PULMONARY PHARMACOLOGY

ANTICOUGHING AGENTS

There are two types of cough: productive cough, which leads to removal of sputum from the
lungs and dry cough, with no removal of sputum. Mainly, the physician must treat the
underlying cause. A productive cough should not be suppressed until the cause has been
identified, because sputum needs to be cleared.
Classification
 antitussives;
 expectorants.

ANTITUSSIVES

They are symptomatic drugs which diminish or stop the dry coughing reflex by depressing the
coughing center or by depressing the function of sensitive receptors located in the respiratory
mucosa.

 OPIUM and MORPHINE

Mechanism of action
 they have an anticoughing action, by depressing the bulbar coughing center;
 they block moderate or intense pain;
 they reduce the psihoaffective implications of coughing.
Indications
 bronchopulmonary cancer (anticoughing effect and major analgesic effect);
 aortic aneurysm;
 pulmonary infarct;
 costal fractures;
 pneumothorax;
 hemoptysis.
Adverse effects
 high addictive risk;
 possible bronchial spasm;
 they thicken the bronchial secretions;
 depression of the respiratory center to respiratory arrest, at high doses.
Therapeutic notes
 less used because of the adverse effects.

 CODEINE (METHILMORPHINE)

Mechanism of action
 it has an anticoughing action, by depressing the bulbar coughing center;
 Codeine has a mild analgesic action, significantly weaker than Morphine;
 weak sedative action.
Pharmacokinetics
  Biotransformation: Codeine is considered a prodrug, since it is metabolised to the
primary active compounds morphine and codeine-6-glucuronide; the conversion
occurs in the liver and is catalysed by the CYP 450 enzyme.
Indications
 dry cough;
 diarrhea;
 irritable bowel syndrome;
 mild to severe pain, in association with analgesics.
Contraindications
 administration at children under 3 years, because of the risk of inducing convulsions;
 in patients with severe respiratory failure.
Adverse effects
 sleepiness;
 constipation;
 depression of the repiratory center.
Therapeutic notes
 the effect appears slowly, in aproximatively two hours and remains for six hours;
 it has no addictive risk (unlike Morphine).
Preparations
Codeine plus Phenobarbital – Codenal tab.
Codeine – Codeine phosphate tab.

 NOSCAPINE

Mechanism of action
 Noscapine has an anticoughing action similar to Codeine, but it does not depress the
respiratory center, has no analgesic effect and has no addictive risk.
Preparations
Noscapine – Noscapine syrup

 GLAUCINE

Pharmacodynamic effects
 compared to Codeine, Glaucine has a weak anticoughing effect, which lasts for a short
while; it needs frequent administration and has low therapeutically compliance.

 CLOFEDANOL

Pharmacodynamic effects
 compared to Codeine, Clofedanol has a weak anticoughing effect, which lasts for a
short while, leading to low compliance;
 it has also a local anestetic effect and a weak antihistaminic H1 action.
Presentations
Clofedanol - Calmotusin oral sol.

 DEXTROMETHORPHAN

Pharmacodynamic effects
 it is an antitussive that has no analgesic or sedative effects, does not depress
respiration in usual doses and is nonaddictive.
Preparations
Dextromethorphan – Humex, Tussin syrup, tab.

 OXELADINE

Pharmacodynamic effects
 Oxeladine acts like Codeine, by depressing the respiratory center and is preferred for
children.
Preparations
Oxeladine – Paxeladine caps., syrup

EXPECTORANTS

Expectorants are drugs which ease the elimination of bronchial secretions, by increasing their
quantity and/or fluidifying them.
Classification
 Secretolytic expectorants (mucolytics);
 Secretostimulant expectorants.

SECRETOLYTIC EXPECTORANTS (MUCOLYTICS)

 BROMHEXIN

Mechanism of action
 it is a mucolytic with mild action which lowers the viscosity of the sputum, by altering
the mucine structure.
Presentation
Bromhexin – Bromhexin tab., oral sol.

 AMBROXOL

Pharmacodynamic effects
 Ambroxol is a mucolytic with intense action and a longer half-life (t1/2) than Brofimen
(better therapeutic compliance).
Indications
 acute and chronic bronchitis;
 COPD.
Presentation
Ambroxol – Tussefar syrup
  ACETYLCYSTEINE

Mechanism of action
 mucolytic with intense action because of the group “thiol”, a reducing group with
action in destroying the disulphide bonds (S-S) of the mucus and forming of new
bonds between mucus and the fragments of the mucoproteine (from sputum).
Indications
 acute or chronic bronchitis;
 bronchiectasy;
 pneumonia;
 mucoviscidosis;
 lung tuberculosis;
 intoxication with Paracetamol, as the antidote (IV drip).
Contraindications
 bronchial asthma, because it can produce bronchospasm.
Preparations
Acetylcysteine - ACC, Brunac, Fluimucil, Siran syrup, caps., tab., vials

 CARBOCISTEINE

Mechanism of action
 mucolytic which helps the recover of the bronchial epithelium; improves the function
of bronchial cilia and antagonize the local kinins involved in bronchial inflammatory
processes.
Preparations
Carbocisteine – Humex syrup
SECRETOSTIMULANT EXPECTORANTS
Mechanism of action
 increase the secretory activity of the tracheobronchial glands by increasing the water
content in the mucus of the bronchial mucosa;
 amplify the movements of bronchial mucosa cilia;
 increase the peristaltic of bronchial mucosa and improve the elimination.
Their therapeutic action is definitely lower than of the mucolytics.

 GUAIAFENESIN

Indications
 acute or chronic bronchitis;
 gout, because of the uricosuric action.
Adverse effects
 nausea, vomiting;
 sedation, after high doses;
 kidney stones of uric acid (rarely).
Preparations
Guaiafenesin – Coldrex Broncho, Robitussin Expectorans syrup, oral sol.
 ANTIASTHMATICS

Classification
 Bronchodilators
 Anti-inflammators

BRONCHODILATORS

Classification
 Beta 2 adrenergic agonists;
 Cholinergic antagonists;
 Musculotropes.

BETA 2 ADRENERGIC AGONISTS (2 SYMPATHOMIMETICS)

Classification
 with short action
TERBUTALINE CLENBUTEROLE
SALBUTAMOLE REPROTEROL
FENOTEROLE METAPROTERENOL
 with long action
SALMETEROL
FORMOTEROL
Mechanism of action
 the stimulation of the 2-adrenergic receptors at bronchial level (smooth muscle)
causes the activation of adenilatcyclase, increasing the cAMP, activating proteinkinase
and inhibiting the myosin phosphorilation, lowering the intracellular calcium level,
with the final result the relaxation of bronchial muscles;
 may increase mucociliary transport;
 the mechanism for long duration of Salmeterol and Formoterol is the high
liposolubility, creating a depot effect.
Indications
 the first choice drugs for bronchial asthma patients in all stages.
Adverse effects
 tolerance after repetead administrations.

Therapeutic notes
 the bronchodilators with short action are considered symptomatic medication having
an intense bronchodilator action which appears in 15 minutes, reaches a peak in 60-90
minutes and declines in 3-4 hours; they have no anti-inflammatory action;
 the bronchodilators with short action are administered in the prophylaxis or treatment
of bronchial asthma chrises;
 the bronchodilators with long action have an intense bronchodilator action that lasts
for aproximatively 12 hours, plus an anti–inflammatory action;
 the bronchodilators with long action are administered in persistent bronchiolar asthma
(easy, moderate and severe stage);
 they can be administered orally, via inhalation or parenteral.
Preparations
Terbutaline – Aironyl syrup
Salbutamole – Ventolin aerosole
Fenoterole – Berotec aerosole
Salmeterol – Serevent aerosole
Formoterol – Oxis inhalatory powder

CHOLINERGIC ANTAGONISTS

Mechanism of action
 they block the bronchial muscarinic receptors, the vagal constriction of the smooth
muscles and the bronchiolar secretion.
Adverse effects
 dry mouth, pharyngeal irritation;
 tachycardia;
 urinary retention;
 agitation;
 loss of ocular accommodation;
 increase of intraocular pressure at glaucoma patients.
Therapeutic notes
 they are prescribed as an alternative to 2-adrenergic bronchodilators in patients with
coronary diseases;
 they are weaker bronchodilators compared to 2-adrenergic drugs and that’s why they
are considered as an alternative medication;
 the effect appears in 30 minutes and lasts for about 8 -12 hours;
 Ipratropium is especially effective in the management of asthma in the elderly and a
treatment of choice for -blocker-induced bronchospasm.
Preparations
Atropine – Atropine vials
Ipratropium bromide – Ipravent aerosole

MUSCULOTROPES

Chemistry
 Theophylline is a xantic base related with caffeine:
o Theophylline: 1,3-dimethylxanthine;
o Caffeine: 1,3,7-trimethylxanthine.
Mechanism of action and pharmacodynamic actions
 they inhibit the phosphodiesterase, increasing the intracellular cAMP with relaxation
of bronchial muscles and cardiac stimulation;
 are weaker bronchodilators than 2-adrenergics;
 weak anti-inflammatory action;
 CNS effects:
o increased alertness, insomnia;
o tremor;
o convulsions, after very high doses.
 cardiovascular effects:
o direct positive chronotropic;
o direct enhanced myocardial contractility;
o reduced blood viscosity (unknown mechanism).
 GI tract effects:
 o stimulates secretion.
 renal effects:
o weak diuretics, because of increased glomerular filtration and reduced
tubular sodium reabsorption.
Pharmacokinetics
 Biotransformation and elimination: metabolic products include demethylated
xanthines which are excreted in the urine.
Indications
 bronchial asthma crisis;
 spastic chronic bronchitis;
 interchrises treatment of bronchial asthma, not satisfactory controlled by inhalator
corticotherapy.
Adverse effects
 nausea, vomiting;
 irritability, insomnia;
 palpitations, precordial pain.
Therapeutic notes
 they are used as an alternative medication for bronchial asthma;
 pay attention to dose because overdosing is easy to obtain;
 after IV administration, the effect appears in 5 minutes.
Preparations
Theophylline – Teotard caps.
Aminophylline – Miofilin tab., caps., vials

ANTI-INFLAMMATORS

CORTICOTHERAPY
Inhalatory corticotherapy
Mechanism of action
 they have a strong anti-inflammatory action in all phases of inflammation,
evidentiated at:
o cellular level: binds on specific cytoplasmic receptors, creating a complex
which enters in the nucleus where it interacts with DNA causing activation of
Lipocortine which activates A2 phospholipase and lowers the leucotrienes and
prostaglandins;
o histological level: reduce/abolish the histological lesions on the bronchial
mucosa - diminish the swell of mucosa, mucus hypersecretion, subepithelial
fibrosis.
Indications
 persistent bronchial asthma, despite correct antiasthma treatment;
 COPD;
 mucoviscidosis.
Adverse effects
 oropharingian candidosis (prevented by using spacers, mouth washes with
bicarbonated water or spitting after each inhalation);
 irritative cough after inhalation, because of the solvent (oleic acid);
 dysphonia due to miopathy of vocal chords musculature;
 a lower resistance to infections;
 low bone density.
Therapeutic notes
  the most efficient anti-inflammatory medication;
 the first choice medication in persistent bronchial asthma light, moderate and severe
stage;
 makes possible in the case of severe bronchial asthma treated with systemic
corticotherapy (oral, IV) a significant decrease of doses, which means lowering the
side effects;
 the clinical effect appears in a few weeks of treatment: reduced number of asthma
attacks during the day and the night and significantly improves the performance at
effort.
Preparations
Beclometasone – Becotide aerosole
Fluticasone - Flixotide aerosole
Flunisolide – Aerobid aerosole
Budesonide – Pulmicort inhalatory powder

Systemic corticotherapy
 it is administrated only in severe cases of bronchial asthma, as short as possible:
o oral administration - Prednisone tab. 5 mg; after improvement oral doses are
gradually reduced in a few days to total suppressing of the therapeutic scheme,
being replaced by inhalatory corticotherapy;
o IV administration - Hemisuccinate hydrocortisone vials (1-4 vials once) or
Metilprednisolone 1 mg/kg every 6 hours.

INHIBITORS OF MASTOCITAR DEGRANULATION

 DISODIC CROMOGLICATE

Mechanism of action
 inhibits the release of histamine from mastocites and the release of excessive amounts
of leukotrienes from leucocytes and mastocites, preventing the onset of bronchial
asthma chrises;
 inhibits the actions of platelet aggregation factor;
 it has no bronchodilating activity.
Pharmacokinetics
 Absorption: poorly absorbed (approximatively 10%).
Indications
 prophylaxis of allergic bronchial asthma;
 prophylaxis of aspirin-induced bronchoconstriction;
 prophylaxis of allergic rhinitis and conjunctivitis;
 prophylaxis of bronchial asthma to cold and irritative substances (e.g. toluene
diisocyanate, wood dusts).
Adverse effects
 sometimes throat irritation, cough, dry mouth, wheezing;
 occasionally local nasal irritation at the beginning of the treatment.
Preparations
Disodic cromoglicate – Intal aerosole, nasal sol.

 NEDOCROMILE

Chemistry
  it is a high potent derivative of disodic cromoglicate.
Preparations
Nedocromile – Tilade aerosole

 KETOTIFENE

Mechanism of action
 inhibits the release of histamine from mastocites and excessive production of
leukotrienes;
 inhibits bronchoconstriction, eosinophiles accumulation, and aerial ways
hiperreactivity induced by PAF;
 determines prolonged blocking of the H1-histaminergic receptors from bronchia and
vessels.
Indications
 prophylaxis of bronchial asthma, rhinitis, keratoconjunctivitis (allergic).
Therapeutic notes
 it has no effect on the installed crises!
Preparations
Ketotifene – Zaditen tab., caps., oral sol.

ANTILEUKOTRIENES - a new class of drugs, since 1998.

 MONTELUKAST SODICUM

Mechanism of action
 acts as selective antagonist of leukotrienic receptor.
Indications
 bronchial asthma in adults and children older than 2 years;
 bronchial asthma induced by Aspirin;
 prophylaxis of effort induced bronchoconstriction.
Contraindications
 hypersensitivity to any of the components.
Adverse effects
 abdominal pain;
 headaches;
 allergic reactions.
Therapeutic notes
 the treatment with Montelukast sodicum brings an extra clinical advantage in patients
with inhalatory corticotherapy;
 the dose of corticosteroids may be reduced progressively, under medical observation;
 at some patients inhalator corticotherapy may be discontinued;
 do not use in bronchial asthma crisis!
Preparations
Montelukast sodicum – Singulair tab.

LIPOOXYGENASE INHIBITORS

Mechanism of action
 they inhibit the lipooxygenase, an important enzyme involved in the leucotrienes
synthesis.
Interactions
 it is metabolized by CYP 450 and can decrease the Cl (increase the concentration) of
Theophylline, Warfarin, Propranolol.
Indications
 long term prophylaxis of bronchial asthma crysis.
Preparations
Zileuton – Zyflo tab.