ERBRECHEN UND ANTIEMETIKA THEORETISCHE GRUNDLAGEN Slide 1 Univ.Prof.Dr.Herbert Watzke Klinik für Innere Medizin I Medizinische Universität Wien

CHEMOTHERAPIE INDUZIERTES ERBRECHEN MECHANISMEN ERBRECHEN WIRD DURCH DAS GEHIRN GESTEUERT „CHEMOREZEPTOR TRIGGER ZONE“ WIE SCHAUT DIE AUS ? Slide 2 The emetic response, which is primarily a protective reflex, is an extremely complicated mechanism. While this defensive response can occur in various situations, ranging from surgical procedures to motion sickness and morning sickness in pregnancy, we will narrow our discussion to chemotherapy-induced nausea and vomiting (CINV).1 The proposed pathophysiology of CINV occurs primarily via two different mechanisms—one located in the central nervous system (central) and the other mediated in the gastrointestinal (GI) tract (peripheral).2 The central mechanism is hypothesized to occur by activation of the chemoreceptor trigger zone (CTZ) by a chemotherapeutic agent.2 Located in the area postrema, the CTZ is outside the blood-brain barrier and can be accessed through either the blood or cerebrospinal fluid.2,3 Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center.2 The peripheral mechanism is postulated to occur by a chemotherapeutic agent causing local GI irritation and damage to the GI mucosa, which results in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers.2 In both instances, the neurotransmitters may act independently or in combination to induce vomiting.2 KEIN MENSCH WEISS ES! WO IM GEHIRN IST SIE ? AM BODEN DES 4.VENTRIKELS „AREA POSTREMA“ References Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87–94. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796.

CHEMOTHERAPIE INDUZIERTES ERBRECHEN MECHANISMEN ERBRECHEN WIRD DURCH DAS GEHIRN GESTEUERT „CHEMOREZEPTOR TRIGGER ZONE“ WIE SCHAUT DIE AUS ? Slide 2 The emetic response, which is primarily a protective reflex, is an extremely complicated mechanism. While this defensive response can occur in various situations, ranging from surgical procedures to motion sickness and morning sickness in pregnancy, we will narrow our discussion to chemotherapy-induced nausea and vomiting (CINV).1 The proposed pathophysiology of CINV occurs primarily via two different mechanisms—one located in the central nervous system (central) and the other mediated in the gastrointestinal (GI) tract (peripheral).2 The central mechanism is hypothesized to occur by activation of the chemoreceptor trigger zone (CTZ) by a chemotherapeutic agent.2 Located in the area postrema, the CTZ is outside the blood-brain barrier and can be accessed through either the blood or cerebrospinal fluid.2,3 Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center.2 The peripheral mechanism is postulated to occur by a chemotherapeutic agent causing local GI irritation and damage to the GI mucosa, which results in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers.2 In both instances, the neurotransmitters may act independently or in combination to induce vomiting.2 WO IM GEHIRN IST SIE ? WIESO IST DAS WICHTIG ? IST VOM LIQUOR UMSPÜLT LIQUOR TAUSCHT STOFFE MIT BLUT AUS KEINE „BLUTHIRN SCHRANKE“ References Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87–94. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796.

CHEMOTHERAPIE - INDUZIERTEN EBRECHENS PATHOPHYSIOLOGIE DES CHEMOTHERAPIE - INDUZIERTEN EBRECHENS 4.Ventrikel Chemorezeptor TriggerZone

CHEMOTHERAPIE INDUZIERTES ERBRECHEN MECHANISMEN ERBRECHEN WIRD DURCH DAS GEHIRN GESTEUERT „CHEMOREZEPTOR TRIGGER ZONE“ WIE SCHAUT DIE AUS ? Slide 2 The emetic response, which is primarily a protective reflex, is an extremely complicated mechanism. While this defensive response can occur in various situations, ranging from surgical procedures to motion sickness and morning sickness in pregnancy, we will narrow our discussion to chemotherapy-induced nausea and vomiting (CINV).1 The proposed pathophysiology of CINV occurs primarily via two different mechanisms—one located in the central nervous system (central) and the other mediated in the gastrointestinal (GI) tract (peripheral).2 The central mechanism is hypothesized to occur by activation of the chemoreceptor trigger zone (CTZ) by a chemotherapeutic agent.2 Located in the area postrema, the CTZ is outside the blood-brain barrier and can be accessed through either the blood or cerebrospinal fluid.2,3 Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center.2 The peripheral mechanism is postulated to occur by a chemotherapeutic agent causing local GI irritation and damage to the GI mucosa, which results in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers.2 In both instances, the neurotransmitters may act independently or in combination to induce vomiting.2 WO IM GEHIRN IST SIE ? WIESO IST DAS WICHTIG ? WAS PASSIERT DANN ? EMETOGENE STOFFE IM BLUT TRETEN IN DEN LIQUOR ÜBER REIZEN CTZ CTZ SENDET IMPULSE IN DAS BRECHZENTRUM ÜBER GEHIRNBAHNEN („NERVEN“) References Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87–94. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796.

CHEMOTHERAPIE INDUZIERTES ERBRECHEN MECHANISMEN ERBRECHEN WIRD DURCH DAS GEHIRN GESTEUERT „CHEMOREZEPTOR TRIGGER ZONE“ „BRECHZENTRUM“ Slide 2 The emetic response, which is primarily a protective reflex, is an extremely complicated mechanism. While this defensive response can occur in various situations, ranging from surgical procedures to motion sickness and morning sickness in pregnancy, we will narrow our discussion to chemotherapy-induced nausea and vomiting (CINV).1 The proposed pathophysiology of CINV occurs primarily via two different mechanisms—one located in the central nervous system (central) and the other mediated in the gastrointestinal (GI) tract (peripheral).2 The central mechanism is hypothesized to occur by activation of the chemoreceptor trigger zone (CTZ) by a chemotherapeutic agent.2 Located in the area postrema, the CTZ is outside the blood-brain barrier and can be accessed through either the blood or cerebrospinal fluid.2,3 Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center.2 The peripheral mechanism is postulated to occur by a chemotherapeutic agent causing local GI irritation and damage to the GI mucosa, which results in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers.2 In both instances, the neurotransmitters may act independently or in combination to induce vomiting.2 WIE SCHAUT DAS AUS ? KEIN MENSCH WEISS ES! WO IM GEHIRN IST ES ? MEDULLA OBLONGATA „HINTER“ BLUT HIRN SCHRANKE WAS IST DORT? KERN DES TRACTUS SOLITARIUS FORMATIO RETICULARIS References Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87–94. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796.

CHEMOTHERAPIE - INDUZIERTEN EBRECHENS PATHOPHYSIOLOGIE DES CHEMOTHERAPIE - INDUZIERTEN EBRECHENS 4.Ventrikel Chemorezeptor TriggerZone Brechzentrum

CHEMOTHERAPIE INDUZIERTES ERBRECHEN MECHANISMEN ERBRECHEN WIRD DURCH DAS GEHIRN GESTEUERT „CHEMOREZEPTOR TRIGGER ZONE“ „BRECHZENTRUM“ Slide 2 The emetic response, which is primarily a protective reflex, is an extremely complicated mechanism. While this defensive response can occur in various situations, ranging from surgical procedures to motion sickness and morning sickness in pregnancy, we will narrow our discussion to chemotherapy-induced nausea and vomiting (CINV).1 The proposed pathophysiology of CINV occurs primarily via two different mechanisms—one located in the central nervous system (central) and the other mediated in the gastrointestinal (GI) tract (peripheral).2 The central mechanism is hypothesized to occur by activation of the chemoreceptor trigger zone (CTZ) by a chemotherapeutic agent.2 Located in the area postrema, the CTZ is outside the blood-brain barrier and can be accessed through either the blood or cerebrospinal fluid.2,3 Once activated, the CTZ releases multiple neurotransmitters, which in turn activate the brain stem vomiting center.2 The peripheral mechanism is postulated to occur by a chemotherapeutic agent causing local GI irritation and damage to the GI mucosa, which results in the release of neurotransmitters. This then activates receptors in the GI tract, which are mediated by afferent fibers of the vagus nerve. The activated vagal afferent fibers send signals to the brain stem vomiting centers.2 In both instances, the neurotransmitters may act independently or in combination to induce vomiting.2 WAS TUT ES ? ES IST DIE ZENTRALE STEUEREINHEIT EMPFÄNGT BRECHBEFEHL VON CTZ EMPFÄNGT ANDERE SIGNALE VAGUS, CORTEX, VESTIBULARIS AKTIVIERT ALLES WAS MAN ZUM ERBRECHEN BRAUCHT MAGEN, DARM, ZWERCHFELL, SPEICHEL, ATMUNG etc References Saito R, Takano Y, Kamiya H. Roles of substance P and NK1 receptor in the brainstem in the development of emesis. J Pharmacol Sci 2003;91:87–94. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:2869–2880. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796.

CHEMOTHERAPIE - INDUZIERTEN EBRECHENS PATHOPHYSIOLOGIE DES CHEMOTHERAPIE - INDUZIERTEN EBRECHENS 4.Ventrikel Chemorezeptor TriggerZone Brechzentrum

WIESO „KÖNNEN MANCHE LEUTE NICHT BRECHEN“ ? 4.Ventrikel Chemorezeptor TriggerZone Brechzentrum

WIESO KANN EINEM NACH DEM ERBRECHEN IMMER NOCH SCHLECHT SEIN? „NICHTS MEHR IM MAGEN UND BRICHT IMMER NOCH“ 4.Ventrikel Chemorezeptor TriggerZone Brechzentrum

HOCHSCHAUBAHNFAHREN SCHLECHT? WIESO WIRD EINEM BEIM HOCHSCHAUBAHNFAHREN SCHLECHT? 4.Ventrikel Chemorezeptor TriggerZone Brechzentrum

CHEMOTHERAPIE - INDUZIERTEN EBRECHENS ZUM BRECHZENTRUM UND ZUR CTZ ?? PATHOPHYSIOLOGIE DES CHEMOTHERAPIE - INDUZIERTEN EBRECHENS ÜBER NEUROTRANSMITTER (BOTENSTOFFE) ?? WIE GELANGEN DIE REIZE VOM ENTSTEHUNGSORT ZUM BRECHZENTRUM UND ZUR CTZ ?? 4.Ventrikel Chemorezeptor TriggerZone Brechzentrum

NEUROTRANSMITTER DES ERBRECHENS MEHR ALS 30 VERSCHIEDENE SUBSTANZEN, DIE IM BEREICH DES CTZ UND DES BRECHCHZENTRUMS REIZE ÜBERTRAGEN = ZENTRALE NEUROTRANSMITTER Dopamin, Histamin, Acetylcholin, Serotonin, Neurokinin, Opioide, ……. STEIGENDE ZAHL AN SUBSTANZEN, DIE AUßERHALB DES CTZ UND DES BRECHZENTRUM REIZE ÜBERTRAGEN = PERIPHERE NEUROTRANSMITTER

NEUROTRANSMITTER DES ERBRECHENS WIE REIZEN NEUROTRANSMITTER DIE GEHIRNZELLEN IM CTZ UND/ODER IM BRECHZENTRUM ?? Dopamin, Histamin, Acetylcholin, Serotonin, Neurokinin, Opioide, ……. SIE DOCKEN AN REZEPTOREN AN DER ÖBERFLÄCHE DER GEHIRNZELLEN AN

NEUROTRANSMITTER DES ERBRECHENS STOFFE IM BLUT DIREKT AN DIE CTZ KEINE BLUT HIRN SCHRANKE KEIN NEUROTRANSMITTER

NEUROTRANSMITTER DES ERBRECHENS CTZ GIBT INFOS AN BRECHZENTRUM

NEUROTRANSMITTER DES ERBRECHENS BRECHZENTRUM BEKOMMT INFOS VON LEBER NACH MECHN. REIZUNG NACH CHEM REIZUNG GEHT ÜBER NERVUS VAGUS NEUROTRANSMITTER

NEUROTRANSMITTER DES ERBRECHENS BRECHZENTRUM BEKOMMT INFOS VOM: MAGEN/DARMTRAKT NACH MECHN. REIZUNG NACH CHEM REIZUNG VON 5 HT3 REZEPTOREN GEHT ÜBER NERVUS VAGUS NEUROTRANSMITTER

NEUROTRANSMITTER DES ERBRECHENS BRECHZENTRUM BEKOMMT INFOS VOM: PLEURA PERITONEUM etc. NACH MECHN. REIZUNG GEHT ÜBER NERVUS VAGUS NEUROTRANSMITTER

NEUROTRANSMITTER DES ERBRECHENS BRECHZENTRUM BEKOMMT INFOS VOM: VESTIBULARAPPARAT HÖHEREN HIRNZENTREN

NEUROTRANSMITTER DES ERBRECHENS BRECHZENTRUM BEKOMMT INFOS VOM: VESTIBULARAPPARAT HÖHEREN HIRNZENTREN CTZ IST STÄNDIG DURCH ENKEPHALINE UNTERDRÜCKT

WIE ENTSTEHT DIE ANTIEMNETISCHE WIRKUNG VON MEDIKAMENTEN MEDIKAMENTEN BINDEN AN REZEPTOREN UND BLOCKEN DADURCH DIE WIRKUNG DER NEUROTRANSMITTER AB MEDIKAMENTEN BINDEN MEHR ODER WENIGER SPEZIFISCH AN GEWISSE REZEPTOREN

WIE ENTSTEHT DIE ANTIEMNETISCHE WIRKUNG VON MEDIKAMENTEN MEDIKAMENT REZEPTOR ORT INDIKATION NEBENWIRKUNG HALOPERIDOL D2 CTZ Opiod, chem, Dyskinesie HALDOL® METOCLOPRAMID D2 CTZ, GIT Stasis, Ileus Dyskinesie, Kolik 5HT4 GIT 5HT3 CTZ, GIT Chemoth. PASPERTIN® DOMPERIDONE D2 CTZ, GIT Stasis, Ileus Kolik MOTILIUM® CISAPRIDE 5HT4,Ach GIT Stasis, Ileus Kolik, Arrythmie. PREPULSID® PHENOTHIAZINE D2,H1,Ach CTZ, GIT Übelk.,Erbr. Hypotonie,Sedierung 5TH2 BZ,ZNS ANTIHISTAMINIKA H1 BZ Übelk., Erbr. Sedierung,Xerosto. ANTICHOLINERG. Ach m BZ, GIT Obstr., Periton. Xerosto., Agitier.

WIE ENTSTEHT DIE ANTIEMNETISCHE WIRKUNG VON MEDIKAMENTEN MEDIKAMENT REZEPTOR ORT INDIKATION NEBENWIRKUNG 5-HT3 ANTAGON. 5HT3 CTZ, GIT,(BZ) Chemo, Postop Obstip, Diarrhoe NK1 ANTAGON. NK1 ZNS (Striatum) Chemo

NEUROTRANSMITTER DES ERBRECHENS Substance P Acetylcholine Histamine Endorphins Dopamine Serotonin GABA* Emetic Reflex Slide 5 This slide depicts our current understanding of the neurotransmitters involved in chemotherapy-induced nausea and vomiting (CINV), including the most recently identified emetic neurotransmitter, substance P.1–3 Peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, substance P, dopamine, histamine, and other endogenous neurotransmitters. When these receptors are activated, emesis is induced.1,2 In the past 15 years or so, enormous advances have been made in our understanding of the neurochemical pathways involved in CINV. The advent of selective 5-HT3 receptor antagonists has served as a pharmacologic tool for studying the emetic pathways associated with CINV. The introduction of this class of drugs stimulated considerable clinical research and improved our understanding of CINV.4 Where the original preclinical efficacy trials of 5-HT3 receptor antagonists once involved an observation period of 4 hours,4 today we have a better appreciation of delayed symptoms, which can span several days following chemotherapy. The discovery of substance P was first reported in 1931. Some 70 years later, we now understand that this neurotransmitter plays an integral role in relaying noxious sensory information to the brain. As a modulator of nociception, it is involved in several physiologic activities, including the vomiting reflex.5 *Gamma-aminobutyric acid. References Diemunsch P, Grélot L. Potential of substance P antagonists as antiemetics. Drugs 2000;60:533–546. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796. Hornby PJ. Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis. Am J Physiol Gastrointest Liver Physiol 2001;280:G1055–G1060. Andrews PL, Naylor RJ, Joss RA. Neuropharmacology of emesis and its relevance to anti-emetic therapy. Support Care Cancer 1998;6:197–203. DeVane CL. Substance P: A new era, a new role. Pharmacotherapy 2001;21:1061–1069.

Cisplatin Biphasic Pattern of Chemotherapy-Induced Nausea and Vomiting (CINV) Acute Delayed Slide 10 The time course and intensity of CINV seen with cisplatin administration have been well characterized. Traditionally, the pattern of CINV as shown in this graph displays an initial peak in the intensity of cisplatin-induced nausea and vomiting within the first 24 hours after administration, followed by a second, more prolonged phase of lesser intensity occurring during Days 2 to 4.1 Closer examination of the data demonstrates that maximal emetic intensity occurs within 8 to 12 hours after chemotherapy.1 This corresponds with data from other studies documenting the release of serotonin following cisplatin in this same time frame.2,3 A time course study demonstrated a peak of urinary serotonin metabolite excretion at 6 hours following chemotherapy, with levels returning to baseline by 16 hours2 Investigators in a second study also observed a peak of urinary serotonin metabolite excretion at 6 hours as well3 Time (Days) Maximal emetic intensity seen within 24 hours postdose Distinct second phase seen, occurring on Days 2–5 postdose References Tavorath R, Hesketh PJ. Drug treatment of chemotherapy-induced delayed emesis. Drugs 1996;52:639–648. Wilder-Smith OH, Borgeat A, Chappuis P et al. Urinary serotonin metabolite excretion during cisplatin chemotherapy. Cancer 1993;72:2239–2241. Janes RJ, Muhonen T, Karjalainen UP et al. Urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion during multiple-day high-dose chemotherapy. Eur J Cancer 1998;34:196–198.

WAS IST DAS BESONDERE AN DER ANTIEMETISCHEN WIRKUNG DER SUBSTANZ P ? SIE TRIGGERT DAS VERZÖGERTE ERBRECHEN NACH CHEMOTHERAPIE