Drugs for Respiratory SystemDrugs for Respiratory System

GAO Fen-FeiGAO Fen-Fei

IntroductionIntroduction

Symptom of respiratory system:Symptom of respiratory system:

nono sputumsputum---antitussives---antitussives CoughCough sputumsputum --- expectorants --- expectorants

AsthmaAsthma ----- antiasthmatic drugs ----- antiasthmatic drugs

炎症初期浆液腺分泌增多

大量炎性渗 出 物 痰液变稀而多

炎症后期慢性炎症

浆液腺减少粘液腺增多 痰液变粘稠

纤毛因病变而运动减退，粘液不能及时排出,水分重吸收

进一步破坏呼吸道组织

细菌滋生继发感染

痰液为良好培养基

大量痰液阻塞呼吸道 气急. 窒息

加重咳嗽

咳、痰、喘症状进一步加重

咳.痰.喘相互关系图

支气管痉挛、粘膜水肿

管腔狭窄 排痰困难

喘 息 阻塞细支气管 呼吸道积痰

刺激气管粘膜继发感染、加重症状

咳 嗽 排 痰呼气阻力增加

祛痰药

平喘药

镇咳药

ANTITUSSIVESANTITUSSIVES

ClassificationClassification::一．一．Central antitussivesCentral antitussives

1.1. DependentDependent central antitussivescentral antitussives2.2. Independent central antitussivesIndependent central antitussives

二．二．Peripheral antitussivesPeripheral antitussives

DependentDependent Central AntitussivesCentral Antitussives

Opioid alkaloids. Morphine is the most effective drug for t

he suppression of cough, but have addiction.

Mechanism: suppressing of cough center

CodeineCodeine

Selectively suppress cough center in meSelectively suppress cough center in medulla oblongatadulla oblongata(( 延髓延髓 ))..

PotencyPotency: : • Suppression of cough: ≈1/10 of morphineSuppression of cough: ≈1/10 of morphine• Analgesia: ≈1/7 of morphineAnalgesia: ≈1/7 of morphine• Respiratory depression, constipation, toleraRespiratory depression, constipation, tolera

nce, dependence nce, dependence ＜ ＜ that of morphinethat of morphine

PharmacokineticsPharmacokinetics::• Well absorbed from oral and injection.Well absorbed from oral and injection.• 10% converted to morphine through demethyl. 10% converted to morphine through demethyl.

Clinical UsesClinical Uses::• Dry coughDry cough

Adverse ReactionsAdverse Reactions::• Respiratory suppression in high dose;Respiratory suppression in high dose;• Tolerance and physical dependence with frequentlTolerance and physical dependence with frequentl

y repeated administration;y repeated administration;• Suppress secretion of bronchial gland and movemeSuppress secretion of bronchial gland and moveme

nt of cilia.nt of cilia.

Independent Central AntitussivesIndependent Central Antitussives Stereoisomers of opioid molecules that are devStereoisomers of opioid molecules that are dev

oid of analgesic effects and addiction liability.oid of analgesic effects and addiction liability. ClassificationClassification::

1)1) -orphan-orphan(( 吗啡南类吗啡南类 ))-antitussives-antitussives : dextromethorphan : dextromethorphan(( 右美沙芬 ))

2)2) AmidoAmido(( 胺基胺基 ))-antitussives-antitussives: pentoxyverine: pentoxyverine(( 喷托维林 ; 咳必清 )), clofedanol, clofedanol(( 氯苯达诺 ; 敌退咳 ))

3)3) piperidinepiperidine(( 哌啶基哌啶基 ))-antitussives-antitussives: cloperastine: cloperastine(( 氯哌斯汀 ))

4)4) morpholinemorpholine(( 吗啉基吗啉基 ))-antitussives-antitussives: promolate: promolate(( 普罗吗酯 )), fominoben, fominoben(( 福米诺苯 ));;

5)5) OthersOthers: eprazinone: eprazinone(( 依普拉酮 )), zipeprol, zipeprol(( 齐培丙醇 ))..

DextromethorphanDextromethorphan

Dextrorotatory stereoisomers of a methDextrorotatory stereoisomers of a methylated derivative of levorphanolylated derivative of levorphanol(( 羟甲左吗南 ))..

Clinical UseClinical Use::• Dry cough. Often + Antihistamine drugDry cough. Often + Antihistamine drug

PentoxyverinePentoxyverine

Suppression of cough: ≈1/3 of Suppression of cough: ≈1/3 of codeine.codeine.

Direct suppression of cough center Direct suppression of cough center Atropine-like action and local Atropine-like action and local

anesthesia action.anesthesia action.

CloperastineCloperastine

Derivative of diphenhydramineDerivative of diphenhydramine(( 苯海拉苯海拉明明 ))..

Suppression of cough centerSuppression of cough center Blocking HBlocking H11-receptor-receptor

Peripheral AntitussivesPeripheral Antitussives

Inhibiting receptor, afferent nerve, effeInhibiting receptor, afferent nerve, efferent nerverent nerve of cough reflex arc → cough of cough reflex arc → cough suppression.suppression.

1.1. local anesthesia actionlocal anesthesia action: narcotine: narcotine(( 那可丁 )), , benzonatatebenzonatate(( 苯佐那酯 ));;

2.2. Alleviative actionAlleviative action: extractum glycyrrhizae l: extractum glycyrrhizae liquidumiquidum(( 甘草流浸膏甘草流浸膏 )), Syrup, Syrup(( 糖浆糖浆 ))

ExpectorantsExpectorants

Mucokinetic drugsMucokinetic drugs ClassificationClassification::I.I. By the mechanism of action:By the mechanism of action:

1.1. Mucus secretagogue drugsMucus secretagogue drugs: stimulating gastric m: stimulating gastric mucosa → reflex secretion of bronchial gland↑ → ucosa → reflex secretion of bronchial gland↑ → dilution of sputum. dilution of sputum. ammonium chlorideammonium chloride. .

2.2. Mucolytic drugsMucolytic drugs::1)1) break acid mucin: break acid mucin: bromhexinebromhexine(( 溴己新 ; 必嗽平 ))2)2) drug-SH S-S of mucin → Fragmentation: drug-SH S-S of mucin → Fragmentation: acetylcysteiacetylcystei

nene(( 乙酰半胱氨酸 ))3)3) Enzymolysis: Enzymolysis: α-chymotrypsinα-chymotrypsin(( 糜蛋白酶 ))4)4) Surfactant: Surfactant: tyloxapoltyloxapol(( 泰洛沙泊 ))--------Fog inhalationFog inhalation

II.II. By route of administrationBy route of administration ：：

1.1. Oral drugsOral drugs::

2.2. Fog inhalation drugsFog inhalation drugs: 1.8%NaCl, : 1.8%NaCl,

2%~7.5%NaHCO2%~7.5%NaHCO33..

AsthmaAsthma

Pathophysiology:Pathophysiology:• Asthma is a disease characterized by airwaAsthma is a disease characterized by airwa

y inflammation and episodicy inflammation and episodic(( 发作性的发作性的 )), rev, reversible bronchospasmersible bronchospasm(( 支气管痉挛支气管痉挛 ))..

• Two characteristic features:Two characteristic features:1)1) Inflammatory changes in the airway;Inflammatory changes in the airway;2)2) Bronchial hyperreactivity to stimuli.Bronchial hyperreactivity to stimuli.

• Important mediators: histamine, LTCImportant mediators: histamine, LTC44, LTD, LTD44, etc., etc.

Antiasthmatic DrugsAntiasthmatic Drugs

I.I. BronchodilatorsBronchodilators1.1. β receptor agonistsβ receptor agonists2.2. TheophyllineTheophylline3.3. Muscarinic antagonistsMuscarinic antagonists

II.II. Anti-inflammatory agentsAnti-inflammatory agents1.1. SteroidsSteroids2.2. Anti-leukotriene agentsAnti-leukotriene agents

III.III. Anti-allergic agentsAnti-allergic agents1.1. Stabilizer of inflammatory cell membraneStabilizer of inflammatory cell membrane2.2. HH11 receptor blocker receptor blocker

BronchodilatorsBronchodilators

Beta Adrenoceptor AgonistsBeta Adrenoceptor Agonists

Adrenaline: α,β agonistAdrenaline: α,β agonist Ephedrine: α,β agonistEphedrine: α,β agonist IsoprenalineIsoprenaline ：： ββ11 ,β ,β22 agonist agonist ββ22-selective agonists-selective agonists

• SalbutamolSalbutamol(( 沙丁胺醇，舒喘灵沙丁胺醇，舒喘灵 ))::• TerbutalineTerbutaline(( 特布他林，博利康尼特布他林，博利康尼 )) : : • ClenbuterolClenbuterol(( 克仑特罗克仑特罗 ))::• FormoterolFormoterol(( 福莫特罗福莫特罗 ))::• SalmeterolSalmeterol(( 沙美特罗沙美特罗 ))::• BambuterolBambuterol(( 班布特罗班布特罗 ))::

intermediate-acting

long-actinglong-acting

Adverse Reactions of βAdverse Reactions of β22 agonists: agonists:

1)1) Skeletal muscle tremorSkeletal muscle tremor

2)2) Cardiac effectCardiac effect: tachycardia: tachycardia(( 心悸亢进 )), arrhy, arrhy

miasmias

3)3) Metabolism disturbanceMetabolism disturbance: ketone bodies↑, a: ketone bodies↑, a

cidosis, [Kcidosis, [K++]]oo↓ ↓

TheophyllineTheophylline

Methylxanthine derivatives.Methylxanthine derivatives. Mechanism of ActionMechanism of Action::

1.1. Inhibit phosphdiesterase (PDE);Inhibit phosphdiesterase (PDE);2.2. Block adenosine receptors;Block adenosine receptors;3.3. Increase endogenous catecholamine (CA) rIncrease endogenous catecholamine (CA) r

eleasing;eleasing;4.4. Interfere with receptor-operated CaInterfere with receptor-operated Ca2+2+ chan chan

nels → [Canels → [Ca2+2+]]ii↓;↓;5.5. Anti-inflammatory actionAnti-inflammatory action

Clinical UseClinical Use::1.1. Asthma: Asthma: maintenance treatmentmaintenance treatment2.2. Chronic obstructive pulmonary disease (CChronic obstructive pulmonary disease (C

OPD)OPD)3.3. Central sleep apnea (CSA)Central sleep apnea (CSA)

Adverse ReactionsAdverse Reactions::• Narrow margin of safety. Toxic effects are relate

d to its plasma concentrations.• Gastrointestinal distress, tremor, and insomnia. • Cardiac arrhythmias, convulsions( 惊厥 ) → lethal.

Muscarinic AntagonistsMuscarinic Antagonists

There are MThere are M11, M, M22, M, M33 receptor subtype in receptor subtype in the airway. the airway.

Selectively blocking MSelectively blocking M11, M, M3 3 receptor is rereceptor is resulted in bronchodilating effect.sulted in bronchodilating effect.

Ipratropium bromideIpratropium bromide binds to all M-R su binds to all M-R subtypes (Mbtypes (M11, M, M22 and M and M33 ), and inhibits acet ), and inhibits acetylcholine-mediated bronchospasm. ylcholine-mediated bronchospasm.

Anti-inflammatoryAnti-inflammatory AgentsAgents

Glucocorticoids (GCs)Glucocorticoids (GCs)

Mechanism of ActionMechanism of Action::1.1. Broad anti-inflammatory efficacyBroad anti-inflammatory efficacy

①① Block the synthesis of arachidonic acidBlock the synthesis of arachidonic acid(( 花生四烯花生四烯酸酸 )) by phospholipase A by phospholipase A22..

②② Reduce bronchial reactivity.Reduce bronchial reactivity.2.2. Increase the responsiveness of β-adrenoceIncrease the responsiveness of β-adrenoce

ptors in the airway.ptors in the airway.

Routes of administrationRoutes of administration::• Systemic administrationSystemic administration: including oral : including oral

and injection. More severe toxicity.and injection. More severe toxicity.• InhalationInhalation: :

Common inhalant GCsCommon inhalant GCs::• FP, BDP, BUD, TAA, FNSFP, BDP, BUD, TAA, FNS

Anti-leukotriene agentsAnti-leukotriene agents

Cysteinyl leukotrienes is a important inflCysteinyl leukotrienes is a important inflammatory mediator:ammatory mediator:• BronchoconstrictionBronchoconstriction, , increased bronchial reincreased bronchial re

activityactivity, , mucosal edemamucosal edema, , mucus hypersecremucus hypersecretiontion, etc., etc.

Leukotrienes resulte from the action of Leukotrienes resulte from the action of 5-lipoxygenase on arachidonic acid. 5-lipoxygenase on arachidonic acid.

Common agents:Common agents:

I.I. zafirlukastzafirlukast and and montelukastmontelukast: LTD: LTD44-r-r

eceptor antagonistseceptor antagonists

II.II. zileutonzileuton: 5-lipoxygenase inhibitor: 5-lipoxygenase inhibitor

Anti-allergic AgentsAnti-allergic Agents

Madiators release inhibitors.Madiators release inhibitors.

No bronchodialator action but can prevNo bronchodialator action but can prevent bronchoconstriction caused by a chent bronchoconstriction caused by a challenge with antigen to which the patienallenge with antigen to which the patient is allergic.t is allergic.

Disodium Cromoglycate (SCG)Disodium Cromoglycate (SCG)

Mechanism of ActionMechanism of Action::1.1. Stabilizer of mass cell membrane: decreasStabilizer of mass cell membrane: decreas

e the release of mediators from mast cells.e the release of mediators from mast cells.2.2. Inhibit the function of sensory nerve endinInhibit the function of sensory nerve endin

g andg and neurogenic inflammation in airway.neurogenic inflammation in airway.3.3. Decrease bronchial hyperreactivity. Decrease bronchial hyperreactivity.

KetotifenKetotifen

H1 receptor blocker.H1 receptor blocker.

Prevent and inverse down-regulation Prevent and inverse down-regulation of βof β22-receptor.-receptor.