Conversely, antagonism of the H1, α1-adrenergic, and muscarinic acetylcholine receptors is thought to contribute to its side effects. Blockade of the H1 receptor is specifically responsible for the antihistamine effects of clomipramine and side effects like sedation and somnolence (sleepiness). Antagonism of the α1-adrenergic receptor is thought to cause orthostatic hypotension and dizziness. Inhibition of muscarinic acetylcholine receptors is responsible for the anticholinergic side effects of clomipramine like dry mouth, constipation, urinary retention, blurred vision, and cognitive/memory impairment. In overdose, sodium channel blockade in the brain is believed to cause the coma and seizures associated with TCAs while blockade of sodium channels in the heart is considered to cause cardiac arrhythmias, cardiac arrest, and death. On the other hand, sodium channel blockade is also thought to contribute to the analgesic effects of TCAs, for instance in the treatment of neuropathic pain.The exceptionally strong serotonin reuptake inhibition of clomipramine likely precludes the possibility of its antagonism of serotonin receptors (which it binds to with more than 100-fold lower affinity than the SERT) resulting in a net decrease in signaling by these receptors. In accordance, while serotonin receptor antagonists like cyproheptadine and chlorpromazine are effective as antidotes against serotonin syndrome, clomipramine is nonetheless capable of inducing this syndrome.
Cowden syndrome (also known as Cowdens disease and multiple hamartoma syndrome) is an autosomal dominant inherited condition characterized by benign overgrowths called hamartomas as well as an increased lifetime risk of breast, thyroid, uterine, and other cancers. It is often underdiagnosed due to variability in disease presentation, but 99% of patients report mucocutaneous symptoms by age 20–29. Despite some considering it a primarily dermatologic condition, Cowdens syndrome is a multi-system disorder that also includes neurodevelopmental disorders such as macrocephaly.The incidence of Cowdens disease is about 1 in 200,000, making it quite rare. Furthermore, early and continuous screening is essential in the management of this disorder to prevent malignancies. It is associated with mutations in PTEN on 10q23.3, a tumor suppressor gene otherwise known as phosphatase and tensin homolog, that results in dysregulation of the mTOR pathway leading to errors in cell proliferation, cell cycling, and apoptosis. The most common malignancies associated with the syndrome are adenocarcinoma of the breast (20%), followed by adenocarcinoma of the thyroid (7%), squamous cell carcinomas of the skin (4%), and the remaining from the colon, uterus, or others (1%). Signs and symptoms
As Cowdens disease is a multi-system disorder, the physical manifestations are broken down by organ system:
Skin
Adolescent patients affected with Cowden syndrome develop characteristic lesions called trichilemmomas, which typically develop on the face, and verrucous papules around the mouth and on the ears. Oral papillomas are also common. Furthermore, shiny palmar keratoses with central dells are also present.