4 INIBITORI DELLE MONOAMINOOSSIDASI (I) EPATOTOSSICITA’CRISI IPERTENSIVEEMORRAGIER.I.P.
5 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
20 Principali vantaggi degli inibitori selettivi della ricaptazione della serotonina Mancanza di effetti collaterali anticolinergici e vascolariBassa tossicità acutaNessuna reazione con i componenti della dieta
21 Principali svantaggi degli inibitori selettivi della ricaptazione della serotonina Nausea, anoressia, insonniaDisfunzione sessualeSindrome serotoninergica (tremore, ipertermia, collasso cardiocircolatorio) quando vengono somministrati in associazione con I-MAOPossibile aumento del comportamento aggressivo e suicida
27 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.
28 FARMACI STABILIZZANTI DELL’UMORE Sali di LitioAcido valproicoCarbamazepina