MarketDosulepin
Company Profile

Dosulepin

Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression. Dosulepin was once the most frequently prescribed antidepressant in the United Kingdom, but it is no longer widely used due to its relatively high toxicity in overdose without therapeutic advantages over other TCAs. It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has other activities including antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and sodium channel-blocking effects.

Medical uses
Dosulepin is used for the treatment of major depressive disorder. There is clear evidence of the efficacy of dosulepin in psychogenic facial pain, though the drug may be needed for up to a year. ==Contraindications==
Contraindications
Contraindications include: • Epilepsy as it can lower the seizure threshold • TCAs should not be used concomitantly or within 14 days of treatment with monoamine oxidase inhibitors due to the risk for serotonin syndrome • Acute recovery phase following myocardial infarction as TCAs may produce conduction defects and arrhythmias • Liver failure • Hypersensitivity to dosulepin ==Side effects==
Side effects
Common adverse effects: • Drowsiness • Extrapyramidal symptoms • Tremor • • Disorientation • Dizziness • Paresthesias • Alterations to ECG patterns • Dry mouth • Sweating • Urinary retention • Hypotension • Postural hypotension • Tachycardia • Palpitations • Arrhythmias • Conduction defects • Increased or decreased libido • Nausea • Vomiting • Constipation • Blurred vision Less common adverse effects: • Disturbed concentration • DelusionsHallucinations • Anxiety • Fatigue • Headaches • Restlessness • Excitement • Insomnia • Hypomania • Nightmares • Peripheral neuropathyAtaxia • Incoordination • Seizures • Paralytic ileus • Hypertension • Heart block • Myocardial infarction • Stroke • Gynecomastia (swelling of breast tissue in males) • Testicular swelling • Impotence • Epigastric distress • Abdominal cramps • Parotid swellings • Diarrhea • Stomatitis (swelling of the mouth) • Black tongue • Peculiar taste sensations • Cholestatic jaundice • Altered liver function • Hepatitis (swelling of the liver) • Skin rash • Urticaria (hives) • Photosensitisation • Skin blisters • Angioneurotic edema • Weight loss • Urinary frequency • Mydriasis • Weight gain • Hyponatremia (low blood sodium) • Movement disorders • Dyspepsia (indigestion) • Increased intraocular pressure • Changes in blood sugar levels • Thrombocytopenia (an abnormally low number of platelets in the blood. This makes one more susceptible to bleeds) • Eosinophilia (an abnormally high number of eosinophils in the blood) • Agranulocytosis (a dangerously low number of white blood cells in the blood leaving one open to potentially life-threatening infections) • Galactorrhea (lactation that is unassociated with breastfeeding and lactation) ==Overdose==
Overdose
The symptoms and the treatment of an overdose are largely the same as for the other TCAs. Dosulepin may be particularly toxic in overdose compared to other TCAs. The onset of toxic effects is around 4–6 hours after dosulepin is ingested. In order to minimise the risk of overdose it is advised that patients only receive a limited number of tablets at a time so as to limit their risk of overdosing. It is also advised that patients are not prescribed any medications that are known to increase the risk of toxicity in those receiving dosulepin due to the potential for mixed overdoses. The medication should also be kept out of reach of children. ==Interactions==
Interactions
Dosulepin can potentiate the effects of alcohol and at least one death has been attributed to this combination. TCAs potentiate the sedative effects of barbiturates, tranquilizers and depressants. Guanethidine and other adrenergic neuron blocking drugs can have their antihypertensive effects blocked by dosulepin. Sympathomimetics may potentiate the sympathomimetic effects of dosulepin. Due to the anticholinergic and antihistamine effects of dosulepin anticholinergic and antihistamine medications may have their effects potentiated by dosulepin and hence these combinations are advised against. Dosulepin may have its postural hypotensive effects potentiated by diuretics. Anticonvulsants may have their efficacy reduced by dosulepin due to its ability to reduce the seizure threshold. ==Pharmacology==
Pharmacology
Pharmacodynamics Dosulepin is a reuptake inhibitor of the serotonin transporter (SERT) and the norepinephrine transporter (NET), thereby acting as an SNRI. Unlike the sulfoxide metabolites, northiaden is thought to play an important role in the effects of dosulepin. Although Heal & Cheetham (1992) reported relatively high Ki values of 12 and 15 nM for dosulepin and northiaden at the rat α2-adrenergic receptor and suggested that antagonism of the receptor could be involved in the antidepressant effects of dosulepin, Richelson & Nelson (1984) found a low KD of only 2,400 nM for dosulepin at this receptor using human brain tissue. This suggests that it in fact has low potency for this action, similarly to other TCAs. Pharmacokinetics Dosulepin is readily absorbed from the small intestine and is extensively metabolized on first-pass through the liver into its chief active metabolite, northiaden. Peak plasma concentrations of between 30.4 and 279 ng/mL (103–944 nmol/L) occur within 2–3 hours of oral administration. It is distributed in breast milk and crosses the placenta and blood–brain barrier. It is highly bound to plasma proteins (84%), and has a whole-body elimination half-life of 51 hours. ==Chemistry==
Chemistry
Dosulepin is a tricyclic compound, specifically a dibenzothiepine, and possesses three rings fused together with a side chain attached in its chemical structure. It is the only TCA with a dibenzothiepine ring system to have been marketed. The drug is a tertiary amine TCA, with its side chain-demethylated metabolite northiaden (desmethyldosulepin) being a secondary amine. Other tertiary amine TCAs include amitriptyline, imipramine, clomipramine, doxepin, and trimipramine. Dosulepin exhibits (E) and (Z) stereoisomerism like doxepin but in contrast the pure E or trans isomer is used medicinally. The drug is used commercially as the hydrochloride salt; the free base is not used. ==History==
History
Dosulepin was developed by SPOFA. It was patented in 1962 and first appeared in the literature in 1962. ==Society and culture==
Society and culture
Generic names Dosulepin is the English and German generic name of the drug and its and , while dosulepin hydrochloride is its and . Dothiepin is the former of the drug while dothiepin hydrochloride is the former and remains the current . It is also available in Japan, Hong Kong, Taiwan, India, Singapore, and Malaysia. The drug is not available in the United States or Canada. ==References==
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