There are three methylxanthine alkaloids: theobromine, theophylline, and caffeine. Cocoa and chocolate contain theobromine and some caffeine. Tea contain caffeine and some theophylline. Coffee and many cola-flavored beverages are rich sources of caffeine.
Theophylline and caffeine are used in drug therapy.
Methylxanthines stimulate the CNS, induce dieresis, relax smooth muscle ( bronchial muscle), and stimulate cardiac functions. Caffeine also augment the analgesic properties of salicylates and is contained in many analgesic products.
Pharmacokinetics:
Xanthine derivatives are well absorbed orally, reaching peak distribution within two hours. The compounds are metabolized by the liver to methylxanthine and methyluric acid derivatives.
In adults caffeine undergoes both oxidation and Ndemethylation, with approximately 1 % excreted unchanged in the urine, Caffeine is metabolized to theophylline by the cytochrome P-450 enzyme system. However, in neonates approximately 85 % of a dose is excreted unchanged in the urine. Decreased elimination and a prolonged half-life may increase caffeine toxicity in neonates and premature infants. The metabolism of a child approaches that of an adult at the approximate age of 8 months.
Pathaphysiology:
Caffeine has many effects in the body:
(1) Adenosine receptor antagonism.
(2) Phosphodiesterase inhibition.
(3) Enhanced intracellular calcium levels.
Adenosine receptor antagonism leads to vasoconstriction, hypertension, tremor, and agitation. These effects are frequently
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seen in caffeine overdose. These effects are the reverse of those seen with adenosine agonist activity, such as arterial vasodilation, inhibition of catecholamine release, and slowing of cardiac pacemaker cells.
Caffeine inhibits phosphodiesterases, causing increased levels of cyclic AMP, which results in increased levels of catecholamines. Muscle contractility is enhanced through increased intracellular calcium levels . Stimulation of gastric acid and intestinal secretions and lowering of lower esophageal sphincter tone by caffeine commonly result in diarrhea and abdominal cramping.
Beneficial effects of caffeine include bronchodilation and vasodilation in the treatment of apnea in premature infants.
Although caffeine-induced vasodilation may lower blood pressure, caffeine-induced medullary stimulation and increased catecholamine release offset this effect.
Theophylline, in addition, inhibits the action of extracellular adenosine (bronchodilation effect), stimulates endogenous catecholamines (central stimulant effect), and directly promotes mobilization of intracellular calcium and β-adrenergic agonist activity (airway smooth muscle relaxation), so its used in the treatment of bronchial asthma and other respiratory related disorders.
Clinical presentation of caffein:
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Acute Toxicity
In adults, ingestion of 500–1000 mg of caffeine may result in nausea, vomiting, diarrhea, tremors, and agitation. Most patients have sinus tachycardia and a mild hypertension. Increases in cardiac output and glomerular filtration rate (GFR) can increase urine production. Dehydration and hypokalemia are common.
Death due to caffeine overdose is rare and it is related to dysrhythmias, seizures, and neurologic effects. The estimated
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lethal dose of caffeine in an untreated adult is 5–10 g, and in children 78 mg/kg has caused serious symptoms. This may be due to the slower elimination of caffeine by children.
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Chronic Toxicity
Chronic excessive ingestions of over-the-counter sympathomimetic and caffeine frequently result in tachycardia, hypertension, and palpitations. Myocardial infarction, vasculitis, cardiomyopathy, and dysrhythmias (paroxysmal atrial tachycardia, premature ventricular contractions, bigeminy, ventricular tachycardia, and ventricular fibrillation). Chronic use and misuse may lead to sustained hypertension and subsequent hemorrhage. With chronic use, certain individuals may tolerate extremely large ingestions with minimal side effects, although others may experience severe symptoms at a fraction of the dose.
Treatment:
Treatment in all cases is supportive with attention to airway, breathing, and circulation. Oral activated charcoal, 1–2 g/kg of body weight is the primary mode of gastrointestinal decontamination. Gastric lavage may be considered if the patient presents to the emergency department within 1 hour after ingestion. With significant aciduria the addition of sodium bicarbonate is required to maintain a urine pH value greater than
6.0 and to protect the renal tubules and improve the prognosis of acute renal failure.
Caffeine may produce hypokalemia so Potassium and other electrolytes should be monitored and replaced as needed.
An antiemetic such as metoclopromide or ondansetron may be considered if protracted vomiting occurs. Hyperthermia should be treated aggressively utilizing fans, ice water lavage, and ice water baths when necessary. Benzodiazepines such as diazepam and lorazepam should be given to patients who are agitated, hypertensive, or tachycardic, With hypertensive crisis unresponsive to benzodiazepines, sodium nitroprusside is the
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drug of choice. Nitroglycerine should be considered in cases with myocardial ischemia and infarction. Beta-adrenergic receptor antagonists should be avoided in a hypertensive crisis because unopposed α-adrenergic receptor agonist effects may result in further increases in blood pressure and adverse cardiac effects.
Signs and symptoms and clinical management of theophyllin toxicity:
Theophylline toxicity is more common. Therapeutic blood levels are strictly regulated at 10 to 20 µg/ml, but vary depending on interactions with other drugs, or inaccurate dosing,. Seizures occur between 25 to 40 µg g/ml. As with caffeine toxicity, rapid i.v. administration of theophylline is associated with headache, hypotension, dizziness, restlessness, agitation, and arrhythmias. In order to relieve the gastric irritation and nausea related with oral tablets, most theophylline preparations are available as controlled-release dosage forms.
Tolerance and withdrwal:
Caffeine withdrawal is associated with chronic use and is demonstrated abruptly within 12 to 24 h after the last dose.
Initial symptoms, including headache, anxiety, and fatigue, last for about one week. There is a tolerance to the diuretic action and the insomnia produced with theophylline, but no tolerance develops to the CNS stimulation or bronchodilation.
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