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Home , Ambroxol, Bromhexine, Butamirate, Carbocisteine, Dornase alfa, Oxeladin

Drugs used in the treatment of the

The common cold is the most common human disease and all peoples globally are affected. Adults typically have two to five annually and children may have six to ten colds a year.

1 The common cold is a complex of symptoms caused by 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 ; 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 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. . , , , carbocysteine and 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 , 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 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 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)

. and sulfoguaiacol are drugs which facilitate expectoration of mucus. Certain inorganic salts, such as 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 (, 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 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 CH3 N Metabolism of codeine

CYP3A4 N-Nor-codeine O Codeine Codeine-6-O-glucuronidHe3CO OH

CYP2D6 CYP3A4 10% N-Nor-morphine Morphine Morphine-6-O-glucuronide (O-Nor-codeine)

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 . 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 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. . and bronchial 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. . acts antitussively and expectorantly. It inhibits the cough reflex without any depressive influence on the respiratory center. Oxeladin is recommended in the treatment of cough of various etiology.

CH3 CH3 O N CH O 3 H3C O

Oxeladin, OXELADIN, TUSSIMOL

18 Nonopioid antitussive drugs (2)

. decreases the sensitivity of the cough and respiratory centers. It also acts anticholinergically and as a local and is recommended in dry cough of various etiology. . acts antitussively, secretolytically and spasmolytically. It dilates the bronchi, but it does not dilate the coronary vessels. Butamirate is recommended in the treatment of cough and acute or chronic . CH CH3 3 O O N CH O O 3 O N CH3 O CH3

PENTOXYVERIN, TOCLASE SINECOD Pentoxyverine, Butamirate, 19 Nonopioid antitussive drugs (3) . is an amide derivative of benzoic acid and acts antitussively and analgetically. Fominoben is used to remedy breathing difficulty accompanying chronic cough resulting from bronchitis, pulmonary emphysema and cough in smokers. . demonstrates strong and rapid action, similarly to dionine. Eprazinone acts spasmolytically and dilates the bronchi. It has mucolytic and expectorant action, too. It is recommended in acute and chronic cough, in chronic bronchitis and bronchial asthma. CH 3 O N N H O O N Cl O N O CH3 CH3 N

20 Fominoben, DERONYL Eprazinone, MUKOLEN Nonopioid antitussive drugs (4)

. An ideal antitussive expectorant drug should not only be safe but also act immediately and for a long time.

. The main concern over of antitussive drugs is to ensure immediate action. When drugs acting centrally are used, a delay of 20-45 min is observed, which is caused by absorption from the gastrointestinal tract and transport to the place of action. This delay is called a therapeutic gap.

. When an antitussive or expectorant drug is administered together with a bioadhesive compound, drug action appears faster.

21 (Narcotine) is a benzylisoquinoline alkaloid from plants of the Papaveraceae family, without significant painkilling properties.

CH3 O O O CH3 H C O 3 O H H CH O N 3

O

Noscapine's antitussive effects appear to be primarily mediated by its activity.

22 . In the treatment of the common cold pseudoephedrine is also used. . Pseudoephedrine causes the blood vessels of the mucous membrane to contract and unblocks the nose as a result. . Pseudoephedrine is very often used in complex preparations together with analgetic, antihistaminic or expectorant drugs (ACTIFED, ACTIGESIC = pseudoephedrine + triprolidine; LINCTIFED = pseudoephedrine + triprolidine + codeine). . Triprolidine is an antagonist at H1 receptors.

CH3 HO CH3 N H N H N

H3C Pseudoephedrine, Triprolidine SUDAFED, SUDAGESIC 23 Treatments that help alleviate symptoms include simple and antipyretics such as ibuprofen and acetaminophen/paracetamol, and antihistaminic drugs. IBUPROM H N CH Ibuprofen + Pseudoephedrini hydrochloride 3 O HO CH3 OH CH Paracetamol/Acetaminophen 3 Ibuprofen O PANADOL, APAP H3C CIRRUS Cetirizini dihydrochloride + Pseudoephedrini hydrochloride

N N O COOH Cetirizine

24 Cl Antibiotics and antivirals

Antibiotics have no effect against viral infections and thus have no effect against the viruses that cause the common cold. Due to their side effects they cause overall harm; however, they are still frequently prescribed. Some of the reasons that antibiotics are so commonly prescribed include: people's expectations for them, physicians' desire to do something, and the difficulty in excluding complications that may be amenable to antibiotics.

There are no effective antiviral drugs for the common cold even though some preliminary research has shown benefit.

25 Infant respiratory distress syndrome (IRDS) is caused by lack of surfactant, commonly suffered by premature babies born before 28-32 weeks of gestation.

Pulmonary surfactant is a surface-active lipoprotein complex (phospholipoprotein) formed by type II alveolar cells. Composition ~40% dipalmitoylphosphatidylcholine (DPPC) ~40% other phospholipids ~5% surfactant-associated proteins (SP-A, B, C and D) Cholesterol (neutral lipids)

Traces of other substances 26 SP-A and SP-D confer innate immunity as they have carbohydrate domains that allow them to coat bacteria and viruses promoting phagocytosis by macrophages. SP-A is also thought to be involved in a negative feedback mechanism to control the production of surfactant.

SP-B and SP-C are hydrophobic membranes proteins that increase the rate that surfactant spreads over the surface. SP-B and SP-C are required for proper biophysical function of the .

27 Function

. increases pulmonary compliance . prevents atelectasis (collapse of the lung) at the end of expiration . facilitates recruitment of collapsed airways

28 Synthetic pulmonary surfactants . Exosurf - a mixture of DPPC with hexadecanol and added as spreading agents . Pumactant (Artificial Lung Expanding Compound or ALEC) - a mixture of DPPC and PG . KL-4 - composed of DPPC, palmitoyl-oleoyl phosphatidylglycerol, and palmitic acid, combined with a 21 amino acid synthetic peptide that mimics the structural characteristics of SP-B. . Venticute - DPPC, PG, palmitic acid and recombinant SP-C

O Hexadecanol O CH3

O CH3 * O O O P O- O + CH N 3 CH3 CH3 DPPC Tyloxapol 29 Animal derived surfactants

. Alveofact - extracted from cow lung lavage fluid . Curosurf - extracted from material derived from minced pig lung . Infasurf - extracted from calf lung lavage fluid . Survanta - extracted from minced cow lung with additional DPPC, palmitic acid and tripalmitin

Exosurf, Curosurf, Infasurf, and Survanta are the surfactants currently FDA approved for use in the U.S.

30 Cystic fibrosis (CF or mucoviscidosis)

Cystic fibrosis (also known as CF or mucoviscidosis) is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine. It is characterized by abnormal transport of chloride and sodium across epithelium, leading to thick, viscous secretions.

The WHO states that "In the European Union 1 in 2000-3000 newborns is found to be affected by CF" .

In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age.

31 CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This gene is required to regulate the components of sweat, digestive juices, and mucus. The most common mutation, ΔF508, is a deletion (Δ) of three nucleotides that results in a loss of the amino acid phenylalanine at the 508th position on the protein. This mutation accounts for two-thirds (66- 70%) of CF cases worldwide and 90% of cases in the United States; however, there are over 1500 other mutations that can produce CF.

Although most people have two working copies (alleles) of the CFTR gene, only one is needed to prevent cystic fibrosis. CF develops when neither allele can produce a functional CFTR protein. Thus, CF is considered an autosomal recessive disease.

32 Molecular structure of the CFTR protein 33 Management

The most consistent aspect of therapy in cystic fibrosis is limiting and treating the lung damage caused by thick mucus and infection, with the goal of maintaining quality of life.

. Intravenous, inhaled, and oral antibiotics are used to treat chronic and acute infections.

. Mechanical devices and inhalation are used to alter and clear the thickened mucus.

. In addition, therapies such as transplantation and gene therapy aim to cure some of the effects of cystic fibrosis.

Gene therapy aims to introduce normal CFTR to airway. 34 Antibiotics Inhaled therapy with antibiotics such as tobramycin, colistin, and aztreonam is often given for months at a time to improve lung function by impeding the growth of colonized bacteria. Oral antibiotics such as ciprofloxacin or are given to help prevent infection or to control ongoing infection.

Other treatments for lung disease Aerosolized medications that help loosen secretions include and hypertonic saline. Dornase is a recombinant human deoxyribonuclease, which breaks down DNA in the sputum, thus decreasing its viscosity. 35 Treatment of other aspects

Diabetes is the most common non-pulmonary complication of CF.

While oral anti-diabetic drugs are sometimes used, the only recommended treatment is the use of insulin injections or an insulin pump, and, unlike in type 1 and 2 diabetes, dietary restrictions are not recommended.

Development of osteoporosis can be prevented by increased intake of vitamin D and calcium, and can be treated by bisphosphonates, although adverse effects can be an issue.

Poor growth may be avoided by insertion of a feeding tube for increasing calories through supplemental feeds or by administration of injected growth hormone. 36