drugs affecting the respiratory system anjie institute of pharmacology, school of medicine, shandong...
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Drugs Affecting theDrugs Affecting the Respiratory SystemRespiratory System
anjieInstitute of Pharmacology,
School of Medicine, Shandong University
introductionintroduction
Cough, sputum and AsthmaCough, sputum and Asthma are main are main
symptoms in respiratory systemic symptoms in respiratory systemic
diseases.diseases.
So we are going to learn agents used in So we are going to learn agents used in
therapy of therapy of Cough, sputum and Asthma.Cough, sputum and Asthma...
Antiasthmatic drugsAntiasthmatic drugs
AsthmaAsthmaAsthma is a chronic inflammatory Asthma is a chronic inflammatory
pulmonary disorder that is pulmonary disorder that is
characterized by reversible obstruction characterized by reversible obstruction
of the airways. of the airways.
Asthma affects 4 to 5% of the whole Asthma affects 4 to 5% of the whole
population.population.
recurrent dyspnearecurrent dyspnea
Shortness of breathShortness of breath
CoughingCoughing
Chest tightnessChest tightness
WhistlingWhistling
AsthmaSYMPTOMS
AsthmaAsthma
Most people have a mild form of the Most people have a mild form of the disease, with symptoms occurring odisease, with symptoms occurring only nly occasionally occasionally .( e.g, on exposure t.( e.g, on exposure to allergens or certain pollutants , on o allergens or certain pollutants , on exercise, or after a viral infection.) exercise, or after a viral infection.)
AllergensAllergens– molds, dust mites, molds, dust mites,
cockroaches, animal cockroaches, animal danderdander, pollens,, pollens, foodsfoods
IrritantsIrritants– secondhand smokesecondhand smoke, ,
strong odors, aerosols, strong odors, aerosols, volatile organic volatile organic compounds, ozone, compounds, ozone, particulate matterparticulate matter
OtherOther– Viral respiratory Viral respiratory
infectionsinfections– Changes in weather Changes in weather
(cold air, wind, humidity)(cold air, wind, humidity)– ExerciseExercise– MedicationMedication– Endocrine factors Endocrine factors
(menstrual period, (menstrual period, pregnancy, thyroid pregnancy, thyroid disease)disease)
CommonasthmaTriggers
* 5 major indoor asthma triggers
Pathogenesis of asthmaPathogenesis of asthma
1.allergic reaction ( -type)Ⅰ1.allergic reaction ( -type)Ⅰ : :
mediate d by IgE antibodies . mediate d by IgE antibodies .
Symptoms:Symptoms:
(1)mediators (HA, PGs) release(1)mediators (HA, PGs) release
(2)(2)broncho-constrictionbroncho-constriction
(3)vascular leakage.(3)vascular leakage.
Pathogenesis of asthmaPathogenesis of asthma
2.inflammation of airway mucosa2.inflammation of airway mucosa::
nonspecific bronchial hyper-reactivity nonspecific bronchial hyper-reactivity
to some stimuli (eg. allergen inhalation ,to some stimuli (eg. allergen inhalation ,
or infection with virus.)or infection with virus.)
Neural mechanism:Neural mechanism:
Treatment of asthmaTreatment of asthma
Treatment should be directed toward reduTreatment should be directed toward redu
ction of ction of inflammationinflammation, as well as to manage, as well as to manage
ment of ment of bronchoconstrictionbronchoconstriction..
ClassificationClassification
BranchodilatorBranchodilator
1.1.2 2 – adrenoceptor agonists : salbutamol– adrenoceptor agonists : salbutamol
2.Theophylline : aminophylline2.Theophylline : aminophylline
3.M – Receptor blockers: ipratropine3.M – Receptor blockers: ipratropine
Anti-inflamation agentsAnti-inflamation agents
1.Glucocorticoids:beclomethasone1.Glucocorticoids:beclomethasone
2.inhibitors of leukotirenes(LTs) 2.inhibitors of leukotirenes(LTs)
Anti-hypersensitive agentsAnti-hypersensitive agents
1. inhibitors of mediator release : 1. inhibitors of mediator release : cromolyn sodiumcromolyn sodium
means of administrationmeans of administration
Drugs can be delivered toDrugs can be delivered to the lungs by the lungs by inhalation,inhalation, oral,oral, or or injectioninjection..
InhalationInhalation is often preferred because the is often preferred because the drug is delivered directly to the targetdrug is delivered directly to the target tissuetissue and is effective in doses that do not cause and is effective in doses that do not cause significant systemic side effects.significant systemic side effects.
AntiasthmaticAntiasthmatic DrugsDrugs
The drugs most commonly used drugs for The drugs most commonly used drugs for management of asthma are management of asthma are adrenoceptor aadrenoceptor agonistsgonists (used as “relievers” or broncho-dilat (used as “relievers” or broncho-dilators ) and ors ) and inhaled corticosteroidsinhaled corticosteroids (used as “c (used as “controllers” or anti-inflamatory agents)ontrollers” or anti-inflamatory agents)
BronchodilatorsBronchodilators
The major drugs used to treat bronchThe major drugs used to treat bronch
ospasm are the ospasm are the
ββ22- - adrenoceptor agonistsadrenoceptor agonists and the and the theotheo
phyllinephylline..
adrenadrenoline receptor oline receptor agonistsagonists
adrenalineadrenaline
pharmacological actionspharmacological actions::
AD is a nonselective adrenoceptor aAD is a nonselective adrenoceptor agonist which can activate all of the gonist which can activate all of the α, β-receptors nonselectively.α, β-receptors nonselectively.
★ ★ mechanism of anti-asthma actionsmechanism of anti-asthma actions
1. activate 1. activate β2-Rβ2-R → ↑AC→↑cAMP→↑PKA →↓C → ↑AC→↑cAMP→↑PKA →↓C
a2+ →relaxation of airway smooth musclea2+ →relaxation of airway smooth muscle
2. activate 2. activate α-Rα-R→vascular constriction of bronchi→vascular constriction of bronchi
al mucosa→edema lightened →airflow improal mucosa→edema lightened →airflow impro
vedved
3. inhibit 3. inhibit mast cellmast cell degranulation →release of ale degranulation →release of ale
rgicrgic mediators decreasedmediators decreased
clinical useclinical use::
S.C(subcutanous) : S.C(subcutanous) : acute attacks of aacute attacks of a
sthma sthma
side effects:side effects:
stimulatesβstimulatesβ11 as well asβ as well asβ22 receptors, receptors,
can result in can result in cardiac adverse reactioncardiac adverse reaction
ss (eg. tachycardia, arrhythmias) (eg. tachycardia, arrhythmias)
EphedrineEphedrine
★ ★ characteristics (VS AD)characteristics (VS AD)::
slow onset; moderate effect; long slow onset; moderate effect; long
duration; vasoconstriction and CNS duration; vasoconstriction and CNS
excitation. excitation.
★★clinical useclinical use
The oldest agents used to treat asthma, The oldest agents used to treat asthma,
and can be used in prevention and and can be used in prevention and
treatment of mild asthma.treatment of mild asthma.
Isoprenaline (Isop)Isoprenaline (Isop)
was introduced in the 1940s as a pure β-agwas introduced in the 1940s as a pure β-agonist. onist.
★ ★ anti-asthmatic action:anti-asthmatic action:
potent , quick-onsetpotent , quick-onset
used in acute asthmaused in acute asthma
★★ severe toxicity on heart:severe toxicity on heart:
arrythmiaarrythmia
SelectiveβSelectiveβ22- R agonists- R agonists
The most widely used adrenoceptor agoThe most widely used adrenoceptor ago
nist for the treatment of asthma at the pnist for the treatment of asthma at the p
resent time .resent time .
They are effective after They are effective after inhaled or oralinhaled or oral a a
dministration and have a dministration and have a long durationlong duration
of action and significant of action and significant ββ2 2 selectivityselectivity..
SelectiveβSelectiveβ22- R agonists- R agonists
Salbutamol(Salbutamol( 沙丁胺醇沙丁胺醇 ),), p.o. p.o. & & inhaleinhale ,, ivd ivd
Clenbuterol(Clenbuterol( 克伦特罗)克伦特罗) , potent effect, potent effect
Terbutaline (Terbutaline ( 特布他林特布他林 ) ) p.o. p.o. & & s.c.s.c. long duration long duration
formaterol(formaterol( 福莫特罗福莫特罗 ), sameterol(), sameterol( 沙美特罗沙美特罗 ) :) :
long durationlong duration, also inhibit release of inflammatory , also inhibit release of inflammatory
mediator. Mainly used in chronic asthma and Chrmediator. Mainly used in chronic asthma and Chr
onic obstructive lung disease.onic obstructive lung disease.
Bambuterol(Bambuterol( 班布特罗班布特罗 ) P.O.) P.O.
SelectiveβSelectiveβ22- R agonists- R agonists
Clinical useClinical use
acute attacks of asthma.acute attacks of asthma.
interact with inhaled corticosteroids to interact with inhaled corticosteroids to
improve asthma control.improve asthma control.
Adverse effectsAdverse effects: :
cardiac reactioncardiac reaction
skeletal muscle tremor (skeletal muscle tremor (ββ22- R- R))
metabolic disordermetabolic disorder
TheophyllineTheophylline
aminophylline( 氨茶碱 ),
choline theophylline( 胆茶碱 ),
glyphylline( 甘油茶碱 , 喘定 )
※ ※ EffectsEffects::
relaxation of smooth musclerelaxation of smooth muscle
cardiac stimulation cardiac stimulation
CNS stimulationCNS stimulation
Excitation of skeletal muscle Excitation of skeletal muscle
diuresis diuresis
※ ※ MechanismMechanism
1)1) ↓PDE ( phosphodiesterase ) ↓PDE ( phosphodiesterase )
2)2) ↑Release of CA (catecholamine) ↑Release of CA (catecholamine)
3)3) Block adenosine Block adenosine
(a bronchoconstrictor)(a bronchoconstrictor)
4)4) Anti-inflammatory effect Anti-inflammatory effect
Therapeutic usesTherapeutic uses
Chronic asthmaChronic asthma
Chronic obstructive lung diseaseChronic obstructive lung disease
TheophyllineTheophylline
※ ※ adverse reactions:adverse reactions:
gastrointestinal distressgastrointestinal distress
CNS stimulationCNS stimulation
Cardiovescular reaction: arrythmia, Cardiovescular reaction: arrythmia, ↓↓BPBP
Acute nephridial failure Acute nephridial failure
3. M-receptor blocker3. M-receptor blocker :: ipratropium(ipratropium( 异丙阿托品异丙阿托品 ))
Slow onsetSlow onset
Oxitropium (Oxitropium ( 氧托品氧托品 ))
Tiotropium (Tiotropium ( 泰乌托品泰乌托品 )) :: potent effect, long duationpotent effect, long duation
Anti-inflammatory steroidsAnti-inflammatory steroids
GlucocorticoidsGlucocorticoids
Most effective anti-inflamatory drugsMost effective anti-inflamatory drugs
Used in continuous and severe asthma atUsed in continuous and severe asthma at
tack tack
GlucocorticoidsGlucocorticoids
EffectEffect : :
effective in improving all index of asthmeffective in improving all index of asthm
a control and can improve quality of life.a control and can improve quality of life.
(1) (1) reduce bronchial reactivityreduce bronchial reactivity;;
(2)(2) increase airway caliberincrease airway caliber;;
(3)(3) reduce the frequency of asthma ecurrence reduce the frequency of asthma ecurrence
Mechanisms:Mechanisms:
1) reduce microvascular leakage. 1) reduce microvascular leakage.
2) inhibit influx of inflammatory cells int2) inhibit influx of inflammatory cells int
o the lungs.o the lungs.
3) inhibit of production of inflammatory 3) inhibit of production of inflammatory
cytokines. cytokines.
4) increase the effect of β-R agonists4) increase the effect of β-R agonists
BeclomethasoneBeclomethasone (倍氯米松)(倍氯米松)
Characteristics:Characteristics:
1) inhaled: potent local anti-inflammatory act1) inhaled: potent local anti-inflammatory action (500 times than Dex).ion (500 times than Dex).
2)far fewer systemic adverse reaction2)far fewer systemic adverse reaction
3) slow onset, used in3) slow onset, used in prevention prevention of attack of of attack of moderate or severe asthmamoderate or severe asthma
flunisolide(flunisolide( 氟尼缩松氟尼缩松 ) , ) ,
budesonide(budesonide( 布地萘德,布的松布地萘德,布的松 ))
leukotrienes (LTs) leukotrienes (LTs) pathway inhibitorspathway inhibitors
LTs:LTs: LTC4 and LTD4:LTC4 and LTD4:
inflimatory reaction inflimatory reaction increased bronchial reactivity increased bronchial reactivity mucosal edema mucosal edema mucus hypersecretion mucus hypersecretion
two approachestwo approaches: :
1) inhibition of 5-lipoxygenase:1) inhibition of 5-lipoxygenase: zileuton zileuton(( 齐留通齐留通 ))
2) LTD2) LTD44 -receptor antagonists: -receptor antagonists:
zafirlukast(zafirlukast( 扎鲁司特扎鲁司特 ), ),
montelukast(montelukast( 孟鲁司特孟鲁司特 )) Principle advantagePrinciple advantage can be taken orally can be taken orally Clinical useClinical use : all kinds of asthma , especially : all kinds of asthma , especially
aspirin-induced asthmaaspirin-induced asthma..
Drugs stabilizing cellular Drugs stabilizing cellular membranemembrane
☆ ☆ Sodium cromoglycateSodium cromoglycate
Mechanism of action: Mechanism of action:
stabilizing cellular membranestabilizing cellular membrane
1)on mast cell: inhibits the early response t1)on mast cell: inhibits the early response t
o antigen challenge. o antigen challenge.
2) on eosinophils: inhibit the inflammatory 2) on eosinophils: inhibit the inflammatory
response to inhalation of allergens.response to inhalation of allergens.
3) inhibit sensory nerve endings3) inhibit sensory nerve endings
Clinical use:Clinical use:
pretreatmentpretreatment of asthma caused by of asthma caused by
antigen inhalation, by exercise, by aspirin, antigen inhalation, by exercise, by aspirin,
etc. etc.
administrated shortly before exercise or administrated shortly before exercise or before unavoidable exposure to an before unavoidable exposure to an allergenallergen..
Adverse reactions: Adverse reactions: throat irritation throat irritation
Nadocrimil sodium(Nadocrimil sodium( 奈多罗米钠奈多罗米钠 ))
Ketotifen(Ketotifen( 酮替芬酮替芬 ))
AntitussivesAntitussives
OverviewOverview
Coughing is a protective mechanism thrCoughing is a protective mechanism thr
ough which foreign materials and secreough which foreign materials and secre
tions are cleared from the respiratory trations are cleared from the respiratory tra
ct.ct.
But severe and prolonged coughing can But severe and prolonged coughing can
be painful and exhausting.be painful and exhausting.
OveriewOveriew
Some drugs act at one or more sites withSome drugs act at one or more sites with
in the respiratory tract; others act at the in the respiratory tract; others act at the
cough center to inhibit activation of the ecough center to inhibit activation of the e
fferent limb of the response.fferent limb of the response.
ClassificationClassification
Ⅰ Ⅰ Central antitussives Central antitussives
ⅰ ⅰ Dependence : CodeineDependence : Codeine (可待因) (可待因) , ,
DihydrocodeineDihydrocodeine (二氢可待因 ) (二氢可待因 ) ⅱ ⅱ Nondependence: Dextromethorpham,Nondependence: Dextromethorpham,
Cloperastine, PentoxyverineCloperastine, Pentoxyverine
Ⅱ Ⅱ Peripheral antitussives:Peripheral antitussives:
BenzonatateBenzonatate (苯佐那酯)(苯佐那酯) , narcotin(, narcotin( 那可那可丁)丁)
Central antitussivesCentral antitussives
Codeine Codeine andand dihydrocodeine dihydrocodeine: opium receptor a: opium receptor a
gonists, mainly used in dry cough .gonists, mainly used in dry cough .
Mechanism: Act on cough center to suppress Mechanism: Act on cough center to suppress
cough.cough.
DextromethorphanDextromethorphan (a synthetic non- opium co (a synthetic non- opium co
mpound)mpound)
Pentoxyverine:Pentoxyverine:Act on cough center and sensorAct on cough center and sensor
y nerve ending in branchial tracty nerve ending in branchial tract
Peripherial antitussivesPeripherial antitussives
BenzonatateBenzonatate
Have a local anesthetic actionHave a local anesthetic action
Two mechanismsTwo mechanisms: :
(1)the selective anesthesia of stretch rec(1)the selective anesthesia of stretch receptors within the lungs eptors within the lungs
(2) central suppression of cough.(2) central suppression of cough.
Section 3 ExpectorantsSection 3 Expectorants
Ⅰ Ⅰ Agents promoting mucous secretionAgents promoting mucous secretion
ammonium chlorideammonium chloride
[ Effects][ Effects]
(1)Expectorant action(1)Expectorant action
(2) Diuretic action(2) Diuretic action
(3) Acidified urine and blood(3) Acidified urine and blood
[Uses ][Uses ]
(1) Expectoration(1) Expectoration
(2) Alkalemia(2) Alkalemia
(3) Influence on excretion of some (3) Influence on excretion of some drugsdrugs
Ⅱ Ⅱ MucolyticsMucolytics
Acetylcysteine(Acetylcysteine( 乙酰半胱氨酸乙酰半胱氨酸 ))
BromhexineBromhexine (溴己新)(溴己新) Ⅲ Ⅲ Hypertonic salineHypertonic saline
NaCl ( 1.8%NaCl ( 1.8% )) solution,solution,
NNaaHCOHCO33 (2%-7.5%) solution (2%-7.5%) solution