jiří slíva drugs affecting respiratory system. absolute number of patients suffering from ab in...
TRANSCRIPT
Jiří Slíva
Drugs affecting respiratory systemDrugs affecting respiratory system
Absolute number of patients suffering from AB in CZ
Period
Number of patients
http://issar.cenia.cz
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
THE MOST IMPORTANTALERGENES
JANUARY
FEBRUARY
MARCH
APRIL
MAY
1. DEC. 2. DEC. 3. DEC. Pollen situation of„Alnusglutinosa“ in the Europe
DIAGNOSIS
1. ANAMNESIS
3. LABORATORYTESTS
2. CLINICALFEATURES
4. ALLERGOLOGICAL TESTS
pharmacoterapylife style
specific imunotherapy (SCIT vs SLIT)
symptomaticantiinflammatoric
preventive
• sympatomimetics
• anticholinergics
• corticosteroides
• methylxantines
• antileukotriens
• antihistamines
• MABs
Groups of drugs:
Novolizer:
Ventodisk, Turbuhaler:
β-mimetics
- nonselective - adrenaline, isoproterenol, orciprenaline, ephedrine
- selective - metaproterenol, albuterol, salbutamol, terbutalin, fenoterol => more effective via inhalation then p.o.
administration => increase of cAMP
=> SABA, LABA, RABA
Parasympatolytics
ipratropium
Antiasthmatics with rapid effect:
β2-mimetics with long-term effect:
• via inhalation salmeterol • via per os (tbl, susp) clenbuterol, procaterol
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)
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/
ADRs of 2-mimetics
• muscle tremor (higher doses)
• palpitation, tachycardia, arrhythmia,
sudden death
• headache
• paradox bronchospasm (after inhalation)
• rarely allergy
Action of beta-mimetics…Action of beta-mimetics…
1.1. Smooth muscle rec.Smooth muscle rec.1. bronchodilation
2.2. Other receptors (epitelium, mastocytes Other receptors (epitelium, mastocytes etc.)etc.)
1. mastocytes stabilization
2. inhibition of release mediators from eo, macro, T-cells or neu
3. decreased plasma exsudation to airways
4. etc.
Hanania, 2004
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
Corticosteroids:Corticosteroids:
ICS & beta-mimeticsICS & beta-mimetics
Synergism:Synergism: CS recover bronchial responsivity to beta-2 mimetics CS recover bronchial responsivity to beta-2 mimetics
==>> mechanism (?) mechanism (?)
Mechanism (?):Mechanism (?):
– increased affinity of agonists to receptorsincreased affinity of agonists to receptors
– decreased degradation of receptorsdecreased degradation of receptors
– decreased activity of COMTdecreased activity of COMT
– decreased up-take of mediators to presynaptic decreased up-take of mediators to presynaptic
buttonbutton
…Pauwels, 1985
ADRs of ICSADRs of ICS
Local ADRsLocal ADRs
Most frequent:Most frequent: oropharyngel candidosis dysphonia cough
Prevention:Prevention: mouth washing after admin. use of prodrugs (activation in lungs:
ciclesonide ciclesonide => C C21-des-methylpropionyl-21-des-methylpropionyl-ciclesonideciclesonide)
Systemic ADRs I.Systemic ADRs I.
absorption from lung & GI
no important ADRs after admin. of
budesonide 400 g or its equivalent
GINA, 2006
Frequently discussed:Frequently discussed:
suprarenal supressiondecreased BMDglaucoma & cataracta
Systemic ADRs II.Systemic ADRs II.
theophylline - myotropic influence via inhibition of phosphodiesterase and via antagonism on the adenosine receptors A2
=> bronchodilatation
=> prevention from bronchoconstriction caused by histamine, cholinergic agonists (metacholine) or exertion.
Aminophylline = theophylline + ethylendiamine
Methylxantines:
Antiinflammatory theophyllineAntiinflammatory theophylline
Watanabe S, 2008
Antiinflammatory theophyllineAntiinflammatory theophylline
Watanabe S, 2008
Note: aminoglutethimide = inhibitor of GC synthesis; mifepristone = anta GCR
Mechanism of actionMechanism of action
??? SYNERGISM with ICS ?????? SYNERGISM with ICS ???
- both in vitro & in vivo higher activity of HDAC (histon
deacetylases) in epit. cells & macrophages => higher eff.
of ICS on genes with antiinflammatory properties
Ito K, 2002
Anticholinergics
CNS
bronchialepithelium
bronchial muscle cellsmucus producing cells
parasympat.ganglion
neurokinines
rec. M2 a M3rec. M1 & M3
n. vagus
tiotropium
rec. M1
Anticholinergicsipratropium /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
inhibition of degranulation of mastocytes after exposition to specific agents full effect after 4-6 weeks
Cromones
cromoglycate sodium
nedocromil• similar to cromoglycate in mechanism of action
zafirlukast montelukast
zileuton = inhib. of 5-lipooxygenase
Antileukotriens &
Leukotriene Receptor Antagonists (LTRAs):
Antihistamines:Antihistamines:
Histamine receptors:Histamine receptors:
HH1119661966 smooth muscles, endothelium, smooth muscles, endothelium,
dendritic cells, neu, mono, eo,dendritic cells, neu, mono, eo,
T a B ly, hepato, chondrocytes, T a B ly, hepato, chondrocytes, CNSCNS
HH2219721972 gastric parietal cells, myocardium, gastric parietal cells, myocardium,
uterus, CNSuterus, CNS
HH3319831983 CNS, airways, GITCNS, airways, GIT
HH4420002000 mast cellsmast cells
= sedative antihistamines
inverse agonists of H1 receptor
low selectivity = influence of other receptors
short interaction with the receptor => a need of more frequent
administration (b.i.d. or t.i.d.)
ANTIHISTAMINES ANTIHISTAMINES 11stst generation generation
Common ADRs:Common ADRs:
– antimuscarine eff.
– arrhythmia
– sedation (cross via HEB)
– potentiation of alcohol
– adrenolytic & antiserotonergic eff.
ANTIHISTAMINES ANTIHISTAMINES 11stst generation generation
ANTIHISTAMINES ANTIHISTAMINES 11stst generation generation
ORALORALBisulepineBisulepine
Bilastine Bilastine DimetindenDimetinden
Clemastine Clemastine Promethazin Promethazin KetotifenKetotifen
PARENTERALPARENTERALBisulepin Bisulepin
Promethazin Promethazin
ClemastinClemastin
TOPICALTOPICAL Dimetinden Dimetinden
KetotifenKetotifen
COMBINED PREPARATIONS – COMBINED PREPARATIONS – locallocalSpersallerg – eyeSpersallerg – eye
Sanorin-Analergin – eye, noseSanorin-Analergin – eye, nose
Vibrocil – noseVibrocil – nose
= higher selectivity = better safety profile= higher selectivity = better safety profile
Substances for systemic administration:Substances for systemic administration: acrivastine, cetirizine, loratadine, mizolastineacrivastine, cetirizine, loratadine, mizolastine
Substances for local administration:Substances for local administration: azelastine, emedastine, epinastine, azelastine, emedastine, epinastine,
levocabastine, olopatadinelevocabastine, olopatadine
ANTIHISTAMINES ANTIHISTAMINES 22ndnd generation generation
= active enantiomers (levocetirizine) or metabolites = active enantiomers (levocetirizine) or metabolites (desloratadine or fexofenadine) (desloratadine or fexofenadine)
higher selectivity => better tolerability & safety profilehigher selectivity => better tolerability & safety profile
For systemic administration:For systemic administration: levocetirizine, desloratadine, fexofenadinelevocetirizine, desloratadine, fexofenadine
ANTIHISTAMINES ANTIHISTAMINES 33rdrd generation generation
verapamilenifedipine etc.
inhibition of calcium influx => inhibition of contraction of smooth muscle cells
induction of bronchodilation
used experimentally
Inhibitors of calcium channelsInhibitors of calcium channels
Asthma vs glaucomaAsthma vs glaucoma
Asthma vs. glaucomaAsthma vs. glaucoma
Concomitant glaucoma and AB
- in glaucoma – BBBB = drug of choice (CI: in AB)
- in AB – CSCS = drug of choice (CI: in glaucoma)
„„News“News“
„ULABAULABA“ – „ultra-long acting beta-2 agonists“ -
arformoterol, carmoterol, indacaterol, GSK-159797arformoterol, carmoterol, indacaterol, GSK-159797 …in
clinical praxis from 2010 for AB & COPD (once daily)
omalizumabomalizumab - anti IgE – effective in all. rhinitis as well
bimosiamosbimosiamos – inhalatory pan-selectine anta =>
inhibition of rolling & extravasation of infl. cells
Comparison of numbers of drugs Comparison of numbers of drugs used in therapy of bronchial asthmaused in therapy of bronchial asthma
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
Secretomotorics – plant etheric oils - ol. menthae piperitae
Secretolytics - saponines & alcaloids - ipekakuana, primula, NaI, KI, NH4Cl
Mucolytics - acetylcystein, carbocystein, mesna, bromhexin, ambroxol