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