CAFERGOT TABLETS

Indications

• Acute treatment of migraine attacks
• Cluster headache (off-label use)

Dosage

Adults: 1 mg taken once daily for 6 nights in 7, occasionally given for 1-2 weeks, dose to be taken at night.

Mechanism of action

Ergotamine tartrate acts as an agonist at serotonin (5-HT) receptors, particularly 5-HT1B and 5-HT1D subtypes, leading to vasoconstriction of cranial blood vessels. It modulates neurotransmitter release and inhibits the release of pro-inflammatory neuropeptides, which are involved in the pathophysiology of migraine.

Pharmacodynamics

The pharmacodynamic effects of ergotamine tartrate include vasoconstriction and a reduction in blood flow within the cranial vasculature, effectively alleviating headache symptoms. Additionally, it can influence dopaminergic pathways, contributing to its efficacy in treating migraine.

Pharmacokinetics

Ergotamine tartrate is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1-2 hours after oral administration. It undergoes extensive first-pass metabolism in the liver, resulting in a bioavailability of about 3-4%. The drug is primarily excreted via the kidneys, with a half-life of approximately 2 hours.

Contra-indications

• Acute porphyrias
• Coronary heart disease
• Hyperthyroidism
• Inadequately controlled hypertension
• Obliterative vascular disease
• Peripheral vascular disease
• Sepsis

Adverse effects

• Abdominal pain
• Dizziness
• Nausea
• Vomiting
• Cyanosis
• Diarrhoea
• Muscle weakness
• Pain in extremities
• Sensation abnormal
• Arrhythmias
• Cardiac valve fibrosis
• Dyspnoea
• Ergot poisoning
• Myocardial infarction
• Myocardial ischaemia
• Skin reactions
• Anxiety
• Arthralgia
• Blood disorder
• Cerebral ischaemia
• Confusion
• Constipation
• Depression
• Drowsiness
• Dry mouth
• Extrapyramidal symptoms
• Hallucination
• Renal artery spasm
• Seizure
• Sleep disorder
• Thrombosis
• Tremor
• Urinary retention
• Vision blurred

Precautions

• Anaemia
• Cardiac disease
• Dependence
• Elderly
• Risk of peripheral vasospasm

Pregnancy

Avoid; oxytocic effect on the uterus.

Breast-feeding

Avoid; ergotism may occur in infant; repeated doses may inhibit lactation.

Storage

Store in a refrigerator (2-8°C) and protect from light.

Formulations

• Tablets
• Injectable solution

Indications

• Management of apnea of prematurity
• Enhancement of alertness and cognitive performance
• Relief of headaches, particularly when combined with analgesics
• Enhancement of physical performance in sports

Dosage

Children: For infants, particularly for apnea of prematurity

Adults: The usual adult dose for alertness enhancement is 100 to 200 mg, taken as needed. For the management of apnea of prematurity, doses may vary and should be determined by a healthcare professional.

Mechanism of action

Caffeine acts primarily as an antagonist of adenosine receptors, inhibiting the action of adenosine, which normally promotes sleep and relaxation. This antagonism leads to increased neuronal firing and the release of neurotransmitters such as dopamine and norepinephrine. Caffeine also inhibits phosphodiesterase enzymes, enhancing levels of cyclic AMP and cyclic GMP, which are important for various cellular functions. Additionally, in the context of respiratory function, caffeine stimulates the respiratory centers in the central nervous system, enhancing ventilation.

Pharmacodynamics

Caffeine stimulates the central nervous system, increasing alertness and reducing fatigue. It relaxes smooth muscles, increases cardiac muscle contraction, and can enhance physical performance. Caffeine also promotes gastric acid secretion and gastrointestinal motility, and it exhibits mild diuretic properties. Its effects can lead to restlessness and agitation in some individuals, particularly at higher doses.

Pharmacokinetics

Caffeine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 30 to 120 minutes after ingestion. It is distributed widely throughout body tissues, readily crossing the blood-brain barrier. Caffeine is metabolized primarily in the liver by cytochrome P450 1A2, producing three primary metabolites: paraxanthine, theobromine, and theophylline. The elimination half-life varies significantly among individuals, influenced by factors such as age, liver function, pregnancy, and the use of certain medications. It is primarily excreted in urine.

Adverse effects

• Restlessness
• Agitation
• Insomnia
• Increased heart rate
• Nausea
• Gastrointestinal discomfort
• Headaches

Interactions

• caffeinecitrate+adenosine: Unknown (decreases efficacy)
• caffeinecitrate+antiarrhythmics: Unknown (decreases efficacy)

Precautions

• Use cautiously in patients with a history of anxiety disorders, insomnia, or cardiac arrhythmias.
• Monitor caffeine intake in individuals with certain medical conditions, such as hypertension.

Pregnancy

Caffeine crosses the placenta; excessive intake during pregnancy may be associated with adverse outcomes. It is generally recommended to limit caffeine consumption.

Breast-feeding

Caffeine is excreted in breast milk; moderate consumption is considered safe, but excessive intake may affect the infant's sleep and behavior.

Storage

Store in a cool, dry place away from direct light. Keep out of reach of children.

Formulations

• Tablets
• Oral solutions
• Injectable preparations
• Caffeine citrate

Indications

• Acute migraine attacks
• Cluster headaches

Dosage

Adults: The usual dosage for adults is 1 to 2 mg taken orally at the onset of a migraine attack. Doses may be repeated after 30 minutes if necessary, but should not exceed 6 mg in a 24-hour period or 10 mg per week.

Mechanism of action

Ergotamine acts on migraine through two proposed mechanisms: firstly, it activates 5-HT1D receptors on intracranial blood vessels, leading to vasoconstriction and relief of migraine headache. Secondly, it activates 5-HT1D receptors on sensory nerve endings in the trigeminal system, inhibiting pro-inflammatory neuropeptide release. Moreover, ergotamine stimulates alpha-adrenergic receptors, causing peripheral vasoconstriction, while its competitive alpha-adrenergic blocking effects emerge at higher doses. Additionally, it inhibits norepinephrine reuptake, enhancing its vasoconstrictor action.

Pharmacodynamics

Ergotamine exhibits complex pharmacological properties, acting as a vasoconstrictor and alpha adrenoreceptor antagonist. Its actions are multifaceted, with varying effects on tryptaminergic, dopaminergic, and alpha adrenergic receptors depending on the site of action. It is a potent uterine stimulant and effectively reduces extracranial blood flow, leading to decreased pulsation amplitude in cranial arteries and diminished hyperperfusion in the territory of the basilar artery, while not affecting cerebral hemispheric blood flow.

Pharmacokinetics

Ergotamine is well absorbed after oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes, and has a half-life of about 2 hours. The drug is excreted mainly in the urine as metabolites, and its pharmacokinetics can be significantly altered by concomitant medications that affect liver enzymes.

Contra-indications

• Hypersensitivity to ergotamine or any of its components
• Severe renal or hepatic impairment
• Pregnancy
• Peripheral vascular disease
• Ischemic heart disease
• Uncontrolled hypertension
• Severe infections
• Concurrent use with potent CYP3A4 inhibitors

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Chest pain
• Ischemia
• Ergotism (characterized by cold, numb extremities, pain, and possibly gangrene)
• Headache
• Dizziness
• Tachycardia
• Hypertension

Interactions

• miconazole: Severe (increases exposure)
• hiv-protease inhibitors: Severe (increases risk of ergotism)
• macrolides: Severe (increases risk of ergotism)
• ribociclib: Severe (increases exposure)
• selpercatinib: Severe (increases exposure)
• clarithromycin: Severe (increases risk of ergotism)
• fedratinib: Moderate (increases exposure)
• larotrectinib: Moderate (increases exposure)
• palbociclib: Moderate (increases exposure)
• rucaparib: Moderate (increases exposure)

Precautions

• Use with caution in patients with a history of cardiovascular disease
• Monitor for signs of ergotism, especially with prolonged use or high doses
• Assess renal and hepatic function before treatment
• Consider alternative treatments for patients with risk factors for ischemic conditions

Pregnancy

Ergotamine is contraindicated in pregnancy due to the risk of uterine contractions and potential harm to the fetus.

Breast-feeding

Ergotamine is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Tablets
• Suppositories
• Injectable forms

Indications

• Acidity regulator
• Stabilizing agent in pharmaceutical formulations
• Potential use in metabolic processes

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations, as pediatric dosing should be based on individual clinical scenarios.

Adults: Refer to specific guidelines for formulations containing tartarate, as dosing may vary based on the therapeutic context.

Mechanism of action

Tartarate acts as a salt that can influence the solubility and stability of various pharmaceutical compounds. It is known to interact with calcium ions and may affect the crystallization processes of certain compounds. In metabolic pathways, tartarate may participate in the citric acid cycle, contributing to energy production and various enzymatic reactions.

Pharmacodynamics

The pharmacodynamics of tartarate are largely related to its role as a buffering agent and stabilizer in formulations. It does not have direct pharmacological effects in the way that active drugs do but can influence the solubility and bioavailability of co-administered medications. Its effects on metabolic pathways can indirectly influence physiological responses.

Pharmacokinetics

The pharmacokinetics of tartarate, particularly potassium tartrate, involve absorption in the gastrointestinal tract, where it dissociates into potassium and tartrate ions. These ions can be absorbed and utilized in various biochemical processes. Excretion primarily occurs via the kidneys. The pharmacokinetic profile may vary based on the formulation and route of administration.

Mechanism of action

The mechanism of action of caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: **General and cellular actions** Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. **Respiratory** The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. **Central nervous system** Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. **Renal system** Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. **Cardiovascular system** Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain. Caffeine competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3',5'-adenosine monophosphate (AMP). Increased levels of intracellular cyclic AMP mediate most of caffeine's pharmacologic actions. Caffeine stimulates all levels of the CNS... Caffeine's cortical effects are milder and of shorter duration than those of amphetamines. In slightly larger doses, caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. Caffeine constricts cerebral vasculature. In contrast, the drug directly dilates peripheral blood vessels...

Pharmacodynamics

Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic.

Mechanism of action

Ergotamine acts on migraine by one of two proposed mechanisms: 1) activation of 5-HT_1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache, and 2) activation of 5-HT_1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. Ergotamine has complex pharmacologic effects. In therapeutic doses, ergotamine causes peripheral vasoconstriction (if the vascular tone is low) primarily by stimulating alpha-adrenergic receptors; however, the drug causes vasodilation in very hypertonic vessels. With higher doses, ergotamine is also a competitive alpha-adrenergic blocker, but this effect is somewhat masked by the drug's alpha-adrenergic agonist activity. With therapeutic doses, ergotamine also inhibits reuptake of norepinephrine, thereby maintaining a high concentration of circulating norepinephrine and increasing ergotamine's vasoconstrictor action. Ergotamine has greater vasoconstrictor activity than the other ergot alkaloids but less alpha-adrenergic blocking activity than dihydroergotamine. Ergotamine is a weaker antagonist of serotonin (5-hydroxytryptamine) than is methysergide, but ergotamine does reduce the increased rate of platelet aggregation induced by serotonin. The mechanism by which ergotamine aborts vascular headaches is probably direct vasoconstriction of the dilated carotid artery bed with a concomitant decrease in the amplitude of pulsations; the drug's effects on catecholamines and serotonin are also at least partly involved. Sumatriptan, dihydroergotamine and methysergide inhibit 1% formalin-induced nociception by activation of peripheral 5-HT1B/1D receptors. This study set out to investigate the pharmacological profile of the antinociception produced by intrathecal and intraplantar administration of ergotamine (a 5-HT1B/1D and 5-HT5A/5B receptor agonist) and valerenic acid (a partial agonist at 5-HT5A receptors). Intraplantar injection of 1% formalin in the right hind paw resulted in spontaneous flinching behavior of the injected hindpaw of female Wistar rats. Intrathecal ergotamine (15 nmol) or valerenic acid (1 nmol) blocked in a dose dependent manner formalin-induced nociception. The antinociception by intrathecal ergotamine (15 nmol) or valerenic acid (1 nmol) was partly or completely blocked by intrathecal administration of the antagonists: (i) methiothepin (non-selective 5-HT5A/5B; 0.01-0.1 nmol); (ii) SB-699551 (selective 5-HT5A; up to 10 nmol); (iii) anti-5-HT5A antibody; (iv) SB-224289 (selective 5-HT1B; 0.1-1 nmol); or (v) BRL-15572 (selective 5-HT1D; 0.1-1 nmol). Likewise, antinociception by intraplantar ergotamine (15 nmol) and valerenic acid (10 nmol) was: (i) partially blocked by methiothepin (1 nmol), SB-699551 (10 nmol) or SB-224289 (1 nmol); and (ii) abolished by BRL-15572 (1 nmol). The above doses of antagonists (which did not affect per se the formalin-induced nociception) were high enough to completely block their respective receptors. Our results suggest that ergotamine and valerenic acid produce antinociception via 5-HT5A and 5-HT1B/1D receptors located at both spinal and peripheral sites. This provides new evidence for understanding the modulation of nociceptive pathways in inflammatory pain. It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT1B/1D receptors and alpha2-adrenoceptors. The present study has reanalyzed this suggestion by using more selective antagonists alone and in combination. Fifty-two anesthetized dogs were prepared for ultrasonic measurements of external carotid blood flow. The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 mL/kg; control), or the antagonists SB224289 (300 ug/kg; 5-HT1B), BRL15572 (300 ug /kg; 5

Pharmacodynamics

Ergotamine is a vasoconstrictor and alpha adrenoreceptor antagonist. The pharmacological properties of ergotamine are extremely complex; some of its actions are unrelated to each other, and even mutually antagonistic. The drug has partial agonist and/or antagonist activity against tryptaminergic, dopaminergic and alpha adrenergic receptors depending upon their site, and it is a highly active uterine stimulant. It causes constriction of peripheral and cranial blood vessels and produces depression of central vasomotor centers. The pain of a migraine attack is believed to be due to greatly increased amplitude of pulsations in the cranial arteries, especially the meningeal branches of the external carotid artery. Ergotamine reduces extracranial blood flow, causes a decline in the amplitude of pulsation in the cranial arteries, and decreases hyperperfusion of the territory of the basilar artery. It does not reduce cerebral hemispheric blood flow.