Side effects
Adverse effects include:
Nausea, vomiting, and diarrhea
Dizziness
Pulmonary hypertension
Coronary artery vasoconstriction
Severe systemic hypertension (especially in patients with pre-eclampsia)
ConvulsionsIn excessive doses, methylergometrine can also lead to cramping, respiratory depression and coma. Interactions
Methylergometrine likely interacts with drugs that inhibit the liver enzyme CYP3A4, such as azole antifungals, macrolide antibiotics and many HIV drugs. It can also increase constriction of blood vessels caused by sympathomimetic drugs and other ergot alkaloids. Pharmacology
Pharmacodynamics
Methylergometrine is an agonist or antagonist to serotonin, dopamine, and α-adrenergic receptors. Its specific binding and activation pattern on these receptors leads to a highly, if not completely, specific contraction of smooth uterus muscle via serotonin 5-HT2A receptors, while blood vessels are affected to a lesser extent compared to other ergot alkaloids. It has been found to interact with the serotonin 5-HT1A, 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, and 5-HT7 receptors.Methylergometrine is a synthetic analogue of ergometrine, a psychedelic alkaloid found in ergot, and many species of morning glory. Methylergometrine is a member of the ergoline family and chemically similar to LSD, ergine, ergometrine, and lysergic acid. According to Jonathan Ott, methylergometrine produces LSD-like psychedelic effects at doses of 2 mg and above. This can be attributed to due to its agonistic action at the 5-HT2A–mGlu2 receptor protomers. Clinical efficacy occurs around 200 µg, ten times lower than the hallucinogenic threshold.Methylergometrine is an agonist of the serotonin 5-HT2B receptor and has been associated with cardiac valvulopathy.
In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older.No seizures have been observed with darolutamide in clinical trials. Darolutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy. It may impair male fertility. When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce feminizing breast changes including breast tenderness and gynecomastia. Overdose
Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials. There were no dose-limiting toxicities seen at this dosage. Due to its saturable absorption and lack of acute toxicity, overdose of darolutamide is not expected to result in systemic toxicity in people with intact hepatic and renal function. There is no specific antidote for overdose of darolutamide. In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal. If there is suspicion of toxicity, general supportive measures should be undertaken until clinical toxicity has decreased or resolved and then treatment may be continued. Interactions
Combined P-glycoprotein and strong or moderate CYP3A4 inducers such as rifampicin may decrease exposure to darolutamide, while combined P-glycoprotein and strong CYP3A4 inhibitors such as itraconazole may increase exposure to darolutamide. Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) transporter and can increase exposure to substrates for this protein such as rosuvastatin. It has been found to increase exposure to rosuvastatin by approximately 5-fold.