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