User:Unregistered pharmacists/sandbox

= Bellergal =

Bellergal is a combination of belladonna, ergotamine tartrate and phenobarbital, used for the treatment of functional menopause, such as hot flashes and night sweats.

Belladonna, including atropine, hyoscyamine, and scopolamine, are antimuscarinic agents. They block acetylcholine from binding to its receptors. It generally reduces the secretion of the body, including mouth, nose, and skin, and causes drowsiness and other anticholinergic effects. Phenobarbital provides sedative and anesthetic effects by depressing the central nervous system. Ergotamine constricts blood vessels in the brain and alleviates headache through stimulating alpha-1, dopamine, and serotonin receptors.

Common side effects of Bellergal include drowsiness, flushing, nausea, vomiting, diarrhea, constipation, decreased sweating, visual disturbances, unusual fatigue or weakness, and dry mouth. Bellergal has a high potential for potentially serious drug interactions due to strong CYP3A4 inhibition by ergotamine. Ergotamine is a vasoconstrictive CYP3A4 substrate.

Bellergal was widely used during the 1970s and 1980s. Its limited efficacy on decreasing hot flashes frequency and severity were demonstrated by several randomized controlled trials. On 6th June 2018, Bellergal was discontinued by Paladin Labs due to its raw material availability and limited efficacy. There are no Bellergal tablets available in the markets now.

Menopause associated symptoms
Bellergal was indicated for hot flashes, perspiration, palpitations, dizzy spells, restlessness, apprehension, fatigue, insomnia, and headache.

Dose and administration
Prolong use of bellergal is not recommended due to the risk of ergotism and rare fibrotic complications. Patients should be made aware of the maximum dosages permitted as well as the initial signs of overdosage, which include hypoesthesia, paresthesia in the fingers and toes, nausea, and vomiting, as well as symptoms of myocardial ischemia and ergotism, such as brain ischemia.

Recommended Daily Dose:
The recommended dose of Bellergal is 3-4 tablets daily in oral administration. The maximum dose in one week is 16 tablets. The exact dose depends on symptoms and indications that should be followed the instruction given by doctors or pharmacists.

Pharmacology
Belladonna alkaloids, ergotamine tartrate, and phenobarbital are the three main components of Bellergal. These three active components cooperate to alleviate menopausal symptoms.

ERGOTAMINE
Ergotamine is a partial agonist (or partial antagonist) that acts on dopamine and serotonin receptors depending on the site of action, and it is a highly potent stimulant to the uterine. Ergotamine alleviates headache by activating serotonin (5-hydroxytryptamine 1D, 5-HT1D) receptors on the blood vessels within the cranium and arterio-venous anastomoses. As a result, blood vessels narrow and the blood flow through the cerebral blood vessels is subsequently decreased. It also agonizes 5-HT1D receptors on sensory nerve endings of the trigeminal nerves, and hence inhibits the release of pro-inflammatory neuropeptide, resulting in the anti-inflammatory effect. It is also a partial agonist that selectively acts on the alpha-1 receptor in the sympathetic nervous system. The stimulation of the alpha-1 receptor activates the phospholipase C that raises the level of IP3 and DAG, increasing calcium levels inside the smooth muscle cells. The smooth muscles surrounding the blood vessels contract, subsequently constricting both arteries and veins. This constriction relieves headaches while also reducing blood flow to the area of a hot flash, lessening its intensity and frequency.

PHENOBARBITAL
Phenobarbital is a nonselective central nervous system depressant. Phenobarbital's exact mechanism of action is not completely understood. There are some possible mechanisms of action of Phenobarbital.

Gamma-aminobutyric acid (GABA), a primary inhibitory neurotransmitter in the central nervous system, its synaptic activity may be boosted and/or mimicked by phenobarbital which reduces neuronal excitability. Phenobarbital's sedative-hypnotic effects may be brought on by an inhibition of conduction in the reticular formation, which would reduce the number of impulses that reach the cerebral cortex and slow down the activity of the brain.

BELLADONNA
Belladonna alkaloids, containing atropine, hyoscyamine, and scopolamine, are natural-existing muscarinic receptor antagonists. They compete with acetylcholine at peripheral and central muscarinic receptors and inhibit the muscarinic effect in exocrine glands, smooth muscle, cardiac muscle, and intramural neurons. Different organs have different physiological responses to muscarinic receptor blockage. Scopolamine has a larger effect on the eyes, central nervous system, and secretory glands compared to atropine and hyoscyamine. While exerting similar effects to atropine, hyoscyamine has more significant effects on the central and peripheral nervous systems. Higher doses of atropine can cause pupil dilation, an increase in heart rate by blocking vagal nerves on the heart, and the suppression of bowel motility. Lower doses of atropine reduce salivary and bronchial secretion as well as perspiration.

Absorption
Ergotamine is poorly absorbed via sublingual administration and is absorbed in the digestive tract slowly and incompletely via oral administration. Its absorption can be enhanced by the co-administration of caffeine. The peak plasma concentration is attained in around 1 hour.

Distribution
There is limited information on the distribution of ergotamine in human tissues. Ergotamine has a high affinity to plasma proteins. Around 93-98% of ergotamine binds to plasma protein.

Metabolism
The bioavailability is lower than or equal to 5% through oral or rectal administration. The reason is that ergotamine is extensively metabolized by the hepatic first pass.

Elimination
90% of ergotamine metabolites are excreted in bile while a trace amount of ergotamine is excreted unchanged through feces and urine (4%). A trace level of ergotamine and its metabolites may be found in saliva and breast milk.

Absorption
Phenobarbital is rapidly and completely absorbed from the digestive tract after oral administration especially it is diluted or taken on an empty stomach. The peak plasma concentration is reached around 6-18 hours. Its bioavailability is 100%.

Distribution
Phenobarbital is quickly distributed into all body fluids and tissues, mainly in the liver, brain, and kidney. The volume of distribution is around 0.54 L/kg by intravenous administration.

Metabolism and Elimination
Phenobarbital only has a small extent of hepatic metabolism, and 75% of it is excreted unchanged in the urine. Resulting in the long-acting characteristic.

Absorption
Atropine is quickly and efficiently transported to systemic circulation after being adequately absorbed in the digestive system. Hyoscyamine can be fully absorbed through oral administration. Scopolamine has a low bioavailability of around 13%. The peak plasma concentration is attained around 23.5 ± 8.2 minutes.

Distribution
Atropine is distributed throughout the whole body while the volume of distribution is around 1.0 to 1.7 L/kg by intravenous administration. There is limited information about the volume of distribution of hyoscyamine and scopolamine in the human body.

Metabolism
The major metabolism of atropine is hydrolysis by hepatic enzymes. A little quantity of hyoscyamine is hydrolyzed into tropine and tropic acid, although the majority of it remains unmetabolized. There is limited information about the metabolism of scopolamine in the human body.

Elimination
Around 13 to 50% of Atropine is eliminated in the urine as an unaltered parent drug. Most of the hyoscyamine is excreted in the urine unaltered. By oral administration, around 2.6% of unaltered scopolamine is excreted through urine.

History and Development
Bellergal was widely used during 1970s and 1980s. Its limited efficacy on decreasing hot flashes frequency and severity were demonstrated by several randomized controlled trials. After 2 weeks of therapy, bellergal significantly reduced hot flashes. The difference between the therapy and placebo, however, vanished after 8 weeks with decreases of 68% and 75%, respectively. Although Bellergal reduced hot flashes compared to placebo, there was a considerable amount of toxicity, with more than 30% of users discontinuing the medication owing to side effects as dry mouth, drowsiness, dizziness, and rash.

There were shortage reports related to phenobarbital from 18th July 2017 to 1st March 2018, disrupting the flow of production process with quality, time and cost control. With all the factors considered, on 6th June 2018, Bellergal was discontinued by Paladin Labs due to its raw material availability and limited efficacy; while the remaining supply date was on 1st October 2017.

There are no bellergal tablets available in the markets now. Sandoz in Spain, France and Germany, Novartis in Switzerland, Thailand, Turkey and South Africa and Paladin in Canada discontinued the preparations. Instead, it is replaced by new and similar formulations named as Bellegal-S, manufactured by Novartis in the United States of America. One of the active ingredients is changed to bellafoline (levorotary alkaloids of belladonna).

Contraindications
This combination is contraindicated in those with hypersensitivity to the three active ingredients, and in those with narrow-angle glaucoma, hypertension, cardiovascular, liver, kidney, or circulation problems. People with high temperature, pregnant women, nursing mothers should also avoid this medication.

CYP3A4 inhibition Ergotamine is a vasoconstrictive CYP3A4 substrates. The concurrent use of vasoconstricting ergot derivatives and strong CYP3A4 inhibitors, such as HIV protease or reverse transcriptase inhibitors, azole antifungals, or macrolide antibiotics, was associated with ergot toxicity. The inhibition of CYP3A4 leads to an increase level in serum concentration of Ergot derivatives. Extreme ischemia, coma or even death is resulted. For this reason, the use with potent CYP3A4 inhibitors should be avoided when prescribing. Moderate CYP3A4 inhibitors such as berotralstat, conivaptan, crizotinib, dilriazem, dronedarone, duvelisib, fedratinib, fluconazole, fosnetupitant, grapefruit juice, imatinib, isavuconazonium sulfate, lefamulin, should also be monitored closely. Cramping, pain and angina were reported. Patient should be monitored closely for ergot toxicity and the use with this treatment should be done with cautions.