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Drugs Used in the Treatment of the Common Cold

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Drugs Used in the Treatment of the Common Cold Drugs used in the treatment of the common cold The common cold is the most common human disease and all peoples globally are affected. Adults typically have two to five infections annually and children may have six to ten colds a year. 1 The common cold is a complex of symptoms caused by infection of the upper airways by one of two hundred serologically different viruses which belong to five families such as . rhinoviruses, . respiratory viruses, . influenza A and B viruses, . adenoviruses and . coronaviruses. Human rhinoviruses occur worldwide and are the primary cause of common colds. Symptoms include sore throat, runny nose, nasal congestion, sneezing and cough; sometimes accompanied by muscle aches, fatigue, malaise, headache, muscle weakness, or loss of appetite. Fever and extreme exhaustion are more usual in influenza. 2 Rhinoviruses The best known viruses are rhinoviruses, which are viruses of the RNA series. The protein capsule of a rhinoviruses consists of 12 pentamers (60 subunits) and has the shape of a twenty-side solid. The receptor places are located in the apertures or hollows surrounding the top of every pentamer. The virus binds to ICAM-1 (Inter-Cellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) receptors on respiratory epithelial cells. As the virus replicates and spreads, infected cells release distress signals known as chemokines and cytokines (which in turn activate inflammatory mediators). 3 Coronaviruses are species in the genera of virus belonging to the subfamily Coronavirinae in the family Coronaviridae. Coronaviruses are enveloped viruses with a positive-sense single- stranded RNA genome and a helical symmetry. Proteins that contribute to the overall structure of all coronaviruses are the spike (S), envelope (E), membrane (M) and nucleocapsid (N). In the specific case of SARS a defined receptor-binding domain on S mediates the attachment of the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2). Members of the group 2 coronaviruses also have a shorter spike-like protein called hemaglutinin esterase (HE) encoded in their genome , but for some reason this protein is not always brought to expression (produced) in the cell. 4 Coronaviruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds. Four to five different currently known strains of coronaviruses infect humans. The most publicized human coronavirus, SARS-CoV which causes SARS, has a unique pathogenesis because it causes both upper and lower respiratory tract infections and can also cause gastroenteritis. Coronaviruses are believed to cause a significant percentage of all common colds in human adults. Coronaviruses cause colds in humans primarily in the winter and early spring seasons. 5 6 The common cold (1) . The mucociliary clearance of the nasal tract does not protect from rhinoviruses. The proliferation of viruses in the cells of the nasal epithelium is very fast. 24 hours after infection the cold is fully developed and it is a viral infection of both the nose and sinuses, as a result of which inflammatory processes may begin. In this process such inflammatory mediators as kinins, interleukines and prostaglandins are involved. They are responsible for symptoms which are characteristic of the cold, such as dilation of blood vessels, inflammatory exudates, stimulation of the sneezing reflex and of pain sensory endings. 7 The common cold (2) . The period between the appearance of viruses in the nose and their replication is very short (8-10 hours), so treatment should start as soon as possible. To stop the release of mediators and nervous reflexes, the replication of viruses should be inhibited. At present no effective drugs against viruses causing the cold are available. In general, symptomatic treatment is used. 8 Mucolytic and expectorant drugs (1) . Mucolytic and expectorant drugs are administered to facilitate the clearing of the respiratory tract (airways) of the retained secretion. These drugs decrease the viscosity of the secretion and make it easier to expectorate. Mucolytic drugs decrease the viscosity of secretion in the airways by depolymerization of mucopolysaccharides. Bromhexine, ambroxol, acetylcysteine, carbocysteine and mesna are classified as popular mucolytic drugs. Some of them (bromhexine, ambroxol) also act expectorantly. 9 Mucolytic and expectorant drugs (2) Br Br CH3 H N Br N Br NH 2 OH NH2 Bromhexine, VISCOLYT, BISOLVON, Ambroxol, FLEGAMIN, FLEGAMINA AMBROXOL, AMBROSOL, N-(2-Amino-3,5-dibromobenzylo)-N- BRONCHOPRONT, MUCOREN cykloheksylo-N-metyloamina O H N 2 S COOH HN CH3 COOH HS COOH Carbocisteine, S-(Karboksymetylo)cysteina Acetylcysteine, N-Acetylo-L-cysteina MUCODYNE, MUCOPRONT, TUSSICOM PARVOLEX, ACC, MUCISOL, MUCOSOLV, SO Na MUCOSOLVIN, TUSSICON HS 3 Mesna, 2-Merkaptoetylosulfonian sodu 10 ANTI-URON, MISTABRON, MUCOFLUID Mucolytic and expectorant drugs (3) . Ambroxol is a metabolite of bromhexine with stronger expectorant action. N-Acetylcystein after oral administration shows strong and fast mucolytic activity. Under its influence the disulphide bonds are broken and hydrophilic complexes are created. N-Acetylcystein stimulates mucus production. It stimulates the activity of the cilia of the bronchi at low concentrations and inhibits their activity at higher concentrations. N-Acetylcystein shows protective action against free radicals and active metabolites in the lungs by preventing a decrease in the level of glutathione. Similar action is demonstrated by preparations of carbocysteine and mesna. 11 Mucolytic and expectorant drugs (4) . Guaifenesin and sulfoguaiacol are drugs which facilitate expectoration of mucus. Certain inorganic salts, such as potassium iodide or ammonium chloride also act expectorantly. Guaifenesin is used in monotherapy and in complex preparations, together with other drugs acting expectorantly or with antitussive drugs with central action (codeine, dextromethorphane). Guaifenesin acts expectorantly in doses of 150 – 200 mg. SO K SO K OH 3 3 O OH + OH OCH3 OCH3 OH OCH3 Guaifenesin, GUAJAZYL, Sulfogaiacol, APIPULMOL, KALIUM WICK FORMEL 44 plus 12 GUAJACOSULFONICUM Hustenloser Antitussive drugs . Coughing excites cough receptors, which are present in the larynx, trachea and bronchi. Signals from the receptors are transmitted to the cough center in the brain through the upper trachea nerve and the vagus nerve. The incoming impulses are added together and when they exceed a threshold point, they release the mechanism of cough. From the cough center the impulses are transferred by nerves to the glottis, muscles of the chest and the diaphragm. Cough is a symptom which accompanies over 100 diseases but it always occurs with diseases of the airways. Cough caused by the virus of the cold is the main symptom of this disease. Cough may be dry or moist. Dry cough does not have any beneficial effect and should be treated. 13 Opioid antitussive drugs (1) CH3 N . Until recently codeine was the most popular antitussive drug. It suppresses the cough center in the medulla by making it less O sensitive to peripherial stimulation. H3CO OH . When codeine is administered, over-sedation, hypersomnia, Codeine dizzinesses and constipation may occur. Codeine may cause drug dependence. It is used alone in preparations and in complex preparations, such as ASCODAN, THIOCODIN, PANADEINE, ANALGET. These preparations are administered mainly to treat the cold with fever. 14 Metabolism of codeine CYP3A4 N-Nor-codeine Codeine CH3 Codeine-6-O-glucuronide N CYP2D6 N-Nor-morphine CYP3A4 10% Morphine Morphine-6-O-glucuronide O H CO OH (O-Nor-codeine) 3 60% Coupling Morphine-3-O-glucuronide The main metabolite of codeine is N-nor-codeine. Additionally, 6-O-glucuronide and O-desmetylation of codeine to morphine have a great importance. At overdosing or in the case of individuals with a genetic polymorphism CYP2D6 (ultrafast metabolism) codeine is mainly metabolised to morphine. It can lead to the accumulation of morphine-6-O-glucuronide with intoxication symptoms (respiratory depression, coma). 15 Opioid antitussive drugs (2) CH3 N . Dihydrocodeine shows similar action to the activity of codeine. O H3CO OH . Pholcodin is a synthetic derivative with 3 times stronger antitussive action than codeine. The depressive action of Dihydrocodeine pholcodin on the respiratory center is weaker than that of DHC Continus codeine and it does not cause constipation. It is used in therapy alone (TIXYLIX, LINCTUS, PHOLCODIN, NEOCODIN ) or in complex preparations, such as PAVACOLD or RUBELIX. 16 CH3 N Opioid antitussive drugs (3) H3CO . Recently dextromethorphan is used in the treatment of cough. Dextromethorphan – a synthetic derivative of morphine that acts on the cough center to supperss the cough reflex, used as an antitussive, administered orally - is the dextrorotatory isomer of levorphanol, which shows antitussive action but does not have analgetic or drug dependence action. The power of its antitussive action is similar to that of codeine. Respiratory failure and bronchial asthma are the main contraindications for the use of dextromethorphan. In some cases, when analgetic action is also necessary, morphine is used in the treatment of cough. Chemical structure of opioid antitussive drugs was discussed earlier. 17 Nonopioid antitussive drugs (1) . In the treatment of cough, esters and amides of carboxylic acid are also used. In terms of their chemical structure they are similar to drugs with spasmolytic action. Oxeladin acts antitussively and expectorantly.
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