Antitussives, expectorants,
and
antiasmatic drugs
Ximei Wu
Dept. of pharmacology,
ZJUMS
Drugs acting on respiratory system
• Cough
•
•
antitussive drugs
centrally acting
peripherally acting
• Sputum expectorant drugs
•
•
sputum-diluting drugs
mucolytic drugs
• Asthma antiasthmatic drugs
•
•
•
•
•
•
•
bronchial dilators
 receptor agonists
theophyllines
muscarinic antagonists
anti-inflammatory drugs
glucocorticosteroids
mediator release inhibitors
1.
Antitussives
• Centrally acting
•
•
•
•
•
Addictive drugs:
codeine 可待因
Non-addictive drugs:
dextromethorphan 右美沙芬
pentoxyverine 喷托维林(咳必清)
• Peripherally acting
•
benzonatate 苯佐那酯
Codeine
可待因
H3CO
O
N
HO
CH 3
• 1. Pharmacological effects
•
suppression of cough
•
analgesia
• 2. Clinical uses
•
Cough without sputum
• 3. Adverse effects
•
Respiratory depression (at larger doses)
•
•
Addiction
Contraindicated in patients with thick sputum
Dextromethorphan
右美沙芬
• 1. Pharmacological effects
•
•
suppression of cough
muscarinic and NMDA receptor antagonism
• 2. Clinical uses
•
Upper respiratory infection, cough without sputum
• 3. Adverse effects
•
•
Atropine-like side effects
Contraindicated in patients with glaucoma,
pregnancy (< 3 m), psychotic disorders, etc.
Pentoxyverine
喷托维林(咳必清)
Pharmacological effects
• Suppression of cough
• Muscarinic antagonism and local
anesthetic effects
• Uses and adverse effects are similar to
dextromethorphan
Benzonatate
苯佐那酯
Pharmacological effects
•
•
•
•
Peripherally acting
Blocking cough reflex
Local anesthetic effects
CNS depression
2.
Expectorants
 Sputum-diluting drugs
 Stimulating bronchial secretion


Amonium chloride 氯化铵
Potassium iodide 碘化钾
 Mucolytic drugs






Bromhexine 溴己新
Ambroxol 氨溴索
Acetylcysteine 乙酰半胱氨酸
Methylcysteine 美司坦
Carbocisteine 羧甲司坦
Mesna 美司钠
3.
Antiasthmatic
drugs
Asthma
• Asthma is physiologically characterized by
increased responsiveness of the trachea and
bronchi to various stimuli and by widespread
narrowing of the airways that changes in severity
either spontaneously or as a result of therapy.
• Its pathologic features are contraction of airway
smooth muscle, mucosal thickening from edema
and cellular infiltration, and inspiration in the
airway lumen of abnormally thick, viscid plugs of
mucus.
Asthma
• Symptom: dyspnea, wheezing, stridor,
coughing, an inability for physical exertion.
The cough may sometimes produce clear
sputum.
• Between episodes, most patients feel well but
can have mild symptoms and they may remain
short of breath after exercise for longer periods
of time than the unaffected individual.
Immunological and
non-immunological stimuli
inflammation
bronchoconstriction
2 receptor agonists
glucocorticosteroids
disodium cromoglycate
Theophylline
muscerinic antagonists
Airway hyperresponsiveness
Wheezing (asthmatic symptoms)
1. Bronchial dilators
  Receptor agonists



Non-selective：adrenaline, isoprotererol
2-selective: moderate-acting: salbutamol, terbutaline
long-acting: salmeterol, formoterol
 Theophyllines: aminophylline
 Muscarinic antagonists: ipratropine
2. Anti-inflammatory drugs
 Glucocorticosteroids:


Systemic: hydrocortisone, dexamethasone
Inhalation: beclomethasone, budesonide
 Inhibitors of mediator release:
cromolyn sodium, nedocromil
 Bronchial dilators

2 receptor selective agonists
Salbuterol
沙丁胺醇
Terbutaline
特布他林
Salbuterol 沙丁胺醇
 1. Pharmacological effects

Relaxing bronchial smooth muscles
 2. Clinical uses

Controlling asthmatic symptoms

Given by inhalation, oral or injection
 3. Adverse effects

Skeletal muscle tremor


Cardiac stimulation (larger doses)
Dysfunction of metabolism (hypokalemia, etc.)
Selectivity of 2 agonists
Aerosol
inhalation
less systemic toxicity
定量手控
气雾器
Spacer used for aerosol inhalation
Spacer will aid patients
inhale the aerosolized
drugs easier
2 receptor selective agonists
long-acting
Formoterol
Salmeterol
Bronchial dilators
Theophyllines
Aminophylline
--
--
O
H3C
N
O
--
.
NH
N
CH3
CH2NH2
CH2NH2
N
-- 2
. 2H2O
Theophyllines
1. Pharmacological effects
Bronchus dilation
Inhibiting phosphodiesterase;
Blocking adenosine receptors;
Increasing catecholamine release;
Immunomodulation;
Increasing respiratory muscle contractility;
CNS stimulation, diuretic, gastric acid secretion,
etc.
Theophyllines
 2. Clinical uses


Bronchial asthma (p.o., i.v.)
Others: acute pulmonary edema, etc.
 3. Adverse effects



GI reactions
CNS stimulation
Acute toxication ( i.v. injection too rapidly )
tachycarida, arrhythmia, seizure, coma, death
Bronchial dilators
Muscarinic antagonists
Ipratropine
CH2
CH
CH3
(CH3)2CHNCH3 CH
CH2
CH
CH3
O
O
C
CH
C6H5
CH2 OH
• Relaxing bronchial smooth muscles
• No effect on sputum secretion
• Replaced with or combined with 2
receptor selective agonists
Glucocorticosteroids










Systemic (adverse effect):
hydrocortisone
prednisone
dexamethasone
Inhalation:
beclomethasone dipropionate
budesonide
triamcinolone acetonide
fluticasone propionate
flunisolide
Beclomethasone dipropionate
CH2OCOC2H5
C
HO
OCOC2H5
CH3
Cl
O
O
Beclomethasone dipropionate
 1. Pharmacological effects (Antiinflammation)
 Inhibiting inflammatory cell activities,
 Antibody production, mediator release,
 Inhibit increased responsiveness of the trachea and
bronchi
 2. Clinical uses



As first-line drugs, currently
Controlling chronic symptoms
Ineffective for acute symptoms
Adverse effects
•
Local: oropharyngeal candidiasis－using spacer
• Systemic effects
• a) Hypercorticism-like syndrome: central obesity
(moon face, buffalo hump, etc.); hypertension;
glycosuria, hypokalemia; etc.
• b) Increasing susceptibility to infections
• c) Ingestive system: peptic ulcers, etc.
• d) Cardiovascular system: hypertension,
arteriosclerosis
• e) Myopathy and osteoporosis: vertebral
compression fractures, spontaneous fractures,
especially in postmenopausal women
• f) Adrenal suppression
Inhibitors of mediator release
Disodium cromoglycate ( cromolyn )
NaOOC
O
O
O
OCH2CHCH2O
OH
O
COONa
Disodium cromoglycate
 1. Pharmacological effects
 Inhibiting mediator release from mast or other cells
 Inhibiting sensory neuropeptide release and nonspecific stimulus induced bronchus contraction
 2. Clinical uses (only inhalation)


Prevention of allergic asthma
Acting slowly (2-4 weeks)
 3. Adverse effects

Oropharyngeal irritation
Other inhibitors of mediator release
• Nedocromil sodium: GI effect
• Tranilast
• Ketotifen (H1 receptor antagonist)
Leukotriene pathway inhibitors
• Airways
LTC4, LTD4, LTE4----bronchoconstrictors,
increase microvascular permeability, mucus
secretion
LTB4----chemoattractant for neutrophils
• Leukotriene pathway inhibitors
CysLT1 receptor antagonist (zafirlukast):
for mild or moderate asthma, but not use alone
for acute asthma
5-LOX inhibitor (zileuton)