Respiratory system

drug
Cough
• Cough is a protective reflex, its purpose being expulsion of respiratory
secretions or foreign particles from air passages.
• It occurs due to stimulation of mechano- or chemoreceptors in throat,
respiratory passages or stretch receptors in the lungs.
• Cough may be useful or useless.
• Useless (nonproductive) cough should be suppressed.
• Useful (productive) cough serves to drain the airway, its suppression is not
desirable, may even be harmful, except if the amount of expectoration
achieved is small compared to the effort of continuous coughing.
• Apart from specific remedies (antibiotics, etc. see box), cough may be treated
as a symptom (nonspecific therapy) with:
• 1. Pharyngeal demulcents
• Lozenges, cough drops, linctuses containing syrup, glycerine, liquorice.
• 2. Expectorants (Mucokinetics)
• (a) Bronchial secretion enhancers:
• Sodium or Potassium citrate, Potassium iodide, Guai phenesin (Glyceryl guaiacolate), balsum of Tolu, Vasaka, Ammonium chloride.
• (b) Mucolytics:
• Bromhexine, Ambroxol, Acetyl cysteine, Carbocisteine
• 3. Antitussives (Cough centre suppressants)
• (a) Opioids:
• Pholcodeine. Codeine, Ethylmorphine,
• (b) Nonopioids:
• Noscapine, Dextromethorphan, Chlophedianol.
• (c) Antihistamines:
• Chlorpheniramine, Diphen hydramine, Promethazine.
• (d) Peripherally acting:
• Prenoxdiazine.
• 4. Adjuvant antitussives
• Bronchodilators: Salbutamol, Terbutalin.
ANTITUSSIVES

• These are drugs that act in the CNS to raise the threshold of cough
centre or act peripherally in the respiratory tract to reduce tussal
impulses, or both these actions.
• Because they aim to control rather than eliminate cough, antitussives
should be used only for dry nonproductive cough or if cough is unduly
tiring, disturbs sleep or is hazardous (hernia, piles, cardiac disease,
ocular surgery).
Codeine
• An opium alkaloid, quali tatively similar to and less potent than
morphine, but is more selective for cough centre.
• Codeine is regarded as the standard antitussive; suppresses cough for
about 6 hours.
• The antitussive action is blocked by naloxone indicating that it is
exerted through opioid receptors in the brain.
• Indication
• Cough
• Pain (mild-moderate)
• Restless leg syndrome
• Persistent diarrhea
• Dose
• 10–30 mg; children 2–6 years 2.5–5 mg, 6–12 years 5–10 mg.
• Adverse Effects
• Abuse liability is low, but present;
• constipation is the chief drawback.
• At higher doses respiratory depression and drowsiness can occur, especially in children.
• Driving may be impaired.
• Contraindication
• contraindicated in asthmatics and in patients with diminished respiratory reserve;
should be avoided in children.
• Precaution
• Abuse, misuse, and addiction can occur, and patients should be appropriately counseled.
Abrupt discontinuation in those who are physically dependent can lead to withdrawal
reactions. Slow tapering (about 15% per week) is recommended for long-term users
Dextromethorphan
• A synthetic central NMDA (N-methyl D-aspartate) receptor antagonist; the d-
isomer has antitussive action while l-isomer is analgesic.
• Dextromethorphan does not depress mucociliary function of the airway mucosa
and is practically devoid of constipating action.
• Though considered nonaddicting, some drug abusers indulge in it.
• The antitussive action of dextromethorphan has been rated equivalent to
codeine, but some clinical studies have found it to be no better than placebo.
• Dextromethorphan received FDA approval in 1958 for its use as a cough
suppressant.
• It is one of the most common compounds found in most over-the-counter
antitussives for the past 50 years.
MOA
• Mechanism of Action
• Dextromethorphan has multi-faceted pharmacodynamic and pharmacokinetic
properties. The drug is a lipophilic molecule with an ionizable amine at one
end. It is structurally related to alkaloid opioids such as morphine but does not
interact with the mu receptor. It derives from levorphanol, first designed as a
morphine alternative. The main mechanism of action for its use in the cough
suppressant is not completely understood. One proposed mechanism is that
DM works on the nucleus tractus solitarius, the estimated site where the
pulmonary vagal afferent fibers synapse in the central nervous system.
Indication
• In 2010, the FDA approved the use of DM for pseudobulbar affect (PBA) combined with quinidine
• Depression: DM has a fast-acting antidepressant activity for its similarity to ketamine.
• Stroke: Studies have shown that DM has a role in the improvement of some neurological and
psychiatric complications, however, not the overall functional outcomes.
• Traumatic Brain Injury: Although the studies have shown limited effects, there are proposed
mechanisms that confer the benefits of DM in TBI, including its activity at NMDA and sigma-1
receptors.
• Seizure: Some clinical studies have shown that DM has efficacy in refractory seizures.
• Pain: There are studies on the analgesic effects of DM for pain conditions such as cancer-related, post-
operative, neuropathic, and gastrointestinal pain.
• Methotrexate Neurotoxicity: DM showed a complete resolution in neurologic deficits associated with
MTX toxicity in 5 cases.
• Parkinson disease: DM meliorated primary Parkinson disease in 2 studies.
• Autism: Contradicting data regarding DM's role in behavioral improvement.
• Side effect:
• Dizziness, nausea, drowsiness; at high doses hallucinations and ataxia may occur.
• Dose:
• 10–20 mg, children 2–6 years 2.5–5 mg, 6–12 years 5–10 mg. It is a common ingredient of many
proprietary cough formulations (see antitussive combinations below).
• Contraindications
• Dextromethorphan is contraindicated for patients with known or established hypersensitivity and
those with an idiosyncratic reaction upon administration of the drug.
• It should not be given to patients on selective serotonin reuptake inhibitors because of the risk of
serotonin syndrome.
• It is not recommended to coadminister dextromethorphan with monoamine oxidase inhibitor
(MAOI) or for two weeks after stopping the MAOI drugs.[11]
• Since DM comes in combination with different medicines, consider contraindications of each
ingredient for safe prescribing of combination products.
EXPECTORANTS
• Expectorants (Mucokinetics) are drugs believed to increase bronchial
secretion or reduce its viscosity, facilitating its removal by coughing.
• A variety of expec torant formulations containing an assortment of
the above ingredients, often in combination with
antitussives/antihistaminics are marketed and briskly promoted, but
objective evidence of efficacy of these is non-conclusive. The US-FDA
has stopped marketing of all expectorants, except guaiphenesin.
Steam inhalation and proper hydra tion may be more helpful in
clearing airway mucus.
Ammonium chloride
• Ammonium chloride is an inorganic compound with the
formula NH4Cl. It is highly soluble in water producing
mildly acidic solutions.
MOA
• Ammonium chloride can be used as an expectorant due
to its irritative action on the bronchial mucosa. This
effect causes the production of respiratory tract fluid
which in order facilitates the effective cough
Indication
• Ammonium Chloride Injection, USP, after dilution in
isotonic sodium chloride injection, may be indicated in
the treatment of patients with: (1) hypochloremic states
and (2) metabolic alkalosis.
• Expectorant in cough syrups
Mucolytics: Bromhexine
• Bromhexine is a derivative of the alkaloid vasicine obtained from Adhatoda
vasica (Vasaka), is a potent mucolytic and mucokinetic, capable of inducing
thin copious bronchial secretion.
• Bromhexine is a medicine used to thin out and break down
excessive or thick mucus that gets clogged in the respiratory
system. This process makes breathing easier for the patient.
Mucus is a thin, clear liquid containing water, salts, and
protective immune cells. When it becomes thick or excessive,
it causes breathing difficulties, coughing, and congestion.
• This medicine is usually available in dosage forms, tablet and
oral suspension (syrup).
MOA
• Bromhexine stimulates increased production of water secretions within our
respiratory passages. This helps to break up and thin out stubborn, sticky
mucus, making it easier to expel. Additionally, Bromhexine enhances the
movement of tiny hair-like structures called cilia that line our airways. These
actively whip and propel the thinned mucus outwards, promoting clear
breathing.
• Firstly, Bromhexine directly triggers the increased release of serous (watery)
secretions. These aqueous fluids dilute the thick, viscous mucus, changing its
consistency.
• Simultaneously, it boosts ciliary activity - the rhythmic beating of thousands of
microscopic cilia that coat the respiratory tract. This accelerated movement
pushes the now-thinned mucus upwards, ready for effective coughing and
clearance.
• It depolymerises mucopolysaccharides directly as well as by liberating lysosomal enzymes—
network of fibres in tenacious sputum is broken.It is particularly useful if mucus plugs are present.
• Bromhexine Uses
• Assisting the removal of excess mucus from airways. Doctors
prescribe it for the following conditions:
• Common cold - Bromhexine thins mucus, easing chest congestion,
so coughing clears airways.
• Respiratory infections like bronchitis and pneumonia - Bromhexine
aids mucus expulsion, improving breathing and recovery.
• Flu - Bromhexine is often combined with other medicines to
manage chest congestion and cough.
• Bromhexine also benefits chronic respiratory conditions, including
COPD, emphysema, and asthma. It helps manage excessive mucus
buildup
• Side effects
• rhinorrhoea and lacrimation, nausea, gastric irritation, hypersensitivity.
• Dose:
• adults 8 mg TDS, children 1–5 years 4 mg BD, 5–10 years 4 mg TDS.
• Precautions
• Although bromhexine is typically safe, there are certain scenarios where caution
must be taken:
• If you're expecting or nursing, consult a doctor before using this medication. The
benefits should outweigh the potential risks.
• For those with liver or kidney issues, dosage adjustments may be required. Close
monitoring is recommended, as bromhexine could worsen these conditions.
• Dizziness is a possible side effect, so avoid operating vehicles or machinery while
taking bromhexine.
• This medicine isn't meant for long-term use beyond two weeks without medical
supervision
• Bronchial asthma is characterised by hyperres ponsiveness of
tracheobronchial smooth muscle to a variety of stimuli, resulting in
narrowing of air tubes, often accompanied by increased secre tion,
mucosal edema and mucus plugging. Symptoms include dyspnoea,
wheezing, cough and may be limitation of activity.
• Chronic obstructive pulmonary disease (COPD) is also an
inflammatory disease of the lungs characterized by progressive
emphysema (alveolar destruction) and bronchiolar fibrosis in variable
proportions.
• CLASSIFICATION
• I. Bronchodilators
• A. β2 Sympathomimetics:
• Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formoterol, Ephedrine.
• B. Methylxanthines:
• Theophylline (anhydrous), Aminophylline, Choline theophyllinate, Hydroxyethyl theophylline, Theophylline ethanolate of piperazine, Doxophylline.
• C. Anticholinergics:
• Ipratropium bromide, Tiotropium bromide.
• II. Leukotriene antagonists
• Montelukast, Zafirlukast.
• III. Mast cell stabilizers
• Sodium cromoglycate, Ketotifen.
• IV. Corticosteroids
• A. Systemic:
• Hydrocortisone, Prednisolone and others.
• B. Inhalational:
• Beclomethasone dipropionate, Budesonide, Fluticasone propionate, Fluniso lide, Ciclesonide.
• V. Anti-IgE antibody
• Omalizumab
Salbutamol (Albuterol)
• It is highly selective β2 agonist; cardiac side effects are less prominent.
• Selectivity is further increased by inhaling the drug.
• Inhaled salbutamol delivered mostly from pressurized metered dose inhaler (pMDI)
produces bronchodilatation within 5 min and the action lasts for 2–4 hours.
• It is, therefore, used to abort and terminate attacks of asthma, but is not suitable for
round-the-clock prophylaxis.
• Salbutamol undergoes presystemic metabolism in the gut wall, oral bioavailability is
50%.
• Oral salbutamol acts for 4–6 hours, is longer acting and safer than isoprenaline, but
not superior in bronchodilator efficacy.
• Because of more frequent side effects, oral β2 agonist therapy is reserved for patients
who cannot correctly use inhalers or as alternative/ adjuvant drugs in severe asthma..
• Dose:
• 2–4 mg oral, 0.25–0.5 mg i.m./s.c., 100–200 µg by inhalation Sideeffect
• Sideeffect
• Muscle tremors are the dose related side effect.
• Palpitation, restlessness, nervousness, throat irritation and ankle edema can
also occur.
• Hypokalaemia is a possible complication.
• Mechanism of Action
• Albuterol acts on β2-adrenergic receptors, inducing bronchial smooth
muscle relaxation and inhibiting immediate hypersensitivity mediator
release, particularly from mast cells. Although albuterol also affects
β1-adrenergic receptors, the impact is minimal, exerting little effect on
the heart rate
• Indication
• for treating and preventing acute or severe bronchospasm in patients with
reversible obstructive airway disease like asthma, exercise-induced
bronchospasm
• as an adjuvant treatment for hyperkalemia.
• Contraindications
• Hypersensitivity is a contraindication for albuterol. In cases of
hypersensitivity to milk protein, it is advisable to avoid albuterol formulations
that contain lactose as an excipient
• Warnings and Precautions
• Cardiovascular effects: Albuterol sulfate inhalation aerosol, such as other β-adrenergic agonists, may induce clinically
relevant cardiovascular responses, including changes in pulse rate, blood pressure levels, and symptomatic presentations.
Although infrequent at recommended dosages, if encountered, discontinuation of the drug may be warranted.
Furthermore, beta-agonists have been associated with ECG changes, including T wave flattening, QTc interval
prolongation, and ST segment depression. The clinical implications of these ECG findings remain uncertain. Hence,
prudence is advised, particularly in patients with underlying cardiovascular disorders.
• Asthma deterioration: Asthma may deteriorate acutely over hours or chronically over days. An increased requirement
for albuterol may signify a destabilization of asthma, necessitating a re-evaluation of the patient and treatment regimen.
Special consideration should be given to potentially incorporating anti-inflammatory agents, such as corticosteroids.
• Use of anti-inflammatory agents: Relying solely on β-adrenergic agonist bronchodilators may be insufficient and
detrimental to patient outcomes. Therefore, early consideration of ICS is essential.
• Paradoxical bronchospasm: Inhaling albuterol sulfate may lead to paradoxical bronchospasm, occasionally of severe
consequence. If this occurs, it is crucial to immediately discontinue albuterol sulfate inhalation aerosol and initiate
alternative therapeutic modalities. This phenomenon is notably linked to the benzalkonium chloride preservative in
albuterol nebulizers.[26]
• Hypersensitivity reactions: Although infrequent, immediate hypersensitivity reactions may occur following the
administration of albuterol and can present with urticaria, angioedema, bronchospasm, or anaphylaxis
Salmeterol
• It is the first long acting selective β2 agonist with a slow onset of
action
• It is more β2 selective than salbutamol, as well as more lipophilic
which probably accounts for its longer duration of action.
• a single inhaled dose of salmeterol lasts approximately 12 hours
compared to salbutamol, which lasts 4 to 6 hours.
Salmeterol
• Mechanism of Action
• Salmeterol acts on β2-adrenergic receptors, inducing bronchial smooth
muscle relaxation and inhibiting immediate hypersensitivity mediator
release, particularly from mast cells.
• Bronchodilation remains the primary function of salmeterol; its anti-
inflammatory properties are present to a much lesser degree.
• Indications
• Salmeterol is a highly selective, long-acting beta-2 adrenergic agonist indicated in the treatment of asthma,
maintenance of airflow obstruction in chronic obstructive pulmonary disease (COPD), and prevention of exercise-
induced bronchospasm (EIB).
• Salmeterol is used in combination with inhaled corticosteroids in the treatment of asthma.
• It can be useful in both the maintenance of asthma and the prevention of asthma attacks.
• It is usually prescribed for severe persistent asthma not properly controlled using a short-acting beta-adrenergic
agonist and a corticosteroid.
• Salmeterol is not indicated in patients with mild asthma who are well-maintained on short-acting beta-agonists.
• Salmeterol monotherapy is a contraindication for treating asthma patients due to the increased risk of mortality.
• Salmeterol administration with concomitant inhaled corticosteroid (ICS) has significantly reduced asthma mortality.
• Salmeterol can, however, be used as a monotherapy in the treatment of COPD, particularly as a maintenance
treatment.
• Following the approval in 1994 of salmeterol xinafoate, the FDA approved fluticasone propionate/salmeterol
(FP/SAL) as a fixed-dose combination therapy for the treatment of asthma and COPD. The fluticasone/salmeterol
combination provides sustained bronchodilation, prevention of exacerbation, improved lung function, and reduced
rescue medicine use
Dose
• For the treatment of asthma in patients aged 12 years and older, one inhalation of
fluticasone/salmeterol 100/50, 250/50, 500/50 mcg inhalation powder is taken twice
daily.[1] The starting dosage is determined based on asthma severity. Conversely,
two inhalations of fluticasone/salmeterol 45/21, 115/21, 230/21 mcg inhalation
aerosol are dosed twice daily. After inhalation, patients should understand the need
to rinse their mouths with water and, without swallowing, spit out the contents to
avoid oral candidiasis.[20]
• For the treatment of asthma in children between the ages of 4 and 11, the standard
recommendation is one inhalation of fluticasone/ salmeterol 100/50 mcg twice daily.
[1] Safety and efficacy have not been established in children less than four years old
• For maintenance treatment of bronchospasm associated with chronic obstructive
pulmonary disease, the recommendation is one inhalation of 250/50 mcg twice
daily, approximately 12 hours apart
• Adverse Effects
• The most common adverse reactions of salmeterol (incidence ≥3%) in asthmatics include upper respiratory
infection or inflammation, oral candidiasis, pharyngitis, bronchitis, dysphonia, headaches, cough, nausea, and
vomiting. In patients with chronic obstructive pulmonary disease, the most common adverse effects include
pneumonia, throat irritation, viral respiratory infections, oral candidiasis, dysphonia, headaches, and
musculoskeletal pains.[21]
• Immediate hypersensitivity reactions may occur. Patients may present with urticaria, rash, angioedema,
bronchospasm, headache, tremor, or anaphylaxis.
• More severe adverse effects associated with salmeterol overdose are characterized by excessive beta-adrenergic
stimulation to the heart. Although salmeterol is a highly selective beta-2 agonist, it still exhibits some beta-1
effects and can cause cardiac effects.
• These symptoms include angina, tachycardia, hypertension, hypotension, arrhythmia, palpitation, and fatigue.
These undesirable pharmacologic effects are predominantly a result of reflex activation in response to
peripheral vasodilation, hypoxemia, hypokalemia, and direct stimulation of cardiac beta-adrenoceptors.[22]
• Paradoxical bronchospasm, laryngeal spasm, and throat swelling can occur. In COPD patients, long-acting beta-
agonists (LABA) have been shown to increase the risk of cardiac failure.
• Contraindications/Precaution
• Hypersensitivity is a contraindication for salmeterol. It is contraindicated in patients with a known
hypersensitivity to any ingredient in the preparation, including lactose and milk protein.[24]
• Salmeterol is contraindicated in patients who have had adverse reactions to salmeterol in the past. It should
not be used for status asthmaticus or other acute asthma episodes. Salmeterol should not be used in
combination with other long-acting beta-agonists. Studies have shown an increased risk for death in asthma
patients taking salmeterol vs. placebo; this risk was highest for African-American patients.[25]
• There is an FDA black box warning for asthma patients due to the increased incidence of asthma-related
deaths with this medication. Salmeterol should not be used as a monotherapy in asthma patients. Clinicians
should only use it as an adjunct medication in patients who have failed other asthma therapies, such as low to
medium-dose inhaled steroids or those with severe asthma necessitating two maintenance therapies.
• While not strictly contraindications, salmeterol use requires caution in patients with an existing
cardiovascular disorder, convulsive disorder, hepatic impairment, diabetes mellitus,
hyperthyroidism/thyrotoxicosis, or who use CYP3A inhibitors, as this may increase toxicity and prolong the
patient’s QT interval. There is a (usually transient) risk of hypokalemia; therefore, salmeterol use merits
caution in patients with hypokalemia
Aminophylline

• Aminophylline is FDA-approved to treat reversible airway obstruction

• Aminophylline's mechanism of action is not entirely understood. Upon entering the body, aminophylline releases theophylline, which is
responsible for the bronchodilatory effects. There are various proposals for the molecular mechanism for theophylline, but not all of them take
place at clinically effective concentrations. Theophylline works in three distinct ways:
• Phosphodiesterase Inhibitor
• Theophylline causes non-selective inhibition of type III and types IV isoenzymes of phosphodiesterase, which leads to increased tissue cyclic
adenine monophosphate (cAMP) and cyclic 3′,5′ guanosine monophosphate concentrations, resulting in smooth muscle relaxation in lungs and
pulmonary vessels, diuresis, CNS and cardiac stimulation. The bronchodilatory effect is not maximal at therapeutically effective dosages.[5]
Inhibition of type IV isoenzyme is responsible for inhibiting the release of mediators from the alveolar macrophages but requires much higher
serum concentrations.[6]
• Adenosine Receptor Antagonist
• Theophylline antagonizes adenosine receptors A1, A2 strongly, and A3 less potently. It binds to adenosine A2B receptors to prevent
bronchoconstriction by inhibiting the release of mediators like histamine and leukotrienes from mast cells.[7][8] This activity is thought to
play an indirect role in bronchodilation. Theophylline also increases calcium uptake through the adenosine-mediated calcium channels in the
diaphragm leading to increased contraction and reversal of diaphragm fatigue. This antagonism of the adenosine receptors, specifically A1
receptors, is responsible for some of the side effects of theophylline, like seizures and cardiac arrhythmias.[9][10]
• Histone Deacetylase Activator
• In inflammatory states, histone deacetylase activity becomes reduced due to oxidative stress via the activation of phosphoinositide-3-kinase-
delta (PI3K-Delta).[11] Theophylline increases the action and recruitment of histone deacetylases to the site of active inflammation at
therapeutic concentrations.[12] This action prevents the transcription of inflammatory genes that require acetylation of histones to activate
their transcription and decreases the resistance to steroids of COPD macrophages. This mechanism is distinct from PDE and adenosine
receptor inhibition
• Indications
• Aminophylline is a drug combination of theophylline and ethylenediamine in a ratio of 2
to 1.
• FDA Approved Indication
• Aminophylline is indicated as an adjunct to inhaled beta-2 selective agonists and
systemic corticosteroids to treat acute exacerbations of the symptoms and reversible
airflow obstruction associated with asthma and other chronic lung diseases, e.g.,
emphysema and chronic bronchitis.
• Non-FDA Approved Uses
• Prevention of apnea in preterm infants
• Thigh cellulite creams
• Sleep apnea[
• Dose
• water soluble, can be injected i.v. but not i.m. or s.c.—highly irritating.
250–500 mg oral or slow i.v. injection; children 7.5 mg/kg i.v.
• Adverse Effects
• Aminophylline has a narrow therapeutic index and is associated with a wide range of
adverse effects. The adverse effects depend on the peak serum concentrations of
theophylline in the body.[16] With peak serum concentrations under 20 mcg/ml, the
most common adverse effects are similar to the transient effects of caffeine (structurally
similar) and include
• Nausea, Vomiting, Headache, Insomnia, Irritability, Restlessness, Increase in urine
volume, Shakiness, Increased gastric acid secretion, Gastroesophageal reflex
• Once the serum theophylline exceeds 20 mcg/mL, the chances of adverse events
increases and include:
• Persistent vomiting, Cardiac arrhythmias including multifocal atrial tachycardia[,
Intractable seizures, Fast, slow, or irregular heartbeat, CNS depression, Allergic skin
reaction, Yellowing of skin and eye, Elevated liver enzymes
• Contraindications
• Aminophylline contraindications include patients with hypersensitivity to
theophylline, ethylenediamine, or any component of the drug
formulation. Precautions are necessary for patients with concurrent illnesses like:
• Cardiac disease
• Renal impairment
• Hepatic dysfunction due to any cause
• Hypo/hyperthyroidism
• Epilepsy
• Active peptic ulcer disease
Tiotropium Bromide
• Tiotropium maintenance therapy has well-established benefits for
treating chronic obstructive lung disease. Mortality in chronic
obstructive lung disease is often due to complications, including
hyperinflation, decreased exercise tolerance, pulmonary infections,
and chronic obstructive lung disease exacerbations. Tiotropium has
been extensively studied in clinical trials and proven to prevent the
progression of obstructive lung disease and these complications.
• Mechanism of Action
• Tiotropium is a second-generation and long-acting muscarinic receptor antagonist that exerts its primary
therapeutic effect on the M1, M2, and M3 muscarinic acetylcholine receptors (mAChRs) in the lungs
preventing acetylcholine binding. Once the patient inhales the medication as either an inhalation spray or
inhalation powder, the quaternary ammonium compound reversibly binds to M1 mAChRs of the nerve ganglia of
the lung, M2 mAChRs postganglionic nerve fibers of the lung, and M3 mAChRs of the smooth muscles and
mucous glands of the lung. Specifically, when tiotropium binds to the M1 and M3 mAChRs, this molecule
ultimately inhibits Gq alpha-protein stimulation of the phospholipase C pathway, preventing intracellular calcium
influx from inducing a cellular response in the respiratory airways.[11] The overall effect of tiotropium's
anticholinergic effect on the respiratory airway is bronchodilation, decreased mucous gland secretions, decreased
ciliary beat frequency, inhibition of fibroblast proliferation, and it exhibits a poorly understood anti-inflammatory
effect in the lungs.[11][12]
• A unique chemical property of tiotropium is that it is a quaternary ammonium compound; this makes the
medication highly specific to targeting the mAChRs of the respiratory pathway without the capability to be
absorbed across the alveolar-capillary beds to enter the systemic circulation. Of the 3 mAChRs, tiotropium has
equal binding capabilities to the lungs' M1, M2, and M3 mAChRs. Still, it has been observed to have a
prolonged anticholinergic effect only on the M1 mAChRs and M3 mAChRs and rapid dissociation to the
M2 mAChRs
• Indications
• Tiotropium is a long-acting muscarinic antagonist medication that provides promising therapeutic
benefits for chronic obstructive pulmonary disease (COPD) patients.
• FDA-Approved Indications
• Reduction of bronchospasm
• Reduction of COPD exacerbations
• Maintenance therapy of asthma in patients older than 6 years of age
• Maintenance therapy for patients with chronic obstructive lung disease (COPD)
• Maintenance therapy for bronchitis
• Maintenance therapy for emphysema
• A Non-FDA-Approved Use
• The use of tiotropium as an add-on therapy to inhaled corticosteroids and other maintenance
therapies for pediatric patients from 6 to 11 years old
• Adult Dosing
• Asthma
• Tiotropium oral mist inhaler (1.25 mcg/actuation) 2 inhalations once
daily.
• COPD
• Dry powder oral inhaler (18 mcg/capsule) inhale the contents of 1
capsule once daily using a HandiHaler device. The contents of each
capsule dose should be inhaled twice to ensure complete delivery of
dosage.
• Tiotropium mist inhaler (2.5 mcg/actuation) 2 inhalations once daily.
• Adverse Effects
• Tiotropium Bromide
• The most frequently encountered adverse effects of tiotropium include
pharyngitis, bronchitis, sinusitis, dry mouth, cough, and headaches. Less
common side effects of tiotropium include insomnia, cataract, blurry vision,
epistaxis, rhinitis, laryngitis, dysphagia, gingivitis, chest pain and
palpitations, joint swelling, abdominal pain, gastroesophageal reflux
disease, paralytic ileus of the intestine, abnormal liver function test, dysuria,
urinary retention, angioedema, dry skin, herpes zoster, and dehydration.[13]
Tiotropium should be used cautiously in patients with prostatic hyperplasia
and bladder-neck obstruction, as it can worsen urinary retention
• Contraindications
• Tiotropium bromide and combination therapy of tiotropium bromide and
olodaterol are not indicated for treatment and relief of acute bronchospasm.[14] Following
are the contraindications as per the manufacturer's label.
• Tiotropium Bromide
• Tiotropium bromide is contraindicated in patients with a hypersensitivity to tiotropium,
ipratropium, and atropine (due to the risk of anaphylaxis) and narrow-angle glaucoma.
Powder tiotropium capsules contain milk protein and are contraindicated for use in patients
with allergies to milk. Tiotropium has links to increased risk of heart attacks, stroke, and
cardiovascular death. The use of tiotropium in pregnancy has not yet been shown to pose any
risk due to maternal or fetal complications. The results of animal studies on tiotropium use
during the pregnancy of rats and rabbits resulted in no anatomical abnormalities in offspring.
It should not be used as a rescue medicine for an acute attack. Tiotropium should be
discontinued if a paradoxical bronchospasm occurs.
• LEUKOTRIENE ANTAGONISTS
• Since it was realized that cystenyl leukotrienes (LT-C4 /D4 ) are
important mediators of bron chial asthma, efforts were made to
develop their antagonists and synthesis inhibitors. Two cysLT1
receptor antagonists montelukast and zafirlukast are available.
Montelukast
• Montelukast is an orally dosed drug (available as a film-coated tablet,
chewable tablet, or oral granules) that is FDA-approved for treating
chronic asthma and prophylaxis and the prevention of exercise-induced
bronchoconstriction. It is also approved to relieve seasonal and
perennial allergic rhinitis symptoms.
• Some studies have found that certain patients are ‘responders’ while
others are ‘nonresponders’ to anti-LT therapy. This may reflect differing
extent of involvement of LTs as asthma mediators.
• They are well absorbed orally, highly plasma protein bound and
metabolized by CYP2C9 (montelukast by CYP3A4 as well). The plasma
t½ of montelukast is 3–6 hours, while that of zafirlukast is 8–12 hours.
MOA
• They competitively antagonize cysLT1 receptor mediated
bronchoconstriction, airway mucus secretion, increased vascular
permeability and recruitment of eosinophils. Bronchodilatation,
reduced sputum eosinophil count, suppression of bronchial
inflammation, mucus and hyperreactivity are noted in asthma
patients. Parameters of lung function show variable improvement.
• Mechanism of Action
• Montelukast (empirical formula C35H35ClNNaO3S) is a highly selective leukotriene receptor antagonist that
binds with high affinity to the cysteinyl leukotriene receptor for leukotrienes D4 and E4. These leukotrienes are
excreted by various cells, such as mast cells, and are involved in the inflammatory process that may cause asthma
and allergic rhinitis signs and symptoms. Leukotriene receptors are found in airway cells, such as macrophages and
smooth muscle cells. When bound to leukotriene receptors, montelukast inhibits leukotriene physiologic effects
(such as airway edema, smooth muscle contraction, and impairment of normal cellular activity) without exhibiting
any agonist activity. In asthmatics, low doses of montelukast (5 mg) induce a significant inhibition of
bronchoconstriction caused by leukotriene D4. Furthermore, in a crossover study, montelukast induced inhibition
of both early and late phase bronchoconstriction caused by a challenge with antigen in 12 asthmatic patients.
Although most international asthma guidelines advise that children ≤5 years with asthma be treated with daily low-
moderate dose inhaled corticosteroids (ICS) as the preferred controller and montelukast as an alternative therapy.
[5] See Figure. Montelukast Structural Formula.
• In controlled studies, montelukast is reported to significantly reduce beta2-agonist use (p<0.001), asthma
symptoms (p=0.001), blood eosinophils (p=0.009) and significantly increase morning peak expiratory flow
(p=0.001). These parameters demonstrate that montelukast decreases airway eosinophilic inflammation and
improves clinical symptoms. Its efficacy in the treatment of chronic asthma may be due, in part, to the effect on
airway inflammation.[6]
• Indications
• Montelukast is an orally dosed drug (available as a film-coated tablet, chewable tablet, or
oral granules) that is FDA-approved for treating the following conditions.
• Asthma: Monteleulast is indicated for asthma prophylaxis and chronic treatment in adults
and pediatric patients 12 months of age and older.[1][2]
• Exercise-Induced Bronchoconstriction (EIB): Montelukast is indicated to prevent
exercise-induced bronchoconstriction (EIB) in patients six years of age and older.[3]
• Seasonal Allergic Rhinitis: Montelukast is indicated to relieve symptoms of seasonal
allergic rhinitis in patients two years of age and more; and perennial allergic rhinitis in
patients six months of age and older. Because the benefits of montelukast may not
outweigh the risk of neuropsychiatric adverse reactions in patients with allergic rhinitis,
only used for patients who have an intolerance or an inadequate response to alternative
therapies.[
• Adverse Effects
• Both montelukast and zafirlukast are very safe drugs; produce few
side effects like headache and rashes. Eosinophilia and neuropathy
are infrequent. Few cases of Churg-Strauss syndrome (vasculitis with
eosinophilia) have been reported.
• Contraindications
• Montelukast is contraindicated in patients with a history of hypersensitivity to the
drug or its components. In addition, for patients with phenylketonuria (PKU), caution
should be exercised with phenylalanine-containing formulations.
• Boxed Warning: Neuropsychiatric Events
• Neuropsychiatric events have been described with the use of montelukast sodium.
These postmarketing reports have been highly variable, including agitation,
aggressive behavior, anxiousness, depression, disorientation, disturbance in attention,
irritability, memory impairment, obsessive-compulsive symptoms, hallucinations,
insomnia, restlessness, suicidal thoughts, and behavior (including
suicide). Neuropsychiatric events have been documented in patients with and without
a history of psychiatric disorders. Based on risk-benefit considerations, the asthma
indication has not been changed
• Montelukast: 10 mg OD; children 2–5 yr 4 mg OD, 6–14 yr 5 mg OD; in
the evening.