Acetaminophen¿¡ ´ëÇÑ Mechanism_Of_Action Á¤º¸ Acetaminophen is thought to act primarily in the CNS, increasing the pain threshold by inhibiting both isoforms of cyclooxygenase, COX-1 and COX-2, enzymes involved in prostaglandin (PG) synthesis. Unlike NSAIDs, acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, thus, has no peripheral anti-inflammatory affects. While aspirin acts as an irreversible inhibitor of COX and directly blocks the enzyme's active site, studies have found that acetaminophen indirectly blocks COX, and that this blockade is ineffective in the presence of peroxides. This might explain why acetaminophen is effective in the central nervous system and in endothelial cells but not in platelets and immune cells which have high levels of peroxides. Studies also report data suggesting that acetaminophen selectively blocks a variant of the COX enzyme that is different from the known variants COX-1 and COX-2. This enzyme is now referred to as COX-3. Its exact mechanism of action is still poorly understood, but future research may provide further insight into how it works. Caffeine¿¡ ´ëÇÑ Mechanism_Of_Action Á¤º¸ Caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3¡Ç,5¡Ç-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine act as agonists at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of caffeine. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake. Chlorpheniramine¿¡ ´ëÇÑ Mechanism_Of_Action Á¤º¸ Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. Guaifenesin¿¡ ´ëÇÑ Mechanism_Of_Action Á¤º¸ Guaifenesin may act as an irritant to gastric vagal receptors, and recruit efferent parasympathetic reflexes that cause glandular exocytosis of a less viscous mucus mixture. Cough may be provoked. This combination may flush tenacious, congealed mucopurulent material from obstructed small airways and lead to a temporary improvement in dyspnea or the work of breathing.
Pharmacology
Acetaminophen¿¡ ´ëÇÑ Pharmacology Á¤º¸ Acetaminophen (USAN) or Paracetamol (INN) is a popular 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 so it is not a member of the class of drugs known as non-steroidal anti-inflammatory drugs or NSAIDs. In normal doses acetaminophen does not irritate the lining of the stomach nor affect blood coagulation, the kidneys, 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. Caffeine¿¡ ´ëÇÑ Pharmacology Á¤º¸ 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. Chlorpheniramine¿¡ ´ëÇÑ Pharmacology Á¤º¸ In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Chlorpheniramine, is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It competes with histamine for the normal H1-receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. Guaifenesin¿¡ ´ëÇÑ Pharmacology Á¤º¸ Guaifenesin is an expectorant which increases the output of phlegm (sputum) and bronchial secretions by reducing adhesiveness and surface tension. The increased flow of less viscous secretions promotes ciliary action and changes a dry, unproductive cough to one that is more productive and less frequent. By reducing the viscosity and adhesiveness of secretions, guaifenesin increases the efficacy of the mucociliary mechanism in removing accumulated secretions from the upper and lower airway.
Acetaminophen¿¡ ´ëÇÑ ¹Ý°¨±â Á¤º¸ 1 to 4 hours Caffeine¿¡ ´ëÇÑ ¹Ý°¨±â Á¤º¸ 3 to 7 hours in adults, 65 to 130 hours in neonates Chlorpheniramine¿¡ ´ëÇÑ ¹Ý°¨±â Á¤º¸ 21-27 hours Guaifenesin¿¡ ´ëÇÑ ¹Ý°¨±â Á¤º¸ 1 hour
Absorption
Acetaminophen¿¡ ´ëÇÑ Absorption Á¤º¸ Rapid and almost complete Caffeine¿¡ ´ëÇÑ Absorption Á¤º¸ 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. Chlorpheniramine¿¡ ´ëÇÑ Absorption Á¤º¸ Well absorbed in the gastrointestinal tract. Guaifenesin¿¡ ´ëÇÑ Absorption Á¤º¸ Rapidly absorbed from the GI tract
Acetaminophen¿¡ ´ëÇÑ Biotransformation Á¤º¸ Approximately 90 to 95% of a dose is metabolized in the liver via the cytochrome P450 enzyme pathways (primarily by conjugation with glucuronic acid, sulfuric acid, and cysteine). An intermediate metabolite is hepatotoxic and most likely nephrotoxic and can accumulate after the primary metabolic pathways have been saturated. Caffeine¿¡ ´ëÇÑ Biotransformation Á¤º¸ 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). Chlorpheniramine¿¡ ´ëÇÑ Biotransformation Á¤º¸ Primarily hepatic via Cytochrome P450 (CYP450) enzymes. Guaifenesin¿¡ ´ëÇÑ Biotransformation Á¤º¸ Rapidly hydrolyzed (60% within seven hours) and then excreted in the urine, with beta-(2-methoxyphenoxy)-lactic acid as its major urinary metabolite.
Toxicity
Acetaminophen¿¡ ´ëÇÑ Toxicity Á¤º¸ 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 sulfate and glucuronide, and then excreted by the kidneys. Only a small portion is metabolized via the hepatic cytochrome P450 enzyme system. The toxic effects of acetaminophen are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone imine), not acetaminophen itself nor any of the major metabolites. This toxic metabolite reacts with sulfhydryl groups. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys. The toxic dose of paracetamol is highly variable. In adults, single doses above 10 grams or 140 mg/kg have a reasonable likelihood of causing toxicity. In adults, single doses of more than 25 grams have a high risk of lethality. Caffeine¿¡ ´ëÇÑ Toxicity Á¤º¸ LD50=127 mg/kg (orally in mice) Chlorpheniramine¿¡ ´ëÇÑ Toxicity Á¤º¸ LD50 = 306 mg/kg in humans, mild reproductive toxin to women of childbearing age. Guaifenesin¿¡ ´ëÇÑ Toxicity Á¤º¸ LD50 1510 mg/kg (rat, oral)
Drug Interactions
Acetaminophen¿¡ ´ëÇÑ Drug_Interactions Á¤º¸ Anisindione Acetaminophen increases the anticoagulant effectWarfarin Acetaminophen increases the anticoagulant effectImatinib Increased hepatic toxicity of both agentsIsoniazid Risk of hepatotoxicityDicumarol Acetaminophen increases the anticoagulant effectDicumarol Increases the anticoagulant effectAcenocoumarol Increases the anticoagulant effect Caffeine¿¡ ´ëÇÑ Drug_Interactions Á¤º¸ Not Available Chlorpheniramine¿¡ ´ëÇÑ Drug_Interactions Á¤º¸ Donepezil Possible antagonism of actionGalantamine Possible antagonism of actionRivastigmine Possible antagonism of actionEthotoin The antihistamine increases the effect of hydantoinFosphenytoin The antihistamine increases the effect of hydantoinMephenytoin The antihistamine increases the effect of hydantoinPhenytoin The antihistamine increases the effect of hydantoin Guaifenesin¿¡ ´ëÇÑ Drug_Interactions Á¤º¸ Not Available
Acetaminophen¿¡ ´ëÇÑ Food Interaction Á¤º¸ Take without regard to meals.Avoid alcohol (may increase risk of hepatotoxicity). Chlorpheniramine¿¡ ´ëÇÑ Food Interaction Á¤º¸ Take with food.Avoid alcohol. Guaifenesin¿¡ ´ëÇÑ Food Interaction Á¤º¸ Take with a full glass of water.Take without regard to meals.
Acetaminophen¿¡ ´ëÇÑ Description Á¤º¸ Analgesic antipyretic derivative of acetanilide. It has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. [PubChem] Caffeine¿¡ ´ëÇÑ Description Á¤º¸ A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent. Caffeine& Chlorpheniramine¿¡ ´ëÇÑ Description Á¤º¸ A histamine H1 antagonist used in allergic reactions, hay fever, rhinitis, urticaria, and asthma. It has also been used in veterinary applications. One of the most widely used of the classical antihistaminics, it generally causes less drowsiness and sedation than promethazine. [PubChem] Guaifenesin¿¡ ´ëÇÑ Description Á¤º¸ An expectorant that also has some muscle relaxing action. It is used in many cough preparations. [PubChem]