Drugs for Chronic Obstructive

Pulmonary Disease
Chronic obstructive Pulmonary disease Syndromes

•Asthma - acute episodes of reversible

bronchoconstriction cause by underlying airway
inflammation.
• Chronic bronchitis- excessive mucus production due
to hyperplasia and hyper functioning of mucus
secreting goblet cells.
• Emphysema - abnormal and permanent enlargement
of respiratory air spaces of their walls with fibrosis.
 Asthma statistics
Number of non-institutionalized adults who
currently have asthma: 15.7 million

· Number of children who currently have

asthma: 6.5 million

· Number of hospital emergency department

visits: 1.8 million

· Number of deaths: 3,780

Genetic Enviromental
predisposition exposure

Airway
inflammation

Airway Airway
responsiveness limitation

Asthma symptoms
 inhaled allergens are ingested by a type of cell known as antigen presenting cells, or
APCs. APCs then "present" pieces of the allergen to other immune system . In
asthmatics, IMMUNE CELLS ARE FORMED -(TH2), The resultant TH2 cells activate the
humoral immune system which produces antibodies against the inhaled allergen. Later,
when an asthmatic inhales the same allergen, these antibodies "recognize" it and
activate a humoral response. Inflammation results: chemicals are produced that cause
the airways to constrict and release more mucus, and the cell-mediated arm of the
immune system is activated.
THE FOLLOWING DRUGS ARE KNOWN TO CAUSE
REACTION AMONG ASTHMATICS:

1. ASPIRIN
 aspirin sensitivity – 9 to 44%
2. NSAIDS
3. ACETAMINOPHEN
 6 – 8%
4. BETA-BLOCKERS
 Can exacerbate
5. ACE – INHIBITORS
 Develop cough
Agents Used to treat COPD
I – Bronchodilators
A. Methylxanthines
B.Adrenergic agonists
(Sympathomimetics)
C. Muscarinic antagonist

(Anticholinergics)

II – Mediator Release Inhibitors

A. Cromolyn Sodium (Intal)
B. Corticosteroids

C. IgE BLOCKER
D. Antieukotriene drugs
 DRUGS FOR ASTHMA
MANAGEMENT B. CONTROLLERS
(MAINTENANCE)
A. RELIEVERS 2. MEDIATOR RELEASE
INHIBITORS
2. SHORT ACTING B2
AGONIST - CROMOLYN

- SALBUTAMOL - INHALED
GLUCOCORTICOIDS
- TERBUTALINE
- LEUKOTRIENE MODIFIERS
- MONTELUKAST
2. ANTICHOLINERGIC -ZILEUTON
- IPRATROPUIM 5.ORAL
-ATROPINE GLUCOCORTICOSTEROIDS
4. LONG ACTING B2 AGONIST
-SALMETEROL
-FORMETEROL
5. SUSTAINED RELEASE
THEOPHYLLINE
 Methylxanthines
Degree of
Methylxanthines Bronchodilations
Caffeine +

Theobromine +

Theophylline +++
Enprofylline ++++

(Prototype : Theophylline)
Mechanism of action
1. Inhibits cAMP phosphodiesterase which leads to ↑
cAMP – smooth muscle relaxation bronchodilation.

xanthine

Cyclic 3’5 AMP 5’ AMP

Cyclic AMP
phosphodiesterase
2. Inhibits the re-uptake of catecholamines which
can elevate cyclic AMP. Theophylline is an adenosine
receptor antagonist

Adenosine
Membrane receptors
(endogenous mediator)

Theophylline
antagonizes Adenosine
Pharmacologic Effects:
A. Respiratory system

1. Rapid relaxation of bronchial sm. Muscle –

bronchodilation

2.Decrease histamine release

3.Stimulate ciliary transport of mucus

4. Improve respiratory performances by
improving contractility of the diaphragm and
by stimulating the medullary respiratory
center.
Pharmacologic Effects:
B.Effects on other systems
1. Heart (+) chronotropic and inotropic
effect cardiac stimulation

Caffeine - (+)

Theobromine - (++)

Theophylline - (+++)

Enprofylline - (++++)
Pharmacologic Effects:
B.Effects on other systems
1. Pulmonary and peripheral vasodilatation (↓ B.P)

2. ↑ alertness and cortical arousal medullary

stimulation – can cause severe nervousness and
seizures.
3.Stimulation of gastric acid and pepsinogen
release.

4. Diuresis
Pharmacokinetics : Prototype drug Theophylline

• rapidly and completely absorb from GIT

• metabolize in the liver by oxidation and
demethylation

• half life – children – 3.5 hrs ; Adult – 8-9 hrs

Bronchodilator effect is achieve at bld levels of
10-20 mg/ml

(above this is associated with greater toxicity)

* Aminophylline – is a theophylline – ethylene

diamine complex
Drug Interactions
A. Drugs that ↑ theophylline effects
1. Cimetidine
2. Erythromycin , troleandomycin
3. Oral contraceptives

B. Drugs that ↓ effectiveness of theophylline

1. Lithium
2. blockers
3. Barbiturates
4. Beta
5. Phenytoin

Halothane - given with theophylline may result to

cardiac dysrhythmias
Adverse Effects
1. Vomiting and GI bleeding
2. Cardiac arrhythmais
3. Nervousness , seizures , behavioral problems
in children

Clinical Uses
1. COPD
2.Apnea in pre-term infants

* Initial loading dose – 5mg/kg – by infusion drip

over 30 min.
* Maintenance- 0.6 to 0.7 mg/kg/h
* Pnts with heart or liver disease – 0.3 mg/kg/h
Beta Receptor Agonist (Sympathomimetics)
- relaxes smooth muscle by ↑ cAMP as a result
of activation of adenylate cyclase.

ATP cAMP 

Adenylate cyclase

Activated by
Beta agonist
Agents
1. Epinephrine- given subcutaneously / aerosol
2. Ephedrine
3. Isoproterenol
4. B2 Selective
a.Metaproterenol (Alupent)
b.Terbutaline (Bricanyl)
c.Fenoterol (Berotec)
d.Pirbuterol
e.Procasterol (Meptin)
f.Bambuterol (Bambec)
g.Salmeterol (Serevent)
 Comparison of Beta – Receptor agonist
on Selectivity
Beta 1 Beta 2 Remarks
1. Albuterol + ++++ - highly potent
(Ventolin) - orally active
- safe
- less cardiac
- stimulation
2.Terbutaline + +++ - more side
(Bricanyl) - effects than
- albuterol
3. Procaterol - more potent,
+ ++++
(Meptin) - more effective
- than albuterol
 Comparison of Beta – Receptor agonist
on Selectivity
Beta 1 Beta 2 Remarks
+ ++++ - more selective
4. Fenoterol - for lung tissue 2x
(Berotec) - potent than
- albuterol by aerosol
-long acting

5. Pirbuterol + ++++ - improve cardiac

(Exirel) performances
- more selective on
lung tissue
-rapid onset more
6.Epirephrine ++++ ++++
cardiac side
effects
∝ activity +++
 Comparison of Beta – Receptor agonist
on Selectivity
Beta 1 Beta 2 Remarks

7.Isoproterenol ++++ ++++ - cardiac side

effects

8.Metaproterenol /
++ ++ -less effective
Alupent than albuterol

Long acting beta – receptor agonist , are analogs of albuterol and are
long acting(12 hrs) , more affinity to the beta 2 receptor , has slow
onset of action .
1. salmeterol
2. formeterol
Adverse Effects
1. Cardiac effects – arrhythmias
2.CNS effect – stimulation
3.Skeletal muscle tremor

Anticholinergics:
Mech. of Action – competitively inhibit the
effects of acetylcholine at muscarinic
receptors
- block the contraction of airway sm. muscle
- block ↑ in secretion of mucus in response to vagal
activity.
- Very effective in achieving bronchodilation in
patients with hyperreactive airway disease due to
vagal stimulation.
Ipratropium bromide (Atrovent)
- is a quarternary ammonium deriv of atropine
that is given by aerosol. It does not cross Bld-
Brain barrier and is poorly absorb from GIT ,
thus minimizing Anti-cholinergic side effects.

- useful in chronic bronchitis , emphysema and

in pnts who cannot tolerate Beta receptors
agonist.

Combivent – combination of albuterol + ipratropium

bromide
Mediator Release Inhibitors : (MRI)
• Cromolyn Na (Intal) – Mech. of action – it
stabilizes Mast cell membranes and prevent
release of mediators in response to various
stimuli.

• It inhibits both early and late Phase rxn to

antigen exposure.

• It inhibit release of histamine & leukotriene

Dose – 20 mg inhaled 4x a day
 ANTILEUKOTRIENE DRUGS

1. ZAFIRLUEKAST , MONTELEUKAST
(singulair)
-are selective reversible inhibitor of the cysteinyl
leukotriene 1 receptor ,thereby blocking the effects of
cysteinyl leukotrienes
dose : ADULT -10mgs , children -5 mgs Once a day at 6
pm

2. ZILEUTON- is a selective and specific inhibitor of 5

lipoxygenase ,preventing the formation of LTB4 and the
cysteinyl leukotriene

Adverse effects :
 Elevation of hepatic enzymes
zileuton and zafirlukast are inhibitors of cytochrome P450
both drugs increases levels of warfarin
2. Headache and dyspepsia
3 . Eosinophilic vasculitis ( CHURG- STRAUSS SYNDROME )
(SEE FIG 27.6 pg 319 LIPPINCOT )
 Corticosteroids

MECHANISM OF ACTION:
-REDUCE THE SYNTHESIS OF ARACHIDONIC ACID BY
PHOSPHOLIPASE A2 AND INHIBIT THE EXPERSSION OF
CYCLOOXEGENASE 2 ( COX 2)

- no direct effect on airway

-decreases the number and activity of inflammatory cells .

Inhaled corticosteroids
 Budesonide 3. flunisolide
 Fluticasone 4. beclomethasone

SIDE EFFECTS : CANDIDIASIS ; SORE THROAT

Systemic corticosteroid
- prednisone
-methylprednisone
 Action of steroids on lungs
1. reduces hyperresposiveness of airways to a
variety of bronchoconstrictor stimuli ( such as
allergens , cold air , and exercise )
2 . Reverses mucosal edema
3. decreases the permeability of capillaries
4. inhibit the release of leukotrienes

Advantages of using inhaled steroids

Better asthma control ( fewer symptoms and
flare –ups )
Decrease use of beta agonist and systemic
steroids
Improve lung function
Reduce the need for hospitalization
Monoclonal antibodies

OMALIZUMAB - IS A RECOMBINANT DNA –

DERIVED MONOCLONAL ANTIBODIES THAT
SELECTIVELY BINDS TO HUMAN IgE .
- REDUCES BINDING OF IgE TO RECEPTORS IN
MAST CELLS AND BASOPHILS
- GIVEN PARENTERALY TWICE WEEKLY
 EXPOSURE TO ANTIGEN

AVOIDANCE

ANTIGEN AND IgE on MAST CELLS

CROMOLYN,
STEROIDS
ZILEUTON
MEDIATORS
STEROIDS ,
( LEUKOTRIENES , CROMOLYN,
CYTOKINES,etc )
LEUKOTRIENE
BRONCHODILATORS
ANTAGONIST

EARLY RESPONSE
LATE RESPONSE
BRONCHOCONSTICTION
INFLAMMATION

ACUTE SYMPTOMS
BRONCHIAL HYREPREACTIVITY
 Severity of asthma exacerbations

Respiratory
mild moderate severe
arrest
Walking, can talking , At rest ,
breathless hunched
lie down prefers sitting forward

sentences phrases
talk words

alertness agitated agitated agitated

Use of Paradoxical
accessory none usually usually breathing
muscle

Moderate ,end
wheezes expiratory loud loud absent

More than Less than Cyanosis

paO2 Normal 60 mm Hg 60mmHg

less than Less than More than 45

paCO2 mmHg More than
45 mm Hg 45 mmHg 45 mm Hg
 intermittent
mild moderate
severe

Exacerbation Affects daily activity Limits activity/

sleep
brief and sleep

Once a More than

Daytime once a week
Daily Daily
symptom week

n
Nighttime More than Less than More than
Less than
i
symptom once a week once a week
2x a month 2x a
g
h month
t MORE
PEFR MORE THAN
60- 80 % LESS
80% THAN 80% THAN 60%

CLASSIFICATION OF ASTHMA BASED ON SEVERITY

 Clinical (Mngt) Pharmacology
Home or OPD Mngt of Asthma

A. Mild asthma ( attacks less than 2 per week) – inhaled Beta

agonist (e.g albuteral) on an “as needed basis”

B. M ILD PERSISTENCE (more than two attacks per week)

1. Acute attacks Inhaled short Beta agonist 3- 4x

2. Long term control inhaled antiflammatory – Cromolyn or inhaled
Corticosteroid – 200 – 400 mcg/day.

May use a combination of inhaled long actging beta 2 agonist +

corticosteroid . SERETIDE 250 DISKUS
ONCE A DAY
Seretide 250 diskus –contains salmeterol xinafoate
50mcgs and fluticasone propionate 250mcgs
C. Moderate persistence ( daily attacks , PF =60- 80 % of
normal )
1. acute attacks – short acting beta2 agonist
2. long term control
medium dose corticosteroid 400-800mcgs /day+ long
acting beta2 agonist combination OR
Seretide 250 diskus twice a day

D. SEVERE PERSISTENCE ( CONTIUOUS ATTACK AND PF of less

than 60% of normal )
1. acute attacks – short acting beta 2 agonist
2. long term control
high dose corticosteroid 800mcg to 1,600 mcg per day
+ long acting beta2 agonist combination
Seretide 500 diskus –contains salmeterol xinafoate 50mcgs
and fluticasone propionate 500mcgs
3. sustained release theophylline
Theophylline should be reserved for patients in whom
symptoms remain poorly controlled despite
combination treatment.

• If above regimen is not enough to control symptoms

– add an oral conticosteroid – PREDNISONE 40-50
mgs /day for 5 days
- Or methylprednisolone 16 mgs every other day
Hopitalized patients if :
2. No improvement within 2-6 hrs after corticosteroid treatment
2. High risk patient (hospitalization within one year)
3. Exacerbation is severe
4. There is further deterioration despite all medications
 Treatment of STABLE COPD
MILD COPD
SHORT ACTING BRONCHODILATOR

MODERATE COPD
-REGULAR USE OF MORE THAN ONE BRONCHODILATOR
- INHALED GLUCOCORTICOSTEROIDS

SEVERE COPD
-REGULAR USE OF MORE THAN ONE BRONCHODILATOR
INHALED GLUCOCORTICOSTEROIDS
-ANTIBIOTICS
-LONG TERM OXYGEN THERAPY
Other drugs for COPD

Alpha1 – proteinase inhibitors (Prolastine) – use to

treat emphysema caused by a deficiency in alpha1
– proteinase a peptide that inhibits elastase, in
patients with the deficiency, elastase destroys
lung parenchyma.
Other Agents affecting the Respiratory Tract
Drugs Used to treat Rhinitis

1. Antihistaminics (Hi- receptors

secretion and
antagonist)
a. chlorpheniramine parasympathetic
b. diphenhydramine activity
c.loratidine
Drugs Used to treat Rhinitis
2. µ (alpha) receptor agonist
A. Nasal aerosols
1.Epinephrine
2.Oxymetazoline
Constrict
3.Phenylephrine
dilated arterials
B. Administered orally in nasal mucosa
1.Phenylpropanolamine
2.Pseudoephedrine
3.Xylometazoline
4.Phenylephrine
3. Topical corticosteroids
1 .Beclomethasone (Beconase)
2. Fluticasone (Flixotide)
3. Flunisolide (Nasalide)
4. Cromolyn Na
EXPECTORANTS
A. VAGAL STIMULANTS
1. GLYCERYL GUIACOLATE
2. SALT SOLUTIONS
B. DIRECT STIMULANTS
1. POTASSIUM IODIDE
SATURATED SOLUTION (KISS)
2. BROMHEXINE
3. CARBOCISTEINE
4. AMBROXOL
 ANTITUSIVES
I. NARCOTIC ANTITUSSIVES
• HEROIN / MORPHINE
• CODEINE

II. NON-NARCOTIC ANTITUSSIVES

A. MORPHINAN DERIVATIVES
DEXTROMETHORPHAN
B. BENZYLISOQUINOLINES
NOSCAPINE/ NORCEINE
HYDRASTINE / HOMARYLAMINE
ANTITUSIVES
II. NON-NARCOTIC ANTITUSSIVES
C. DIPHENYLAKYLAMINES
CHLOPHENDIANOL
LEVOPROPXYPHENE
D. PHENYLCYCLOPENTALKYLAMINES
CARAMIPHEN
CARBETAPENTANE
E. MISCELLANEOUS
BENZONATATE
CLOBUTINOL
DIBUNATES
CODEINE
- PHENATHRENE DERIVATIVE OPIATE AGONIST
- PPC: 1 TO 2 HOURS; DURATION: 4 HRS

ACTION:
DIRECT EFFECT ON THE CENTER
DRYING EFFECT
DECREASE VISCOSITY
ANALGESIC & SEDATIVE EFFECT

ADVERSE EFFECT:
 NAUSEA & VOMITING
 CONSTIPATION
 DIZZINESS
 PRURITUS
 TOLERANCE & PHYSICAL DEPENDENCE
 DEXTROMETHORPHAN
- METHYL ETHER OR DEXTROROTATORY FORM OF
LEVORPHANOL
- PPC: 15 – 30 MINS; DURATION: 6 - 8 HRS
- USEFUL FOR CHRONIC NON-PRODUCTIVE COUGH
SIDE EFFECTS:
* NAUSEA * DRYING EFFECT
* DIZZINESS
DRUG INTERACTIONS:
* PENICILLIN *TETRACYCLINES
*SALICYLATES * PHENOBARBITAL
* KISS
BROMHEXINE
- SYSTEMICALLY ACTIVE MUCOLYTIC AGENT

ACTION:
 Depolymerization of Mucopolysaccharide
 Direct Effect on Bronchial Glands
 Liberation of Lysosomal Enzymes producing cells
which digest mucopolysaccharide fibers
INDICATIONS:
 ALL forms of TRACHEOBRONCHITIS
 Emphysema with Bronchitis
 Pneumoconiosis
 Chronic Inflammatory Pulmonary Conditions
 Bronchitis with Bronchospasm
 Asthma
BROMHEXINE

SIDE EFFECT:
EPIGASTRIC DISTRESS

DRUG INTERACTIONS:
INCREASE ANTIBIOTIC
CONCENTRATION
AMBROXOL
- MUCOKINETIC & SECRETOLYTIC
ACTION:
 INCREASE RESP. TRACT SECRETIONS
 ENHANCE PULM. SURFACTANT
PRODUCTION
 STIMULATES CILIA ACTIVITY
IMPROVED MUCUS FLOW &
TRANSPORT
(CILIARY CLEARANCE FACILITATES
EXPECTORATION)
AMBROXOL
USE:
 SECRETOLYTIC THERAPHY IN ACUTE
& CHRONIC BRONCHO-PULMONARY
DISEASES ASSTD WITH ABNORMAL
SECRETIONS & IMPAIRED MUCUS
TRANSPORT.

SIDE EFFECT:
 NAUSEA & VOMITING
 RASHES
 CAN INCREASE ANTIBIOTIC CONC.
 CARBOCISTEINE
(S-CARBOXYMETHYLCYSTEINE)
- MUCOREGULATOR IN RESP. TRACT
DISORDERS CHARS BY EXCESSIVE OR
VISCOUS MUCUS
- ACT BY REGULATING AND
NORMALIZING THE VISCOSITY OF
SECRETION FROM THE MUCUS CELLS
OF RESP. TRACT
- STIMULATES THE LESS VISCOUC
SIALOGLYCOPEPTIDES AND
SULFOGLYCOPEPTIDES
 CARBOCISTEINE
- STIMULATES THE LESS VISCOUS NEUTRAL
GLUCOPEPTIDES DUE TO ACTIVATION OF
SIALYLTRANSFERASE OR INHIBITON OF
NEURAMIDASE
- DECREASE THE SIZE AND NUMBER OF
MUCUS PRODUCING CELLS.

SIDE EFFECT:
GIT BLEEDING, NAUSEA, DIARRHEA, RASH,
DIZZINESS, HEADACHE, PALPITATIONS
MUCOLYTIC AGENTS
ACETYLCYSTEINE: (MUCOMYST)
 REDUCES THE THICKNESS & STICKINESS
OF PURULENT & NONPURULENT PULMONARY
SECRETIONS
 BREAKS DISULFIDE LINDAGES OR BONDS
OF MUCOPROTEIN MOLECULES OF RESP.
SECRETIONS INTO SMALLER, MORE SOLUBLE
& LESS VISCOUS STRANDS
 ANTIDOTE FOR PARACETAMOL POISONING
 MUCOLYTIC AGENTS
ACETYLCYSTEINE (con’t..)
 BRONCHOPULMONARY DSES.
i.e. CYSTIC FIBROSIS
 DXs AID IN BRONCHIAL STUDIES
(bronchospirometry/ bronchograms)
GIVEN:
INHALATION/ INSTILLATION
ADVERSE EFFECTS:
Hemoptysis, resp. irritation & difficulty
N & V, inc temp, throat irritation
Clinical case scenario
Two year ago , a 31 year old female came to your clinic
complaining of paroxysmal cough accommpanied by
chest tightness and shortness of breath . This occur
when her family moved into a new house 4 weeks PTC.
This happened 2-3 x per week and affected her sleep .