Bromhexine-TB Day 2013

Introduc)on

•  Normaly à mucus produc)on / day •  Sputum is mucus that is coughed up from the lower airways

•  Sputum à expectorated excessive secre)ons •  Airways mucus hypersecre)on à impaired mucus clearance, mucus reten)on

•  The characteris)c of mucus change à infec)on and inflamma)on

•  TB pa)ents à produc)ve cough

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•  Sputum produc)on, excessive mucus in the airway lumen, goblet cell hyperplasia, submucosal gland hypertrophy

•  Sputum, mucus >> = hypersecre)on

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Mucus Hypersecre)on

•  Effec)ve mucus clearance à lung health •  Healthy mucus à gel with low viscosity and elas-city à easily transported with ciliary ac)on

•  Pathologic mucus à higher viscosity and elas-city à less easily cleared

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•  Pathologic mucus •  Changes its hydra)on and biochemical cons)tuents – Abnormal secre)ons of mucins –  Infiltra)on of mucus with inflammatory cells – Heightened bronchovascular permeability

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Overproduc-on mucus

Decreased clearance

Accumula-on persistent mucus

infec-on and inflamma-on

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•  Principal symptoms of impaired mucus clearance – Cough: s)mula)on of vagal afferents in the intrapulmonary airways or larynx or pharynx

– Dyspnea: Mucus obstruct airflow of occupying the lumen of numerous airways

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Physical sign of impaired mucus clearance

•  Cough •  Bronchial breath sounds •  Rhonchi •  Wheezing

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ISTC Standard 1 All persons with otherwise unexplained productive cough lasting two-three weeks or more should be evaluated for tuberculosis

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Produc)ve cough > 2-‐3 weeks

Fever Decreased of appe)te

Weight loss

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Penularan TB 210512 10

Pathogenesis TB

TB and mucus produc)on

•  TB à chronic infec)on •  Infec)on à macrophage, Mycobacterium TB à inflamma)on à cells death

•  Bronchus à Goblet cell à mucus produc)on >>

•  Cells death + mucus produc)on

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•  Purulent sputum contain pus, composed of white blood cells, cellular debris, dead )ssue, serous fluid and viscous liquid (mucus)

•  Blood vessels à bloody, streaked-‐sputum

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Inflamma)on

•  Mucus hypersecre)ons •  Cilliary dysfunc)on •  Changes in composi)on and biophysical proper)es of airways secre)on

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Inflammatory cells (neutrophils)

Programmed cell death (apoptosis) Necrosis

Pro-‐inflammatory mediators

Damage the epithelium Recruit more inflammatory cells

DNA F-‐ac)n

Cytosceleton

To form a second rigid network within airways secre)ons 14

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www.ccnonline.org CRITICALCARENURSE Vol 29, No. 2, APRIL 2009 37

status of the patient’s immune sys-tem. Stages include latency, primarydisease, primary progressive disease,and extrapulmonary disease. Eachstage has different clinical manifes-tations (Table 1).

Latent TuberculosisMycobacterium tuberculosis

organisms can be enclosed, as previ-ously described, but are difficult tocompletely eliminate.15 Persons withlatent tuberculosis have no signs orsymptoms of the disease, do not feelsick, and are not infectious.19 How-ever, viable bacilli can persist in thenecrotic material for years or even alifetime,9 and if the immune systemlater becomes compromised, as itdoes in many critically ill patients,the disease can be reactivated.

Although coinfection with humanimmunodeficiency virus is the mostnotable cause for progression toactive disease, other factors, suchas uncontrolled diabetes mellitus,sepsis, renal failure, malnutrition,smoking, chemotherapy, organtransplantation, and long-term cor-ticosteroid usage, that can triggerreactivation of a remote infectionare more common in the criticalcare setting.8,19 Additionally, persons65 years or older have a dispropor-tionately higher rate of disease thanany does other age group,20 oftenbecause of diminishing immunityand reactivation of disease.21

Primary DiseasePrimary pulmonary tuberculosis

is often asymptomatic, so that the

results of diagnostic tests (Table 2)are the only evidence of the disease.Although primary disease essentiallyexists subclinically, some self-limitingfindings might be noticed in anassessment. Associated paratracheallymphadenopathy may occur becausethe bacilli spread from the lungsthrough the lymphatic system. Ifthe primary lesion enlarges, pleuraleffusion is a distinguishing finding.This effusion develops because thebacilli infiltrate the pleural spacefrom an adjacent area. The effusionmay remain small and resolve spon-taneously, or it may become largeenough to induce symptoms suchas fever, pleuritic chest pain, anddyspnea. Dyspnea is due to poorgas exchange in the areas of affectedlung tissue. Dullness to percussion

Table 1 Differences in the stages of tuberculosis

Early infection

Immune system fights infection

Infection generally proceeds without signs or symptoms

Patients may have fever, paratracheal lymphadenopathy,or dyspnea

Infection may be only subclinicaland may not advance to activedisease

Early primary progressive(active)

Immune system does not controlinitial infection

Inflammation of tissues ensues

Patients often have nonspecificsigns or symptoms (eg, fatigue,weight loss, fever)

Nonproductive cough develops

Diagnosis can be difficult: findingson chest radiographs may benormal and sputum smears maybe negative for mycobacteria

Late primary progressive(active)

Cough becomes productive

More signs and symptomsas disease progresses

Patients experience pro-gressive weight loss,rales, anemia

Findings on chest radio -graph are normal

Diagnosis is via cultures ofsputum

Latent

Mycobacteria persist in thebody

No signs or symptoms occur

Patients do not feel sick

Patients are susceptible toreactivation of disease

Granulomatous lesions calcifyand become fibrotic, becomeapparent on chest radiographs

Infection can reappear whenimmunosuppression occurs

Table 2 Diagnostic tests for identifying tuberculosis

Variable

Purpose of testor study

Time requiredfor results

Sputum smear

Detect acid-fast bacilli

<24 hours

Sputum culture

Identify Mycobacteriumtuberculosis

3-6 weeks with solidmedia, 4-14 days withhigh-pressure liquid chromatography

Polymerasechain reaction

Identify Mtuberculosis

Hours

Tuberculin skin test

Detect exposureto mycobacteria

48-72 hours

QuantiFERON-TB test

Measure immunereactivity to Mtuberculosis

12-24 hours

Chest radiography

Visualize lobarinfiltrates withcavitation

Minutes

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Expectorant

Mucoly)c

Mucokine)cs

Mucoregulator

? Treatment

The aim of mucus hypersecre-ons treatment

•  To alter rheological proper)es of bronchial mucus

•  To reduce the degree of airways obstruc)on •  To enhance the func)on of the mucociliary escalator

•  To promote expectora)on

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Management of mucus secre)on

•  Short-‐term relief of symptoms – Facilita)ng mucus clearance – Changing the viscoelas)city of mucus –  Increasing ciliary func)on – Encouraging cough

•  Long-‐term benefit – Reversal the hypersecretory phenotype – Reducing the number of goblet cells and the size of the submucosal glands

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Mucokine)cs-‐Mucoac)ve agents

•  Clearance of mucus from the airways, lungs, bronchus and trachea

•  Mechanism of ac)on – Expectorants – Mucoly-c agents – Hypoviscosity agents – Abhesives/surfactanas

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Expectorant •  Signaling the body to increased the amount or hydra)on of secre)ons à clearer secre)ons, lubrica)ng the irritated respiratory tract

•  Increases bronchial secre)on •  Reduces the thickness or viscosity of bronchial secre)ons à increasing mucus flow à removed easily by cough

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Mucoly-c agent •  Dissolves thick mucus à dissolving various chemical bonds within within secre)ons à can lower the viscosity by altering the mucin-‐containing components

•  Break down the chemical structure of mucus molecules à loosen thick bronchial secre)ons

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uncertainties about mechanism of action and imprecisionin clinical trial design. In contrast, dornase alfa has a well-defined mechanism of action (ie, degrades DNA) and isconsidered below to contrast with N-acetylcysteine. In ad-dition, hypertonic saline and aerosolized surfactant are alsomentioned below as examples of interventions that arecurrently under consideration as agents with potentiallybeneficial effects on airway mucus.

N-Acetylcysteine: How Does it Work? Does it Work?

N-acetylcysteine is the mucolytic compound most-listedin pharmacopoeias worldwide,52 and has been used formany years in the treatment of patients with a variety ofrespiratory conditions.63 N-acetylcysteine is mentioned inthe COPD guidelines of both the European RespiratorySociety54 and the American Thoracic Society.56 However,although it is considered a mucolytic drug, this activity isnot well documented,64 and after oral dosing it is not foundin airway secretions.65 N-acetylcysteine is also consideredto have antioxidant properties, because it contains freethiol groups. A related compound, N-isobutyrylcysteine,has higher levels of free thiols than N-acetylcysteine. How-ever, unlike N-acetylcysteine,66,67 N-isobutyrylcysteine hadno effect on exacerbation rate in COPD,68 which questionsthe validity of the free thiol hypothesis for N-acetylcyste-ine activity.

The pharmacokinetics of N-acetylcysteine depend uponits route of administration. Aerosolized inhaled N-acetyl-

Table 3. Mucoactive Agents

MucolyticsCysteineN-AcetylcysteineNacystelynEthylcysteineNesosteineDithiothreitolMESNA (2-mercaptoethanesulphonate sodium)ThiopronineUreaTasuldineCarbocysteine*Carbocysteine-Lys*Erdosteine*Fudostein*Letosteine*Stepronin*Usherdex-4 (a low-molecular-weight form of dextran)

Expectorants/MucokineticsAmbroxolAmbroxol-theophylline-7-acetateBromhexineGuaiacol and derivativesGuaifenesinGuaimesalHypertonic solutions (saline)Inorganic iodidesOrganic iodidesIpecacuanhaSobrerolSodium citrateSquillVolatile inhalants and balsams!2-Adrenoceptor agonistsSurfactantYM-40461 (surfactant secretagogue)

Peptide Mucolytics (Enzymes)Bromelain"-ChymotrypsinRecombinant human deoxyribonoclease I (aka, dornase-alfa and

rhDNase)FericaseFicinGelsolinHelicidinLeucine amino peptidaseNeuraminidaseOnopronasePapainSerratopeptidaseStreptodornaseStreptokinaseThymosin beta 4Trypsin

*Metabolized endogenously to form compounds with free sulphydryl groups

Table 4. Mucoactive Agents Putative Mechanisms of Action

Mucoactive Agent Putative Mechanism of Action

Expectorant Increases volume and/or hydration of secretions.May also induce cough (eg, guaifenesin,

hypertonic saline)Mucolytic Reduces viscosity of mucus

Non-peptide (“classical”) mucolytics cleavedisulphide bonds (“free” or “blocked”sulphydryl groups).

Low-molecular-weight saccharide mucolyticsinterfere with non-covalent interactions inmucus, and may osmotically pull water intoairway lumen.

Peptide mucolytics degrade deoxyribonucleicacid (DNA) or actin

Mucokinetic Increases “kinesis” of mucus and facilitatescough “transportability” of mucus

!2-adrenoceptor agonists increase airflow, ciliarybeat, Cl!/water secretion, and mucinsecretion (small effect).

Surfactant reduces mucus adherence toepithelium.

Mucoregulator Reduces process of chronic mucus hypersecretion(eg, glucocorticosteroids, anticholinergics,macrolide antibiotics)

MUCOACTIVE AGENTS FOR AIRWAY MUCUS HYPERSECRETORY DISEASES

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Mucoac)ve agent

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Bromhexine •  Some types of TB have symptom like productive cough

or sputum production. •  Bromhexine has a triple effect (thin, loosen, and clear)

on mucus, making it easier to cough up.

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Reduction on viscosity : -46% (p<0.001) Placebo : no significant effect

Effect Bromhexine on viscosity of sputum (mucus)

Difficulty of expectoration (mean±SE) ** p<0.01 (t-test)

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Bromhexine reduce difficulty of expectoration by approx. 59%, significant difference to

placebo (p<0.01)

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Thomson, M.L, et al., Bromhexine and Mucociliary Clearance in Chronic Bronchitis, Brit. J. Dis. Chest., 1974, 68, 21-27

Pada jam ke-6 setelah inhalasi radioaktif,

pengeluaran mukus pada pasien lebih besar

6,8% setelah menerima

dibandingkan sebelum menerima Bromhexine (perbedaan signifikan,

p<0,05) atau peningkatan 14,5%

dibandingkan kontrol.

* Penelitian menggunakan inhalasi radioaktif untuk memperlihatkan pergerakan mukus

The role of mucoac)ve in TB

•  The role of mucoac)ve agent in TB •  To help pa)ent to expectorate sputum à AFB examina)on

•  To reduce the respiratory problems (dyspnea due excessive mucus produc)on)

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Conclusion

•  Op)mal treatment of mucus hypersecretory element of each disease should be disease specific

•  Choose the right selec)on of mucoaca)ve agent

•  The role of mucoac)ve agent in TB to reduce accumula)on of excessive mucus

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Bromhexine-TB Day 2013

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