OS 213: Human Disease and Treatment 3 (Circulation and Respiration)LEC 03: Drugs Acting on the Respiratory SystemExam 2 | Cecilia A. Jimeno, MD | 23 August 2012

Objectives Understand the pharmacologic basis of drugs used in COPD

and ASTHMA Management of other causes of cough, congestion and

mucus problems TO ACHIEVE OPTIMAL THERAPY Differentiate Relievers vs controllers (GINA 2006) Understand therapy of COPD Focus: TREATMENT OF NON INFECTIOUS RESPIRATORY

CONDITIONS

I. BRONCHOSPASTIC CONDITIONSCOMMON DRUGS GIVEN FOR ASTHMA AND COPD

Bronchodilators Anti-inflammatory Drugs / Anti-mediator Drugs

1. β-adrenergic agonists• SABA, LABA

2. Anticholinergic agents• SAMA, LAMA

3. Methylxanthine (theophylline) – • Short acting (aminophylline

theophylline) • Long Acting (Doxofylline)

1. Corticosteroids• When systemically given,

high dose- relievers• Inhaled, low-dose-

controllers2. Leukotriene inhibitors3. Cromones – esp those with

allergy* disease modifying

A. ASTHMA A pulmonary disorder associated with an inflammatory response

to a variety of factors (triggers – e.g. antigens, stress and exercise) o control triggers control response avoid asthmatic attacko Stress increases glucocorticoids but still induces asthma

characterized by increased pulmonary inflammation followed by bronchial hyper-reactivity and eventually, decreased lung function due to airway narrowing (due to bronchial muscle contraction), congestion and edema (“airway remodeling” which can be reversible)

STRUCTURAL AND FUNCTIONAL CHANGES IN ASTHMA Changes are cumulative and are not immediately permanent.

Continued usage of controllers must be maintained to prevent worsening of condition (otherwise increase in usage of relievers)

ADR of frequent use of relievers include hypokalemia and arrhythmia, which may result to death.

Relievers must be used to intervene and reverse these changes. If not used early, more potent drugs must be used to reverse changes. (Asthma is NOT a progressive disease, unlike COPD. If given proper management, it may revert to normal. In between attacks, pulmonary functions are normal.)

Histologic (“airway remodeling”), airway occlusion due to:o mucous plugs (jelly lungs)o mucosal and submucosal edemao smooth muscle hypertrophyo thickening of basement membraneo hypertrophy of submucous glands

Functional o hyper reactive airways (drug: Anti inflam corticosteroids)

o variable airway obstruction (drug: Bronchodilators)

B. CHRONIC OBSTRUCTIVE PULMONARY DISEASE Gel-forming mucins are produced by goblet cells and mucous cells In health, these cells are found in large airways, sparse in small

airways Goblet cells increase in number, mucous cells increase in size Patients usually complain of chronic sputum production End result: impaired mucociliary clearance (terminal and

respiratory bronchioles are not cleared by cough)o Increased mucus secretions

Table 1. Comparison of asthma and COPDAsthma COPD

Similarity Both are characterized by airway narrowing secondary to chronic inflammation

Difference

Eosinophils are predominant throughout the respiratory tract

Neutrophil infiltrates are predominant in the peripheral airwaysrelease proteolytic enzymes* which destroy the lung parenchyma (emphysema) loss of support for airways and early closure on expiration*responsible for permanent destruction

MAIN DIFFERENCE

Treated correctly, can go back to normal (REVERSIBLE)

You can never go back to baseline normal (PERMANENT AND PROGRESSIVE)

C. IMMUNOPATHOGENESIS OF ASTHMA AND COPD

Figure 1. Immunopathogenesis of asthma and COPD.

Early phase quick decrease in FEV1 (within seconds- minutes) due to smooth muscle contraction caused by mast cells degranulation (releasing mediators such as histamine and tryptase); constriction of airways

If untreated, late phase inflammatory cells and eosinophils cause further inflammation and airway obstruction cell wall edema, increase in mucus production

If airways are damaged, it may progress to COPD, and there is a decrease in FEV1.

D. APPROACHES TO DRUG TREATMENT ASTHMA: Inflammation , hyperreactivity, bronchoconstriction

Address: bronchial smooth muscle contractions and/or airway edema

MECHANISM OF ACTION

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ASTHMA, COPD(ABN PULM FXN =>S/S)COUGH/COLD disorders

THERAPEUTICSGOAL: Relief, Restoration, Cure(?)Drug Rx: Basic & Clinical Pharm

Non-Drug Rx, Alternative Rx

NORMAL AIRWAYSNORMAL PULMO FXN

(Pulmonary homeostasis)

LEC 03: Drugs Acting on the Respiratory System Direct relaxation of airway smooth muscle, with consequent

bronchodilation: “bronchodilators” o Short acting beta-agonists: relieverso Examples: β2-adrenergic agents, anticholinergic agents,

methylxanthines Target sites of action at the molecular level (mediator synthesis/

release, receptor activation): “anti-asthmatics ” o Anti-inflammatory action (glucocorticoids)o Addresses the underlying disease condition in order to

prevent the need for bronchodilatorso Examples: glucocorticoids, inhibitors of mediator synthesis,

inhibitors of mediator release, receptor antagonists o Prevent further asthma occurrences

RELIEVERS AND CONTROLLERS RELIEVERS CONTROLLERS (preventers)

1. Short-acting Bronchodilators Short acting beta agonists

(SABA)- Sympathomimetics: β2-selective; non-selective; drug of choice

Anti-cholinergics (short acting ones)

Methylxanthines (quick acting – e.g., Theophylline)

2. Systemic Glucocorticosteroids (oral, IV, IM) – more rapid onset of action

1. Inhaled glucocorticoids (prolonged effect – takes 1 to 2 weeks before you get the full effect); will also inhibit bronchial airway reactivity2. Leukotriene Inhibitors (NSAIDs)3. Anti-allergic agentschromones4. Long-acting SR Bronchodilators Long acting β2-agonists (LABAs) Methylxanthines (long acting –

e.g., Doxofylline)

Table 2. Comparison between Relievers and ControllersNOTE: The two classifications have the same component drugs for asthma treatment despite category differences. SABA, if used chronically, can act as controller. But it is not supposed to be

given as maintenance monotherapy SABA are used as needed, and for immediate relief; relief is not persistent,

to control inflammation, you need to give anti-inflammatory drugs. Sife effects of SABA include tachycardia, hypokalemia, tremors, irritability. Red flag: the frequency of use of SABA. If it’s used frequently, there might

be a need to switch to LABA (controllers). Frequent use of SABA may cause arrhythmia, and sometimes, death.

In persistent asthma, check for exacerbation. If severe, before giving inhaled steroids (which take awhile to take effect), give systemic steroids.

TREATMENT BASED ON ASTHMA SEVERITY (Old Classfication)Severity Daily Controller Alternative Controller Reliever

Intermittent None needed SABA PrnMild to

Moderate Persistent

(ICS + LABA) combination

inhaler

ICS high or regular dose + either SR theoph/ LTx/oLABA

SABA Prn

Severe Persistent

(OCS + ICS + LABA) + either SR theoph/

LTx/oLABA

SABA Prn

Table 3. Treatment of asthma based on severity (old classification)SABA: Short-Acting Β Agonist; LABA: Long-Acting Β Agonist; ICS: Inhaled Corticosteroids; OCS: Oral Corticosteroids; LTx: Leukotriene; SR Theophylline: Sustained-release Theophylline; Prn = “pro re nata” if the need arises (if there is an attack)

CLASSIFICATION OF CHRONIC ASTHMA SEVERITY ON TREATMENTDomains / Estimates

Intermittent PersistentMild to

ModerateSevere**

Daytime symptoms

Monthly Weekly Daily

Nocturnal awakening

Less than monthly

Monthly to weekly

Nightly

Rescue β2

agonist useLess than

weeklyWeekly to daily Several times a day

PEF or FEV1* > 80% predicted

60 to 80% predicted

< 60% predicted

Treatment needed to control asthma

Occasional prn β2 only

Regular ICS + LABA

combination

Combination ICS + LABA + OCS

Table 4. Classification of chronic asthma severity*Objective measures take precedence over subjective complaints. The higher severity level of any domain will be the basis of the final severity level. **Patients who are high risk for asthma-related deaths initially classified here

II. BRONCHODILATORSAction: relaxes airway smooth muscle

Beta-adrenergic Receptor Agonist (Salbutamol etc) Anti-cholinergic / Anti – Muscarinic (Ipatroprium Bromide etc) Methylxanthines (Theophylline etc)

A. β-ADRENERGIC RECEPTOR AGONISTS Βetamimetic or sympathomimetic Particularly B2 adrenergic agonists Action: activate adenylyl cyclase, which catalyzes conversion of

ATP to cyclic AMP (cAMP) Increased cAMP relaxation of airway smooth muscle in lungs

and other sites Other effects: attenuation of mast cell degranulation,

improvement of mucociliary transport, cardiac, cns, metabolico Causes effects in cardiac (tachycardia because they are

chronotropic), CNS (increased alertness, insomnia), metabolic (increase in blood sugar, insulin resistance, hypokalemia)

o Thus, inhaled preparations are preferred so that lungs are directly targeted; however, 90% of dose is swallowed systemic effects

o Oral salbutamol is popular because it’s cheaper than the inhaler but more side effects (difficulty of sleeping, insomnia)

β2-agonists relax airway smooth muscle directly, and may also cause bronchodilation indirectly by inhibiting release of mediators from inflammatory cells or neurotransmitters from cholinergic nerves. (Increase airway caliber by relaxing smooth muscles and decreasing the mediators, so there will be a decrease in airway inflammation and decrease in edema). Acetylcholine has secondary role in bronchoconstriction.

CLINICAL USES OF Β-ADRENERGIC AGONISTS Mainstay for asthma control during acute attack Potent bronchodilators: relax airway smooth muscle

1. Inhaled short-acting β adrenergic agonists (SABA)o Mild asthma or as relieverso Emergency ‘rescue’ drugs for acute exacerbations o Onset of action in 15-30 mins and provide relief for 4-6 hrso For symptomatic treatment of bronchospasm in asthma and

COPDo as relievers or “rescue” agents to combat acute

bronchoconstriction AND ANTI-INFLAMMATORY ACTION (last year’s trans says no inflammatory action, but right now, meron na daw)

o Never used as single therapyin moderate to severe asthma – steroids are essential

o Side effects (due to β1 effects – especially if systemic): more apparent in oral: tachycardia, hyperglycemia, hypokalemia, tremors, palpitation, increased wakefulness

o Examples: Salbutamol (prototype drug) Albuterol (US), Terbutaline. Preferentially inhaled. Terbutaline hypokalemic effect; can be used for

hyperkalemia

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LEC 03: Drugs Acting on the Respiratory System

2. Long Acting Β-Adrenergics (LABA)o maintenance for persistent asthma or as controllerso Never used as single therapy in moderate to severe asthma –

steroids essential (note: has same systemic effects as SABA cos it still is beta-adrenergic, so it also may cause tachycardia, etc. So, you cannot use it as a single therapy. Corticosteroids may be used as a single therapy though.)

o Salmeterol chemical analog of salbutamol with a prolonged time of

action for at least 12 hrs but has slow onset of action so it cannot be used for acute asthmatic attacks

prolonged action is mainly due to its bulky methyl group in its terminal amino acid.

Allows greater affinity to β-2 receptor - longer effect stimulates β2 receptors and apparently has little or no

effect on alpha, β1 or β3 selectivity of salmeterol for β2 versus β1 adrenergic

receptors is greater than that of other β agonists. o Formoterol

Unique among LABA’s now recognized for its rapid action (“SABA property”)

and longer half life, and hence can be used as both reliever and controller

o Other agent: Procaterol

STRUCTURE-ACTIVITY RELATIONSHIPS Catecholamines (e.g. epinephrine ): OH group in 3 and 4 position of

phenyl ring methylated by COMT in gut, other tissueso Epinephrine for anaphylactic bronchoconstriction; not used

as reliever because of toxicityo Methylated: cannot be taken orally because it will be quickly

metabolized; for instant relief only Non-Catecholamines (eg, salbutamol, terbutaline): orally active Ventolin expectorant (salbutamol) is given in children esp. when

there is difficulty in using inhaler, but oral forms have systemic ADR’s.

Substitution on alpha-C atom blocks action by MAO longer duration of action (long-acting vs. short-acting non-catecholamines)

B. ANTI-CHOLINERGIC DRUGS / ANTI MUSCARINIC ANTAGONISTS

“Parasympatholytic”: inhibits vagally-mediated reflexes by antagonizing Ach

Action: Blocks acetylcholine in the muscarinic receptoro Blocks Ach-induced smooth muscle contraction and excessive

mucus productiono Prevents increase in intracellular concentration of cyclic

guanosine mono-phosphate (cGMP) Prototype drugs: Ipratropium bromide (prototype drug, short

acting), tiotropium (long-acting) May play an important role in regulating acute bronchomotor

response BUT are generally less effective than β-adrenergic agonists better used in COPD

Effect on COPD patients more remarkable than in asthma patients o Preferred in COPD patients over LABA drugso (2014) In COPD, even without the attack, there is already a

narrowing of the lumen; this is maintained by increase in vagal tone; any increase in vagal tone will further narrow airway lumen. Thus, controlling vagal tone is more essential for someone with already constricted airways than someone who still has normal airways (asthma)

anti-cholinergics are used for people with asthma if they cannot tolerate side effects of SABAs

Effects of anticholinergic drugs.Anticholinergic drugs inhibit vagally-mediated airway tone leading to bronchdilatation. This effect is small in normal airways but greater in the

airways of COPD patients, which are structurally narrowed. (note that the airways will never return to its baseline diameter when anti-cholinergics are used.)

IPRATROPIUM BROMIDE Atropine-like structure but lacks atropine effects on pupils,

respiratory secretions, pulse rate, BP Structure activity relationships: quaternary derivatives (CNS,

pharmacologic) Alternative for patients unable to tolerate inhaled β2 adrenergic

agonists (meter dosed inhaler and nebulized forms) May be used in combination with SABA (inhaled); has an additive

effect Slow onset of bronchodilation (max 30-60 mins) and may persist

for 8 hours Selective and long acting like tiotropium more selective

formulation than ipatropium but costly! – 150/day Tiotropium (Spiriva)- dry powder inhaler, crushed inside inhaler;

careful! Some patient’s have taken the tablet orally because they thought it was an oral drug

TREATMENT OF ASTHMA AND COPD: COMBINATION TX FIXED dose combinations of anti-cholinergics and β-agonists (or

anti-cholinergics and steroids) are popular both in asthma and COPD: these have additive effects providing an advantage over increased doses of β agonists in patients with less side effects

β-agonists and steroids are clearly indicated for asthma as well as SEVERE / VERY SEVERE COPD (again, different from the knowledge before where it says that it is not so much indicated for COPD)

Can inhaled anticholinergics be added to β2 agonists for treating acute childhood and adolescent asthma? Children are more sensitive to ADR ofβ2 agonists A systematic review of RCTs (10 relevant, 6 high quality) Outcome measure: hospital admissions, pulmonary function

tests, number of nebulized treatments, relapse and adverse events

Result of the study: Adding multiple doses (vs. single dose) to β2 agonists seems safe, improves lung function and may avoid hospital administration – shown for school age children and adolescents, not younger o Decreases doses of β2 agonists to decrease its side effects:

↓ hospitalizations, ↑ quality of life*preferred agents for school age children and adolescentsare B-agonists for relievers and controllers

C. METHYLXANTHINES Related to tea, coffee and chocolate asthmatics get addicted to

these due to small bronchodilator effect Action: blocks adenosine receptor; inhibits cyclic nucleotide

phosphodiesterase enzymes (PDEs); o PDEs catalyze the breakdown of cAMP&cGMPo Inhibition of PDE leads to accumulation of cAMP and cGMP

increased signal transductiono Remember: cAMP important in bronchodilatation

Prototype Drug: Theophylline (others: Aminophylline [IVdrip], Doxofylline[long acting derivative, but with narrow margin])

Inexpensive BUT w/ many side effects and relatively low efficacy o now replaced mostly by β2 agonists in asthma hence, has a

limited role (e.g. nocturnal asthma) Possible mechanisms of action

o Phosphodiesterase inhibition o Adenosine receptor antagonism o Stimulation of epinephrine releaseo Mediator inhibitiono Inhibition of intracellular calcium release (for

bronchoconstriction)

THEOPHYLLINE PDE inhibitors also enhance activity of endogenous autacoids,

hormones and neurotransmitters that signal via cyclic nucleotide messengers

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LEC 03: Drugs Acting on the Respiratory System A competitive antagonist at adenosine receptors (adenosine

causes bronchoconstriction and potentiates immunologic mediator release from mast cells

Narrow margin of safety: toxic/fatal effects Therapeutic level: 10 – 20 μg/mL

o Toxicity starts at around 15 which is within the therapeutic level: (GI irritation) to 20 μg/mL: cardiac (tachycardia, arrhythmia), CNS toxicity (agitation, seizures), especially in the elderly (prolonged half-life) and in premature infants (for periodic apnea)

Adverse effects: nausea and vomiting, headaches, gastric discomfort, diuresis, cardiac arrhythmias, seizures

Effects of Theophylline

Theophylline has effects on several other cells in addition to airway smooth muscle; some of these effects are mediated via inhibition of phosphodiesterases.

(2014) Methylxanthines have multiple targets. Thus, there is a need to titrate according to age and lifestyle. For easier use, use β-adrenergic drugs instead! Conversely, it’s good because it has a wide range of action. Used as a reserve drug (unfortunately, very narrow therapeutic index/safety margin)

Factors that affect Theophylline Clearance or Half-life Increased Clearance → Reduced half-life

o Age (children, 3.5 h), Cigarette smoking, Drugs: phenytoin, barbs, rifampin, OC

Decreased Clearance → Increased half-lifeo Age (elderly), Viral infection, Cirrhosis, CHF, Acute pulmonary

congestion, Drugs: interferon, cimetidine, macrolides (erythromycin)

Other Agents Doxofylline(PO): longer action agent designed to decrease the side

effects assoc with theophylline. More expensive and more used. Aminophylline (IV): usually adjunctive in the emergency treatment

of asthma or COPD (especially in situations wherein despite supplemental O2 patient still has difficulty in breathing, tachycardic with tremors)

III. ANTI-ASTHMATIC / CONTROLLERS Target sites of action at the molecular level (mediator

synthesis/release, receptor activation): Bronchodilators are not enough as they do NOT affect the

inflammation that occurs in asthma especially for patients with moderate to severe type of asthma.

A. GLUCOCORTICOIDS o Systemic (acute) vs Inhaled (maintenance)o Leukotriene Receptor Antagonistso Leukotriene Synthesis Inhibitorso Inhibitors of Mediator Release - Cromones

Action: Anti-inflammatory via inhibition of arachidonic acid release by y phospholipase A2, reducing synthesis of mediators (PGs and LTs)

Principally, inhibition of cytokine production (central in initiation of cascade) and eosinophil chemotaxis. o Facilitate release of lipocortino Reverse mucosal edema, decrease permeability of capillaries

and inhibit release of leukotrieneso Decrease the number and activity of cells involved in airway

inflammation – macrophages, eosinophils and T-lymphocyteso On prolonged use (months), reduces hyper-responsiveness of

the airway smooth muscle to a variety of bronchoconstrictor stimuli such as allergens, irritants, cold, air and exercise

Do not directly relax airway smooth muscle: little/ no effect on acute bronchoconstriction

Adverse effects on long-term use and sudden withdrawal (may lead to steroid shock fatal!)

Can be systemic or inhaled

Corticosteroid Action.

Corticosteroids bind to cytoplasmic glucocorticoid receptors which then bind to glucocorticoid response elements in the promoter region of genes, preventing synthesis of inflammatory proteins. If transcription factors such as nuclear factor B and activator protein-1 have been activated by cytokines, corticosteroids may bind directly to them, preventing interaction with inflammatory genes.

SYSTEMIC CORTICOSTEROIDSSystemic corticosteroids – for acute exacerbations and persistent asthma (prednisone, methyl-/prednisolone, hydrocortisone) Prednisone is 4 times more potent than hydrocortisone but with

half the mineralocorticoid activity. Mainstay in acute asthma . Mineralocorticoid cause retention of

water (edema). Recall from the lecture on glucocorticoids, the choice of drug is

also with consideration of its mineralocorticoid activity, as it can have reversal of effect. To further explain at this point, let us look at hydrocortisone.

Methyl-/prednisolone is longer acting and better lung penetration than prednisone

Hydrocortisone is used for its rapid action but has its downside, as it can lead to reversal of action which is further narrowing of the airways. This narrowing can be due to:o an allergic reaction o its MINERALOCORTICOID activity (recall again: fast-acting

glucocorticoids have greater mineralocorticoid activity than long-acting ones)

Advantages: quicker onset of action, systemic effectsDisadvantages: greater probability of ADRS

Routes of Administrationo Oral – prednisone, methyl-/prednisolone

Maximal benefit at 30-40 mg/day (1 mkd) Usual maintenance is 10-15 mg/day

o Intravenous for acute asthma exacerbations Hydrocortisone is preferred due to rapid action.

INHALED (TOPICAL) CORTICOSTEROIDSInhaledcorticosteroids: for maintenance and prevention(beclomethasone, budesonide, fluticasone) more useful due to direct targeting of inflammatory site (lungs) enhanced therapeutic index (higher efficacy with less toxicity) Though inhaled, there is still systemic absorption through GI tract

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LEC 03: Drugs Acting on the Respiratory SystemAdvantages: Minimal ADR’s, drug is delivered to site where action is most neededDisadvantages: Slow onset of effects

Mainstay in prophylaxis and Chronic treatment ADV DADV route of administration

o Inhaled a great advance because it made possible control of

symptoms without adrenal suppression or side effects These drugs are often in combination with other β

agonists Tell Px to always gargle everytime they use it. They may

develop oral thrush and further exacerbate asthma MDIs are difficult for children to use because they should

be timed with inhalation, nebulizers are more convenient because of the continuous flow of drugs into the respiratory tract

Pharmacokinetics of inhaled corticosteroids

ADVERSE DRUG REACTIONS WITH LONG-TERM SYSTEMIC USE

1. Osteoporosis2. Peptic Ulcers3. Poor wound healing4. Hyperglycemia5. Psychoses6. Increased risk of infection7. Hypertension

8. Edema9. Oropharyngeal candidiasis

(oral thrush)- patients are asked to gargle after taking drug to prevent this

10. Stunted growth in children (if high dose)

Are Inhaled Corticosteroids effective in COPD? GENERALLY NO ; maintenance of COPD patients are the long-

acting Beta agonists and long acting anticholinergics Main outcome parameter: FEV1 Additional end points: exacerbation frequency, oral steroids

use, with short-term benefits Little benefit in preventing subsequent decline in pulmonary

function Only smoking cessation works! BUT May work in moderate to severe COPD:

o prevents further exacerbations by helping attenuate whatever inflammatory process MIGHT be going on.

o Usually, you give them systemic, and if positive effect, you give inhaled

B. LEUKOTRIENE PATHWAY MODIFIERS Rationale : cysteinyl-leukotrienes are produced in asthma with

potent effects on airway function, inducing bronchoconstriction, airway hyperresponsiveness, plasma exudation and mucus secretion

Effective as controllers, in the past, role was adjunctive;prophylactic

due to its availability in tablet form and favorable outcome, it is used as maintenance treatment for children with chronic asthma (for adults, role was adjunctive)

2 types:a. Leukotriene Receptor Antagonists (oral)

montelukast and zafirlukast

act through selective, high-affinity, competitive antagonism of cys-LT1 (leukotriene) receptor

b. Leukotriene Synthesis Inhibitors Zileuton (not in clinical use-research pa lang) inhibit the formation of all 5-lipoxygenase products

Effects of cysteinyl-leukotrienes on the airways and their inhibition by antileukotrienes.

C. REVIEW

Controller Medication Inhaled glucocorticosteroids Long-acting inhaled β2-agonists Systemic glucocorticosteroids Leukotriene modifiers Long acting Theophylline/doxofylline Cromones Long-acting oral β2-agonists Anti-IgE Long-Acting Muscarinic Antagonists (COPD)

Reliever Medication Rapid-acting inhaled β2-agonists (SABA) Systemic glucocorticosteroids Anticholinergics/SAMA Theophylline Short-acting oral β2-agonists

IV. GLOBAL INITIATIVE FOR ASTHMA (GINA) 2006 Old Classification: intermittent vs. persistent, for research purpose

only New: “Controlled”, “Partly Controlled”, “Uncontrolled”

Levels of Asthma classification

Characteristic ControlledPartly Controlled (any present in

any week)Uncontrolled

Daytime symptoms None(≤2/week)

≥2/week

3 or more features of

partly controlled

asthma present in any

week

Limitations of activities

None Any

Nocturnal symptoms / awakening

None Any

Need for rescue / “reliever” treatment

None(≤2/week)

≥2/week

Lung function (PEF or FEV1)

Normal

< 80% predicted or personal best

(if known) on any day

Exacerbation None ≥1/year 1 in any week

Goals of Clinical Control of Asthma No (or minimal, <2/week) daytime symptoms No limitations of activity No nocturnal symptoms No (or minimal) need for rescue medication Normal lung function No exacerbationsThis can be reached in a majority of patients with pharmacologic intervention strategy developed in partnership between the patient/family and the doctor.

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Low-dose ICS(typically twice a day)

Decrease to once daily dosing

Med-high dose ICS

Reduce by 50% every 3 months

ICS-LABA

Reduce ICS by 50%Maintain LABA dose

Further reduce ICS dose or stop LABA and continue ICS or decrease ICS-Laba to once daily dosingDecrease to once daily dosing

LEC 03: Drugs Acting on the Respiratory System

TREATING TO ACHIEVE ASTHMA CONTROL

Treatment steps (See Appendix II):**In the local setting, for the majority of symptomatic patients, the consensus is to start a step 3, with low doses of fixed-dose ICs+LABA combination inhaler.

Basic premise: When a patient presents himself, the severity of his asthma must be classified. Intermittent asthma uses step 1 control, severe uses step 5, and it is a consensus that any symptomatic patient uses step 3 (here in the Philippines because of the tendency of patients to discontinue the glucocorticoids once they realize that they are relieved using the bronchodilators)After initial medication, and if asthma is controlled, one can attempt to step down the level of therapy. If patient worsens, then the therapy is stepped up again.

Step 1 – As-needed reliever medication Patients with occasional daytime symptoms of short duration, or

with intermittent asthma A rapid-acting inhaled β2-agonist is the recommended reliever

treatment (Evidence A) When symptoms are more frequent, and/or worsen periodically,

patients require regular controller treatment (step 2 or higher)

Step 2 – Reliever medication plus a single controller A low-dose inhaled glucocorticosteroid is recommended as the

initial controller treatment for patients of all ages (Evidence A) Alternative controller medications include leukotriene modifiers

(Evidence A) appropriate for patients unable/unwilling to use inhaled glucocorticosteroids or one could increase the dose of glucocorticosteroid.

Step 3a – Reliever medication plus one or two controllers For adults and adolescents, combine a

o low-dose inhaled glucocorticosteroido + an inhaled long-acting β2-agonist either in a combination

inhaler device or as separate components (Evidence A) Inhaled long-acting β2-agonist must not be used as monotherapy For children, increase to a medium-dose inhaled

glucocorticosteroid (Evidence A)

*SYMPTOMATIC PATIENT WHO IS IN MODERATE, where will you start? GINA guidelines say that as long as it’s not severe, start at step 2In the local setting, for the majority of symptomatic patients, the consensus is to start at step 3, with low doses of a fixed dose ICS + LABA combination inhaler

Step 3b – Two Controllers + prn reliever Low-doses of fixed-dose ICS + LABA are recommended as first-line

controller in symptomatic patients with persistent asthmao Consensus: if symptomatic, Step 3 as long as not severeo The more severe, the higher the starting dose

The low-dose steroid is usually sufficient, and need only be increased if control is not achieved with this regimen (Evidence A)

Single inhaler maintenance and relief therapy strategy If a combination inhaler containing formoterol and budesonide is

selected, it may be used for both rescue and maintenance This approach has been shown to result in:

o Reductions in exacerbationso Improvements in asthma control in adults and adolescents at

relatively low doses of treatment (Evidence A)

Additional Step 3c Options for Adolescents and Adults Increase to medium-dose inhaled glucocorticosteroid (Evidence A) Low-dose inhaled glucocorticosteroid combined with leukotriene

modifiers (Evidence A) Low-dose sustained-release theophylline (Evidence B)

Step 4 – Reliever medication plus two or more controllers In most patients, the increase from a medium to a high-dose of ICS

provides relatively little additional benefit (Evidence A) The high dose is recommended only on a trial basis for 3 to 6

months when control cannot be achieved with medium dose ICS +

LABA and/or a third controller (e.g., leukotriene modifiers or sustained-release theophylline) (Evidence B)

Medium- or high-dose inhaled glucocorticosteroid combined with a long-acting inhaled β2-agonist (Evidence A)

Medium- or high-dose inhaled glucocorticosteroid combined with leukotriene modifiers (Evidence A)

Low-dose sustained-release theophylline added to medium- or high-dose inhaled glucocorticosteroid combined with a long-acting inhaled β2-agonist (Evidence B)

Selection of treatment at Step 4 depends on prior selections at Steps 2 and 3

Where possible, patients not controlled on Step 3 treatments should be referred to a pulmonary specialist with expertise in the management of asthma for investigation of alternative diagnoses and/or causes of difficult-to-treat asthma

Step 5 – Reliever medication plus additional controller options Addition of oral glucocorticosteroids to other controller

medications may be effective (Evidence D) but is associated with severe side effects (Evidence A)

Addition of anti-IgE treatment to other controller medications improves control of allergic asthma when control has not been achieved on other medications (Evidence A)

Figure Stepping down treatment when asthma is controlled

Treating to Maintain Asthma Control When control has been achieved, ongoing monitoring is essential

to:o maintain control o establish lowest step/dose treatment

Asthma control should be monitored by the health care professional and by the patient

Stepping Up Treatment in Response to Loss of Control Treatment has to be adjusted periodically in response to

worsening control which may be recognized by the minor recurrence or worsening of symptoms

Treatment options:o Rapid-onset, short-acting or long-acting bronchodilators:

repeated dosing provides temporary reliefo A four-fold or greater increase in inhaled glucocorticoids

Severity of Asthma Exacerbations

Management: Acute Care Setting (ABC’s of treatment!) Oxygen therapy Rapid-acting inhaled Β2-agonist SC Epinephrine (Do not disregard epinephrine!) Plus: systemic/inhaled GCS LT modifiers

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LEC 03: Drugs Acting on the Respiratory System Others: Mg, helium O2, sedatives If still not relieved, then intubate

Table 5. GINA 2006 Asthma MedicationsRELIEVERS CONTROLLERS

SABA – Inhaled Systemic

glucocorticosteroids Anticholinergics –

inhaled Theophylline SABA – oral

Glucocorticosteroids – inhaled and systemic Leukotriene modifiers LABA – inhaled and oral Theophylline Cromones(for children with allergic asthma) Anti-IgE Anti-allergic compounds – oral

Summary: Drug Therapy for Asthma Reliever Medications: reverse airflow obstruction

1. Short-acting bronchodilators (SABA)2. Systemic corticosteroids : Oral > IV

Controller medications: “preventers”1. Corticosteroids : Inhaled > oral2. Long-acting sustained-release bronchodilators (LABA)3. Leukotriene modifiers

Delivering Inhaled Asthma Therapy Most common form of asthma therapy Strong logic by inhaled route Important factors: particle size and breathing patterns

o deposition in lower RT increasingly occur as particle size decrease from 4 to 2 micra

meter dosed inhaler / dry powder inhaler and nebulizers Nebulization is more effective than inhalers of the same drug! If

nebulizer is well-applied, they will get a dose with every breath. So, usually given to children who really have trouble with inhalers; however, not v. useful in adults who can properly use inhalers.

Spacers for children (those which have difficulty in timing inhalation to pumping and coordination)

When? How much? Combi?

There is no reason for an asthmatic to suffer, or even die, from his/her disease, with such an array of pharmacologic weapons.

B. UPDATES IN MGMT OF COPDAIMS OF ASSESSMENT OF COPD

Determine Impact of disease on patient’s life Determine risk of future effects (exacerbations / mortality) Guide Therapy

ASPECTS OF DISEASE Symptoms Degree of airflow limitation (using spirometry) Risk of exacerbations Comorbidities

ASSESS SYMPTOMS COPD Assessment Test (CAT) or modified British Medical

Research Council (mMRC) Breathlessness Scale

Table. mMRC Breathlessness ScaleGrad

e Description of Breathlessness

0 I only get breathless with strenuous exercise 1 I get short of breath when hurrying on level ground or

walking up a slight hill 2 On level ground, I walk slower than people of the same age

because of breathlessness or have to stop for breath when walking at my own pace

3 I stop for breathing after walking about 100 yards or after a few minutes on level ground

4 I am too breathless to leave the house or I am breathless when dressing

ASSESS RISK OF EXACERBATION

Exacerbation: acute event characterized by a worsening of the patient’s respiratory symptoms that are beyond normal day-to-day variations and leads to a change in medication

Best predictors of having exacerbation (2+ / yr)o History of previous treated eventso Increase as airflow limitation worsens

ASSESS COMORBIDITIES Cardiovascular diseases, osteoporosis, depression & anxiety,

skeletal muscle dysfunction, metabolic syndrome, & lung cancer

may influence mortality and hospitalizations, & should be looked for routinely and treated appropriately

Figure. Combined Assessment of COPD

GOALS OF TREATMENT FOR STABLE COPD REDUCE SYMPTOMS

o RELIEVE SYMPTOMSo IMPROVE EXERCISE TOLERANCEo IMPROVE HEALTH STATUS

REDUCE RISKo PREVENT DISEASE PROGRESSIONo PREVENT AND TREAT EXACERBATIONSo REDUCE MORTALITY

Figure. Goals of COPD Management

DRUGS USED IN COPD

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Bronchodilatorso For both beta2 agonists & anticholinergics, long-

acting formulations are preferred over short-acting formulations

o The combined use of short or long-acting beta2 agonists and anticholinergics if symptoms are not improved with single agents

o Monotherapy with either long acting anticholinergic or long acting B agonists for symptomatic patients with FEV1< 60%

o ¯ exacerbations o quality of lifeo + mortality and hospitalizationso inhaled bronchodilators are preferred over oral

bronchodilatorso Based on evidence of relatively low efficacy and

greater side effects, treatment with theophylline is not recommended unless other bronchodilators are not available or unaffordable for long term treatment

Corticosteroidso no evidence to recommend a short-term

therapeutic trial with oral corticosteroids in patients with COPD to identify those who will respond to ICS or other medications

o Long term treatment with ICS is recommended for patients with severe and very severe airflow limitation and for patients with frequent exacerbations that are not adequately controlled by long-acting bronchodilators

o Long-term monotherapy with oral corticosteroids is not recommended in COPD

o Long term monotherapy with ICS is not recommended in COPD because it is less effective than the combination of ICS + LABA

Phosphodiesterase-4 inhibitoro Roflumilast used to reduce exacerbations for

patients with the following symptoms chronic bronchitis, severe & very severe airflow limitation, and frequent exacerbations that are not

adequately controlled by long-acting bronchodilators

o Acute exacerbations associated with accelerated disease progression

o Airway inflammationo Continues after smoking cessationo Responds incompletely to CS

o Neutrophil predominanto Theophylline: nonselective PDE inhibitoro PDE4 is expressed in airway smooth muscle & pro-

inflammatory cellso Targeting PDE4 could arrest airway remodelling in

COPDo Studies show ¯ in induced sputum neutrophils,

eosinophils, lymphocytes

V. ADDITIONAL RESPIRATORY DRUGS1. Cromones (for allergic induced)Pharmacologic Action Inhibition of mediator release from bronchial mast cells (mast cell

stabilizers) Reversal of leukocyte activation and trafficking in asthmatic

airways Suppression of activating effects of chemotactic peptides on

human neutrophils, eosinophils, and monocytes Inhibition of parasympathetic and cough reflexes Useful for the treatment of both allergic rhinitis and allergic

asthma (REMEMBER: drugs can precipitate asthma) Complete mechanism of action is not known: alter the function of

delayed chloride channels in the cell membrane inhibiting cellular activation

Inhibit the liberation of the mediators of anaphylaxis that are released by the degranulation of mast cells after antibody-antigen interaction

Prototype Cromones: Cromolyn Na and Nedocromil Effective prophylactic anti-inflammatory agents but are not useful

in managing acute asthmatic attacks because they are not direct bronchodilators

Block the precipitation of immediate and delayed asthmatic reactions

Given in dry powder form

2. Ketotifen An antihistamine drug used for the prophylaxis of diverse allergic

conditions Prevents allergic reactions by similar mechanisms which are

independent of its antihistaminic properties Used as an adjunct for the treatment of asthma Probably related to its effect on eosinophils

DRUGS FOR OTHER RESPIRATORY PROBLEM

A. TREATMENT OF COMMON COLDS/ALLERGIC RHINITIS

STEPS IN THE TREATMENT OF COLDS/ ALLERGIC RHINITIS1. Non-pharmacologic treatment: Rest, water therapy especially

if viral in nature2. Ascertain if the colds are due to allergic rhinitis Rhinitis – inflammation of the mucus membranes of the nose;

characterized by sneezing, nasal itching, watery rhinorrhea and congestion

In allergic rhinitis, treatment is directed both to treating symptoms and blocking either the release or effects of the mast cell mediators

Pharmacologic Therapy for Common Colds/ Allergic RhinitisPharmacologic therapy for common colds is debatable because it can be relieved by adequate rest and water therapy.However, if symptoms persist, the usual medications prescribed are the same as those used for treatment of allergic rhinitis. If patient does not respond to steam inhalation and hydration, decongestants can be used. To a certain extent, the statement “Huwagpabayaanangsipon” is true if there is congestion. Congestion, especially chronic, might lead to sinusitis, which needs antibiotics for treatment.

1. Antihistamines (H1 receptor blockers)First gen Clemastine, Diphenyhdramine, ChlorpheniramineSecond gen Loratadine, CetirizineNew 2nd gen Desloratadine, Fexofenadine

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LEC 03: Drugs Acting on the Respiratory SystemNote: has a sedative effect2. Alpha-adrenergic agonists nasal decongestants - constrict dilated arterioles in the nasal

mucosa Oral: phenylephrine, phenylpropanolamine, pseudoephedrine Aerosol/Nasal drops: for those with contraindications for oral

decongestants; oxymetazoline (much preferred since rapid action w/ few systemic effects)

Use limited for only a few days due to rebound nasal congestion, ergo NOT for long-term treatment of allergic rhinitis – never for more than 7-10 days (2014- 5 days)

Rationale for combination of antihistamines with alpha-adrenergic agonist for decongestant Rx?

3. Corticosteroids May be in combination with antihistamine (e..gloratidine +

betamethasone claricor) typically given as local or topical agents Optimal effects (improvement) expected in 1-2 wks (e.g.

beclometasone, fluticasone) May be more effective than antihistamines in relieving the nasal

symptoms of both allergic and non-allergic rhinitis4. Cromolyn Na a mast cell stabilizer; may be useful when administered before

contact with an allergen (prophylaxis)

B. TREATMENT OF COUGHMUCOREGULATORS used to reduce mucus hyper-secretion occurs in chronic bronchitis

and asthma; cystic fibrosis In chronic bronchitis, hypersecretion is due to: chronic irritation by

cigarette smoke, and, activation of neutrophils to release enzymes (e.g., elastase) with powerful effects on mucus secretion

Mast cell derived chymase is a potent mucus secretagogue

1. Mucolytics Decrease sputum viscosity Usually derivatives of cysteine; reduce disulfide bridges that bind

glycoproteins to other proteins such as albumin Also act as antioxidants and may decrease airway inflammation Orally available drugs are well-tolerated; but of little benefit in

acute respiratory conditions (throwaway drugs) Examples: N-acetylcysteine (also inh, IM, IV form), ambroxol;

(carbocisteine?)

Clinical studies in chronic bronchitis, asthma and bronchiectasis: disappointing (meaning it does not improve effects of pulmonary function)a. N-acetylcysteine (also INH, IM, IV form) – may decrease

exacerbations or hospitalizations in COPD and may improve pulmonary function, symptoms and quality of life. Duration of treatment: 3-6 months

b. Mesna– to allow greater mucus mobilization for suctioning among patients on an endotracheal tube or those with tracheostomy For hospitalized patients Expensive

c. Lagundi – small body of evidence on its therapeutic effect, but has minimal side effects that is why it is available in the market Has only had limited clinical trials in MILD asthma Minimal side effects because comparable to placebo

2. Expectorants drugs that enhance the clearance of mucus when administered

orally Commonly prescribed but with little or no objective evidence for

their efficacy (throw-away drugs) Throw away drugs! Little or no effect. Are often emetics (ipecac, guaifenesin) Adequate hydration may have similar outcome

Current Therapies For Mucus Hyper-secretion (Limited Use) Few dedicated therapies available

Paucity of information on potential therapies (approach via muscarinic Ach, P2Y2 or CysLT1 receptors)

Species difference: data from small animal models cloud interpretation

COUGH SUPPRESSORS What is cough?

o A protective reflex mechanism that removes foreign material and secretions from the bronchi and bronchioles

o Common symptom but mechanisms are poorly understoodo Before treatment with antitussives, identify underlying cause

that may require therapy When to suppress?May suppress cough in these situations:

o Dry painful cough of neoplasia or pleural diseaseo Irritative cough in inflammation of the respiratory tract

(epiglottitis); in hemoptysis (might exsanguinate) DO NOT suppress in bacterial lung infections, asthma,

bronchiectasis (suppurating bronchial inflammation) or chronic bronchitis where antitussives can cause harmful sputum thickening and retention

Antitussive Agents DO NOT influence the underlying condition; merely suppresses the

symptom Most drugs have CENTRAL mechanism of action: decreased

sensitivity of the medullary/ CNS cough centers to peripheral stimuli and ¯ mucosal secretion

1. Opioid analgesics (opiates) Prototype drug: codeine or methymorphine Less addiction potential than other opiates An effective cough suppressant Side effects:

o Decreases secretions in the bronchioles, thickens sputum and inhibits ciliary activity, reducing clearance of thickened sputum

o Constipation Example: Morphine: effective but indicated only in intractable

cough with bronchial carcinoma

2. Dextromethorphan (vicks) Related to levorphanol A synthetic narcotic analgesic Antitussive potency is equivalent to codeine Has NO analgesic or addictive potential Produces only marginally less constipation and inhibition of

mucociliary clearance

3. Butamirate Citrate (sinecod) Centrally acting antitussive but is neither chemically or

pharmacologically related to opioids

4. Levodropropizine (Levopront) Non-opioid with peripheral MoA of modulation of sensitive C-fiber

activity

END OF TRANSCRIPTION

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APPENDIX I: Steroid action on mediators derived from arachidonic acid (eicosanoids)

APPENDIX II: STEPS TO ACHIEVING ASTHMA CONTROL

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