Professional Documents
Culture Documents
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.
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)
O
H2N
S COOH
HN CH3 COOH
HS
COOH
Carbocisteine, S-(Karboksymetylo)cysteina
Acetylcysteine, N-Acetylo-L-cysteina MUCODYNE, MUCOPRONT, TUSSICOM
PARVOLEX, ACC, MUCISOL,
MUCOSOLV,
MUCOSOLVIN, TUSSICON SO3Na
HS
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.
SO3K SO3K
OH
O OH
+
OCH3 OCH3 OH
OH OCH3
14
CH3
N
Metabolism of codeine
N-Nor-codeine CYP3A4
Codeine Codeine-6-O-glucuronide
H3CO O
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
15
symptoms (respiratory depression, coma).
Opioid antitussive drugs (2)
CH3
N
Dihydrocodeine shows similar action to the activity of
codeine.
H3 CO O
OH
Pholcodin is a synthetic derivative with 3 times stronger
antitussive action than codeine. The depressive action of Dihydrocodeine
DHC Continus
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.
16
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.
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
H3 C
Pseudoephedrine, Triprolidine
SUDAFED, SUDAGESIC 23
Treatments that help alleviate symptoms include simple
analgesics and antipyretics such as ibuprofen and
acetaminophen/paracetamol, and antihistaminic drugs.
IBUPROM H
N CH3
Ibuprofen + Pseudoephedrini hydrochloride
O
HO
CH3
OH
CH3
Ibuprofen Paracetamol/Acetaminophen
O PANADOL, APAP
H3 C
CIRRUS
Cetirizini dihydrochloride + Pseudoephedrini
hydrochloride
N N
O COOH Cetirizine
24
Cl
Antibiotics and antivirals
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.
27
Function
28
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
Hexadecanol
O CH3
O CH3
*
O
O
O P O-
O + CH3
N
CH
CH3 3
DPPC
Tyloxapol 29
Animal derived surfactants
Exosurf, Curosurf, Infasurf, and Survanta are the surfactants currently FDA
approved for use in the U.S.
30
Cystic fibrosis (CF or mucoviscidosis)
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