Bez nadpisu

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Drugs affecting respiratory system
Jirí Slíva
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Absolute number of patients suffering from AB in
CZ
http//issar.cenia.cz
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Asthma in numbers

• 100-150 million worldwide 180 000 deaths/year
• total number of AB patients has doubled during
  last decade
• Australia every 6th child suffers from AB

Source WHO
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THE MOST IMPORTANT ALERGENES
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Pollen situation ofAlnus glutinosa in the Europe
1. DEC. 2. DEC. 3. DEC.
JANUARY FEBRUARY MARCH APRIL MAY
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DIAGNOSIS
2. CLINICAL FEATURES
1. ANAMNESIS
4. ALLERGOLOGICAL TESTS
3. LABORATORY TESTS
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THERAPY
life style
pharmacoterapy
specific imunotherapy (SCIT vs SLIT)
preventive
antiinflammatoric
symptomatic
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Groups of drugs

• sympatomimetics
• anticholinergics
• corticosteroides
• methylxantines
• antileukotriens
• antihistamines
• MABs

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Novolizer
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Ventodisk, Turbuhaler
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Antiasthmatics with rapid effect
ß-mimetics - nonselective - adrenaline,
isoproterenol, orciprenaline, ephedrine -
selective - metaproterenol, albuterol,
salbutamol,
terbutalin, fenoterol gt more effective
via inhalation then p.o. administration
gt increase of cAMP gt SABA, LABA, RABA
Parasympatolytics ipratropium
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ß2-mimetics with long-term effect

• via inhalation salmeterol
• via per os (tbl, susp) clenbuterol, procaterol

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Rapid short-term acting
?2- sympatomimetics (RABA)

• fast and short-term bronchodilation after
  inhalation
• for acute treatment
• onset of action in 5-10 min (inhal.), 15-90 min
  (p.o.)
• duration of action 4-6 hrs
• salbutamol /Ventolin/
• fenoterol (Berotec)
• terbutalin (Bricanyl)

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Long-term acting ?2- sympatomimetics (LABA)

• bronchodilation ? 12 hrs
• not suitable for acute treatment, for prophylaxis
  only
• ICS are prefered (20x higher eff. than p.o.,
• ?
  systemic ADRs)
• commonly in combination with ICS
• moderate severe BA in combination with ICS
• salmeterol /Serevent/
• formoterol /Oxis/
• procaterol /Lontermin/

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ADRs of ?2-mimetics

• muscle tremor (higher doses)
• palpitation, tachycardia, arrhythmia, sudden
  death
• headache
• paradox bronchospasm (after inhalation)
• rarely allergy

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Action of beta-mimetics

1. Smooth muscle rec.
2. bronchodilation
3. Other receptors (epitelium, mastocytes etc.)
4. mastocytes stabilization
5. inhibition of release mediators from eo, macro,
   T-cells or neu
6. decreased plasma exsudation to airways
7. etc.

Hanania, 2004
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Corticosteroids

• beclometasone
• budesonide
• flunisolide
• fluticasone
• triamcinolone
• potent antiinflammatory effect
• decrease of number of inflammatory potent
• cells
• inhibition of bronchoconstrictory mechanisms
• direct relaxation of smooth muscle cells

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ICS beta-mimetics

• Synergism
• CS recover bronchial responsivity to beta-2
  mimetics gt mechanism (?)
• Mechanism (?)
• increased affinity of agonists to receptors
• decreased degradation of receptors
• decreased activity of COMT
• decreased up-take of mediators to presynaptic
  button
• Pauwels, 1985

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ADRs of ICS
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Local ADRs

• Most frequent
• oropharyngel candidosis
• dysphonia
• cough
• Prevention
• mouth washing after admin.
• use of prodrugs (activation in lungs ciclesonide
  gt C21-des-methylpropionyl-ciclesonide)

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Systemic ADRs I.

• absorption from lung GI
• no important ADRs after admin. of budesonide 400
  mg or its equivalent

GINA, 2006
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Systemic ADRs II.

• Frequently discussed
• suprarenal supression
• decreased BMD
• glaucoma cataracta

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Methylxantines
theophylline - myotropic influence via
inhibition of phosphodiesterase and via
antagonism on the adenosine receptors A2 gt
bronchodilatation gt prevention from
bronchoconstriction caused by histamine,
cholinergic agonists (metacholine) or exertion.
Aminophylline theophylline ethylendiamine
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Antiinflammatory theophylline
Watanabe S, 2008
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Antiinflammatory theophylline
Note aminoglutethimide inhibitor of GC
synthesis mifepristone anta GCR
Watanabe S, 2008
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Mechanism of action

• ??? SYNERGISM with ICS ???
• both in vitro in vivo higher activity of HDAC
  (histon deacetylases) in epit. cells
  macrophages gt higher eff. of ICS on genes with
  antiinflammatory properties

Ito K, 2002
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Anticholinergics
CNS
n. vagus
bronchial epithelium
rec. M1
parasympat. ganglion
tiotropium
neurokinines
rec. M1 M3
rec. M2 a M3
bronchial muscle cells
mucus producing cells
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Anticholinergics

• ipratropium /Atrovent, in comb. with ?2 mimet.
  Berodual/
• similar structure to atropine
• shorter eff. 4-8 hrs, rapid onset 5?15 min
• for acute use with RABA
• for long-term therapy with LABA
• tiotropium /Spiriva/
• longer eff. up to 48 hrs, slower onset
• for long-term therapy of BA or COPD

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Cromones
cromoglycate sodium

• inhibition of degranulation of mastocytes after
  exposition to specific agents
• full effect after 4-6 weeks

• nedocromil
• similar to cromoglycate in mechanism
• of action

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Antileukotriens Leukotriene Receptor
Antagonists (LTRAs)
zafirlukast montelukast zileuton inhib. of
5-lipooxygenase
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Antihistamines
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Histamine receptors
H1 1966 smooth muscles, endothelium, dendritic cells, neu, mono, eo, T a B ly, hepato, chondrocytes, CNS
H2 1972 gastric parietal cells, myocardium, uterus, CNS
H3 1983 CNS, airways, GIT
H4 2000 mast cells
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ANTIHISTAMINES 1st generation

• sedative antihistamines
• inverse agonists of H1 receptor
• low selectivity influence of other receptors
• short interaction with the receptor gt a need of
  more frequent administration (b.i.d. or t.i.d.)

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ANTIHISTAMINES 1st generation

• Common ADRs
• antimuscarine eff.
• arrhythmia
• sedation (cross via HEB)
• potentiation of alcohol
• adrenolytic antiserotonergic eff.

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ANTIHISTAMINES 1st generation
ORAL Bisulepine Bilastine Dimetinden Clemastine Promethazin Ketotifen PARENTERAL Bisulepin Promethazin Clemastin
TOPICAL Dimetinden Ketotifen COMBINED PREPARATIONS local Spersallerg eye Sanorin-Analergin eye, nose Vibrocil nose
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ANTIHISTAMINES 2nd generation

• higher selectivity better safety profile
• Substances for systemic administration
• acrivastine, cetirizine, loratadine, mizolastine
• Substances for local administration
• azelastine, emedastine, epinastine,
  levocabastine, olopatadine

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ANTIHISTAMINES 3rd generation

• active enantiomers (levocetirizine) or
  metabolites (desloratadine or fexofenadine)
• higher selectivity gt better tolerability
  safety profile
• For systemic administration
• levocetirizine, desloratadine, fexofenadine

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Inhibitors of calcium channels

• verapamile
• nifedipine
• etc.
• inhibition of calcium influx gt inhibition of
  contraction of smooth muscle cells
• induction of bronchodilation
• used experimentally

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Asthma vs glaucoma
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Asthma vs. glaucoma

• Concomitant glaucoma and AB
• in glaucoma BB drug of choice (CI in AB)
• in AB CS drug of choice (CI in glaucoma)

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News

• ULABA ultra-long acting beta-2 agonists -
  arformoterol, carmoterol, indacaterol, GSK-159797
  in clinical praxis from 2010 for AB COPD (once
  daily)
• omalizumab - anti IgE effective in all.
  rhinitis as well
• bimosiamos inhalatory pan-selectine anta gt
  inhibition of rolling extravasation of infl.
  cells

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Comparison of numbers of drugs used in therapy of
bronchial asthma
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ANTITUSSICS
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1) peripheral sensors inhibition - benzonatate,
dropropizine 2) afferent signals modulation -
prenoxdiazine 3) cough centre inhibition -
a) opioid codein, dextromethorphan - b)
non-opioid - butamirate, pipazetate -
clobutinol RC stimulation cough centre
inhibition 4) efferent signals modulation -
myorelaxants 5) effector modulation -
penthoxyverine - bronchodilation
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EXPECTORANTS
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Secretolytics - saponines alcaloids -
ipekakuana, primula, NaI, KI, NH4Cl
Mucolytics - acetylcystein, carbocystein, mesna,
bromhexin, ambroxol
Secretomotorics plant etheric oils - ol.
menthae piperitae