Pharmacology

Pulmonary Pharmacology LECTURE (RP)

Vincent Laguardia, MD | October 26, 2023

PULMONARY PHARMACOLOGY

OUTLINE
ROUTES OF DRUG DELIVERY TO THE LUNGS.......................1
INHALED ROUTE.......................................................................... 1
ORAL ROUTE................................................................................ 3
PARENTERAL ROUTE................................................................. 3
BRONCHODILATORS................................................................. 3
B2 ADRENERGIC AGONISTS....................................................3
METHYLXANTHINES: THEOPHYLLINE................................. 4 Figure 1. Schematic representation of the deposition of inhaled drugs
MUSCARINIC CHOLINERGIC ANTAGONISTS such as β2 agonists (such as salbutamol) and corticosteroids (such
as budesonide)
(ANTICHOLINERGICS)................................................................ 4
NOVEL CLASSES OF BRONCHODILATORS........................ 5
● Inhalation therapy directly deposits drugs but not exclusively in
CORTICOSTEROIDS................................................................... 5 the lungs:
SIDE EFFECTS OF INHALED CORTICOSTEROIDS.................6 ○ 10-20% - proceed to the lungs; preferred route of
administration due to its proximity to site and faster delivery
CROMONES.................................................................................. 6 ○ 80-90% - swallowed and absorbed from the GI tract
PHOSPHODIESTERASE INHIBITORS..................................... 6 ● Metered dose inhaler (MDI): decreases amount of drug
deposition in oropharynx → decreased amount of swallowed
MEDIATOR ANTAGONISTS....................................................... 6
drug → limiting of systemic effects
IMMUNOMODULATORY THERAPIES.....................................7
MUCOREGULATORS, MUCOLYTICS, AND ● 1st profile - lungs as target organ
EXPECTORANTS..........................................................................7 ● 2nd profile - minimizing systemic side effects
ANTITUSSIVES............................................................................. 7
Q&A NOTES................................................................................. 8 CICLESONIDE
● marketed as Omnaris
ROUTES OF DRUG DELIVERY TO THE LUNGS ● an inhaled corticosteroid (ICS) and prodrug
● activated by respiratory esterases found only in the
The choice depends on the drug and on the respiratory disease. respiratory tree (very specific) → active form:
des-ciclesonide
● Indications:
INHALED ROUTE
○ Allergic rhinitis
● The preferred mode of delivery of many drugs with a
○ Reactive diseases
direct effect on airways such as in cases of asthma
and COPD
DELIVERY DEVICES
● Is the only way to deliver some drugs (e.g. cromolyn
sodium and anticholinergic drugs)
● The preferred route of delivery for β2 agonists and
corticosteroids to reduce systemic side effects

PARTICLE SIZE
● Important in determining the site of deposition in the
respiratory tract
● Optimum size for particles to settle in the airways:
2-5 µm MMAD (mass median aerodynamic
diameter) FIgure 2. Ease or difficulty of preparation and use of inhalation
○ >5 µm - particles settle out in the upper devices
airways
○ <2 µm - remain suspended and are PRESSURIZED METERED-DOSE INHALER (pMDI)
therefore exhaled ● Drugs propelled from a canister with the aid of a
propellant in the form of hydrofluoro-alkane (HFA)
● Convenient, portable, and delivers 50-200 doses of
drug
● Some have dose indicators (i.e. amount left in the
canister)

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Figure 3. Ventolin or Salbutamol, an example of pMDI

Figure 6. Spacer with ideal particle-absorption wall

Spacer chambers are placed in between the pMDI in the mouth of

the patient. When the substance or the drug is released from the
pmDI, most of the particles are suspended inside the space
chamber before reaching the mouth, hence, there are negligible or
very few particles that are deposited in the oropharynx.

Figure 4. Schematic diagram of a pMDI

DRY POWDER INHALERS
● Not given to children because they have to inhale
forcefully ● Scatters fine powder dispersed by air turbulence on
inhalation
SPACER CHAMBERS ● Difficult to use by children >7 years of age

● Reduce the velocity and size of particles entering

the upper airways
● Effect:
○ Reduced amount of drug impinging on the
oropharynx
○ Increased proportion of drug inhaled into
the lower airways
● Useful in reduction of oropharyngeal deposition (of
ICS) and consequent reduction in local side effects Figure 7. Example of a Dry Powder Inhaler
● Useful in delivering inhaled drugs to small children
who are not able to use a pMDI
●

Figure 8. Examples of commercially available dry powder inhalers

Figure 5. Commercially available inhaled with annotated space
chamber

Figure 9. A step-by-step process on how to use Dry Powder Inhalers

● Always remember to give clear instructions on how

to use DPIs. Do not assume patients will immediately

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be able to use the DPI correctly. Some instruct

gargling after use to remove residues in the mouth PARENTERAL ROUTE
● Intravenous (IV) route should be reserved for
NEBULIZERS delivery of drugs in severely ill patients who are
unable to swallow or absorb drugs from the GI tract
● 2 types:
● For severe asthma: epinephrine (IM or SC),
○ Jet nebulizers – driven by a stream of gas
terbutaline (SC), or intubate
(air or O2)
● Side effects are generally frequent due to high
○ Ultrasonic nebulizers – do not require a
plasma concentrations since IV route has almost
source of compressed gas but a rapidly
100% bioavailability
vibrating piezoelectric crystal
● Nebulized drugs may be inspired during tidal
BRONCHODILATORS
breathing (no need to inhale deeply) and it is
Sympathetic (adrenergic) receptors
possible to deliver much higher doses of drug
● ⍺: arteries, sphincters of GIT and GUT, iris
compared with a pMDI
● β1: heart, kidney
● β2: smooth muscles (bronchioles, vascular), skeletal
muscles

Parasympathetic (muscarinic) receptors

● M1: CNS (undefined effects)
● M2: heart, brain
● M3: smooth muscles, exocrine glands

B2 ADRENERGIC AGONISTS

Figure 10. Examples of nebulizers PRACTICE QUESTIONS

● Useful in: 1. Which component of the autonomics mediates

bronchodilation? What receptor?
○ Treating acute exacerbations of asthma
2. Which component of autonomics mediates secretion of
and COPD
glands? Which receptor is involved?
○ Delivering drugs during extreme airway
obstruction (e.g., severe COPD) ANSWER: 1) Sympathetic, Beta 2 receptor 2) Parasympathetic, M3
○ Delivering inhaled drugs to infants and
small children who cannot use other
● Inhaled β2 agonists are the bronchodilator treatment
inhalation devices, such as pMDI and DPI,
of choice in asthma because they are the most
that require coordination between delivery
effective bronchodilators with minimal side effects
and breathing
● Activation of Gs-adenylyl cyclase-cAMP-PKA
○ Giving drugs (e.g., antibiotics) when
pathway → phosphorylative events → bronchial
relatively high doses must be delivered to
smooth muscle relaxation (sympathetic response)
the airway
● May cause bronchodilation indirectly by inhibiting
release of:
ORAL ROUTE ○ Bronchoconstrictor mediators from
● Oral dose is much higher than the inhaled dose inflammatory cells
required to achieve the same effect (ratio of about
○ Bronchoconstrictor neurotransmitters from
20:1)
airway nerves
○ Since it undergoes hepatic first-pass
metabolism before reaching the lungs
○ Salbutamol SABAs (SHORT-ACTING B2 AGONISTS)
■ μg in a respule, mg in an oral drug
■ Should be reserved for few Albuterol (salbutamol*), Levalbuterol,
patients unable to use inhalers Metaproterenol, Terbutaline*, Pirbuterol
*Available in PH
(e.g., small children, patients with
physical problems such as severe
arthritis of the hands) ● Resistant to uptake and enzymatic degradation by
○ Theophylline COMT (catecholamine-O-methyltransferase) and
■ Ineffective by the inhaled route; MAO (monoamine oxidase)
must be given systemically ● May be used by inhalation or orally but inhaled route
■ Oral and parenteral availability; no is preferred due to less systemic side effects
inhaled route ● Similar duration of action (~3-4h, but less in severe in
○ Corticosteroids asthma)
■ Given orally for parenchymal lung ● Similar side effects
diseases (e.g., interstitial lung ● Bronchodilators of choice in treating acute severe
diseases) asthma
● When there is…

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● Should be used “as required” by symptoms and not ● Recommended dose of 6 mg/kg given intravenously
on a regular basis in the treatment of mild asthma; over 20–30 mins followed by maintenance dose of
increased use indicates the need for more 0.5 mg/kg per hour
anti-inflammatory therapy or corticosteroids

LABAs (LONG-ACTING B2 AGONISTS)

Twice daily: salmeterol, formoterol, arformoterol

Once daily: indacaterol, vilanterol, olodaterol

● >12h duration of bronchodilator action and

protection against bronchoconstriction
● Improve asthma control (2x/day) treatment with
SABAs (4-6x/day)
● In COPD
○ May be used alone or in combination with
anticholinergics or ICSs
● Improve symptoms and exercise tolerance by
reducing both air trapping and exacerbations
● In bronchial asthma: Figure 11. Effects of Theophylline
○ Should NEVER be used alone
● Do not treat the underlying chronic inflammation FACTORS AFFECTING CLEARANCE OF THEOPHYLLINE
● May increase risk of life-threatening and fatal asthma Increased Clearance → Dec. Decreased Clearance → Inc.
exacerbations Half-life → Inc. Dose Half-life → Dec. Dose
● Should always be used in combination with an ICS in Enzyme induction (mainly CYP inhibition (cimetidine,
a fixed-dose combination inhaler (pMDI or DPI) CYP1A2) by co-administered erythromycin, ciprofloxacin,
drugs (rifampin, barbiturates, allopurinol, fluvoxamine, zileuton,
○ Fluticasone-salmeterol combination
ethanol) zafirlukast)
○ Budesonide-formoterol combination Smoking (tobacco, marijuana) via Congestive heart failure
○ Mometasone-formoterol combination CYP1A2 induction
Barbecued meat Liver disease
COMBINATION INHALERS (LABA + CORTICOSTEROID) High-protein, low-carbohydrate High-carbohydrate diet
● More convenient for patients, simplify therapy, and diet
improve adherence with ICS Childhood Old age
● Delivering the 2 drugs in the same inhaler ensures Viral infection and vaccination
they are delivered simultaneously to the same cells Pneumonia
in the airways and allows beneficial molecular
interactions between LABAs and corticosteroids to SIDE EFFECTS OF THEOPHYLLINE AND MECHANISMS
occur. SIDE EFFECT PROPOSED MECHANISM
● Preferred therapy for patients with persistent Nausea and vomiting -
asthma Headaches PDE4 inhibition
Gastric discomfort -
Diuresis A1 receptor antagonism
SIDE EFFECTS OF β2 AGONISTS
Behavioral disturbance -
Muscle tremor Direct effect on skeletal muscle β2 receptors Cardiac arrhythmias PDE3 inhibition, A1 receptor
Tachycardia Direct effect on atrial β2 receptors, reflex antagonism
effect from ↑ peripheral vasodilation via β2 Epileptic seizures A1 receptor antagonism
receptors
Hypokalemia Direct β2 effect on skeletal muscle uptake of K+
MUSCARINIC CHOLINERGIC ANTAGONISTS
Restlessness -
Hypoxemia ↑ V/Q mismatch due to reversal of hypoxic (ANTICHOLINERGICS)
pulmonary vasoconstriction ● Competitive antagonists of endogenous ACh at
Metabolic effects ↑ FFA, glucose, lactate, pyruvate, insulin muscarinic receptors (M1, M2, M3 receptors for
acetylcholine)
METHYLXANTHINES: THEOPHYLLINE ● Inhibit direct constrictor effect on bronchial smooth
● Still remains a useful drug as an add-on therapy in muscle mediated by M3-Gq-PLC-IP3-Ca2+ pathway
patients with severe asthma and COPD ○ Effects of ACh on the respiratory system which
● Bronchodilation action and many non-bronchodilator are inhibited:
effects but with uncertain mechanisms of action ■ Bronchoconstriction
● Therapeutic range: 5–15 mg/L ■ Tracheobronchial mucus secretion
○ Dose required to give these therapeutic ● Only inhibit reflex ACh-mediated
concentrations varies among subjects bronchoconstriction
largely because of differences in drug ● No blocking effect on inflammatory mediators
clearance.
● Rapidly and completely absorbed
● Metabolized in the liver, mainly by CYP1A2

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USES OF MUSCARINIC CHOLINERGIC ANTAGONISTS CORTICOSTEROIDS

ASTHMA COPD ● Inhaled or ICS: considered first-line therapy for
asthma, except for mild cases, and less effective in
● Less effective as ● May be as effective or even COPD
bronchodilators than β2 superior to β2 agonists
● Oral or OCS: mainstay treatment for conditions
agonists and offer less
efficient protection against affecting the lung parenchyma:
bronchial challenge ○ Sarcoidosis
○ Interstitial lung diseases (ILDs)
● Currently used as an ● Reduce air trapping and
additional bronchodilator improve exercise tolerance ○ Pulmonary eosinophilic syndromes
in asthmatic patients not
controlled on a LABA

SAMA: IPRATROPIUM BROMIDE

● Available as pMDI and nebulizer preparation, usually
along with Salbutamol
● Relatively slow onset of bronchodilation
● Usually maximal 30–60 m after inhalation but persist
for 6-8 h
● Usually given by MDI 3–4x daily on a regular basis,
rather than intermittently for symptom relief

LAMA: TIOTROPIUM BROMIDE

● Once-daily dosing as DPI (Spiriva®) or via soft mist
mini-nebulizer device
● Significantly reduces COPD exacerbations
● Binds to all muscarinic receptor subtypes but Figure 12. Anti-inflammatory action of corticosteroids in asthma; CBP:
dissociates slowly CREB-binding protein; HAT: histone acetyltransferase
● From M3 and M1 receptors, giving it a degree of
kinetic receptor selectivity for these receptors Without corticosteroid: inflammatory stimulus → cell activation via
compared with M2 receptors from which it nuclear factor kappa B pathway → gene activation for transcription
dissociates more rapidly of cytokines, chemokines, adhesion molecules, etc.
○ Pronounced effect on M3 and M1 receptors With corticosteroid: lipophilic so readily enters cell membrane →
binds to intranuclear/intracytoplasmic receptors called
COMBINATION INHALERS glucocorticoid receptors → inhibits acetylation of proteins →
● SABA/SAMA combination inhibits gene transcription of inflammatory cells (indirect mechanism:
○ Albuterol-ipratropium recruits HDAC2, histone deacetylase enzyme → further gene
repression)
● LABA/LAMA combination
○ Once daily:
■ Indacaterol-glycopyrronium
■ Vilanterol-umeclidinium bromide
■ Olodaterol-tiotropium bromide
○ Twice daily:
■ Formoterol-glycopyrronium bromide
■ Formoterol-aclidinium bromide
● Adverse effects:
○ Bitter taste of inhaled ipratropium (may
contribute to poor compliance)
○ Glaucoma in elderly patients (increased volume)
○ Paradoxical bronchoconstriction
○ Dryness of mouth
○ Urinary retention in elderly patients

NOVEL CLASSES OF BRONCHODILATORS

Currently undergoing clinical trials

● Magnesium sulfate – treatment for preeclampsia in Figure 13. Effects of corticosteroid
pregnant women
● Potassium channel openers – Cromakalim, ● Rapid anti-inflammatory effects:
Levcromakalim ○ ↓ Airway hyperresponsiveness
● VIP analogues ○ ↓ Inflammatory mediator concentrations
● Bitter taste receptor agonists – Quinine, ● Suppress inflammation in the airways but DO NOT
Chloroquine CURE the underlying disease (no definite treatment
for asthma)

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● Potentiate effects of beta agonists and vice-versa ● Nedocromil sodium

○ Derivative of khellin (an Egyptian herbal
SYSTEMIC CORTICOSTEROIDS (IV AND ORAL) remedy)
○ Protects against allergen challenge but no
● IV: indicated in acute asthma attacks bronchodilator effect
○ <30% predicted lung function ○ Good safety profile but rarely used today
○ Patients who show no significant improvement because of the more effective ICS
after nebulized β2 agonist
● Hydrocortisone: steroid of choice PHOSPHODIESTERASE INHIBITORS
○ Most rapid onset (5–6 h) ● PDE4: relax smooth muscles and inhibit
○ 4 mg/kg initially then 3 mg/kg every 6 h inflammatory cells by increasing cAMP
○ 1:1 ratio when acting on glucocorticoid (GR) and ● In asthma (animal models):
mineralocorticoid (MR) receptors ○ PDE4 inhibitors reduce eosinophil infiltration
○ Physiologic steroid and responses to allergens
● Prednisone or prednisolone (40–60 mg): most ● In COPD:
commonly used oral steroids ○ Effective against smoke-induced inflammation
and emphysema
INHALED CORTICOSTEROIDS (ICS) ○ Roflumilast (PDE4 inhibitor) is indicated for
patients with severe disease
● Beclomethasone dipropionate
● FEV1 <50% predicted
● Equally effective as anti-asthma drugs but differ in
● Frequent exacerbations
pharmacokinetic properties as compared to BDP:
● Chronic bronchitis
○ Budesonide, Fluticasone, Mometasone,
Ciclesonide
■ Lower oral bioavailability from greater MEDIATOR ANTAGONISTS
first-pass hepatic effect ANTIHISTAMINES
○ Budesonide, Fluticasone propionate ● Little evidence that histamine H1 receptor
■ Fewer systemic effects at high doses antagonists (e.g. cetirizine, diphenhydramine)
(>1000 μg) provide any useful benefit, esp. in asthma and COPD
○ Ciclesonide ● NOT recommended in the routine management of
■ Low oral bioavailability and high asthma
therapeutic index
○ Fluticasone furoate
■ Longest duration of action, OD dosing only
ANTILEUKOTRIENES

SIDE EFFECTS OF INHALED CORTICOSTEROIDS

Local Side Effects
Dysphonia
Oropharyngeal candidiasis
Cough
Systemic Side Effects
Adrenal suppression & insufficiency (d/t [–] feedback loop to HPA
axis)
Growth suppression
Bruising
Osteoporosis
Cataracts
Glaucoma
Metabolic abnormalities (glucose, insulin, triglycerides)
Psychiatric disturbances (euphoria, depression)
Pneumonia Figure 14. Effects of cysteinyl-LTs on the airways and inhibition by
anti-LTs
● Antileukotrienes
Reminders after using ICS: ○ 5-lipoxygenase (LPO) inhibitor
● Clean the mouthpiece ■ Zileuton
● Gargle or rinse mouth to disperse excess steroids ○ Leukotriene (LT) antagonists
deposited in the mouth/oropharynx and minimize local
side effects
■ Montelukast: Some are chewable
● Use chambers if possible drugs; easy for children. Used for
For steroids in general: start with largest dose then taper slowly = refractory asthma
do not discontinue immediately ■ Zafirlukast
■ Pranlukast (not available in the
CROMONES Philippines)
● Cromolyn sodium

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LPO inhibitors and LT antagonists both inhibit some steps in the ● Systemic anticholinergics (muscarinic antagonists)
lipoxygenase pathway in order to inhibit Cys-LT receptors that are – control mucus secretion but not reduce
responsible for inflammatory effects. mucociliary clearance
● In asthma: ● β2 agonists – ↑ mucus production and mucociliary
○ Significant improvement in lung function & clearance
asthma symptoms ● Inhaled corticosteroids – very effective in reducing
○ Reduction in the use of rescue inhaled β2 increased mucus production in asthma
agonists
○ Indicated as add-on therapy on patients not well MUCOLYTICS
controlled by ICS
● No role in COPD therapy
Dissolve mucus.
● Adverse effects:
○ Hepatic dysfunction (rare) – ↑ SGPT/SGOT so
recommended to monitor liver panel N-ACETYLCYSTEINE, CARBOCYSTEINE, ERDOSTEINE,
BROMHEXINE
○ Churg-Strauss syndrome
● Reduce viscosity of sputum in vitro
● Also act as antioxidants → reduce airway
IMMUNOMODULATORY THERAPIES
inflammation
METHOTREXATE, CYCLOSPORINE A, GOLD, IVIg ● No effect in disease progression or in preventing
● Considered in asthma: exacerbations in patients with COPD
○ When other treatments have been unsuccessful ● N-acetylcysteine can be used to decrease
○ To reduce dose of oral steroids required creatinine levels
● Less effective and greater propensity for side effects
than oral corticosteroids DNAse (DORNASE ALFA)
● Reduces mucus viscosity in patients with cystic
fibrosis
OMALIZUMAB ● No evidence in efficacy in COPD and asthma
● Anti-IgE receptor therapy
● Very expensive EXPECTORANTS
● Can be another add-on therapy
● Humanized monoclonal antibody that blocks
binding of IgE to high- and low-affinity IgE receptors Enhance mucus clearance
● Reduces levels of circulating IgE ● Given with mucolytics in some formulations
● Used for severe asthma ● Little or no objective evidence for efficacy
● Administered subcutaneously every 2-4 weeks, ● Guaifenesin is less beneficial than:
dose depending on IgE titer ○ Adequate hydration
● Major side effect: anaphylactic response (<0.1%) ○ Steam inhalation

ANTITUSSIVES

Cough suppressants

OPIATES
● Central mechanism of action on mu opiate receptors
(MORs) in the medullary cough center
● Codeine
○ Little evidence of clinical efficacy
○ May be used for post-viral cough
○ Side effects: sedation and constipation
● Morphine, Methadone
○ Effective but only for intractable cough
associated with bronchial carcinoma

Figure 15. Anti-immunoglobulin E plays a central role in allergic

diseases DEXTROMETHORPHAN
● Centrally active NMDA receptor antagonist
MUCOREGULATORS, MUCOLYTICS, AND ● May also antagonize opioid receptors
EXPECTORANTS ● Poorly effective
MUCOREGULATORS ● Can cause hallucinations at higher doses
● Significant abuse potential

Control mucus hypersecretion.

LOCAL ANESTHETICS
● Benzonatate

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○ Acts peripherally by anesthetizing stretch

receptors located in respiratory passages,
lungs, and pleura → ↓ cough reflex
○ 100 mg TID: recommended dose
○ 600 mg/d if needed
○ Not as effective as a cough suppressant
○ Side effects: dysphagia and dizziness

NEUROMODULATORS
● Gabapentin, Pregabalin
○ GABA analogues that inhibit neurotransmission
○ Used in neuropathic pain syndromes and
post-stroke such as diabetic neuropathy
○ Show benefit in chronic idiopathic cough
○ Side effects: somnolence and dizziness
■ Best given at bedtime

Q&A NOTES
● Beta agonists: Promote bronchodilation by activating
beta 2 receptors
● Anticholinergics: Inhibit bronchoconstriction

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