Tricyclic antidepressants as long-acting local anesthetics

Amitriptyline, nortriptyline, imipramine, doxepin, desipramine, protriptyline, trimipramine, and maprotiline are tricyclic antidepressants (TCAs) used orally in treating major depressive disorders. Recent studies showed that amitriptyline is more potent in blocking the sciatic nerve functions in vivo by local injection than bupivacaine, a long-acting local anesthetic. We therefore tested whether various TCAs could likewise act as local anesthetics in vivo after single injection via the rat sciatic notch. The duration of complete sciatic nerve blockade by TCAs and the time to reach full recovery were measured with neurobehavioral assays and compared with results from bupivacaine. Amitriptyline, doxepin, and imipramine at 5mM elicited a longer complete sciatic nerve blockade than did bupivacaine at 15.4mM (0.5%), whereas trimipramine and desipramine at 5mM produced a shorter blockade. In contrast, nortriptyline, protriptyline, and maprotiline failed to elicit complete sciatic nerve blockade. Thus, TCAs have very different efficacy as local anesthetics in vivo. The duration of rat sciatic nerve blockade in vivo by TCAs is not well correlated with the 50% inhibitory concentration (IC(50)) of TCAs in blocking human cardiac Nav1.5 Na(+) channels expressed in human embryonic kidney cells. With this in vitro expression system, TCAs appear more potent than bupivacaine as Na(+) channel blockers in Nav1.5 Na(+) channels. We suggest that the ability of TCAs to pass through various membrane barriers within peripheral nerve trunks is crucial to their local anesthetic efficacy in vivo. TCAs with a tertiary amine appear more effective in penetrating these membrane barriers than TCAs with a secondary amine.     

Tricyclic antidepressants and histamine H1 receptors.

Tricyclic antidepressants and some structurally related compounds were tested for their ability to antagonize histamine H1 and muscarinic acetylcholine receptors of cultured mouse neuroblastoma cells. As a group, tertiary amine tricyclic antidepressants tended to be more potent than secondary amine drugs at both receptors. The most potent antihistamine, doxepin hydrocholoride, was about 4 times more potent than amitriptyline hydrochloride, about 800 times more potent than diphenhydramine hydrochloride, and about 8,000 times more potent than desipramine hydrochloride, the least potent tricyclic antidepressant at both the histamine H1 and the muscarinic acetylcholine receptors. All tricyclic drugs except desipramine hydrochloride were more potent as antihistamines than as anticholinergics. Doxepin hydrochloride and amitriptyline hydrochloride may be the most potent antihistamines known, and the antihistaminic potencies of these and the other tricyclic antidepressant drugs may relate directly to their ability to cause sedation and drowsiness in patients.     

The use of antidepressants in school-age children.

Approximately 5% of the pediatric population suffers from depression. Children suffering from depression should be treated first with some type of psychotherapy, cognitive therapy, and/or education. Pharmacotherapy (medications) should be used only as a last resort for those children suffering from severe, chronic, or recurring depression. The only antidepressant approved by the U.S. Food and Drug Administration for the treatment of depression in children is fluoxetine (Prozac), a selective serotonin reuptake inhibitor. In the school setting, children should be monitored closely upon the initiation of antidepressant therapy and changes in dosing or medication. They also should be monitored for side effects of the medication, response to therapy, and new signs of depression or worsening symptoms. After starting an antidepressant, children must be monitored closely for any changes in behavior, especially increased preoccupation with suicide. Any changes should be reported to the physician immediately for follow-up.     

Tricyclic Antidepressant Overdosage

Abstract

Cannabis sativa grows abundantly among other natural vegetation in the northern part of Pakistan. Buffalo, the common dairy animals of the region, are allowed to graze upon this vegetation. These animals ingest significant amounts of marijuana, which after absorption is metabolized into a number of psychoactive agents which are ultimately excreted through the urine and milk. This potentially contaminated milk is used by the people of the region. Depending upon the amount of milk ingested and the degree of contamination, the milk could result in a low to moderate level of chronic exposure to Delta-9-Tetrahydrocannabinol (THC) and other metabolites especially among the children raised on this milk.

This research was conducted to investigate the extent of passive consumption of marijuana by the consumers of potentially contaminated milk. Urine and milk specimens were obtained from buffalo and were analyzed for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) which is a major metabolite for THC. The analysis was done by using gas chromatography/mass spectrometry. It was observed that during the months of June and July, 60 percent of the buffalo contained detectable levels of THC-COOH in their urine and 50 percent of these animals produced milk which was contaminated with THC or other metabolites. Analysis of the urine obtained from children with ages ranging from six months to 3 years, who were being raised on the milk from these animals, indicated that 29 percent of them had low levels of THC-COOH in their urine.

The present study indicates that the passive consumption of marijuana through diary products is a serious problem in the regions where this weed grows unrestricted and that children are prone to be exposed more than the adults. Presently this problem is unlikely to be serious in the United States of America, but could be a problem in the future. More extensive research into this potential risk factor is needed.     

Tricyclic antidepressive agents

The tricyclic antidepressive agents are still the drugs of choice because of their reliable action and the percentage of successes obtained (60 to 75%), especially in major depressions with deep melancholia. The course of antidepressive drugs is well documented, any depression needs at least three to four months' maintenance treatment after an initial phase of one month's treatment, frequently intravenous treatment is required. Current research is aimed at providing tricyclic agents without anticholinergic activity, the cause of most of their undesirable side-effects.     

Tricyclic antidepressant poisoning

Tricyclic antidepressant poisoning causes predictable electrocardiographic abnormalities and can be lethal. Cardiac arrhythmias, hypotension, seizures, and coma are common. Sodium bicarbonate is still considered the treatment of choice for severe toxicity, although a variety of supportive measures may be taken. Hypertonic saline appears to be a promising alternative. A QRS interval longer than 100 ms appears to be a better predictor of serious complications than is an elevated serum tricyclic antidepressant level. Cardiovascular toxicity is classically manifested as ventricular dysrhythmias, hypotension, heart block, bradyarrhythmias, or asystole. Activated charcoal binds tricyclic antidepressants. Give 30 to 50 g orally or by nasogastric tube with or without a cathartic (sorbitol 0.5 g/kg or 30 g of magnesium sulfate). Sodium bicarbonate is indicated if the QRS duration is more than 100 ms or the terminal right-axis deviation is more than 120 degrees. The suggested dosage is 1 to 2 mEq/kg, repeated as needed. Tricyclic antidepressants are used not only for depression but also for chronic pain syndromes, obsessive-compulsive disorder, panic and phobic disorders, eating disorders, migraine prophylaxis, and peripheral neuropathies.     

Tricyclic antidepressant blood levels

Plasma concentrations of tricyclic antidepressant drugs vary widely among patients. At routine dosage, unexpectedly low plasma levels are noted in some patients, while toxic levels can occur in others. Individual variability may be due to genetic differences in metabolism or to other factors including drug interactions and poor compliance. Pharmacologic management of depressed patients is often improved when guided by plasma concentration monitoring.     

Tricyclic antidepressant and cardiovascular drug interactions.

Tricyclic antidepressants have anticholinergic, adrenolytic and quinidine-like activity. These actions result in a variety of cardiac and blood pressure effects. Tricyclic antidepressants can reverse the antihypertensive effect of guanethidine and clonidine. Orthostatic hypotension may be increased with diuretics and hydralazine. Myocardial depression may occur with lidocaine, phenytoin or propranolol. Dangerous additive effects may result from concomitant use of a tricyclic antidepressant and either quinidine or procainamide.