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Dr ugs fo rDr ugs fo rRespiRat o Ry syst emRespiRat o Ry syst em
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Regulation of Airway Muscles , Blood Vessels & GlandsRegulation of Airway Muscles , Blood Vessels & Glands
Efferent pathways controlling the airways include
Cholinergic parasympathetic nerves
Non-adrenergic non-cholinergic (NANC) inhibitory
nerves
Excitatory NANC nerves
Sympathetic nerves
Irritant receptors & C fibers respond to exogenous stimuli
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Exogenous stimuli include
Cold
Irritant such as
Ammonia
Cigarette smoking
Endogenous inflammatory mediators stimulate sensory fibers
Stimulation of C fibers causes
Coughing
Bronchoconstriction
Mucus secretion
Total lung capacity( TLC) involved
Tidal volume the air exhaled during quiet breathing
Inspiratory reserve volume the maximal air inhaled above tidal
volume
Expiratory reserve volume the maximum air exhaled below tidal
volume
Residual volume the air remaining in the lung after maximal
exhalation
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The most frequent encountered respiratory diseases are
Chronic obstructive pulmonary disease (COPD)
Asthma
Respiratory tract infection
Bronchiectasis
Pulmonary embolic disease
Interstitial lung disease
Obstructive lung disease is defined as an inability to get air
out of the lung & is identified on spirometry when the
FEV1/FVC is less than 70% to 75%
Reversible airway obstruction is common in asthma &
chronic obstructive pulmonary disease
Restrictive lung disease is defined as a reduction in total lung
capacity (TLC) but is suspected when the forced vital capacity
(FVC) is low & the FEV1/FVC is normal
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Bronchial Asthma
An inflammatory condition with recurrent reversible airwaysobstruction
Airways obstruction occurs is in response to irritant stimuli
Asthma is characterised by
Inflammation of airways
Bronchial hyper-reactivity
Reversible airways obstruction
Pathogenesis of asthma involves both genetic & environmental
factors
Pathophysiology & Therapeutic ApproachPathophysiology & Therapeutic Approach
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Changes in Bronchioles Occur with Severe Chronic AsthmaChanges in Bronchioles Occur with Severe Chronic Asthma
Exercise-induced bronchospasm (EIB) defined as drop in
FEV1>15% - 20% of baseline
Triggers include Respiratory tract infection
Allergens
Environment such as
Cold air
Fog
Ozone
Sulfur dioxide
Nitrogen dioxide
Tobacco smoke
Wood smoke
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Emotions such as
Anxiety
Stress
Exercise particularly in cold or dry climate
Drugs
Aspirin & β-blockers
Occupational stimuli
PathophysiologyPathophysiology
Major characteristics of asthma include variable degree of air
flow obstruction related to
Bronchospasm
Edema
Hypersecretion
Airways inflammation
Inhaled allergen challenge in allergic patients leads to an early-
phase allergic reaction that in some cases may be followed bylate-phase reaction
Early-phase allergic reaction characterized by rapid activation
of airways mast cells & macrophages
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Activated cells rapidly release
Histamine Eicosanoids
Reactive oxygen species that induce
Contraction of airway smooth muscle
Mucus secretion
Vasodilatation
The late-phase inflammatory reaction occurs 6 - 9 hours after
allergen provocation & involves recruitment & activation of
Eosinophils
CD4+ T cells
Basophils
Neutrophils
Macrophages
Activation of T cells after allergen challenge leads to release of
T-helper (Th2)–like cytokines
Cytokines generation promote
Differentiation & activation of eosinophils
IgE production & release
Expression of IgE receptors on mast cells &
eosinophils
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Important mediators includeLeukotrine B4
Cysteinyl leukotrien (C4 & D4 )
Interlukines ( IL-4, IL-5 & IL-13)
Treatment is monitored by measuring
Force expiratory volume in 1 second (FEV 1 )
Expiratory flow rate
In acute severe disease treatment monitored by measuringOxygen saturation
Arterial blood gases
Immediate phase Late phaseImmediate phase Late phase
AllergensAllergensNonNon--specific stimulispecific stimuli
Mast cellsMast cells
Mononuclear cellsMononuclear cells
SpasmogenSpasmogen
CysTsCysTs, PG, PG DD2,2,HH11
ChemotaxinsChemotaxins
ChemokinesChemokines
BronchospasmBronchospasm
Reversed by βReversed by β22agonistsagonists
CystLTCystLT--receptorreceptor
antagonists &antagonists &
theophylinestheophylines
++
++
Infiltration of cytokines Th2Infiltration of cytokines Th2cells &cells & monocytesmonocytes
Activation of inflammatoryActivation of inflammatory
cellscells
MediatorsMediators
CysLTsCysLTs
EpithelialEpithelial
damagedamage
BrnchospasmBrnchospasm
Airway hyperAirway hyper--
activityactivity
EMBP, ECPEMBP, ECP
++
InflammationInflammationAirwayAirway
++++
++
++
Inhibited byInhibited by
glucocorticoidsglucocorticoids
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Classification of Asthma Severity: Clinical Features Before
Treatment
Symptoms Lung FunctionStep 1Step 1
Mild intermittentMild intermittent
Daytime ≤ 2 times/wkDaytime ≤ 2 times/wk
Asymptomatic between exacerbationsAsymptomatic between exacerbations
Exacerbations brief (from a few hours to a fewExacerbations brief (from a few hours to a few
days); intensity may varydays); intensity may vary
Nocturnal ≤ 2 times/moNocturnal ≤ 2 times/mo
FEV1 or PEF ≥ 80%FEV1 or PEF ≥ 80%
PEF variability < 20%PEF variability < 20%
Step2Step2
Mild persistentMild persistent
Daytime > 2 times/wk but < 1 time/dayDaytime > 2 times/wk but < 1 time/day
Mild Persistent Exacerbations may affect activityMild Persistent Exacerbations may affect activity
Nocturnal > 2 times/moNocturnal > 2 times/mo
FEV1 or PEF ≥ 80%FEV1 or PEF ≥ 80%
PEF variabilityPEF variability
20%20% -- 30%30%
Step3Step3
Moderate persistentModerate persistent
Daily symptomsDaily symptoms
Daily use of inhaled, shortDaily use of inhaled, short--acting β2acting β2--agonistsagonists
Exacerbations affect activityExacerbations affect activity
Exacerbations ≥ 2 times/wk; may last daysExacerbations ≥ 2 times/wk; may last days
Nocturnal > 1 time/wkNocturnal > 1 time/wk
FEV1 or PEF > 60% toFEV1 or PEF > 60% to
< 80%< 80%
PEF variability > 30%PEF variability > 30%
StepStep
Severe persistentSevere persistent
Continual symptomsContinual symptoms
Limited physical activityLimited physical activity
Frequent exacerbationsFrequent exacerbations
Nocturnal frequentNocturnal frequent
FEV1 or PEF ≤ 60%FEV1 or PEF ≤ 60%
PEF variability >PEF variability >
30%30%
Escalation of Drug Treatment of Chronic/Stable AsthmaEscalation of Drug Treatment of Chronic/Stable Asthma
Step 1(mild or occasional asthma)
Short-acting bronchodilator
Step2 (patients need more than one or two inhaled β2 –agonist/day)
Regular inhaled corticosteroid
Step3 (uncontrolled symptoms)
Long-acting brnochodilator Increase dose of inhaled corticosteroid
Leukotrine antagonist
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Step4 (patient’s condition poorly controlled)Oral thiophylline
Oral β2 -agonist
Step5
Regular oral corticosteroid
DrugsDrugs Used to Treat AsthmaUsed to Treat Asthma
There are two categories of drugs used
Bronchodilators
&
Anti-inflammatories
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BronchodilatorsBronchodilators
The main drugs used are
β2 –receptors agonist
Muscarinic receptors antagonists
Xanthines
Leukotirne receptors antagonists
β2
- receptor agonists
Stimulate β2 –receptors in bronchial smooth muscles
β2 –receptors results in activation of adenylate cyclase
Two categories of β2 –receptors are used
Short-acting β2 –receptors agonist (SABAs)
Long-acing β2 –receptors agonists (LABAs)
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Short-acting β2 –receptors agonists (SABAs)
Salbutamol
Terbutaline
Fenoterol
Given by inhalation
Maximum effect occurs within 30 mints
Duration of action 3-5 hours
Used as on “needed” basis to control symptoms
Salbutamol is given by I.V infusion in status asthmaticus
Long -acting β2 –receptor agonists (LABAs)Salmeterol
Formoterol
Given by inhalation
Duration of action 8-12 hours
Given regularly twice daily
Given as adjunctive therapy in patients inadequately controlled by
glucocorticoids
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Clinical usesClinical uses
Prevention or treatment of wheezing in patients with reversible
COPD ( short-acting drugs by inhalation)
Prevention of bronchospasm in patients requiring long-term
bronodilataion therapy (long-acting agents)
XanthineXanthine drugsdrugs
Naturally occurring methylxanthines
Theophylline
Theobromine
Caffeine
Theophylline is the main therapeutic drug in this group
Theophylline used as ethylendiamine “ aminophylline”
Third-line drug for asthma
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MethylxanthinesMethylxanthines
Non-selective phosphodiesterase (PDE)inhibitors
Increase cAMP
Activate PKA
Inhibit TNFα
Inhibit leukotriene synthesis
Reduce inflammation & innate immunity
Competitive antagonists of adenosine A1 & A2 receptors
Methylxanthines are given orally in sustained release preparations
Aminophylline is given by slow I.V infusion “status asthmaticus ’’
Methylxanthines stimulate CNS
Increase alertness
Can cause tremor & nervousness
Interfere with sleep
Stimulate respiration
Methylxanthines have positive chronotropic & inotropic effects
Cause generalised vasodilatation
Possess weak diuretic effects
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Theophylline is well absorbed
Metabolised by CYP450
Half-life is about 8hours
Theophylline half-life is increased
Liver disease
Cardiac failure
Viral infections
Theophylline half-life decreased
Heavy cigarette smokers
Drinkers
Clinical usesClinical uses
Second-line drug in addition to steroids in patients DO NOT
respond adequately to β2 –adrenoceptor agonists
Given I.V in acute severe asthma
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Unwanted effectsUnwanted effects
Theophylline is narrow therapeutic index drug
Unwanted effects include
Cardiac dysrhythmia
Seizures
GIT disturbances
Drug interactionsDrug interactions
Theophyline is influenced by many unwanted drug interactions
Enzyme inducers decrease theophylline plasma concentration
Rifmapicin
Phenobarbital
Phenytion
Carbamazepine
Enzyme inhibitors increase thiophylline plasma concentration
Erythromycin
CalrithromycinCiprofloxacin
Dilitazem
Fluconazole
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MuscarinicMuscarinic Receptor AntagonistsReceptor Antagonists
Ipratropium
The main compound used as bronchodilator
Inhibits the augmentation of mucus secretion
Has No effect on late inflammatory phase of asthma
Given by aerosol inhalation
Maximum effect occurs ~ 30 mints & persist 3-5hours
Generally safe & well tolerated
TiotropiumTiotropium Long-acting drug
Used in maintenance treatment of COPD
Clinical usesClinical uses
Adjunct therapy to β2 –adrenoceptor agonists in asthmatic
patients
Chronic obstructive pulmonary disease (COPD)
Bronchospasm participated by β2 –adrenoceptor antagonists
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CysteinylCysteinyl leukotrieneleukotriene receptor antagonistsreceptor antagonists
All cycteinyl leukotrienes (LTC4 LTD4 & LTE4 ) have same
high affinity on cysteinyl leukotriene receptors
Act on leukotriene receptors termed CysLT1
Two receptors have been cloned CysLT1 & CysLT2
Two types of receptors are expressed in
Respiratory mucosa
Infiltrating inflammatory cells
Lukast drugs (montelukast & zafirlukast )antagonise Only
CysLT1
Inhibit exercise induced asthma
Decrease both early & late responses to inhaled allergen
Reduce reaction to aspirin sensitive patients
Relax airways in mild asthma “ less effective than slabutamol”
Reduce sputum eosinophilia
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Their action is additive to β2 –agonists
Given orally “ montelukast once daily & zafirlukast twice
daily”
Used in combination with inhaled corticosteroids usually at
step 3
Few side effects consisting mainly of
Headache
GIT disturbances
Histamine (HHistamine (H11-- receptor antagonists )receptor antagonists )
Have No routine place in asthma therapy
Modestly effective in mild asthma specially in patients with
concomitant allergy “ hay fever”
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AntiAnti--inflammatory Drugsinflammatory Drugs
Glucocorticoids
Reduce the inflammatory component in chronic asthma
↓Formation of cytokines “Th2 cytokines”
↓Activation of eosinophils Inhibit production of PGE2 & PGI2
Life-saving in status asthmaticus
Do not prevent immediate response to allergen or other challenges
Up-regulate β2 – receptors
Decrease mirovascular permeability
Reduce synthesis of IL-3
Glucocorticoids some are ineffective even in high doses
“glucocorticoid resistance ’’
The main compounds used
Beclomethasone
Budesonide
Fluticasone
Mometasone
Ciclesonide
Given by inhalation
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Clinical usesClinical uses
Patients require regular brocnhodialtors
Inhaled beclomethasone
Severely affected patients
Inhaled budesonide
Acute extracerbations of asthma
I.V hydrocortisone
Oral perdnisolone
Severe asthmatic patients Oral perdnisolone
Inhaled steroids
Unwanted effectsUnwanted effects
Oral pharyngeal candidiasis “thrush” with inhaled steroid
Voice problems
Systemic effects occur with high doses “ adrenal suppression”
Systemic effects are less likely with mometasone
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SodiumSodium cormoglicatecormoglicate
Mast cell satbiliser
Inhibits mast cell histamine release
Weak anti-inflammatory effect
Used topically for allergic rhinitis or conjunctivitis
AntiAnti--IgEIgE treatmenttreatment
Humanised monoclonal anti-IgE
Effective in patients with allergic rhinitis & asthma
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StatusStatus AsthmaticusAsthmaticus (severe acute asthma )(severe acute asthma )
Medical emergency
Require hospitalisation
Treatment includes
Oxygen
I.V hydrocortisone
I.V salbutamol or aminophylline
Following patient stabilization
Oral perdnisolone
Neubulised ipratropium
Treatment is monitored by
PEFR
FEV1
Arterial blood gases
Oxygen saturation
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Peak flow meter (left) Nebulizer (right )
Allergic emergenciesAllergic emergencies
AnaphylaxisAnaphylaxis
Emergency involved acute airways obstruction
Adrenaline is given I.M or occasionally I.V
Oxygen
Antihistamine
Hydrocotisone
AngioAngio--oedemaoedema
Intermittent occurrence of focal swelling of skin or intra-abdominal
organs Caused by plasma leakage from capillaries
Often Most mild & idiopathic
Can occur as part of allergic reaction
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Can be caused by drugs
Hereditary form is associated with lack of C1 esterase inhibitor
Tranexamic acid & danazol may be used to prevent attacks in
patients with hereditary angioneurotic oedema
Administration of C1 esterase inhibitor & fresh plasma can
terminate acute attack
Chronic Obstructive Pulmonary DiseaseChronic Obstructive Pulmonary Disease
Major global health problem
Cigarette smoking is the main cause
Clinical picture starts with
Attacks of morning cough
Progressive breathlessness
Pulmonary hypertension is a late complication Exacerbation may be complicated by type 1 or type 2
respiratory failure
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PathogenesisPathogenesis
Chronic inflammation predominantly in small airways & lung
parenchyma
Inflammation characterised by ↑number of
Macrophages
Neutrophils
T lymphocytes
All of the following are implicated in the pathogenesis
Lipid mediators
Reactive oxygen
Nitrogen species
Chemokines
Cytokines
Growth factors
There is small airways fibrosis
Obstruction &/or destruction of alveoli
Emphysema
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TreatmentTreatment
Oxygen
PerdinsoloNebulised salbutamol (5mg) & ipratropium (500μg)
4-6 times/day
ne 30mg daily for 7-10 days
Antibiotics ( in case of infection)
I.V aminophylline if patient failed to respond to above
measures
Smoking cessationSmoking cessation
Recommended Therapy for Stable COPD
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CoughCough
Protective mechanism removes foreign materials & secretions
Can be triggered by respiratory tract inflammation
Two types of cough
Dry cough
Productive cough
Antitussive drugs act by an ill-defined effect in the brain stem
depressing cough centre
Antitussive drugs are to be avoided in chronic pulmonary
infections
All opioid narcotics have antitussive effect
Dextramethophran & pholcodine have fewer adverse effect
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AntitussivesAntitussives “Cough suppressants”“Cough suppressants”
• Used for dry cough
• Decrease frequency & intensity of cough
• Act
– Centrally
» Peripherally
• Peripherally acting drugs include
Linctuses
• Centrally acting
Opioids “Dextromorphan”
Respiratory stimulants “ Analeptic drugs “Respiratory stimulants “ Analeptic drugs “
Aminophylline
Doxpram
• Increase rate & depth of respiration
• Drugs with narrow therapeutic index
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SurfactantsSurfactants
Beractant & poractant alpha
Effective in prophylaxis & management of respiratory distress
syndrome in newborn
Act with their physiochemical prosperities within airways
Administered directly via endotracheal tube