Transcript Antihistamines

Drugs affecting respiratory system
Jiří Slíva
Absolute number of patients
suffering from AB in CZ
Number of
patients
Period
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
IMPORTANT
ALERGENES
Pollen situation of„Alnus
glutinosa“ in the Europe
1. DEC. 2. DEC. 3. DEC.
JANUARY
FEBRUARY
MARCH
APRIL
MAY
DIAGNOSIS
2. CLINICAL
FEATURES
1. ANAMNESIS
3. LABORATORY
TESTS
4. ALLERGOLOGICAL
TESTS
life style
pharmacoterapy
specific imunotherapy
(SCIT vs SLIT)
symptomatic
preventive
antiinflammatoric
Groups of drugs:
• sympatomimetics
• anticholinergics
• corticosteroides
• methylxantines
• antileukotriens
• antihistamines
• MABs
Novolizer:
Ventodisk, Turbuhaler:
Antiasthmatics with rapid effect:
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
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…
1. Smooth muscle rec.
1. bronchodilation
2. Other receptors (epitelium, mastocytes
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
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
ICS & beta-mimetics
Synergism:
 CS recover bronchial responsivity to beta-2
mimetics => 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
ADRs of ICS
Local ADRs
Most frequent:
 oropharyngel candidosis
 dysphonia
 cough
Prevention:
 mouth washing after admin.
 use of prodrugs (activation in lungs:
ciclesonide => C21-des-methylpropionylciclesonide)
Systemic ADRs I.
 absorption from lung & GI
 no important ADRs after admin. of budesonide
400 mg or its equivalent
GINA, 2006
Systemic ADRs II.
Frequently discussed:
suprarenal supression
decreased BMD
glaucoma & cataracta
Methylxantines:
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
Antiinflammatory theophylline
Watanabe S, 2008
Antiinflammatory theophylline
Note: aminoglutethimide = inhibitor of GC synthesis; mifepristone = anta GCR
Watanabe S, 2008
Mechanism of action
??? 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
n. vagus
bronchial
epithelium
rec. M1
parasympat.
ganglion
neurokinines
rec. M1 &
M3
mucus producing
cells
rec. M2 a M3
bronchial muscle cells
tiotropium
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
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
Antileukotriens
&
Leukotriene Receptor Antagonists
(LTRAs):
zafirlukast
montelukast
zileuton = inhib. of
5-lipooxygenase
Antihistamines:
Histamine receptors:
H1
1966
smooth muscles, endothelium,
dendritic cells, neu, mono, eo,
T a B ly, hepato, chondrocytes,
CNS
gastric parietal cells, myocardium,
uterus, CNS
H2
1972
H3
1983
CNS, airways, GIT
H4
2000
mast cells
ANTIHISTAMINES
1st generation
 = 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
1st generation
Common ADRs:
– antimuscarine eff.
– arrhythmia
– sedation (cross via HEB)
– potentiation of alcohol
– adrenolytic & antiserotonergic eff.
ANTIHISTAMINES
1st generation
ORAL
PARENTERAL
Bisulepine
Bilastine
Dimetinden
Clemastine
Promethazin
Ketotifen
Bisulepin
Promethazin
Clemastin
TOPICAL
COMBINED PREPARATIONS –
local
Dimetinden
Ketotifen
Spersallerg – eye
Sanorin-Analergin – eye, nose
Vibrocil – nose
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
ANTIHISTAMINES
3rd generation

= active enantiomers (levocetirizine) or metabolites
(desloratadine or fexofenadine)

higher selectivity => better tolerability & safety profile

For systemic administration:

levocetirizine, desloratadine, fexofenadine
Inhibitors of calcium channels
verapamile
nifedipine
etc.
 inhibition of calcium influx =>
inhibition of contraction of smooth
muscle cells
 induction of bronchodilation
 used experimentally
Asthma vs glaucoma
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)
„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 =>
inhibition of rolling & extravasation of infl. cells
Comparison of numbers of drugs used
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
Secretolytics - saponines & alcaloids ipekakuana, primula, NaI, KI, NH4Cl
Mucolytics - acetylcystein, carbocystein,
mesna, bromhexin, ambroxol
Secretomotorics – plant etheric oils
- ol. menthae piperitae