1
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.
2
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.
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.
3
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).
4
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.
5
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.
6
7
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.
8
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.
9
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.
10
Mucolytic and expectorant drugs (2)
NBr
Br
NH2
CH3
Bromhexine, VISCOLYT, BISOLVON,
FLEGAMIN, FLEGAMINA
N-(2-Amino-3,5-dibromobenzylo)-N-
cykloheksylo-N-metyloamina
NH2
Br
BrNH
OH
Ambroxol, AMBROXOL, AMBROSOL,
BRONCHOPRONT, MUCOREN
CH3
HS
H
O
COOH
N
Acetylcysteine, N-Acetylo-L-cysteinaPARVOLEX, ACC, MUCISOL,
MUCOSOLV,
MUCOSOLVIN, TUSSICON
COOH
H2NCOOHS
Carbocisteine, S-(Karboksymetylo)cysteina
MUCODYNE, MUCOPRONT, TUSSICOM
HSSO3Na
Mesna, 2-Merkaptoetylosulfonian sodu
ANTI-URON, MISTABRON, MUCOFLUID
11
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.
12
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.
O
OCH3
OH
OH
SO3K
OH
SO3K
OH
+
OCH3
OCH3
Guaifenesin, GUAJAZYL,
WICK FORMEL 44 plus
Hustenloser
Sulfogaiacol, APIPULMOL, KALIUM
GUAJACOSULFONICUM
13
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.
14
Opioid antitussive drugs (1)
Until recently codeine was the most popular antitussive drug.
It suppresses the cough center in the medulla by making it less
sensitive to peripherial stimulation.
When codeine is administered, over-sedation, hypersomnia,
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.
Codeine
N
CH3
H3COO
OH
15
Codeine
Morphine
(O-Nor-codeine)
CYP3A4
CYP2D6
Codeine-6-O-glucuronideN-Nor-codeine
CYP3A4N-Nor-morphine Morphine-6-O-glucuronide
Morphine-3-O-glucuronide
10%
60%
Coupling
Metabolism of codeine
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).
N
CH3
H3COO
OH
16
Opioid antitussive drugs (2)
Dihydrocodeine shows similar action to the activity of
codeine.
Pholcodin is a synthetic derivative with 3 times stronger
antitussive action than codeine. The depressive action of
pholcodin on the respiratory center is weaker than that of
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.
DihydrocodeineDHC Continus
N
CH3
H3COO
OH
17
Opioid antitussive drugs (3)
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.
N
CH3
H3CO
18
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. It inhibits the cough
reflex without any depressive influence on the respiratory center.
Oxeladin is recommended in the treatment of cough of various
etiology.
H3C
CH3
CH3
CH3
OO
N
O
Oxeladin, OXELADIN, TUSSIMOL
19
Nonopioid antitussive drugs (2)
Pentoxyverine decreases the sensitivity of the cough and
respiratory centers. It also acts anticholinergically and as a
local anesthetic and is recommended in dry cough of various
etiology.
Butamirate 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 bronchitis.
CH3
CH3
O
OO
N
Pentoxyverine, PENTOXYVERIN, TOCLASE
CH3
CH3
CH3
O
OO
N
Butamirate, SINECOD
20
Nonopioid antitussive drugs (3) Fominoben 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.
Eprazinone 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.CH3
O N
NN
OClH
O
CH3
CH3N
N
O
O
Eprazinone, MUKOLENFominoben, DERONYL
21
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.
22
Noscapine (Narcotine) is a benzylisoquinoline alkaloid from plants
of the Papaveraceae family, without significant painkilling
properties.
N
OH3C
O
O CH3
H
O
H
O OCH3
OCH3
Noscapine's antitussive effects appear to be primarily mediated by its
sigma receptor agonist activity.
23
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.
CH3CH3HO
HN
Pseudoephedrine,
SUDAFED, SUDAGESIC
N
H3C
H
N
Triprolidine
24
Treatments that help alleviate symptoms include simple
analgesics and antipyretics such as ibuprofen and
acetaminophen/paracetamol, and antihistaminic drugs.
IBUPROM
Ibuprofen + Pseudoephedrini hydrochloride
CIRRUSCetirizini dihydrochloride + Pseudoephedrini
hydrochloride
COOH
Cl
N NO Cetirizine
IbuprofenOH
OH3C
CH3
CH3
HO
N CH3
O
H
Paracetamol/AcetaminophenPANADOL, APAP
25
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.
26
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
27
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
lung.
28
Function
increases pulmonary compliance
prevents atelectasis (collapse of the lung) at the end of expiration
facilitates recruitment of collapsed airways
29
Synthetic pulmonary surfactants
Exosurf - a mixture of DPPC with hexadecanol and tyloxapol 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
O
CH3
CH3
O
P
ON
CH3
CH3
CH3
O O-
O
O
*
+
DPPC
Hexadecanol
Tyloxapol
30
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.
31
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.
Cystic fibrosis (CF or mucoviscidosis)
32
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.
33Molecular structure of the CFTR protein
34
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 medications 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.
35
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 azithromycin are given
to help prevent infection or to control ongoing infection.
Other treatments for lung disease
Aerosolized medications that help loosen
secretions include dornase alfa and hypertonic
saline.
Dornase is a recombinant human
deoxyribonuclease, which breaks down DNA in
the sputum, thus decreasing its viscosity.
36
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.
