92.-
FATAL POISONING BY AMITRIPTYLINE
AND METHADONE: TOXICOPATHOLO-GICAL HEPATIC FINDINGS.
Prof.Garfia.A
92.-INTOXICACIÓN DEATH BY AMITRIPTYLINE AND METHADONE:
toxicopathology LIVER.
Prof.Garfia.A
92.-Tödliche Vergiftungen und durch Amitriptyline Methadone: A toxische Hepatitis kute.
Prof. Garfia.A
Introduction
Amytriptyline is a drug frequently prescribed antidepressant That Is Well Known to death investigators, forensic pathologists, and toxicologists. Amytriptyline has sedative effects and is commonly prescribed to those patients experiencing symtoms of depressive illness. This drug , have also been utilized for therapeutic treatment of neuropathic and inflamatory diseases such as chronic fatigue syndrome, migraine, fibromyalgia, irritable bowel syndrome, and atypical facial pain. Besides its anxiolytic properties, amytriptiline has central anticholinergic effects. Amitryptiline inhibits serotonin and noradrenalin uptake in presynaptic nerve endings.
Toxicity of amitriptyline has been observed during standard treatments, and frequently during suicidal or accidental intoxication. Amitriptyline drug has toxic effects over cardiovascular, autonomous nervous , and central nervous system, and may result in cardiotoxicity, cardiac conduction delays, dysrhythmia, hypotension, altered mental status, and seizures (Kiyan et al., 2006). In vitro administration of amitriptilyne to cell cultures induces several signs of toxicity:
1.-Alteration of cellular permeability based on its detergent nature.
2.-Alterations in the glucidic metabolism of neurons resulting in a decrease of both uptake and transport of glucose.
3.-Provoke an increase of intracellular lipid peroxidation in mouse 3T3 fibroblasts.
Many oh these toxic effects are prevented by antioxidants.
However, recently has been demonstrated that amitriptilyne treatment induced oxidative stress and mitochondrial dysfunction in primary human fibroblasts cultures (Moreno Fernández et al., 2008). Mitochondrial dysfunction in amitriptilyne treatment was characterized by reduced expression levels of mitochondrial proteins and coenzyme Q10, decreased NADH cytochrome c reductase activity, and a drop in mitochondrial membrane potential. Amitriptilyne reduce significantly the number of cultured cells, and enhaced the production of lipid peroxidation, inverting the lipid reduced/oxidized ratio, decreased catalase protein levels, and decreased of cytochrome c and citrate synthase activity, revealing mitochondrial damage. Moreover, as a consequence of these toxic effects, amitriptilyne treatment induced a significant increased in apoptotic cell death activating mitochondrial permeability transition. Coenzyme Q10 and alphatocopherol supplementation attenuated ROS production, lipid peroxidation, mitochondrial dysfunction, and cell death, suggesting that oxidative stress affecting cell membrane components is involved in amitriptilyne cytotoxicity (Cordero,MD et al., 2009).
1.-Alteration of cellular permeability based on its detergent nature.
2.-Alterations in the glucidic metabolism of neurons resulting in a decrease of both uptake and transport of glucose.
3.-Provoke an increase of intracellular lipid peroxidation in mouse 3T3 fibroblasts.
Many oh these toxic effects are prevented by antioxidants.
However, recently has been demonstrated that amitriptilyne treatment induced oxidative stress and mitochondrial dysfunction in primary human fibroblasts cultures (Moreno Fernández et al., 2008). Mitochondrial dysfunction in amitriptilyne treatment was characterized by reduced expression levels of mitochondrial proteins and coenzyme Q10, decreased NADH cytochrome c reductase activity, and a drop in mitochondrial membrane potential. Amitriptilyne reduce significantly the number of cultured cells, and enhaced the production of lipid peroxidation, inverting the lipid reduced/oxidized ratio, decreased catalase protein levels, and decreased of cytochrome c and citrate synthase activity, revealing mitochondrial damage. Moreover, as a consequence of these toxic effects, amitriptilyne treatment induced a significant increased in apoptotic cell death activating mitochondrial permeability transition. Coenzyme Q10 and alphatocopherol supplementation attenuated ROS production, lipid peroxidation, mitochondrial dysfunction, and cell death, suggesting that oxidative stress affecting cell membrane components is involved in amitriptilyne cytotoxicity (Cordero,MD et al., 2009).
EVENT DESCRIPTION
is a woman, 48, who appeared dead in his home. Among the records of interest, stands an old history of depression, alcohol dependence and psychoactive drugs. On the bedside table, beside the body were empty of psychotropic drugs.
autopsy examination
During the autopsy noted a severe congestion of all organs especially meningeal , lung and liver. In the pericardial cavity was found discrete stroke, lung, a moderate edema. The liver was yellowish brown, soft to the touch, and unctuous to the court. It gave a possible diagnosis of death by poisoning psychotropic drugs.
Blood alcohol was negative and blood revealed a lethal concentration of methadone (10 mg / L) (fatal dose is between 0.1 and 1.8 mg / L) and toxic concentrations of amitriptyline (0.45 mg / L). The toxic dose of amitriptyline in adults is 0.3-0.5 mg / L; in children is 0.005 g / kg.
HISTOPATHOLOGY
liver Microscopic examination revealed the existence of a cytoplasmic vesicles, mixed macro and microvesicular (small and large drop) , which presented a morphological pattern of distribution, meaningful, within the classic liver lobule. Thus, while the macrovesicular affected, especially to hepatocytes located around the centrilobular veins-area 3 of the liver acinus of Rappaport-drop the small vesicles were located in hepatocytes periportal areas and mediozonales, corresponding to areas 1 and 2, respectively, of the liver acinus. Besides the existence of macrovesicular steatosis, there were chronic alcoholic liver disease markers such as fibrous thickening, moderate grade, the walls of veins and radiant extension of fibrosis into the capillary walls satellites pericentral sinusoids. Randomly distributed within the liver parenchyma could be observed numerous hepatocytes with retracted cytoplasm, strongly eosinophilic and pyknotic -Wearing a heavily condensed chromatin, and faded-looking, being pre-apoptotic morphology. Within a few lobules abounded numerous apoptotic bodies that appeared as cellular ghosts without associated inflammatory response. In some areas, foci of necrosis / apoptosis were surrounded by inflammatory leukocyte infiltration, acute, with presence of some eosinophils. In some portal vein thrombi were detected, fibrin-leukocyte own a state of disseminated intravascular coagulation associated with shock.
TOXICITY OF AMITRIPTYLINE
The Amitriptyline, a tricyclic antidepressant, belongs to the pharmacological dibenzocicloheptanos tricyclic that toxicological profile has the following:
1.-Toxicokinetics
rapid gastrointestinal absorption. Half-life between 15 and 40 hours. Maximum plasma peak between 3 and 4 hours post-administration. Plasma protein binding: 95-98%. Enterohepatic circulation has -important detail to take account of its toxic effects on the liver, with hepatic metabolism. The liver is the major route of elimination of tricyclic antidepressants, the inactivation and elimination last several days so that after the last dose taken is to wait, at least a week, for their total elimination. For example, amitriptyline has an elimination half-life in cases of sobedosis, from 25 to 80 hours. 35% of absorbed drug is excreted in urine within 24 hours, in the form of nortriptyline and dinortriptilina. Approximately 80% is excreted by the kidney at 11 days of intake.
Barbiturates and alcohol speed up the metabolism of tricyclic antidepressants, while neuroleptic hydrocortisone and inhibit its degradation.
Amitriptyline has a high solubility and, Therefore, a high volume of distribution, indicating that there is a hijacking of the drug target tissues during life, with consequent high potential for postmortem diffusion from tissues to blood during and after cadaveric destructive phenomena (autolysis and putrefaction of corpses).
The postmortem drug concentration in cardiac blood increases significantly, thanks to this phenomenon called postmortem redistribution. For example, to other antidepressants such as trimipramine the relationship between heart and femoral blood concentration becomes 5:1.
2.-Mechanism of toxic action
Amytriptyline liver is toxic by double-acting mechanism:
-direct hepatotoxicity.
-hypersensitivity.
Most published work on its hepatotoxic effects relate to the production capacity damage cholestatic, although cases have been described damage hepatocellular , along with other mixed type.
( see: Hepatotoxicity. Zimmerman, pp. 496. 2 nd Ed 1999).
In this case of poisoning fatal, associated with methadone, the lesions were predominantly hepatocellular type. We could not demonstrate the existence of bile plugs and canalicular cholestasis.
Fig.1.-amitriptyline-lethal poisoning metadona.Hígado.Pequeño increase.
Emphasizes in this increase, the disruption of hepatocyte laminar pattern, the presence of foci of lymphoplasmacytic infiltration within some lobules (stars), and moth-eaten appearance of the cytoplasm of hepatocytes. In these, the presence of two types of vesicles, optically empty. Some of them are displacing macrovesicular hepatocyte nuclei toward the cell periphery, others are microvesicles which, in some cases, are at the limit of microscopic visibility (0.5-1 micron). In the field differ retracted some hepatocytes (arrows), showing the intensely acidophilic cytoplasm and pyknotic nuclei and retracted. Prof.Garfia.A
Fig.2 .--Metadona.Hígado.Mediano Amitriptyline poisoning rise.
There is a disintegration of the laminar pattern hepatocyte by the presence of apoptotic hepatocytes that have lost their desmosomal contacts and are floating freely within the hepatic sinusoids (f). Arrows indicate hepatocytes apoptotic process of disintegration. Prof.Garfia.A
Arrows indicate apoptotic hepatocytes in cell death.
In the bottom left corner of the photo is an inflammatory focus consisting of lymphoplasmacytic cell. The cytoplasmic mitochondrial microvesiculación visible in many hepatocytes. Prof.Garfia.A
Fig.4.-amitriptyline-methadone. Hígado.Gran increase.
The presence of a large outbreak of hepatocytes showing apoptotic cell death. In the field there are some polymorphonuclear leukocytes. Prof.Garfia.A
Fig.5 .- fatal poisoning by amitriptyline-Methadone. Liver .
centrilobular vein (star), showing fibrous thickening of the wall with formation of a fibrotic pattern-dependent alcohol beaming towards the walls of the sinusoids tax. Note steatosis, macrovesicular-type of thick-localized in the pericentral area. Outside, mediozonal localization of hepatic lobule, hepatocytes that have dominated the cytoplasm occupied by a thin microvesiculación. Microscopic field apoptotic hepatocytes observed. Prof.Garfia.A
Fig.6 .- Poisoning amitriptyline-metadona.Hígado.
portal space in which there is a leucotario fibrin thrombus in the portal venous branch.
This court can see clearly the existence of a mitochondrial microvesiculación fine. Treatment Amitriptyline, in cultured fibroblasts, the activity affects the organization and assembly of mitochondrial protein complexes. The deficit in the expression of mitochondrial proteins and reduced levels of coenzyme Q10 appears to damage the normal mitochondrial electron flow and proton pump, causing a drop in respiratory chain activity and mitochondrial membrane potential. The production of reactive oxygen species (ROS) causes increased mitochondrial permeability (mitochondrial permeability transition, MPT), and the opening of pores in the inner mitochondrial membrane. Pore \u200b\u200bopening causes mitochondria become permeable to all solutes which have a molecular mass of 1500 Da. The consequence is that there is a dramatic mitochondrial swelling as a consequence is the disruption of the outer membrane and release into the cytosol of mitochondrial pro-apoptotic proteins such as cytochrome c, apoptosis inducing factor and Smac / Diablo, among others. Some authors have shown that the use of membrane antioxidants (such as coenzyme Q10 and alpha-tocopherol) may reduce the cytotoxic effects of amitriptyline (Lamb et al., 2009).
In this picture you can see that the microvesicles located in the cytoplasm of hepatocytes, which are not positive osmium impregnation for the demonstration of fat-stay away from the town and have a diameter that is in the limit of microscopic visibility, although there has been coalescence, some of them.
Nótese que, en el centro de la fotografía, aparecen varios núcleos en los que ha desaparecido la membrana nuclear y la héterocromatina, densa, se encuentra fragmentada en grumos.
Existen, hoy día, numerosas pruebas que demuestran que las mitocondrias son un importante punto de partida de las diversas vías que conducen a la muerte celular apoptósica. Se cree que la amitriptilina - a través del bloqueo de la cadena respiratoria mitocondrial- desencadena un aumento de la producción de superóxido y de peróxido de hidrógeno, disminuyendo el potencial de membrana mitocondrial y activando, probably the MPT (mitochondrial permeability transition). As a result, cytochrome c release causes the activation of pro-caspase 9, caspase 3 and endonuclease G, all of which lead to degradation and DNA fragmentation and apoptotic cell death.
Bibliography consulted .-
1. - Cordero MD et al.. - Coenzyme Q10 and alpha-tocopherol Protect Against amitriptyline toxicity. Toxicology and Applied Pharmacology. Vol 235, issue 3, pp. 329-337.2009 .
2.-Moreno-Fernández, J.A. et al., - Cytotoxic effects of amitriptilyne in human fibroblasts. Toxicology 243, 51-58 (2008).
2.-Bernardi P et al.,.-
2.-Bernardi P et al.,.-
Mitochondria and cell death. Mechanistic Aspects and Methodological issues.
Eur J Biochem. 1999 Sep; 264 (3) :687-701.
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