الفهرس 
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Abstract
The role of antidepressants in fatal poisonings has become increasingly important. The experimental investigations reported in this study attempt to compare, the acute lethal and short-term chronic toxicities in rodent animal species, of an older widely used tricyclic antidepressant drug, amitriptyline HCL, with the newer one namely mianserin HCL, a tetracyclic antidepressant drug.
It was apparent that antidepressant drugs exhibit a delay of several weeks before their therapeutic benefit is established. So, they constitute a great hazard because of their liability to toxic accumulation on prolonged intake. Furthermore, depressed patients have tendencies to suicidal acts or ideation, and although these drugs designed to assist them in overcoming their condition, they will often use the antidepressants to attempt suicide. Besides, these drugs might occasionally cause fatalities due to acute overdosage, either accidental or intentional for homicidal purposes. The risk of death from overdose either acute or chronic, should be taken into account when antidepressant drugs are prescribed.
The results recorded in the course of this research were summarized under the following items:
1) Acute toxicity study:
24 hours acute oral toxicity of the two test antidepressant drugs in equal sized groups of normal adult albino rats of both sexes, yielded the following estimates of oral LD50 values:
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Amitriptyline HCL: Oral LD50 = 415 mg/Kg body weight. Mianserin HCL: Oral LD50 = 1 300 mg/Kg body weight.
Positive parallelism between the best fitting oral dose mortality lines of these two drugs was confirmed, reflecting identical mechanism of
lethal toxic action.
The post-mortem examination of fatally intoxicated rats, revealed evidences of tissue anoxaemia, secondary to respiratory failure which was the prime cause of death of these animals. Beside the pathological lesions in the lungs of both groups, microscopical sections from a variety of internal organs of autopsied rats showed cardiotoxicity and nephrotoxicity for amitriptyline, in contrast to hepatotoxicity with mild bone marrow depression for mianserin which didn’t show any cardiotoxic signs at acute
lethal doses.
The lethal toxicity was more evident and demonstrable in case of amitriptyline, while it was mild for mianserin. The toxicity ratio (T.R.) and 95% confidence limits are calculated for amitriptyline with reference to mianserin and amounted to the following value:
Amitriptyline: Mianserin
T.R. = 3.133* (1.983-4.95).
Acute toxic manifestations of amitriptyline-HCL began to appear 5-10 minutes after administration of oral toxic doses, while mianserin intoxicated rats showed immediately acute toxic manifestations after 3-5 minutes from oral dose. In amitriptyline intoxicated rats, passive behaviour was observed with evidence of central nervous depression as
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progressive loss of spontaneous motility with loss of superficial, deep, and postural reflexes, and the animals developped convulsive fits just preceding death. On the other hand, mianserin intoxicated rats showed hyperreflexia followed by muscular weakness and hypotonia, with reduced activity and tremors. Sedation was the most prominent feature in this group of
animals.
Concerning the previously mentioned LD50 results, we can conclude that amitriptyline is more toxic than mianserin. It was also noted that the main cause of death was due to respiratory depression followed by respiratory failure. In case of the effect of these antidepressant drugs on liver and kidneys, it was noticed that amitriptyline-induced mainly cardiotoxic effects and nephrotoxicity, while mianserin had no evidences of cardiotoxicity but induced mild bone marrow depression and hepatotoxic
effects.
2) Short-term chronic toxicity study:
A short-term chronic study for 4 weeks was carried out by daily repeated oral medication to normal adult albino rats of both sexes, with each of the two test antidepressant drugs.
The study was performed on 150 adult rats divided into 3 equal sized groups, each comprising 50 rats. Two of these groups received daily oral doses equivalent to 1/20 th of LD50, amounted to the following values, and expressed in mg/kg body weight:
20.75 mg/kg b.w. for amitriptyline HCL.
65 mg/kg b.w. for mianserin HCL.
The 3rd animal group served as parallel non-medicated control group.
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Retro-orbital venous blood samples were obtained from 6 animals of each group at the end of each of the 4 consecutive weekly intervals of treatment, before subsequent sacrifice for the purpose of dissection of the internal organs and viscera to inspect the microscopical pictures of pathological lesions induced by each drug. The blood samples were served for the performance of a number of biochemical analysis including:
-Fasting blood glucose (F.B.G).
- Serum transaminases (SGPT; SGOT).
- Serum alkaline phosphatase (S.Alk.Ph.).
-Blood urea nitrogen (BUN) and serum creatinine.
-Total and differential leucocytic count.
Amitriptyline caused marked weight gain and induced marked impair-ment of carbohydrate metabolism, reflected by persistent and steadily progressive elevated FBG levels reaching maximum peak at the 4th week amounted to (+85.76%). While mianserin medicated rats showed mild increase in body weight with little alteration of FBG level which was gradually increased to reach peak level of (+8.94%) from the corresponding control group at the end of the 4th week.
Both amitriptyline and mianserin induced impairment in hepatocellular function, but this dysfunction was more pronounced in the former tricyclic one, than in the latter tetracyclic antidepressant. liepatotoxicity of amitriptyline was evidenced by very highly significant rise (P < 0.0005) in serum values of GPT, GOT, and Alk.Ph. enzymes from the first week till the end of medication period (SGPT was +191.5%; S.Alk.Ph. was +491.8% beyond the corresponding normal values). While mianserin induced graduated elevation in the three enzyme levels,being significant (PC 0.05)
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at the 1st week, and highly significant (Pc 0.01) at the 2nd week, then the increase was very highly significant (PC 0.0005) at the last two weeks of treatment reached value of (+96.8% for SGPT;+178.4% for S.Alk.Ph).
Hepatotoxicity of amitriptyline was confirmed histopathologically by the finding of severe hydropic and fatty degenerations with marked focal haemorrhagic necrotic areas, and diffuse lymphocytic infiltrations with vascular congestion and dilatation, from the beginning till the end of treatment. While the liver sections of mianserin group showed the same pathological lesions but with mild degree at the first two weeks of treatment, and gradually increased in severity at the 3rd and 4th week.
Amitriptyline exhibited an apparent cardiotoxic effects evidenced by very highly significant and long sustained elevations in serum GOT (reach up to +91.2% at the end of the 4th week), and was confirmed by lesions in the heart which showed interstitial oedema, vasculitis with lymphocytic infiltration, intravascular thrombosis and subendocardial haemorrhage. In contrast, mianserin had less toxic effects on the cardio-vascular system (SGOT was elevated only by +1 3.4% at the end of the 1st week, and reach up to +50.3% at the end of medication period). The safety of mianserin on the heart was confirmed by the absence of any cardiac lesion in the first two weeks of medication, and the only lesion detected was a mild subendocardial haemorrhage, at the 3rd and
4th week.
Impaired renal function caused by amitriptyline was verified by a very highly significant increase (PC0.0005) in BUN and serum creatinine levels. The elevations were persistent and graduated from the first week
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reached up to +146.9%, and +982.1% from the corresponding control group, at the end of the 4th week. The kidney damage appeared as mild glomerular enlargement with cloudy swelling of the convoluted tubules and perivascular lymphocytic infiltration, at the end of the first week, then graduated to severe degeneration of both the glomeruli and the convoluted tubules with severe cloudy swelling till the end of medication period.
Nephrotoxic effect of mianserin was prominent at the first two weeks of treatment, evidenced by a very highly significant increase (13 < 0.0005) in BUN and serum creatinine levels, but this toxic effect gradually decreased at the last two weeks of medication, evidenced by highly significant rise in BUN and creatinine (P < 0.0025 at the end of the 3rd week; P<0.01 at the end of the 4th week). Confirmatory evidence for the biochemical results was provided by the very highly incidence of nephrotoxic lesions detected in the kidneys, during the first two weeks of medication as severe as congestionlloss of the glomeruli, severe cloudy swelling, tubular necrosis and moderate interstitial haemorrhage with lymphocytic infiltration. Then the lesions decreased in severity at the following two weeks of treatment to reach a mild degree without haemo-
rrhage or necrosis.
Amitriptyline induced a decrease in total and differential leucocytic count which was insignificant (P > 0.05) at the 1st week, but from the second week till the 4th week decrease in the total W.B.Cs mainly due to a reduction in the neutrophilic count was significantly reached (P < 0.05). Confirmatory evidence for our results was provided by the non-significant pathological changes detected at the end of the first week, where the bone marrow showed a normocellular picture. At the second week till
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the end of medication, the bone marrow depression started from mild to moderate hypocellularity, correspondingly.
Mianserin has more toxic effects than amitriptyline, on leucocytic count and bone marrow. This was evidenced by a highly significant decrease (P< 0.01) in total leucocytic and neutrophilic count at the end of the first week, then the decrease in both was very highly significant (P < 0.0005) from the 2nd week till the end of the 4th week of treatment. The histo-pathological findings in the bone marrow of mianserin treated rats con-firmed our results as mild hypocellularity was occurred at the end of the 1st week, then moderate to severe bone marrow depression was detected at the last three weeks of medication.
The lung lesions detected in amitriptyline treated rats were graduated from mild alveolar collapse, marked bronchiolar oedema with interstitial pneumonia, and perivascular lymphocytic infiltration at the end of the first week, to severe alveolar collapse and oedema with severe broncho-pneumonia at the following three weeks of treatment. While mianserin treated rats showed no significant pathological changes at the end of the 1st week, the lung lesions were detected at the following three weeks in the form of severe dilatation of the alveoli, interstitial pneumonia, and severe vascular congestion and dilatation with lymphocytic infiltration.
Amitriptyline induced mild inflammatory process of mucosa with hyper trophic gastritis at the 1st week of treatment, then the degenerative lesion was increased to affect all the muscle layers at the end of the 4th week. Similar lesions were detected in the small intestine, with focal areas of haemorrhage and necrosis of serosa at the end of the 2nd week.
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Mianserin had no significant changes on stomach and small intestine at the first two weeks of medication, except mild mucosal destruction in the stomach at the 2nd week, and at the last two weeks of treatment the lesions were mild to moderate mucosal destruction with lymphocytic infiltration. Recommendations:
Amitriptyline causes increase in weight and marked impairment of
carbohydrate metabolism, but mianserin induces a very mild effect on blood glucose level, so it is a favourable one in diabetic depressed
patients.
*Mianserin is characterised by a very high LD50 and the least toxic
effects, so it can be used safely.
*Amitriptyline is the most cardiotoxic drug while mianserin fail to induce
cardiotoxic effects, therefore it is a drug of choice for elderly and
cardiac depressed patients.
*Bone marrow depression and white blood cell disorders are the most
serious adverse reaction of mianserin, and hence regular blood examina-tion is recommended during mianserin treatment.