Drugs used in pulmonary diseases

Antiasthmatic drugs

Antitussives

Expectorants

Yang yun-xia ( 杨云霞）

Drugs used in pulmonary diseases

Coughing

Wheezing Sputum (phlegm)

Inflammation

Drugs used in pulmonary diseases

Coughing

Wheezing Sputum (phlegm)

Inflammation

Coughing

Wheezing Sputum (phlegm)

Inflammation

Pulmonary Pharmacology: Asthma

General disease characteristics:

increased tracheobronchial responsiveness to many stimuli

↓ physiological air passage narrowing ↓ paroxysmal dyspnea, coughing, wheezing,

chest tightness

Prevalence:

Very common disorder: 4-5% affected

Typically presents in early life:

50% of cases developed before age 10;

33% before age 40

Etiology-----two broad types

①Allergic asthma: (IgE)

• Ag-Ab → mast cell surface• → mediators release • → muscle contraction• vascular leakage• mucus hyper secretion•

Histamine

Trapase

Leukotrienes

Prostaglandins

PAF

Immunopathogenesis of asthma. Exposure to allergen cause synthesis of IgE, which binds to mast cell in airway mucosa. On reexposure to allergen, Ag-Ab interaction on mast cell surface triggers release of mediators of anaphylaxis: Histamine,trypase, Prostaglandin D2, leukotriene C4, and platelet-activating factor. These agent provoke contraction of airway smooth muscle, causing immediate fall in FEV1. Reexposure to allergen also causes synthesis and release of cytokines: interleukins 4 & 5, granulocyte-macrophage colony stimulatory factors, tumor necrosis factor and tissue growth factor from Tcells and mast cells. These cytokines attract and activate eosinophil and neutrophils, whose products include eosinophil cationic protein, major basic protein, proteases, and platelet activating factors. These mediators causes edema, mucus hypersecretion, smoothmuscle contraction, and increases in bronchial reactivity associated with late asthmatic response indicated by fall in FEV1 2-8 hrs after exposure.

Histamine Bronchoconstriction Vascular congestion  Edema Vascular leakage

Prostaglandin D2

Platelet activating factor PAF

trypase

Leukotrienes

②Idiosyncratic asthma: normal serum IgE Nonantigenic stimuli

Stimulation-induced exercises, inhaled irritants ect

Etiology

mast cells

Histamine SRS-A5-HT

Trachea Bronchi

muscle muscle

vascular vascular

mucusmucus

glandgland

muscle contractionmuscle contractionvascular leakagevascular leakageHyper-secretionHyper-secretionedemaedema

airway narrowinginflammation

exercisesexercisesirritantsirritants

AntigenenAntigenen

Ach

M-R antagonist

Sympathomimetic agents

Corticosteroids

theophylline

sablized membrane--cromolyn

Short-term pharmacological relief

bronchodilators (promote airway smooth muscle relaxation increased airway caliber )

ß—adrenoceptor agonistsTheophyllineAntimuscarinic drugs

Long-term(Antiinflammatory) pharmacological management:

Inhaled corticosteroids Leukotriene pathway inhibitors Inhibitors of mast cell degranulation (e.g.,

cromolyn 色甘酸 )

sympathomimetic drugs

β2-R→→smooth muscle→

→ cAMP↑ →→dilation β2-R →→ mast cells→

→mediators release ↓ α -R→ →microvascular constricting →→ edema↓

sympathomimetic drugsdrug Rece

p-toraction Admi-

nistra-tion

use Side action

Epineph-rine

αβ Rapidpotent

Sc, inhale

urgent Arrhyth-mias

nephrine αβ Long durationLess potent

Sc, IM

Pre treat-ment

CNS excitation

Isoprote-renol

β Rapidpotent

Inhale,oral

urgent Arrhyth-mias

Aibuterol, terbutaline

β2 potent Inhale, po, sc

regular Muscle tremorNervous

Muscarinic Antagonists

Mechanism of Action: o M- R:1.contraction of airway smooth

muscle o   2.increased mucous secretion

Clinical Use— Antimuscarinic Drugs

Effective bronchodilators Antimuscarinic drugs are only capable of prev

enting the cholinergic-mediated bronchospasm( 支气管痉挛 )

o Preferred route of administration (enhanced organ selectivity): inhalation

o Antimuscarinic with limited systemic adverse effects: ipratropium bromide

 Adverse Effects: o Local: dry mouth; pharyngeal irritation o Systemic: (dependent on extent of absorptio

n) o  Urinary retention o  Loss of ocular accommodation o  Tachycardia( 心动过速 )

o  May increase intraocular pressure in patients with glaucoma ( 青光眼 )

Theophylline( 茶碱 )

o Aminophyllineo Theophylline-ethylenediamine ( 乙二胺 ) complex Most commonly used is aminophylline( 氨茶碱 )

Theophyllineo It is slightly water-soluble; often administe

red as salts containing various amounts of theophylline base

o  aminophylline: 86% theophylline  oxtriphylline( 胆茶碱 ): 64% theophylline

mechanisms of theophylline

1.high concentrations : phosphodiesterase( 磷酸二酯酶 )inhibition

↓ intracellular cAMP↑

↓ cardiac stimulation smooth muscle relaxation

positive chronotropic

mechanisms of theophylline

• 2.inhibition of adenosine( 腺苷 )cell surface receptors modulators of adenylyl cyclase activity

Adenosine histamine release from lung cells

• airway smooth muscle contraction

Mechanisms of theophylline

3. Anti-inflammatory action: low-dose theophylline: inhibit late response to

antigenic challenge

Cardiovascular Effects: o Direct positive chronotropic o Direct enhanced myocardial contractility

 

low doses: increased catecholamine release

 

high doses: enhanced calcium influx

Renal Effects:

o weak diuretics-- not therapeutically important

increased glomerular filtration reduced tubular sodium reabsorption

Smooth Muscle Effects:

o Major Therapeutic Effect: Bronchodilation  Adverse Effects: dose limiting

Multiple Effects

CNS increased alertness;reduced fatigue

Kidney weak diuretics

cardiovascular positive chronotropic

smooth muscle

Dilation esp. bronchodilation

Gastrointestinal Tract

gastric acid & digestive enzymes↑

skeletal muscle

enhanced contraction

Theophylline Clinical Use

most effective bronchodilator o Relieves airway obstruction in acute

asthma o decreased frequency and severity of

symptoms in chronic asthma

Theophylline Therapeutic/toxic effects: related to plasma conce

ntration o 5-20 mg/L ---improvement pulmonary functiono > 20 mg/L—nausea, vomiting, headache, anxiety,

anorexiao > 40 mg/L—seizures, arrhythmias

Corticosteroids

Corticosteroid Effects: o Diminish bronchial reactivity o Increase airway diameter o Reduced frequency of asthma

attacks

corticosteroids

Mechanisms of Action:o primary: o anti-inflammatory action------o inhibition of cytokine productiono secondary: o enhancement of beta-receptor

agonist effects

Clinical Use: Corticosteroids

management of acutely ill patients • patients not adequately maintained with

bronchodilators • patients whose symptoms are worsening,

despite reasonable maintenance treatment

Cromolyn & Nedocromil ----action

o inhibit: antigen or exercise-induced asthma

o  reduce bronchial reactivity no direct effect on airway smooth muscle tone and will not reverse asthmatic bronchospasm( 支气

管痉挛 )

Cromolyn -------------Mechanism of Action:

alters function of delayed chloride channels→ inhibits cell activation

Airway nerves------cough Mast cells -------degranulation Eosinophils---------inflammatory

Cromolyn------------ Pharmacokinetics

o poorly absorbed o administered by microfine powder

inhalation or aerosol( 雾化 ) o -------- throat irritation

Cromolyn & nedocromil Clinical Use: o pre-treatment: o blocks bronchoconstriction o antigen inhalation aspirin-induced blocks environmental agents

Cromolyn

o Reduces o bronchodilators medication o requirements o symptomatic severityo reducing symptoms allergic o rhinitis

cromolyn

o ◆Adverse/Side effects: o --------minor and localizedo throat irritation cough mouth dryness wheezing chest tightness

Leukotriene Pathway Inhibitors arachidonic acid

5-lipoxygenase( 脂肪氧化酶 ) by eosinophils,

macrophages,basophils

o Leukotriene 　　　　　　　 LTB4--chemattractant LTD4--bronchoconstriction LTC4 mucosal edema mucus hyper-secretion bronchial reactivity↑

Zeleuton( 齐留通 )

Zafirlukast

Montelukast

Other drug groups

o calcium channel blockers o nitric oxide donors o potassium channel activators o Anti-IgE Monoclonal Antibodies

Antitussives

central antitussives peripheral antitussives

Codeine

Dextromethorphan

Benzonatate

Narcotine

Inhibit CNS local anesthetics

Clinical uses: Cough without sputum

Expectorants

Dilute sputum drugs Resolve sputum drugs

Drugs Amine chloride Bromhexine( 必消痰 )

Acety-cysteine （乙酰半胱氨酸）

Action Dilute ropy sputum Decompose glutinous protein in sputum

Uses Cough with ropy sputum