drugs used in allergic disorders (asthma and allergic ... · transport to nucleus interaction on...
TRANSCRIPT
![Page 1: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/1.jpg)
Drugs used in allergic disorders
(asthma and allergic rhinitis)
![Page 2: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/2.jpg)
Chest
x-ray
![Page 3: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/3.jpg)
![Page 4: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/4.jpg)
Asthma - definition
• Asthma is chronic inflammatory airway disease
• The cells involved in pathogenesis are: eosinophilic granulocytes a mast cells, to the less extend neutrophilic a bazophilic granulocytes.
• This inflammation increases airway hyperreactivity resulting in reversible bronchial obstruction
• This dissolves either spontaneously or after treatment
![Page 5: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/5.jpg)
Asthma - characteristics
Asthma is lung disease characterized by:
1. Reversible airway obstruction
(not always complete) which can be
influenced by means of or without
treatment
2. Airway inflammation
3. Airway hyperreactivity
![Page 6: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/6.jpg)
Dysfunction
(Smooth muscles) Inflammation
(Airways)
Remodelation
(Airways)
Asthma - pathophysiology
![Page 7: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/7.jpg)
Grass pollen
![Page 8: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/8.jpg)
Grass pollen
![Page 9: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/9.jpg)
Pollen grain
![Page 10: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/10.jpg)
Mould
![Page 11: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/11.jpg)
Seasonal occurrence of major allergens
![Page 12: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/12.jpg)
Mite
![Page 13: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/13.jpg)
Bronchoconstriction
Before 10 minutes after
allergen trigger P Howarth
![Page 14: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/14.jpg)
Airway mucosal edema
P Howarth
![Page 15: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/15.jpg)
Epithelial disruption
P Jeffery, in: Asthma, Academic Press 1998
![Page 16: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/16.jpg)
Asthma and mediators
• Bronchial hyperreactivity is a result of permanent
inflammation induced by means of various
triggers - allergens, viruses, chemicals, etc.
• Inflammatory mediators are released from the
cells - eosinophiles, neutrophiles, monocytes,
mastocytes, macrophages.
– Histamine is pre prepared
– Other mediators are metabolites of arachidonic acid
• Cyclooxygenase- PGD2
• Lipooxygenase - leucotriens
• PAF
![Page 17: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/17.jpg)
Mediators
![Page 18: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/18.jpg)
Immediate and late allergic reaction
![Page 19: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/19.jpg)
Asthma - epidemiology
• Prevalence - 3 - 10 %
• Predominantly outpatient treatment
• Frequent underestimation of the
diagnosis may bias epidemiological data
![Page 20: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/20.jpg)
Age prevalence of asthma
![Page 21: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/21.jpg)
Asthma – treatment objectives
• Maintain normal activity (including
exercise and sports)
• Maintain lung function close to normal
values
• Prevent problems (cough, dyspnoea)
• Prevent exacerbations
• Prevent AE linked to therapy
![Page 22: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/22.jpg)
Asthma – treatment (management)
• Patient´s education
• Environmental control
• Pharmacotherapy
• Functional monitoring
![Page 23: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/23.jpg)
Antiasthmatics
Bronchodilators
Anti-inflammatory agents
b2-adrenomimetics
Theophylline
Anticholinergics
Glucocorticoids
Antileukotriens
Cromons
Asthma - pharmacotherapy
![Page 24: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/24.jpg)
Antiasthmatics - aplication routes
Inhaled
• Particle size 2 - 5
- MDI – metered dose inhaler (spray)
- MDPI – metered dose powder inhaler
- spacers – large volume containers (to
improve inhalation)
• Used for: corticosteroids, b2-agonists,
cromons, anticholinergics
• Infrequent AE
![Page 25: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/25.jpg)
Inhaled drug
disposition
![Page 26: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/26.jpg)
MDI
(CFC free)
![Page 27: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/27.jpg)
MDPI
Turbohaler
![Page 28: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/28.jpg)
MDPI - …disk
![Page 29: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/29.jpg)
MDPI - Discus
![Page 30: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/30.jpg)
Spacers
![Page 31: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/31.jpg)
Deposition
pattern
of inhaled
antiasthmatic
drug
![Page 32: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/32.jpg)
Deposition
pattern
poor
technique
![Page 33: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/33.jpg)
Antiasthmatics - application routes
Oral
• Theophylline – only long acting
glucocorticoids, b-agonists
• To gain equal effect as in inhaled
application 20 x higher dose is
required
• Systemic AE frequent
![Page 34: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/34.jpg)
b2-agonists
![Page 35: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/35.jpg)
b-agonists – classification according to specificity
1 2 b1 b2
noradrenaline +++ +++ ++ +
adrenaline ++ ++ +++ +++
isoprenaline - - +++ +++
clonidine - +++ - -
salbutamol - - + +++
terbutaline - - + +++
dobutamine - - +++ +
![Page 36: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/36.jpg)
• Adrenomimetic molecule carries 3
important sites influencing efficacy
– Group on N side chain (radical size
influencing affinity)
– OH on C1 side chain
– OH in meta and para position (3 and 4) (OH
substitution influencing intrinsic activity)
b-agonists – structure
![Page 37: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/37.jpg)
b-agonists– structure
CH CH NH
OH
OH
OH
R
1 6
5 4
3
2 Catecholamine prototype
![Page 38: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/38.jpg)
b-mimetic
receptor
adenylatcyclase
ATP cAMP
AMP
phosphodiesterase
methylxantins
Proteinkinase activation
reaction
b-agonists– mode of action
membrane
![Page 39: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/39.jpg)
b-agonists – classification according to selectivity
selectivity
b2 b1 b2b1
isoprenaline 1,0 1,0 1,0
fenoterol 0,6 0,005 120,0
formoterol 20,0 0,05 400,0
salbutamol 0,55 0,0004 1375,0
salmeterol 8,5 0,0001 85000,0
![Page 40: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/40.jpg)
b2-agonists – AE
• Muscular tremor (in higher doses)
• Palpitation
• Headache
• Paradoxal bronchospasms (in inhaled
forms)
• In rare cases allergy
![Page 41: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/41.jpg)
Topic (inhalation) b2-agonists
Generic Brand
Terbutaline
Fenoterol
Formoterol
Salbutamol
Salmeterol
Prokaterol
Bricanyl
Berotec
Foradil, Atimos, Forair, Formovent …
Ventolin, Ventodisc
Serevent
Alvesco
![Page 42: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/42.jpg)
Systemic (p.o., i.v.) b2-agonists
Generic Brand
Terbutaline
Klenbuterol
Prokaterol
Bricanyl
Spiropent
Lontermin
![Page 43: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/43.jpg)
Theophylline
![Page 44: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/44.jpg)
• Mode of action
– Probably competitive inhibition adenosine
receptors.
– Theophylline structure is close to adenosine.
– This effect can be observed in therapeutic
concentrations.
– Phosphodiesterase inhibition NOT
– Therapeutic concentration is 5 – 20 g/L
Theophylline
![Page 45: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/45.jpg)
Theophylline
• Narrow therapeutic window: 5 – 20 g/l
• Serum levels monitoring needed
• Large variability in clearance due to
hepatic metabolism (cytochrome P 450
CYP 3A4)
![Page 46: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/46.jpg)
Increased theophylline clearance
• Enzyme induction
- rifampicin
- phenobarbital
- ethanol
• Tobacco and marihuana smoking
• Age 1 - 16 years
![Page 47: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/47.jpg)
• Enzyme inhibition
- cimetidine
- erythromycin, some fluoroquinolones
- allopurinol
• Impaired liver function
• Infection, vaccination
• Age
Decreased theophylline clearance
![Page 48: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/48.jpg)
Theophylline – summary
• Additive effects with b-agonists
• Only sustained release forms
• Frequent interactions and AEs
![Page 49: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/49.jpg)
Theophylline containing drugs
Generic Brand
Theophylline
Aminofilin
Aflonilum SR, Euphyllin CR, Teotard,
Teoplus, Spophyllin retard
Aminophyllinum retard, Syntophyllin
![Page 50: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/50.jpg)
Anticholinergics
![Page 51: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/51.jpg)
Anticholinergics
• Mode of action
–competitive inhibition of
postsynaptic cholinergic
receptor on vagal nervous
ending
![Page 52: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/52.jpg)
Anticholinergics
• Lower efficacy than b-agonists
• Additive effect with b-agonists
• Possible replacement of theophylline
• Ipratropium
• Thiotropium (CHOPN)
![Page 53: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/53.jpg)
Anticholinergics
Generic Brand
Ipratropium
Thiotropium
Atrovent
Spiriva
![Page 54: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/54.jpg)
Cromons
![Page 55: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/55.jpg)
Cromons
• Mode of action
– Prevent mast cells degranulation
– Active also in late phase of allergic reaction in other cells
– Advantage in pediatrics
– Nedocromil – brand: Tilade
![Page 56: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/56.jpg)
Glucocorticoids
![Page 57: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/57.jpg)
Glucocorticoids
![Page 58: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/58.jpg)
Cortisol
• Synthesis: in adrenals - zona fasciculata and
reticularis
• Daily production 20 mg
• Circadian rhythm ACTH
• CBG (2-globulin) - 75% and albumin - 5%, 20%
free
• Saturation CBG 20-30g/dl
• Synthetic glucocorticoids predominantly bound to
albumin
![Page 59: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/59.jpg)
From cortisol to synthetic
steroids (I)
1
3
2
4
A B
C D
O
H3C
10
9
8
7
6
5
16
15 14
13
12
11
17 CH3
H3C OH
C O
CH2OH
20
21
19
18 cortisol
betamethason
other variations
F
OH
![Page 60: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/60.jpg)
1
3
2
4
A B
C D
O
H3C
10
9
8
7
6
5
16
15 14
13
12
11
17 CH3
H3C OH
C O
CH2COOCH2-CH3
20
21
19
18 beclomethason
(fluticason)
Cl(F)
COOCH2-CH3
(F)
(S-CH2-F)
From cortisol to synthetic
steroids (II)
![Page 61: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/61.jpg)
Glucocorticoids - regulation
hypothalamus
pituitary
adrenal cortex
CRF
ACTH
target tissue
glucocorticoids
exogenic CS
exogenic ACTH
Metyrapon (b-hydroxylation inhib. on C11 cortizol)
![Page 62: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/62.jpg)
• Mode of action
– General anti-inflammatory effect,
inflammatory cells flux and inflammatory
mediators release inhibition.
– Lipocortin induction - decrease in PDE,
PAF and arachidonic acid concentration
Glucocorticoids
![Page 63: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/63.jpg)
Mode of action (I)
Entry into cell
Binding to GR
Hormone - receptor complex, after activation - dimmer –
transport to nucleus
Interaction on gene and regulatory proteins level - GRE
(transcriptional mechanisms)
Without hormone – inhibition of receptor protein
Fast feed back (nontranscriptional) on membrane level
![Page 64: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/64.jpg)
Mode of action (II)
S
CBG
S S
GR
S
GR x2
A
S
GR
A DNA
transcription mRNA
translation
proteins
*GRE *GRE encoded:
GGTACA nnn TGTTCT
![Page 65: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/65.jpg)
Glucocorticoid receptor (I)
![Page 66: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/66.jpg)
Glucocorticoid receptor (II)
![Page 67: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/67.jpg)
• GR belongs to superfamily of structural
proteins (nuclear receptors) transducing
signals from small lipophillic molecules
(D vitamin, retinoids, glucocorticoids,
thyroid hormones)
• Structure of GR:
Glucocorticoid receptor (III)
HSP 70
HSP 90
GR (70 ac
2x Zn)
IP 59 kDa S
![Page 68: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/68.jpg)
receptor affinity intrinsic
(mg/l) activity
Prednisolone 2,60 1,0
BDP (BMP) 0,03 86,7
Flunisolide 0,22 11,8
Triamcinolon acetonide 0,20 13,0
Budesonide 0,04 65,0
Fluticason propionate 0,02 130,0
Derendorf, 1998
Glucocorticoid receptor (IV)
![Page 69: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/69.jpg)
Glucocorticoid receptor (V)
0
5
10
15
20
Dexa B17-m BUD FP
Relative affinity
![Page 70: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/70.jpg)
• Inhalation form (MDI, MDPI)
• Oral form to respect circadian
rhythms (morning - peak)
• Parenteral form only in severe cases
Glucocorticoids and asthma
![Page 71: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/71.jpg)
Inhalation glucocorticoids
• Patient exposed to low dose
• Minimum effect on HPA axis
• Practically no influence on growth
• Almost lack of systemic effect
• Local candidosis
![Page 72: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/72.jpg)
before after
Result of steroid therapy
P Howarth Berlin 1999
![Page 73: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/73.jpg)
Topical (inhalation) steroids
Generic Brand
Beclometason
Budesonid
Flutikason
Mometason
Ciklesonid
Aldecin, Becotide, Becodisc, Becloforte
Budair, Inflammide, Miflonid, Pulmicort,
Pulmax …
Flixotide
Asmanex
Alvesco
![Page 74: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/74.jpg)
Inhalation combinations with b2-agonists
Generic Brand
Fenoterol + ipratropium
Salmeterol + fluticason
Formoterol + budesonid
Berodual
Seretide
Symbicort
![Page 75: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/75.jpg)
Antileucotriens
![Page 76: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/76.jpg)
Leucotriens and antileucotrienes
• In asthma
– Bronchoconstriction
– Stimulate mucus secretion
– Contribute to airway obstruction
• Antileucotriens may modify inflammation in
various diseases
• Anti-inflammatory effect of antileucotrienes is
utilised in asthma
![Page 77: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/77.jpg)
Antileucotriens
• Competitive leucotrien receptor antagonists
(LTRA)
– montelucast, zafirlucast, pranlucast, pobilucast,
verlucast ...
• Leukotrien synthesis inhibitors (LTSI)
– 5-lipooxigenase inhibitors (5-LO): zileuton
– 5-lipooxigenase activating protein inhibitor
(FLAP)
![Page 78: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/78.jpg)
Asthma and antileucotries (I.)
Broncho constriction
Early response
Delayed response
Excersise
zafirlukast + + + +
pranlukast + - + -
montelukast + + + -
pobilukast + + - +
zileuton - - - +
![Page 79: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/79.jpg)
Hyper sensitivity
cold NSAID chronic
zafirlukast - + - +
pranlukast + - + +
montelukast - - + +
pobilukast - - + -
zileuton - + + +
Asthma and antileucotries (II.)
![Page 80: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/80.jpg)
Antileucotriens
Generic Brand
Zafirlucast
Montelucast
Accolate
Singulair
![Page 81: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/81.jpg)
Omalizumab (Xolair)
• Recombinant humanized Mab, with selective
binding to human immunoglobulin E (IgE).
• Reduces amount of free IgE, responsible for
the initiation of allergic cascade.
• Indication – only for patients with asthma
caused by IgE
![Page 82: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/82.jpg)
PEF evaluation
![Page 83: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/83.jpg)
COPD pharmacotherapy
• Anticholinergics
• Selective b2-agonists
• Methylxanthins
• PDE4 inhibitors
• Glucocorticoids
• Oxygenoterapy
![Page 84: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/84.jpg)
PDE4 Inhibitors
Roflumilast: PDE4 inhibitor influencing systemic and lung
inflammation connected with CHOPN.
Mode of action: PDE4 inhibition (main enzyme
metabolizing cAMP)
Indication: maintenance therapy of severe COPD (FEV1
after bronchodilators less than 50 % of appropriate value)
![Page 85: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/85.jpg)
Allergic rhinitis
![Page 86: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/86.jpg)
Allergic rhinitis
![Page 87: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/87.jpg)
Pharmacotherapy
–Local decongestives
–Antihistaminics
–Cromons
–Anticholinergics
–Corticoids - locally
–Corticoids - systemic
![Page 88: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/88.jpg)
Local decongestives
• Main effect - decongestion, vasoconstriction,
• Long term effect - hypoxia - chronic mucosal
changes
![Page 89: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/89.jpg)
Topical nasal decongestives
Generic Brand
Fenylefrin
Nafazolin
Nafazolin + antazolin
Oxymetazolin
Tetryzolin
Xylometazolin
Vibrocil
Sanorin
Sanorin - analergin
Nasivin
Tyzin
Otrivin, Olynth, Nasenspray AL
![Page 90: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/90.jpg)
Cromons
• DSSG
– Mast cells stabilization, prevents degranulation
– Application: 4 - 6 x day locally
![Page 91: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/91.jpg)
Anticholinergics
Ipratropium bromide
– Acetylcholine release inhibition
– Suppression of mucus secretion
– Application: 3 x day locally
![Page 92: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/92.jpg)
Nasal cromons
Nasal
anticholinergics
Antileucotriens
Na cromoglycate
ipratropium bromide
montelukast
zafirlukast
Generic Brand
Allergocrom, Allergo-comod, Cromobene, Cromohexal
Atrovent
Singulair
Accolate
![Page 93: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/93.jpg)
Antihistaminics – 1st generation
• Histamine H1 receptor antagonists
(non selective)
• Sedative effect
• Antiemetic effect
• Muscatine receptor affinity
(anticholinergic activity)
![Page 94: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/94.jpg)
Antihistaminics – 2nd generation
• Selective action - no sedative effect
• Mediator synthesis and release inhibition • mast cells, monocytes and basophiles
• prostaglandin and leucotrien suppression
• Suppression of eosinophils migration,
chemotaxis and their endothelial adhesion
![Page 95: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/95.jpg)
Antihistaminics – 2nd generation
• Advantages • Onset of action
• Long term effect
• Active metabolites
• Good compliance
• Systemic effects (ocular, dermal)
• Disadvantages • Adverse events: weight gain (astemizol)
• Myocardium - QT interval (terfenadin)
• Hepatotoxicity
• Drug interactions e.g. Macrolides, azole antimycotics
![Page 96: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/96.jpg)
Antihistaminics – 2nd generation
Generic
Systemic
Topical
Immunomodul.
effect
Cetirizin
Loratadin
Terfenadin
Azelastin
Levocabastin
Desloratadin
Levocetirizin
Alerid, Cetirizin-SL, Letizen,
Zodac, Zyrtec
Claritin, Flonidan,
Loratadin-SL
Lotanax
Allergodil
Livostin
Aerius
Xyzal
Brand
![Page 97: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/97.jpg)
FDC (antihistaminics + decongestives)
Generic Brand
Loratadin
Fenyramin
Carbinoxamin
+ pseudoefedrin
+ pseudoefedrin
+ fenylefrin
Clarinase
Disophrol
Rhinopront
![Page 98: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/98.jpg)
Topical nasal steroids
Generic Brand
Beclometason
Budesonid
Flunisolid
Flutikason
Mometason
Triamcinolon
Aldecin, Beconase, Beclomet, Nasobec
Rhinocort, Tafen
Syntaris
Flixonase
Nasonex
Nasacort
![Page 99: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/99.jpg)
Treatment of nasal symptoms
sneezing secretion nasal itching eye obstruction symptoms
H1 - antihistaminics
oral
nasal
topical ocular
Corticosteroids
nasal
Cromons
nasal
topical ocular Decongestives
nasal
oral
Anticholinergics
Antileucotriens
++
++
0
+++
+
0
0
0
0
0
++
++
0
+++
+
0
0
0
++
+
+
+
0
+++
+
0
++++
+
0
++
+++
++
0
++
+
0
0
0
0
0
++
0
+++
++
0
++
0
0
0
++
![Page 100: Drugs used in allergic disorders (asthma and allergic ... · transport to nucleus Interaction on gene and regulatory proteins level - GRE (transcriptional mechanisms) Without hormone](https://reader030.vdocuments.us/reader030/viewer/2022040501/5e22dfa90fb5a5706e43ed39/html5/thumbnails/100.jpg)