DESCRIPTION
Ergotamine – A vasoconstrictor found in ergot of Central Europe. It is an alpha-1 selective adrenergic agonist and is commonly used in the treatment of migraine disorders. Caffeine – A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine’s most notable pharmacological effect is as a central nervous system stimulant, increasing alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of adenosine receptors, and modulation of intracellular calcium handling. Paracetamol – Acetaminophen, also known as paracetamol, is commonly used for its analgesic and antipyretic effects. Its therapeutic effects are similar to salicylates, but it lacks anti-inflammatory, antiplatelet, and gastric ulcerative effects.Acetaminophen, also known as paracetamol, is commonly used for its analgesic and antipyretic effects. Its therapeutic effects are similar to salicylates, but it lacks anti-inflammatory, antiplatelet, and gastric ulcerative effects. Prochlorperazine – A phenothiazine antipsychotic used principally in the treatment of nausea; vomiting; and vertigo. It is more likely than chlorpromazine to cause extrapyramidal disorders.
CATEGORIES
Caffeine – Central Nervous System Stimulants,Appetite Depressants,Phosphodiesterase Inhibitors,Purinergic P1 Receptor Antagonists. Paracetamol – Analgesics, Non-Narcotic,Antipyretics. Prochlorperazine – Antipsychotic Agents,Antiemetics,Dopamine Antagonists,Phenothiazines .
CHEMICAL FORMULA
Ergotamine – C33H35N5O5 ,Caffeine – C8H10N4O2. Paracetamol – C8H9NO2. Prochlorperazine – C20H24ClN3S.
COMPOSITION
Ergotamine 1mg + Caffein 100mg + Paracetamol 250mg + Prochlorperazine maleate 2.5mg
INDICATION
Ergotamine – For use as therapy to abort or prevent vascular headache, e.g., migraine, migraine variants, or so called “histaminic cephalalgia”. Caffeine – For management of fatigue, orthostatic hypotension, and for the short term treatment of apnea of prematurity in infants. Paracetamol – For temporary relief of fever, minor aches, and pains. Prochlorperazine – For the symptomatic management of psychotic disorders, short term management of nonpsychotic anxiety in patients with generalized anxiety disorder, and for the control of severe nausea and vomiting of various causes.
PHARMACODYNAMICS
Ergotamine – 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. Caffeine – Caffeine, a naturally occurring xanthine derivative like theobromine and the bronchodilator theophylline, is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of prematurity). Often combined with analgesics or with ergot alkaloids, caffeine is used to treat migraine and other headache types. Over the counter, caffeine is available to treat drowsiness or mild water-weight gain. Paracetamol – Acetaminophen (USAN) or Paracetamol (INN) is a widely used analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. It is a major ingredient in numerous cold and flu medications and many prescription analgesics. It is extremely safe in standard doses, but because of its wide availability, deliberate or accidental overdoses are not uncommon. Acetaminophen, unlike other common analgesics such as aspirin and ibuprofen, has no anti-inflammatory properties or effects on platelet function, and it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. At therapeutic doses acetaminophen does not irritate the lining of the stomach nor affect blood coagulation, kidney function, or the fetal ductus arteriosus (as NSAIDs can). Like NSAIDs and unlike opioid analgesics, acetaminophen does not cause euphoria or alter mood in any way. Acetaminophen and NSAIDs have the benefit of being completely free of problems with addiction, dependence, tolerance and withdrawal. Acetaminophen is used on its own or in combination with pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, doxylamine, codeine, hydrocodone, or oxycodone. Prochlorperazine – Prochlorperazine is a piperazine phenothiazine related to high-potency neuroleptics such as perphenazine. It shares many of the actions and adverse effects of the antipsychotics.
No Information
ABSORPTION
Ergotamine – The bioavailability of sublingually administered ergotamine has not been determined. Caffeine -Readily absorbed after oral or parenteral administration. The peak plasma level for caffeine range from 6-10mg/L and the mean time to reach peak concentration ranged from 30 minutes to 2 hours. Paracetamol – Rapid and almost complete. Prochlorperazine – Rapidly absorbed following oral administration.
VOLUME DISTRIBUTION
Caffeine – 0.8 to 0.9 L/kg [infants],0.6 L/kg [adults] .
METABOLISM
Ergotamine – Hepatic. Ergotamine is metabolized by the liver by largely undefined pathways, and 90% of the metabolites are excreted in the bile. Caffeine – Hepatic cytochrome P450 1A2 (CYP 1A2) is involved in caffeine biotransformation. About 80% of a dose of caffeine is metabolized to paraxanthine (1,7-dimethylxanthine), 10% to theobromine (3,7-dimethylxanthine), and 4% to theophylline (1,3-dimethylxanthine). Paracetamol – Acetaminophen primarily undergoes glucuronidation (45-55% of the dose) in which this process is facilitated by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver or UGT1A10 in the gut. 30-35% of the dose undergoes sulfation. This biotransformation is facilitated by SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. A small percentage of acetaminophen is oxidized by CYP2E1 to form N-acetyl-p-benzo-quinone imine (NAPQI), a toxic metabolite which is then conjugated to glutathione and excreted renally. Studies suggest that CYP3A4 and CYP2E1 are the primary cytochrome P450 isozymes responsible for the generation of toxic metabolites. Accumulation of NAPQI may occur if primary metabolic pathways are saturated. Prochlorperazine -Hepatic. Undergoes metabolism in the gastric mucosa and on first pass through the liver, CYP2D6 and/or CYP3A4.
ELIMINATION
Caffeine – In young infants, the elimination of caffeine is much slower than that in adults due to immature hepatic and/or renal function. Paracetamol – Approximately 80% of acetaminophen is excreted in the urine after conjugation and about 3% is excreted unchanged.
HALF LIFE
Ergotamine – 2 hours,Caffeine – 3 to 7 hours in adults, 65 to 130 hours in neonates . Paracetamol – 1 to 4 hours. Prochlorperazine – 6 to 8 hours
TOXICITY
Ergotamine – Signs of overexposure include irritation, nausea, vomiting, headache, diarrhea, thirst, coldness of skin, pruritus, weak pulse, numbness, tingling of extremities, and confusion. Caffeine – LD50=127 mg/kg (orally in mice) . Paracetamol -Oral, mouse: LD50 = 338 mg/kg; Oral, rat: LD50 = 1944 mg/kg. Acetaminophen is metabolized primarily in the liver, where most of it is converted to inactive compounds by conjugation with glucuronic acid and, to a lesser extent, sulfuric acid. Conjugates are then excreted by the kidneys. Only a small portion is excreted in unchanged in urine or oxidized via the hepatic cytochrome P450 enzyme system (CYP2E1). Metabolism via CYP2E1 produces a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). The toxic effects of acetaminophen are due to NAPQI, not acetaminophen itself nor any of the major metabolites. At therapeutic doses, NAPQI reacts with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is excreted by the kidneys. High doses of acetaminophen may cause glutathione depletion, accumulation of NAPQI and hepatic necrosis. The maximum daily dose of acetaminophen is 4 g. Liver failure has been observed at doses as low as 6 g per day. As such, the maximum daily and single dose of acetaminophen is currently being reviewed in some countries. N-acetyl-cysteine, a precursor of glutathione, may be administered in the event of acetaminophen toxicity. Prochlorperazine -Symptoms of central nervous system depression to the point of somnolence or coma. Agitation and restlessness may also occur. Other possible manifestations include convulsions, EKG changes and cardiac arrhythmias, fever and autonomic reactions such as hypotension, dry mouth and ileus; LD50=400mg/kg (orally in mice).
FOOD INTERACTIONS
avoid alcohol
SIDE EFFECTS
Ergotamine – sudden numbness or weakness, especially on one side of the body,sudden headache, confusion, problems with vision, speech, or balance,fast or slow heart rate,muscle, pain in your arms or legs,leg weakness. Caffeine – Nervous and excitable. – Grouchy or touchy. Not able to sleep. Paracetamol – Upset stomach or throwing up. Harm to the liver may rarely happen. Prochlorperazine – Drowsiness, dizziness, absence of menstrual periods, blurred vision, skin reactions and Neuroleptic Malignant Syndrome (NMS).