Acetaminophen

Indication For temporary relief of fever and minor aches and pains.

Pharmacology 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. Mechanism of Action 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. Absorption Rapid and almost complete Toxicity Oral, mouse: LD 50 = 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.
Protein Binding 25% Biotransformation 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. Half Life 1 to 4 hours

Glyceryl guaiacolate

Indication Used to assist the expectoration of phlegm from the airways in acute respiratory tract
infections. Pharmacology 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. Mechanism of Action 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.

Dextromethorphan

Indication For treatment and relief of dry cough. Pharmacology Dextromethorphan suppresses the
cough reflex by a direct action on the cough center in the medulla of the brain. Dextromethorphan
shows high affinity binding to several regions of the brain, including the medullary cough center. This
compound is an NMDA receptor antagonist and acts as a non-competitive channel blocker. It is one of
the widely used antitussives, and is also used to study the involvement of glutamate receptors in
neurotoxicity. Mechanism of Action Dextromethorphan is an opioid-like drug that binds to and acts as
antagonist to the NMDA glutamatergic receptor, it is an agonist to the opioid sigma 1 and sigma 2
receptors, it is also an alpha3/beta4 nicotinic receptor antagonist and targets the serotonin reuptake
pump. Dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the
bloodstream and crosses the blood-brain barrier. The first-pass through the hepatic portal vein results in
some of the drug being metabolized into an active metabolite of dextromethorphan, dextrorphan, the 3-
hydroxy derivative of dextromethorphan.

Chlorpheniramine

Indication For the treatment of rhinitis, urticaria, allergy, common cold, asthma and hay fever.
Pharmacology 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 H 1-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. Mechanism of Action 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.