Drug information of Dosulepin

By binding to noradrenaline transporter (NAT) and serotonin transporter (SERT) in an equipotent manner and inhibiting the reuptake activity, dosulepin increases the free levels of noradrenaline and 5HT at the synaptic cleft. It is shown that the main metabolite northiaden is a more potent inhibitor of noradrenaline uptake than the parent drug 5.

Dosulepin displays affinity towards α2-adrenoceptors and to a lesser extent, α1-adrenoceptors 4. Inhibition of presynaptic α2-adrenoceptors by dosulepin facilitates noradrenaline release and further potentiates the antidepressant effects 5. It also downregulates central β-adrenoceptors by causing a decline in the number of receptors and reduces noradrenaline-induced cyclic AMP formation 7,5. Dosulepin binds to 5HT1A and 5HT2A receptors in the cerebral cortex and hippocampus as an antagonist. 5HT1A receptors are autoreceptors that inhibit 5HT release and 5HT2A receptors are Gi/Go-coupled receptors that reduces dopamine release upon activation 6. Antagonism at 5HT2A receptors may also improve sleep patterns. Dosulepin also binds to muscarinic acetylcholine receptors and causes antimuscarinic side effects such as dry mouth. By acting as an antagonist at histamine type 1 (H1) receptors, dosulepin mediates a sedative effect.

Dosulepin is a tricyclic antidepressant that interacts with various receptors and transporters. It is a monoamine reuptake inhibitor with approximately equal potency for noradrenaline and 5-HT that increases the availability of these neurotransmitters at the central synapses 8. The metabolites of dosulepin are shown to inhibit 5HT uptake by the human blood platelet 2.

Absorption

Dosulepin is well absorbed from the intestines to reach the peak plasma concentration of 37.6ng/mL at 2.18 hours (Tmax) following oral administration of 25mg 7. The steady state concentrations are variable among individuals due to dynamic relationship between the drug dose and plasma concentration 8.

Volume of distribution

The mean apparent Vd is approximately 45 L/kg after oral administration of 75mg dosulepin 2. It crosses the blood-brain barrier to mediate its antidepressant actions and also crosses the placental barriers, with low concentration of the drug excreted in breast milk .

Protein binding

Approximately 84% of unchanged drug is bound to serum protein.

Metabolism

Dosulepin undergoes extensive hepatic metabolism, to form main metabolites N-demethylated derivative northiaden (desmethyldosulepin or northiaden) and dosulepin S-oxide. Northiaden S-oxide is among 12 basic metabolites that are found in urine. The metabolic pathways of dosulepin is thought to involve N-demethylation, S-oxidation and glucuronic acid conjugation.

Route of elimination

Dosulepin is predominantly cleared via renal elimination, mainly in the form of metabolites. Renal excretion of dosulepin and its metabolites accounts for 50% - 60% of total elimination, and biliary/fecal excretion is about 15%-40%.

Half life

The elimination half life is approximately 20.4 hours following oral administration of 25mg dosulepin.

Clearance

Oral clearance is approximately 1.36 L/kg * hr following a single oral dose of 75mg dosulepin.

Indicated in the treatment of symptoms of depressive illness, especially where an anti-anxiety effect is required.

For depression, the usual dose of dosulepin is 75mg to 150mg a day. Your dose may slowly go up to 225mg a day if your specialist recommends it. The maximum dose for depression is 225mg a day.

For pain relief or preventing migraines, the usual dose is 75mg a day taken in the evening - but this may vary. Your dose may start at 25mg a day and be increased slowly to 75mg a day. The maximum dose of dosulepin for pain or migraine is 150mg a day.

High mortality is associated with overdose of dosulepin (>5mg/kg) with the onset of toxicity occuring within 4-6 hours. Dosulepin may increase the risk of cardiovascular toxicity (cardiac arrhythmias, conduction disorders, cardiac failure and circulatory collapse) and severe hypotension, especially in the elderly. Withdrawal symptoms are reported in case of sudden cessation of therapy, which include insomnia, irritability, headache, nausea, giddiness, panic-anxiety, extreme motor restlessness and excessive perspiration. There have been reports of increased suicidal thoughts or behaviour with dosulepin treatment.

Most common adverse effects involve the central nervous system (drowsiness, extrapyramidal symptoms, tremor, confusional states, disorientation, dizziness, paraesthesia, alterations to EEG patterns), anticholinergic effects (dry mouth, sweating, urinary retention), cardiovascular system (hypotension, postural hypotension, tachycardia, palpitations, arrhythmias, conduction defects), endocrine system (altered libido), gastrointestinal system (nausea, vomiting, constipation) and blurred vision.

• Do not take Dosulepin tablets and speak to your doctor if:
• you know that you are allergic (hypersensitive) to dosulepin or any of the other ingredients of this medicine
•   you have an irregular heart beat or any other heart problems
•  you have liver problems
•  you have been diagnosed as having mania (feeling over-excited with unusual behaviour)
• Dosulepin tablets should not be given to children.
• Talk to your doctor or pharmacist before taking Dosulepin tablets if:

-  you are going to have surgery or dental treatment. Tell your surgeon or dentist that you are taking.

-Dosulepin tablets as it may affect the anaesthetic used.

- you have a history of mania or psychoses.

- you have an inherited disease called porphyria.

- you have a disease called phaeochromocytoma

-you have fits (epilepsy).

-  you have thyroid problems.

-you are a man that has prostate problems (difficulty in passing water or enlarged prostate)

-you have an eye condition known as glaucoma.

-you are undergoing electro-shock treatment.

- you have severe kidney problems.

- Thoughts of suicide and worsening of your depression or anxiety disorder.

If you are depressed and/or have anxiety disorders you can sometimes have thoughts of harming of killing yourself. These may be increased when first starting antidepressants, since these medicines all take time to work, usually about two weeks but sometimes longer.

• You may be more likely to think like this:
• If you have previously had thoughts about killing or harming yourself
• If you are a young adult. Information from clinical trial studies has shown an increased risk of suicidal
• behaviour in adults aged less than 25 years with psychiatric conditions who were treated with an anti-depressant
• If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital straight away. You may find it helpful to tell a relative or close friend that you are depressed or have an anxietydisorder and ask them to read this leaflet. You might ask them to tell you if they think your depression or anxiety is getting worse, or if they are worried about changes in your behaviour.

It's important for you and your baby that you stay well during your pregnancy. If you become pregnant while taking dosulepin speak to your doctor. Do not stop taking your medicine unless your doctor tells you to.

Dosulepin has been linked to a very small increased risk of problems for your unborn baby. However if your depression is not treated during pregnancy this can also increase the chance of problems.

You may need to take dosulepin during pregnancy if you need it to remain well. Your doctor can explain the risks and the benefits, and will help you decide which treatment is best for you and your baby.