : ) : Sensibilità dei recettori Effetto clinico Livelli di neurotrasmettitore ) :

INIBITORI DEL REUPTAKE DELLA SEROTONINA

Principali vantaggi degli inibitori selettivi della ricaptazione della serotonina Mancanza di effetti collaterali anticolinergici e vascolari Bassa tossicità acuta Nessuna reazione con i componenti della dieta

Principali svantaggi degli inibitori selettivi della ricaptazione della serotonina Nausea, anoressia, insonnia Disfunzione sessuale Sindrome serotoninergica (tremore, ipertermia, collasso cardiocircolatorio) quando vengono somministrati in associazione con I-MAO Possibile aumento del comportamento aggressivo e suicida

(Noradrenergic And Specific Serotonergic Antidepressants)

AGOMELATINA MELATONINA MT1 – MT2 5HT2C

FARMACI STABILIZZANTI DELL’UMORE Sali di Litio

Fig. 2. Lithium inhibits key enzymes required for phosphoinositide signalling. Stimulation of phospholipase C (PLC) cleaves phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] and 1,2-diacylglycerol (1,2-DAG). Lithium inhibits the enzymes inositol polyphosphate 1-phosphatase (IPPase) and inositol monophosphatase (IMPase), which blocks recycling and de novo synthesis of inositol. Depletion of inositol lowers the concentration of PtdIns(4,5)P2 and Ins(1,4,5)P3. Ins(1,4,5)P3 is also formed by breakdown from inositol hexaphosphate (InsP6). Inositol is generated from glucose and hence inositol levels might be influenced by the activity of glycogen synthase, which in turn is regulated by glycogen synthase kinase 3 (GSK-3) and therefore is affected by lithium. Abbreviations: glucose-6-P, glucose-6-phosphate; Ins(1)P or Ins(4)P, inositol monophosphate [brackets indicate C-positions]; Ins(1,3,4,5)P4, inositol (1,3,4,5)-tetrakisphosphate; Ins(1,3,4,5,6)P5 inositol (1,3,4,5,6)-pentakisphosphate; Ins(4,5)P2, inositol (4,5)-bisphosphate; PtdIns, phosphatidylinositol; PtdIns(5)P, phosphatidylinositol (5)-phosphate.

FARMACI STABILIZZANTI DELL’UMORE Sali di Litio Acido valproico Carbamazepina