pharmacology blok respirasi

7/23/2019 Pharmacology Blok Respirasi

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Prajogo Wibowo


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Relief of Cough

Two types of cough:

productive- leads to removal of

sputum from the lungs dry cough- no removal of sputum


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Treatment of cough mainly consists of treatingthe underlying cause. A productive cough

should not be suppressed except in special

circumstances (eg when it exhausts thepatient or prevents rest and sleep! and generally not

until the cause has been identi"ed. #uppressing a productive cough is less

advisable because sputum needs to becleared.

$ough remedies are categori%ed asantitussives and expectorants.


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Antitussives

&ither centrally or peripherallyacting. $entrally acting antitussivesinhibitor suppress the cough re'exby depressing the medullary coughcenter or associated higher centers.The most commonly used drugs in

this group are dextromethorphanand codeine.


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Dextromethorphan, a congener ofthe narcotic analgesic levorphanol,has no signicant analgesic orsedative properties does notdepress respiration in usual dosesand is nonaddictive. o evidence of

tolerance has been found duringlong)term use. &xtremely high dosesmay depress respiration.


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Codeine

which has antitussive, analgesic, andslight sedative eects, is especially usefulin relieving painful cough. *t also exerts adrying action on the respiratory mucosathat may be useful (e.g., in bronchorrhea)or deleterious (e.g., when bronchialsecretions are already viscous!. At dosesused for cough suppression codeine has

minimal respiratory depressant e+ects.ausea vomiting constipation toleranceto antitussive as well as analgesic e+ectsand physical dependence can occur butpotential for abuse is low.


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,ther centrally acting antitussivesinclude:

Nonnarcotic : chlophedianollevopropoxyphene and noscapine

Narcotic: hydrocodonehydromorphone methadone andmorphine


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Peripherally acting antitussives may act on

either the a+erent or the e+erent side of the

cough re'ex.

,n the aferent side an antitussive may

reduce the input of stimuli by acting as a mild

analgesic or anesthetic on the respiratory

mucosa by modifying the output and viscosity

of the respiratory tract 'uid or by relaxing the

smooth muscle of the bronchi in the presence

of bronchospasm.


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,n the e+erent side an antitussive mayma-e secretions easier to cough up byincreasing the eciency of the cough

mechanism. Peripherally acting agentsare grouped as demulcents localanesthetics and humidifying aerosolsand steam inhalations.


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/emulcents are useful for coughsoriginating above the larynx. Theyform a protective coating over theirritated pharyngeal mucosa. Theyare usually given as syrups orlo%enges and include acacia licorice

glycerin honey and wild cherrysyrups.


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0ocal anesthetics (e.g., lidocaine,benocaine, hexylcaine hydrochloride, andtetracaine) are used to inhibit the cough

re'ex under special circumstances (e.g.,before bronchoscopy or bronchography!.

1en%onatate a congener of tetracaine is alocal anesthetic2 its antitussive e+ect may

be due to a combination of localanesthesia depression of pulmonarystretch receptors and nonspeci"c centraldepression.


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Humidiying aerosols and steaminhalations exert an antitussive e+ectby acting as a demulcent and by

decreasing the viscosity of bronchialsecretions. *nhaling water as an aerosol oras steam with or without medicaments(sodium chloride compound ben%ointincture eucalyptol! is the most commonmethod of humidi"cation. The ecacy ofadded medicaments has not been clearlyproved.


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Expectorants

These drugs help expel bronchialsecretions from the respiratory tract bydecreasing their viscosity thus facilitating

removal and by increasing the amount ofrespiratory tract 'uid thus exerting ademulcent action on the mucosal lining.3ost expectorants increase secretions

through re'ex irritation of the bronchialmucosa. #ome li-e the iodides also actdirectly on the bronchial secretory cellsand are excreted into the respiratory tract.


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The use of expectorants is highlycontroversial. o objective experimentaldata show that any of the available

expectorants decreases sputum viscosityor eases expectoration. /ata may belac-ing partly because of inade4uatetechnology for obtaining such evidence.

Thus the use and choice of expectorantsare often based on tradition and thewidespread clinical impression that theyare e+ective in some circumstances.


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Ade4uate hydration is the singlemost important measure that can beta-en to encourage expectoration. *fit is unsuccessful using anexpectorant in addition may producethe desired result.


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Iodides

are used to li!uefy tenacious bronchial secretions(e.g., in late stages of bronchitis bronchiectasisand asthma!. A saturated solution of potassiumiodide is the least expensive most commonly

used preparation. Their usefulness is limited bylow patient acceptance because they have anunpleasant taste and because side e+ects (e.g.,acneiform s-in eruptions cory%a erythema offace and chest painful swelling of the salivaryglands! are common. The side e+ects are

reversible and subside when the drug is stopped.*odinated glycerol is better tolerated thanpotassium iodide solution but is probably lesse+ective. Prolonged use of iodides or iodinatedglycerol can lead to hypothyroidism.


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"uaifenesin is the most commonlyused expectorant in #$% coughremedies. &t has no serious adverse

e+ects but there is no clear evidenceof its ecacy.

3any other traditional expectorants(e.g., ammonium chloride, terpin

hydrate, creosote, s4uill! are found innumerous ,T$ cough remedies. Theirecacy is doubtful particularly in thedosages of most preparations.


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0ess commonly used drugs: 3ucolytics (e.g.,acetylcysteine) have free sulfhydryl groups thatopen mucoprotein disul"de bonds reducing theviscosity of mucus. As a rule their usefulness is

restricted to a few special instances such asli4uefying thic- tenacious mucopurulentsecretions (e.g., in chronic bronchitis and cysticbrosis). 'cetylcysteine is given as a 56 to 768solution by nebuli%ation or instillation. *n somepatients mucolytics may aggravate airway

obstruction by causing bronchospasm. *f thisoccurs these patients may inhale a nebuli%edsympathomimetic bronchodilator or ta-e aformulation containing acetylcysteine (568! andisoproterenol (6.698! before ta-ing themucolytic.


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Proteolytic en%ymes (e.g., pancreaticdornase) are useful only when grossly

purulent sputum is a major problem. They

seem to o+er no advantage over mucolytics.0ocal irritation of the buccal and pharyngealmucosa and allergic reactions commonlyfollow repeated doses. /ornase alfa the newhighly puri"ed recombinant humandeoxyribonuclease * (rh/ase! seems li-elyto become important in the treatment ofcystic "brosis although its place has not beende"ned.


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Decongestants

These agents are all )adrenergicagonists. They exert their action byvasoconstriction of nasal bloodvessels reducing the volume of thenasal mucosa and opening up theairways. They can either be used

topically for short)term relief orsystemically for prolonged relief.


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#hort)acting (topical! decongestants:/elivered as nasal sprays these agentshave the bene"t of avoiding deleterious

side)e+ects of systemic introduction of)agonists. The most commonly usedshort)acting agonist decongestant isphenylephrine. ;epeated topical use of

these compounds can lead to down)regulation of the receptors andsubse4uent rebound hyperemia in thenasal blood vessels.


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Long-acting systemic

decongestants


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Treatment of Asthma

Pathophysiology of Asthma

clinically characteri%ed by recurrent episodicbouts of coughing whee%ing and shortness ofbreath.

4uantitated by a reduction in =&>5

physiologically characteri%ed by increasedresponsiveness of trachea and bronchi to variousstimuli and by widespread narrowing that

changes either spontaneously or in response totherapy.

pathologically characteri%ed by contraction ofairway smooth muscle mucosal thic-ening fromedema and cellular in"ltration.


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Pathogenesis of Asthma essentially a hyper)responsiveness to a number

of substances that results in a reduction in therespiratory system?s ability to provide sucient

air'ow . mediated by *g& antibodies bound to mast cells

in airway mucosa re)exposure to antigen (pollen fur etc.!

antigen)antibody reaction triggers the release of

mediators stored in mast cell granules andsynthesis and release of other mediators. early mediators include: histamine tryptase and

other neutral proteases leu-otrienes (0T$@0T/@! prostaglandins


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result of mediators is airway smoothmuscle contraction and vascular lea-age

late mediators include: 3)$#=

interleu-ins (*0@ *09! late mediators attract and activate

eosinophiles and stimulate *g& production released mediators also activate neural

pathways that can result in the release of

compounds such as A$h at smooth muscleby vagal e+erents resulting in contraction:


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Therapeutic Approach to

Asthma asthmatic bronchospasm results from a

combination of a release of mediators andan exaggerated response to their e+ects

from the various steps involved in theprocess there are several points ofattac-:

)prevent mast cell degranulation

)reducing bronchial responsiveness)relax airway smooth muscle

all three approaches are in current use.


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ALBUTEROL

Drug Class: 1eta)7 AdrenergicAgonist (short acting!

Mechanism o Action: #elective C7 agonist. The prime action

of beta)adrenergic drugs is tostimulate adenyl cyclase the en%yme

which cataly%es the formation ofcyclic A3P from ATP. cA3P mediatesthe cellular responses


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ALBUTEROL

Indications: To produce bronchodilation

Prevention and relief ofbronchospasm related to asthmaandDor exercise)inducedbronchospasm

Contraindications: A history of hypersensitivity to

albuterol


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ALBUTEROL

Side fects:

3anifestations of overdosage may

include: tremors

hypo-alemia

hypo) or hypertension

angina E tachycardia with rates up to 766beatsDmin


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ALBUTEROL

3ajor drug *nteractions: ,ther sympathomimetic aerosol

bronchodilators or epinephrine should not

be used concomitantly with albuterol Albuterol should be administered with

extreme caution to patients being treatedwith 3A, inhibitors or tricyclic anti)depressants since the action of albuterolon the vascular system may bepotentiated


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TERBUTALINE

Drug Class: 1eta)7 Adrenergic Agonist Mechanism o Action: same as albuterol

Indications: Prevention or ;eversal of bronchospasm in

patients with bronchial asthma and reversiblebronchospasm associated with bronchitis andemphysema

*n some patients the severity of

bronchoconstriction can limit the delivery ofdrugs by inhalation ma-ing systemic drugadministration necessary
http://tmedweb.tulane.edu/pharmwiki/doku.php/albuterolhttp://tmedweb.tulane.edu/pharmwiki/doku.php/albuterol


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TERBUTALINE

Contraindications:

hypersensitivity

#ide &+ects:

#imilar to those commonly seen with othersympathomimetic agents (e.g. albuterol!

All these reactions are transient in nature andusually do not re4uire treatment

Pharmaco-inetics: typically given by s.c. inection

3ajor drug *nteractions:

same as with albuterol
http://tmedweb.tulane.edu/pharmwiki/doku.php/albuterolhttp://tmedweb.tulane.edu/pharmwiki/doku.php/albuterolhttp://tmedweb.tulane.edu/pharmwiki/doku.php/albuterolhttp://tmedweb.tulane.edu/pharmwiki/doku.php/albuterol


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THEOPHYLLINE

Drug Class: 3ethylxanthine

Mechanism o Action:

Produces direct bronchodilation and has some

anti)in'ammatory actions in the airway. At therapeutic doses theophylline inhibits

adenosine receptors. These receptors modulateadenyl cyclase activity and adenosine cancause contraction of airways and provo-e

histamine release from mast cells. At high concentrations methylxanthines can

also inhibit phosphodiesterase therebyelevating cA3P.


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Indications: treatment of the symptoms and reversible

air'ow obstruction associated with chronic

asthma and other chronic lung diseasese.g. emphysema and chronic bronchitis.

Theophylline is rarely used anymore dueto the availability of short acting beta7

agonists that have both a much largertherapeutic index (safety margin! andsuperior ecacy of bronchodilation.


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!harmaco"inetics:

Theophylline should only be used where methods tomeasure blood levels are available due to its narrowtherapeutic index.

Therapeutic levels range from 9)76 mgD0 and levelsabove @6 mgD0 may cause sei%ures or arrhythmias.

Theophylline is metaboli%ed by the liver withplasma clearance that can be e+ected by liverdisease cigarette smo-ing or by changes in diet.

$hildren clear theophylline faster than adults

#mo-ing causes en%yme induction whichsigni"cantly increases theophylline clearance


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Side fects:

0ow doses ) mild cortical arousal E deferral offatigue

Figh doses ) convulsions cardiac arrhythmias death

1ecause of the high morbidity and mortalityassociated with theophylline)induced sei%urestreatment of sei%ures should be rapid and aggressive.

The initial treatment for sei%ures is i.v. dia%epam.;epetitive sei%ures are treated with phenobarbital.

The doses of these drugs re4uired totreat theophylline induced sei%ures may be close tothose causing respiratory arrest.


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ONTELU!A"T

Drug Class:0eu-otriene *nhibitor

Mechanism o Action:

an $%D&'receptor antagonist

Indications: for the prophylaxis and chronic treatment of

asthma in adults and pediatric patients G years ofage and older.

*t is ,T indicated for use in the reversal ofbronchospasm in acute asthma attac-s.

!harmaco"inetics:

e+ective orally ta-en once a day (typically in theevening!


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#A$IRLU!A"T

Drug Category:0eu-otriene receptorantagonist

Mechanism o Action:

0eu-otriene receptor antagonist !harmaco"inetics:

twice daily dosing food can a+ect bioavailability(ta-e 5 hr before or H7 hrs after meals!

Side fects: cases of life)threatening hepatic failure have been

reported


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#ILEUTON

Drug Class:0eu-otriene pathwayinhibitor

Mechanism o Action: orally active inhibitor o ('

lipoxygenase the en%yme thatcataly%es the formation of

leu-otrienes from arachidonic acid


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Indications: prophylaxis and chronic treatment of

asthma in adults and children 57years of age and older. (It is notindicated or use in the re)ersalo bronchospasm in acute asthma

attac"s!. !harmaco"inetics:

e+ective orally ) @ times a day dosing.


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Cromolyn & Nedocromil

act by inhibiting mast cell degranulationpresumably by inhibiting delayed chloridechannels which are involved in the process ofmast cell activation

e+ective only when used prophylactically cannot reverse bronchospasm or alter bronchial

tone poorly absorbed from the gut so delivered

topically by inhalation of a micro"ne powder or

aerosoli%ed solution. can also be used as a nasal spray to reduce

symptoms of allergic rhinitis very few side e+ects presumably due in part to

the locali%ed application of the drugs


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Methylxanthines such astheophylline act by reducing the brea-down of cA3P through the

inhibition of phosphodiesterases cA3P has bronchodilator activity through increasing

the rate in inactivation of 30$I an importantcomponent in smooth muscle contraction:

)agents that elevate JcA3PK will lead to bronchodilation methylxanthines are ta-en orally and this can lead to

a number of side)e+ects due to increases in JcA3PK ina number of other systems:

$#2 nervousness and tremor

$ardiovascular: positive chronotropic and inotropice+ects

*: stimulate secretion of gastric acid and digestiveen%ymes

;enal: diuretic activity


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need to measure plasma levels ofthese compounds in order ensurethat levels remain in the therapeuticrange (9)76 mgD0 for theophylline!2toxicity is most common atlevelsH@6 mgD0 (remember the

pharmaco-inetics simulationsL! no longer used as a "rst)line therapy.


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Corticosteroids

have anti)in'ammatory action so reduce theresponsiveness of airways.

do not reverse bronchospasm thought to wor- mainly via inhibition of the

production of cyto-ines can be delivered either orally or inhaled oral corticosteroids such as prednisone are usually

only used in cases where urgent treatment is neededdue to the problems with systemic actions of theseagents such as adrenal suppression

treatment with oral corticosteroids is usually for a"xed period only M)56 days

dosages are usually reduced over the period oftreatment to avoid rebound phenomena associatedwith drop in steroid levels.


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inhaled steroids avoid these systemice+ects allowing them to be used inchronicDprophylactic treatment

agents include: beclomethasone (1eclovent >anceril! triamcinolone (A%macort! 'uticasone (=lovent!

most common side e+ect is occurrenceof oropharyngeal candidiasis due tosigni"cant deposition of the steroid onthe oropharynx.


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Beclomethasone

Mechanism o Action: *inds to intracellular glucocorticoid receptors

and modulates gene expression+ Approximately,-. o expressed genes in a cell are regulatedby glucocorticoids+

lucocorticoids have multiple anti)in'ammatorye+ects inhibiting both in'ammatory cells and releaseof in'ammatory mediators.

Impro)ement in asthma control ollo/inginhalation can occur within 24 hourso

beginning treatment in some patients0 althoughmaximum beneft may not be achieved or 1 to 2weeks0 or longer. This is associated with theinhibition of lung in"ltration by eosinophils.


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Indications:

the maintenance treatment o asthma asprophylactic therapy

indicated for asthma patients who re4uire systemiccorticosteroid administration where addingbeclomethasone aerosol may reduce or eliminate theneed for the systemic corticosteroids. (*nhaledbeclomethasone probably acts topically at the site of

deposition in the bronchial tree after inhalation. Anaverage daily dose of @ pu+s twice daily ofbeclomethasone (@66 NgDday! is the e4uivalent of 56O59mgDday of oral prednisone for the control of asthma withfar fewer systemic e+ects!.

1eclomethasone is NOTindicated for the relief of acutebronchospasm.


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Budesonide

Mechanism o Action: 1inds to intracellular glucocorticoid receptors and

modulates gene expression. Approximately 768 ofexpressed genes in a cell are regulated byglucocorticoids.

lucocorticoids ha)e multiple anti'in1ammatoryefects0 inhibiting both in1ammatory cells andrelease o in1ammatory mediators.

*mprovement in asthma control following inhalationcan occur within * hoursof beginning treatment in

some patients although maximum benet may not beachieved for + to wees or longer. This is associatedwith the inhibition of lung in"ltration by eosinophils.


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!harmaco"inetics:

Aerosol inhalation

3ost of budesonide delivered to thelungs is systemically absorbed. *nhealthy patients @8 of the metereddose is deposited in the lungs with an

absolute systemic availability of Q8 ofthe metered dose

*f it is ta-en orally budesonide has avery low (G)58! oral bioavailability


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