Acta Pharmacol Toxicol (Copenh). 1980 Apr;46(4):263-9.
Effects of amitriptyline and clomipramine in the isolated, perfused rabbit heart.

Nielsen-Kudsk F, Quist S.

The cardiac effects of supratherapeutic concentrations of two tricyclic antidepressants were studied in isolated rabbit hearts, which were perfused with a modified Krebs-Henseleit solution containing 0.25 or 0.50 micrograms ml-1 of amitriptyline or 0.28 micrograms mg-1 of clomipramine. The following parameters were continuously recorded:heart rate, amplitude and rate of contraction, coronary flow rate, myocardial oxygen consumption and ECG. The lowest concentration of amitriptyline caused a time correlated decrease (20%) in the frequency of spontaneous beating and a pronounced decrease in the amplitude (62%) and rate of cardiac contraction (58%). Maximum increases of the PQ-interval of about 46% and of the QRS-complex of about 100% were observed. At the higher amitriptyline concentration these effect further increased. Clomipramine 0.28 micrograms ml-1 also had a very pronounced and time correlated negative inotropic effect, but the effects upon the conduction velocities were substantially lesser than those produced by the equimilar concentration of amitriptyline. The compounds caused only insignificant changes in coronary flow. The oxygen consumption did not decrease in proportion to the decrease in contractility, as an expression of decreased myocardial efficiency. The effects of the drugs are discussed in relation to theri myocardial accumulation pharmacokinetics and influence upon the membraneous sodium and calcium flux and intracellular metabolism.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7368944&dopt=Abstract Elavil amitriptyline




Pharmakopsychiatr Neuropsychopharmakol. 1980 May;13(3):102-10.
Amitriptyline, nortriptyline plasma levels and clinical response in women with affective disorders.

Corona GL, Pinelli P, Zerbi F, Fenoglio L, Santagostino G, Frattini P, Cucchi ML.

The relationship between the plasma levels of amitriptyline and its metabolite nortriptyline, as well as their side-effects and clinical response, were studied in 102 depressed female in-patients, treated with different dosages of amitriptyline. For 50 and 100 mg dosages, significant positive correlations were found between amitriptyline concentration and the Hamilton amelioration scores, as well as between Hamilton final values and side effects. For depressive neurosis and involutional melancholia best therapeutic responses were yielded at a dosage of 50 mg, while in the treatment of manic-depressive illness, comparable results occurred at a 150 mg dosage. In the depressive neurosis and in the involutional melancholia the upper plasma concentration limits for the therapeutic effect of nortriptyline were identified. The lower plasma concentration limits of amitriptyline and nortriptyline in the treatment of manic-depressive illness were also pointed out.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7393996&dopt=Abstract Elavil amitriptyline




Nervenarzt. 1995 Sep;66(9):678-85.
[Effects of psychopharmacologic therapy on heart rate variation]

[Article in German]

Rechlin T.

Psychiatrische Klinik, Universitat Erlangen-Nurnberg.

Twenty patients suffering from schizophrenia and 36 patients suffering from endogenous depression underwent a standardized heart rate analysis before drug therapy. The patient's parameters of heart rate variability (HRV), which are controlled by the parasympathetic nervous system and which are independent of heart rate, did not significantly differ from the HRV parameters of normal control subjects. Ten of the patients with schizophrenia were treated with 200-400 mg of clozapine/day as monotherapy, while the other ten patients received a combination of different psychotropic drugs. The depressed patients were either treated with 150 mg of amitriptyline/d (n = 24) or 20 mg of paroxetine/d (n = 12) as monotherapy, respectively. After treatment with an average of 300 mg of clozapine/d for 4 weeks or with 150 mg of amitriptyline/day for 2 weeks, all of the patients HRV parameters had significantly decreased (P < 0.001). At this time, about 90% of these patients fulfilled the criteria of cardiovascular autonomic neuropathy. However, treatment with 20 mg of paroxetine/day for 2 weeks had no impact on any of the heart rate parameters. Under amitriptyline treatment, HRV parameters were found to correlate significantly with the plasma levels of amitriptyline/nortriptyline in a group of 104 depressed patients. Thus, determination of decreased HRV parameters is suggested to be a useful tool for the detection of overdosage with amitriptyline. It has not yet been elucidated whether or not the observed HRV decrease, which is probably at least in part due to the anticholinergic side effects of clozapine and amitriptyline, has any impact on patient health.(ABSTRACT TRUNCATED AT 250 WORDS)

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7477605&dopt=Abstract Elavil amitriptyline




Anesthesiology. 1995 Nov;83(5):1036-45.
Intrathecal amitriptyline. Antinociceptive interactions with intravenous morphine and intrathecal clonidine, neostigmine, and carbamylcholine in rats.

Eisenach JC, Gebhart GF.

Department of Anesthesia, Wake Forest University Medical Center, Winston-Salem, North Carolina, 27157-1009. USA.

BACKGROUND: Systemically administered opioids induce analgesia in part by spinal noradrenergic, serotonergic, and cholinergic mechanisms. The current study tested whether antinociception from systemically administered opioids could therefore be enhanced by intrathecal injection of a monoamine reuptake inhibitor to potentiate the action of spinally released norepinephrine and serotonin (amitriptyline) and intrathecal injection of a cholinesterase inhibitor to potentiate the action of spinally released acetylcholine (neostigmine). METHODS: Rats were prepared with chronic lumbar intrathecal and femoral intravenous catheters and nociceptive threshold was assessed by hind paw withdrawal to a radiant heat stimulus. An isobolographic design was used to distinguish between additive and synergistic interactions. RESULTS: Intravenous morphine and intrathecal neostigmine, but not intrathecal amitriptyline, caused dose-dependent antinociception alone. Combining any two of these three treatments yielded a synergistic interaction compared to each alone, whereas combining all three yielded an additive interaction compared to each two-way interaction. Intrathecal amitriptyline did not affect antinociception from intrathecal clonidine or intrathecal carbamylcholine. CONCLUSIONS: These data suggest that intrathecal doses of amitriptyline resulting in potentiation of intravenous morphine antinociception may not be adequate to block muscarinic receptors, because they did not affect carbamylcholine-induced antinociception. These results further support the relevance of spinal monoamine reuptake and cholinesterase inhibition to synergistically enhance analgesia from systemic opioids.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7486154&dopt=Abstract Elavil amitriptyline




Anesthesiology. 1995 Nov;83(5):1046-54.
Intrathecal amitriptyline acts as an N-methyl-D-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats.

Eisenach JC, Gebhart GF.

Department of Anesthesia, Wake Forest University Medical Center, Winston-Salem, North Carolina 27157-1009, USA.

BACKGROUND: Amitriptyline and other tricyclic antidepressants exhibit high affinity binding to N-methyl-D-aspartate (NMDA) receptors in vitro and inhibit NMDA receptor activation-induced neuroplasticity in hippocampal slices. Because spinal NMDA receptor activation is believed to be central to generation and maintenance of hyperalgesic pain, the purpose of this study was to test whether intrathecal amitriptyline reduced inflammation-induced hyperalgesia in the rat. METHODS: Rats were prepared with chronic lumbar intrathecal and femoral intravenous catheters and nociceptive threshold was assessed by hind paw withdrawal to a radiant heat stimulus. Rats received an injection of carrageenin in one hind paw followed by thermal paw withdrawal testing 3 hr later and intrathecal amitriptyline and/or intravenous morphine injection. In other rats, intrathecal NMDA injection was preceded by either intrathecal saline or 60 micrograms amitriptyline. RESULTS: Intrathecal amitriptyline reversed thermal hyperalgesia in a dose-dependent manner, but had no effect on withdrawal latency of the contralateral, noninjected paw. Intrathecal phentolamine plus methysergide did not alter amitriptyline's effect, except at the lowest dose. Intravenous morphine increased paw withdrawal latency in both inflamed and control paws in a dose-dependent fashion, and morphine interacted additively with intrathecal amitriptyline to reverse hyperalgesia. Thermal hyperalgesia induced by NMDA was completely antagonized by intrathecal amitriptyline. CONCLUSIONS: Amitriptyline and other tricyclic antidepressants have been demonstrated to exhibit modest activity against clinical neuropathic pain after systemic administration. These data suggest that more profound pain relief might be obtained by intrathecal administration. Amitriptyline reverses hyperalgesia in rats by a mechanism unrelated to monoamine reuptake inhibition, and likely due to NMDA receptor antagonism.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7486155&dopt=Abstract Elavil amitriptyline




Eur J Pharmacol. 1995 Jun 23;280(1):19-26.
Biochemical and behaviour changes induced by acute stress in a chronic variate stress model of depression: the effect of amitriptyline.

Ferretti C, Blengio M, Gamalero SR, Ghi P.

Istituto di Farmacologia e Terapia Sperimentale, Torino, Italy.

This paper examines the biochemical and behaviour changes induced by an acute stress (five 10-s, 1-mA foot-shocks) in three groups of rats: (1) never stressed, (2) subjected to chronic variate stress for 20 days, (3) subjected to the same chronic stress and treated with 5 mg/kg per day amitriptyline. After 15 min, acute stress led to a marked reduction in cortical beta-adrenoceptor and 5-HT2 receptor density, whereas the density of the 5-HT1A receptors was unchanged. Chronic stress also increased beta-adrenoceptor and 5-HT2 receptor density and had no effect on 5-HT1A. Acute stress diminished the density of beta-adrenoceptors in chronically stressed animals, but did not alter that of the two 5-HT populations. Amitriptyline alone reduced beta-adrenoceptor and 5-HT2 receptor densities only. Acute stress applied to animals treated with amitriptyline reduced 5-HT1A receptors, and caused a further beta-adrenoceptor decrease, but had no further effect on the 5-HT2 receptors. On behaviour, chronic stress diminished reactivity to the acute stress. This reduction was fully abolished by amitriptyline. An open-field study showed that acute stress reduced motor activity, increased latency times and diminished rearing in the controls, whereas chronic stress reduced motor activity only. No significant changes in behaviour were induced by the acute stress in animals subjected to chronic stress. The combination of chronic stress with amitriptyline was accompanied by a diminution of exploratory activity that persisted after the acute stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7498250&dopt=Abstract Elavil amitriptyline




J Cardiovasc Pharmacol. 1993 Dec;22(6):798-803.
Mechanisms of ventricular arrhythmia during amitriptyline toxicity.

Ansel GM, Coyne K, Arnold S, Nelson SD.

Division of Cardiology, Ohio State University, Columbus 43210.

The ventricular tachycardia (VT) caused by high-dose tricyclic antidepressants has been hypothesized to be due to a quinidinelike effect with generation of repolarization abnormalities and afterdepolarizations. To test this hypothesis further, we infused amitriptyline in a graded fashion (0.5-1 mg/kg/min) in 23 chloralose-anesthetized dogs during endocardial monophasic action potential (AP) recording and continuous hemodynamic monitoring. Three groups of dogs were studied: group A (n = 5), crushed sinus node and fixed atrial pacing at 100 beats/min; group B (n = 12), crushed sinus node and fixed atrial pace plus intermittent accelerated pacing to mimic group C; and group C (n = 6) intact sinus node and unimpeded sinus tachycardia. Amitriptyline infusion induced VT in no (0 of 5) group A dogs, all (12 of 12) group B dogs during accelerated pacing, and 83% (5 of 6) of group C dogs. Dogs with VT had significantly higher heart rates (HR 184.8 +/- 39.3 beats/min) as compared with dogs without VT (115.2 +/- 12.5 beats/min, p = 0.0015). There was a strong positive correlation between the last RR coupling interval to the first VT interval (r = 0.85; p = 0.0033). Amitriptyline infusion caused rate-dependent QRS prolongation in each group, especially group C (p < 0.001). Action potential duration at 50% and 90% of repolarization (APD50, APD90) showed a biphasic response with progressive shortening followed by prolongation as amitriptyline serum concentrations increased. Afterdepolarizations were not detected from any monophasic AP recording, even in dogs with VT.(ABSTRACT TRUNCATED AT 250 WORDS)

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7509896&dopt=Abstract Elavil amitriptyline