8. drugs for respiratory system.pdf

8/19/2019 8. Drugs for Respiratory System.pdf

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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


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


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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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

8. drugs for respiratory system.pdf

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