デシプラミン

DEA NFLIS-Drug Category -> Antidepressants

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

log Kow = 4.90

3.7

4.0

WHITE CRYSTALLINE POWDER; ODORLESS; BITTER TASTE; MELTS WITHIN 5 DEG RANGE BETWEEN 208-218 °C; 1 G IN CA 4 ML CHLOROFORM, 20 ML WATER, 20 ML ALC; FREELY SOL IN METHANOL; INSOL IN ETHER /HCL/

In water, 58.6 mg/l @ 24 °C.

3.96e-02 g/L

Antidepressants -> Tricyclic antidepressants (TCA)

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Antidepressive Agents, Tricyclic

Pharmaceuticals

214-218 °C

214 - 218 °C

10.16

10.23

10.2

10.2

10.4

163.5 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: Antidepressants]

160.93 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

163.3 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Danger

H302 (66.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P261, P264, P270, P271, P273, P301+P317, P304+P340, P308+P316, P319, P321, P330, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Status: Active Update: 08-02-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/22353

5H-Dibenzb,fazepine-5-propanamine, 10,11-dihydro-N-methyl-: Does not have an individual approval but may be used under an appropriate group standard

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line, and initiate gastric decontamination. A minimum of 6 hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. Follow ECG, renal function, CPK, and arterial blood gasses as clinically indicated. (L1712)

ADMIN OF TRICYCLIC ANTIDEPRESSANTS...WITH OR SHORTLY AFTER...MAO INHIBITORS HAS RESULTED IN SEVERE REACTIONS. ... OTHER INTERACTIONS INCL POTENTIATION OF CENTRAL DEPRESSANT DRUGS, BLOCKADE OF ANTIHYPERTENSIVE EFFECTS OF GUANETHIDINE, & AUGMENTATION OF PRESSOR EFFECTS OF SYMPATHOMIMETIC AMINES. /TRICYCLIC ANTIDEPRESSANTS/

Concurrent use /of thyroid hormones/ with tricyclic antidepressants may increase the therapeutic and toxic effects of both medications, possibly due to increased receptor sensitivity to catecholamines; toxic effects include cardiac arrhythmias and CNS stimulation. /Tricyclic antidepressants/

Concurrent use /of sympathomimetics/ with tricyclic antidepressants may potentiate cardiovascular effects possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia; phentolamine can control the adverse reaction. Significant systemic absorption of ophthalmic epinephrine may also potentiate cardiovascular effects; also, local anesthetics with vasoconstrictors should be avoided or a minimal amount of the vasoconstrictor should be used with the local anesthetic. Concurrent use with tricyclic antidepressants may decrease the pressor effect of ephedrine and mephentermine. /Tricyclic antidepressants/

If significant systemic absorption occurs, concurrent use /of ophthalmic naphazoline, nasal or ophthalmic oxymetazoline, nasal or ophthalmic phenylephrine, or nasal xylometazoline/ with tricyclic antidepressants may potentiate pressor effects of these medications. /Tricyclic antidepressants/

For more Interactions (Complete) data for DESIPRAMINE (20 total), please visit the HSDB record page.

Liver test abnormalities have been reported to occur in up to 16% of patients being treated with tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication and without dose adjustment. Rare instances of clinically apparent acute liver injury have been reported due to desipramine, but far fewer than have been reported with amitriptyline or imipramine. The onset of jaundice is usually within 1 to 8 weeks of starting the antidepressant, and the pattern of serum enzyme elevations can be either hepatocellular or cholestatic. Features suggestive of hypersensitivity (fever, rash, eosinophilia) are common, but rarely severe. Autoantibody formation is unusual. These features are typical of tricyclic antidepressant hepatotoxicity.

Desipramine has a broad toxic profile, including an increased risk of suicide, orthostatic hypotension, cardiac abnormalities, seizures, ocular crisis, and fractures. A short-term study demonstrated a significantly increased risk of suicide in children, adolescents, and young adults aged 24 and younger; this represents one of the most significant adverse effects to consider when prescribing desipramine. Orthostatic hypotension, likely due to alpha-1 receptor blockade, is a common reason for drug discontinuation. Reports describe cardiovascular adverse effects, including heart block, arrhythmias, and sudden death associated with desipramine. Clinicians should screen for conduction abnormalities, with particular attention to the QT interval and family history of cardiac disease, before prescribing desipramine.

Signs and Symptoms of Overdose

Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system.

MILD PARKINSONIAN SYNDROME...MAY BE SEEN IN SOME PT, PARTICULARLY OLDER PERSONS TAKING LARGE DOSES. ...HIGH DOSES...MAY PRODUCE GRAND MAL SEIZURES EVEN IN PT WITHOUT HISTORY OF CONVULSIONS. .../IT/ MAY PRODUCE ALLERGIC TYPE OF OBSTRUCTIVE JAUNDICE.../WHICH/ CLEARS WHEN DRUG IS DISCONTINUED. /IMIPRAMINE/

Effects of overdosage include agitation, hallucinations, hyperreflexia, hyperpyrexia, and convulsions. Both hypotension and hypertension also occur.

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

desipramine

Norpramin®

Antidepressants

3

less-DILI-concern drugs

IN CATS UNDER ANESTHESIA IV INJECTION OF 4 TO 25 MG OF DESIPRAMINE HAS BEEN FOUND TO REDUCE SPONTANEOUS ACTIVITY OF RETINAL NEURONES. DOSES OF 5 TO 20 MG/KG INCR C-WAVE IN ELECTRORETINOGRAM, & DOSES OF 20 TO 35 MG/KG REDUCED B-WAVE...

DESPITE ITS CLINICAL ANTIDEPRESSANT EFFECTS, IMIPRAMINE PRODUCES DEPRESSION OF SPONTANEOUS MOTOR ACTIVITY IN LAB ANIMALS. ...IT ALSO...DECR BODY TEMP, & CAUSES ATAXIA. IT IMPAIRS BOTH ACQUISITION & PERFORMANCE OF CONDITIONED AVOIDANCE RESPONSES. /IMIPRAMINE/

IMIPRAMINE LOWERS BLOOD PRESSURE IN ANESTHETIZED DOGS & OBTUNDS VARIOUS CARDIOVASCULAR REFLEXES, INCL CAROTID OCCLUSION REFLEX, BEZOLD-JARISCH REFLEX, & POSTURAL RESPONSES. /IMIPRAMINE/

◉ Summary of Use during Lactation

◈ What is desipramine?

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

N - Nervous system

QN - Nervous system

Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms.

Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system.

MANNER IN WHICH IMIPRAMINE RELIEVES...DEPRESSION...IS NOT CLEAR. .../EFFECT/ DESCRIBED AS DULLING OF DEPRESSIVE IDEATION RATHER THAN AS EUPHORIC STIMULATION PRODUCED BY MAO INHIBITORS...DEFINITIVELY DISCRIMINATIVE EXPT... YET TO BE PERFORMED. ...DOES HAVE STIMULANT ACTION UNDER CERTAIN CIRCUMSTANCES. /IMIPRAMINE/

ACTION OF TRICYCLIC ANTIDEPRESSANTS ON METABOLISM OF CATECHOLAMINES & INDOLEAMINES IN BRAIN HAS CONTRIBUTED SIGNIFICANTLY TO "BIOGENIC AMINE HYPOTHESIS" OF DEPRESSION. ... ALL TRICYCLIC ANTIDEPRESSANTS BLOCK RE-UPTAKE OF NOREPINEPHRINE BY ADRENERGIC NERVE TERMINALS. /TRICYCLIC ANTIDEPRESSANTS/

IMIPRAMINE SLOWS TURNOVER RATE OF 5-HT, EFFECT NOT SHARED BY DESIPRAMINE, WHILE TURNOVER RATE OF NOREPINEPHRINE IS INCR BY DEMETHYLATED DRUGS NORTRIPTYLINE & DESIPRAMINE. EXACT RELATIONSHIP OF THESE EFFECTS TO ACTIONS OF TRICYCLIC ANTIDEPRESSANTS IN HUMAN DEPRESSION IS NOT KNOWN.

7-60+ hours; 70% eliminated renally

...DESIPRAMINE /WAS GIVEN/ IN DOSE OF 25 MG EVERY 8 HR TO 15 PT. ...BIOLOGICAL HALF-LIFE...FROM A FEW HR TO MORE THAN 2 DAYS...

Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control.

DEMETHYLIMIPRAMINE YIELDS BISDEMETHYLIMIPRAMINE, DEMETHYL-2-HYDROXYIMIPRAMINE, DEMETHYL-10-HYDROXYIMIPRAMINE, & IMINODIBENZYL IN MAN. /FROM TABLE/

DEMETHYLIMIPRAMINE YIELDS IMIPRAMINE IN RABBITS AND IN RATS. /FROM TABLE/

Desipramine has known human metabolites that include Desipramine N-glucuronide and 2-hydroxy-desipramine.

Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control. Route of Elimination: Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. Half Life: 7-60+ hours; 70% eliminated renally

TG537D343B

DESIPRAMINE

Established Pharmacologic Class [EPC] - Tricyclic Antidepressant

Desipramine is a Tricyclic Antidepressant.

DESIPRAMINE

Tricyclic Antidepressant [EPC]

Substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block the uptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors. However, the mechanism of their antidepressant effects is not clear because the therapeutic effects usually take weeks to develop and may reflect compensatory changes in the central nervous system.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Drugs that block the transport of adrenergic transmitters into axon terminals or into storage vesicles within terminals. The tricyclic antidepressants (ANTIDEPRESSIVE AGENTS, TRICYCLIC) and amphetamines are among the therapeutically important drugs that may act via inhibition of adrenergic transport. Many of these drugs also block transport of serotonin.

Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration.

Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine.

...DESIPRAMINE /WAS GIVEN/ IN DOSE OF 25 MG EVERY 8 HR TO 15 PT. .../IT/ ACCUM IN BODY FOR PERIODS VARYING FROM 1 TO 16 DAYS, PEAK PLASMA LEVELS RANGING FROM 10 TO 275 UG/L...

IN ANIMALS, TRANSPLACENTAL PASSAGE HAS BEEN DEMONSTRATED RECENTLY OF...DESIPRAMINE...

AFTER IV ADMIN OF SINGLE DOSE OF DESMETHYLIMIPRAMINE...TO DOGS, RATE OF RENAL EXCRETION OF UNCHANGED DRUG DECR DRAMATICALLY IN INCREASING URINARY PH, WITH LITTLE CHANGE IN CREATININE CLEARANCE. ... URINARY EXCRETION...IN MAN WAS ALSO SHOWN TO BE PH-DEPENDENT...

THERE IS WIDE INTERPATIENT VARIATION IN STEADY-STATE PLASMA CONCN OF TRICYCLIC ANTIDEPRESSANTS. ...VARIATION SEEMS TO BE GENETICALLY DETERMINED... /TRICYCLIC ANTIDEPRESSANTS/

Antidepressant

For relief of symptoms in various depressive syndromes, especially endogenous depression. It has also been used to manage chronic peripheral neuropathic pain, as a second line agent for the management of anxiety disorders (e.g. panic disorder, generalized anxiety disorder), and as a second or third line agent in the ADHD management.