Module 2.1.1 (Pharmacology of Drugs used in Asthma)

Question 1

What is the definition of asthma? Can it be cured?

Answer 1

A chronic lung disease which is able to be controlled but not cured. It has both enormous amounts of variable lung function and variable respiratory symptoms such as wheeze, cough, shortness of breath and chest tightness. There is always hyperresponsiveness and narrowing caused by mucous and oedema of the bronchioles.

Question 2

Provide examples of the drugs use to treat asthma for the following drug classes;

A) Bronchodilators (4 types)

B) Anti-inflammatory agents (4 types)

C) Emergency treatments (2 types)

Answer 2

A)

• Short-acting beta-agonists (SABAs)
• Long-acting beta-agonists (LABAs)
• Xanthine drugs
• Cysteinyl leukotriene receptor antagonists

B)

• Inhaled corticosteroids (ICSs)
• Cromones
• Anti-IgE treatments
• Other monoclonal antibodies

C)

• Oxygen
• Hydrocortisone

Question 3

What is the action of reliever medications used in asthma? What are some examples of these medications?

Clue: answer related to intermediate phase

Answer 3

Intermediate phase reaction occurs abruptly in response to allergen

• Reliever medications provide symptomatic relief of bronchospasm
• Medications include B2-adrenoreceptor agonists, CysLT-receptor antagonists and theophylline –> reverse bronchospasm

Question 4

What is the action of preventer medications used in asthma? What are some examples of these medications?

Clue: answer related to late phase

Answer 4

Late phase (progression of inflammatory reaction). Influx of Th2 lymphocytes is of particular importance

• Preventer medications inhibit airway inflammation and hyper-reactivity
• Medications include glucocorticoids –> inhibits bronchospasm, wheezing, coughing (airway inflammation and airway hyper-reactivity)

Question 5

For Bronchodilators;

A) What are examples of Short-acting beta2 agonists (SABAs) –> 2 types

B) What are examples of Long-acting beta-agonists (LABAs) –> 5 types

C) What is an example of a xanthine drug?

D) What is an example of cysteinyl leukotriene receptor antagonist?

Answer 5

A)

• Salbutamol
• Terbutaline

B)

• Formoterol (eformoterol)
• Indacaterol
• Salmeterol
• Vilanterol (only in combination with ICS)
• Olodaterol (only in combination formulations – only COPD)

C)

• Theophylline

D)

• Montelukast

Question 6

What is the MOA/pharmacology of SABA and LABA?

Answer 6

• β2 adrenoreceptor activation → intracellular signaling (mainly produced by inducing cAMP)
• Leads to airway relaxation via phosphorylation of muscle regulatory proteins and modification of cellular Ca2+ concentrations.

Question 7

For Short-acting beta₂ agonists (SABAs) –> salbutamol and terbutaline;

A) What are the indications for it

B) MOA

C) Onset, max effect and DOA?

D) Dose of salbutamol and terbutaline

E) Dosage form?

Answer 7

A)

• To prevent or treat bronchospasm/asthma symptoms
• Prophylaxis for exercise-induced asthma

B)

• Dilate the bronchi by direct action on β2 adrenoreceptors on smooth muscle
• Also inhibit mediator release from mast cells, TNF-α release from monocytes and ↑ mucous clearance by acting on cilia

C)

Onset: work within minutes (used as first aid)

Max effect: within 30 minutes

DOA: 3-5 hours

D)

Failure to obtain relief from these drugs should be treated as a medical emergency

• Salbutamol 100ug per inhalation = 2 inhalation every 4 hours when required*
• Terbutaline 500ug per inhalation = 1 inhalation every 4 to 6 hours when required* (not > 12 inhalations in 24 hours)

* If need these drugs every 4 hours –> at risk of an acute attack

E)

• Main dosage form - inhalation of an aerosol, powder, or nebulized solution
• Can also be given orally or by injection

Question 8

For Long-acting beta2 agonists (LABAs) –> formoterol, salmeterol, indacaterol, vilanterol –> in combo with a muscarinic agent, olodaterol –> COPD only

A) What are the indications for it

B) MOA?

C) What must it be used in combination with?

D) Not recommended in children < … years old?

E) Frequency of dosing? What is the exception?

F) Onset of action and duration

Answer 8

A)

• Maintenance treatment of asthma in patients receiving inhaled or oral corticosteroids

B)

• Stimulate β2 adrenoreceptors to produce prolonged bronchodilation (up to 12 hours)

C)

• LABAs MUST be used in combination with an ICS

> if not used with ICS = increased risk of serious asthma exacerbations and asthma-related deaths

D)

• Less than 6 years old

E)

• Either twice daily or once-daily dosing

> Formoterol and budesonide (symbicort) combinations can be used for maintenance and symptoms relief (without the need for a SABA)

F)

Onset of action: between 1 and 30 min

Duration: between 12 and 24 hours

Question 9

Adverse effects of SABAs and LABAs depends on dosage and route of administration;

A) common AE (>1%)?

B) Infrequent AE (0.1-1%)?

C) Rare AE (<0.1%)?

D) Symptoms of overdose?

Answer 9

A)

• Tremor, palpitations, headache

B)

• hyperglycaemia (high dose), tachycardia, muscle cramps, agitation, hyperactivity in children, insomnia

C)

• paradoxical bronchospasm, allergic reactions including urticaria, angioedema and anaphylaxis, lactic acidosis

D)

• Tachycardia and muscle tremor

Question 10

Explain why the following precautions exist in SABA and LABAs

A) Cardiac disease

B) Cardiac arrhythmias

C) Hypokalaemia

D) Diabetes mellitus

E) Hyperthyroidism

F) Lactic acidosis

Answer 10

A)

• Inhaled at normal doses – no significant systemic effects

B)

• Could predispose or exacerbate existing arrhythmias
• Possibly due to chronotropic effects and ↓serum K+

C)

• Serious but mainly high dose parenteral & nebulized administration
• Worsened by theophyllines, corticosteroids, diuretics & hypoxia

D)

• Inhaled at normal doses – no or little hyperglycaemic effect

E)

• Use with caution in thyrotoxicosis (excess amount of thyroid hormones)

F)

• Monitor during acute treatment of asthma

Question 11

For Xanthine (Bronchodilator):

A) Mode of action

B) Mechanism of action

Answer 11

A)

• Direct relaxation of smooth muscle of bronchial airways and pulmonary blood vessels → bronchodilator and pulmonary vasodilator
• Also CNS stimulation (including the respiratory centre, cardiac stimulation, coronary vasodilatation, diuresis and increased gastric secretion)

B)

Mechanism of action of theophylline is still unclear

–> Proposed mechanisms of smooth muscle relaxation

• Inhibition of phosphodiesterase isoenzymes → ↑ in cAMP
• Competitive antagonism of adenosine at adenosine A1 and A2
• Activation of histone deacetylase (may reverse ICS resistance)

–> Stimulation of respiration via CNS (↑ diaphragm contractility)

Question 12

For Theophylline (xanthine drugs);

rarely used = not first line

A) Indication

B) Therapeutic index

C) Why need to consider drug interactions

D) Dose?

Answer 12

A)

• Maintenance treatment in severe asthma and COPD

B)

• Narrow therapeutic index drug
• Monitoring of plasma drug levels is recommended

C)

• Drug-drug, drug-disease, factors that influence the elimination of theophylline

D)

• Adult dose: 200 to 300mg every 12 hours
• Children’s dose: based on bodyweight 10mg/kg every 12 hours

Question 13

For Theophylline (xanthine drugs);

A) What factors influence increase clearance and decreased effectiveness

B) What factors decrease the clearance and increase toxicity

C) What comorbidities may it exacerbate?

D) Adverse effects (common and rare)?

Answer 13

A)

• Smokers, hyperthyroidism, drugs (phenobarbitone, phenytoin, carbamazepine, rifampicin (possibly St John’s Wort)

B)

• Elderly, hepatic impairment, hypothyroidism, heart failure, pulmonary oedema, severe hypoxia, acute febrile illness (fever), viral infections drug (macrolide & quinolone antibiotics, oral contraceptives, verapamil, propranolol)

C)

• Worsens GORD, arrhythmia exacerbated, epilepsy (may ↓ seizure threshold)

D)

• common: (>1%) nausea, vomiting, diarrhea, GORD, headache, insomnia, irritability, anxiety, tremor, palpitation
• rare: (<0.1%) seizures, arrhythmias (at high conc), tachycardia

Question 14

What is the MOA of Cysteinyl leukotriene receptor antagonists (LTRAs)

Answer 14

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are potent inflammatory mediators released from various cells including mast cells and eosinophils

• CysLTRAs bind to cysteinyl leukotriene receptors (CysLT) and block the effects of CysLT

> CysLT type-1 is found in the airways and on pro-inflammatory cells

> Are associated with pathophysiology of asthma and allergic rhinitis

> In asthma, leukotriene-mediated effects include a number of airway actions including bronchoconstriction, mucous secretion, vascular permeability and eosinophil recruitment

Question 15

For Montelukast (LTRAs) in adults;

A) What is the indication?

B) Why is it used even though it’s not a first-line agent for adults?

C) Dose?

Answer 15

A)

• Maintenance treatment of asthma (not for acute asthma – preventer)

B)

• In adults & adolescents not controlled by low dose ICS (keep in mind it is still less effective than adding a LABA)

> less effective than SABAs for exercise-induced asthma

> no demonstrated benefit in aspirin-intolerant asthma

sometimes prescribed as an add-on therapy

C)

• Dose 10mg once daily

Question 16

For Montelukast (LTRAs) in children;

> not yet determined which patients benefit most from therapy

A) What is the main role?

B) Is Montelukast or ICS more effective in children >6years with persistent asthma?

C) Is Montelukast or LABA more effective to control symptoms in children with exercise-induced asthma using ICS?

D) Dose for 6-15 years old?

E) Dose for 6 years old?

Answer 16

A)

• Alternative to ICS

B)

• In children >6yrs with persistent asthma, ICS more effective than Montelukast

C)

• In children with exercise-induced asthma already using ICS, Montelukast is more effective than LABAs to control symptoms

D)

• Dose 6 – 15 yrs, 5mg once daily

E)

• Dose < 6 yrs, 4mg once daily

Question 17

For Anti-inflammatory agents;

A) What are examples of Corticosteroids –> 6 types

B) What are examples of Cromones –> 2 types

C) What is an example of a anti-IgE drug?

D) What are examples of ‘other monoclonal antibodies’ drugs –> 2 types

Answer 17

A)

• Beclomethasone
• Budesonide
• Ciclesonide
• Fluticasone propionate
• Fluticasone furoate
• Oral prednisolone

B)

• Cromoglygate
• Nedocromil

C)

• Omalizumab

D)

• Mepolizumab
• Benralizumab

Question 18

What is the MOA of corticosteroids –> glucocorticoids (anti-inflammatory agents)? What phase do they inhibit in the inflammatory pathways?

Answer 18

Glucocorticoids inhibit the action of cytokines (IL-4, IL-5, IL-13) which leads to ↓ production and release of IgE and ↓ differentiation and activation of eosinophils (eosinophils cause inflammation)

• Inhibit “late-phase” inflammatory pathways

Glucocorticoids

• Inhibit the allergen influx of eosinophils into the lungs & indirectly ↓ Mediator release from eosinophils by ↓ production of cytokines (IL-5 & GMCSF)
• Upregulate β2 adrenoreceptors
• ↓ synthesis of IL-3 (cytokine which regulates mast cell production) – may explain why long term steroids ↓ mast cells in the respiratory mucosa and suppresses early phase response to allergens and exercise

other important actions of glucocorticoids in asthma

• ↓ clonal proliferation of Th-cells (by ↓ gene transcription) –> decreased TH2
• ↓cytokine formation
• Inhibit generation of vasodilators PGE2 and PGI2 by inhibiting induction of COX-2

Question 19

For Inhaled Corticosteroids ICS (anti-inflammatory agents);

> mainstay of treatment for most people with asthma

A) What are some examples? Name FIVE

B) What are some indications?

C) What effect do they have on the lungs

Answer 19

A)

• beclomethasone, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate

B)

• Prophylactic management and treatment of asthma and COPD
• A mainstay of treatment for most people with asthma

C)

• Decrease airway inflammation and hyper-reactivity

Question 20

What combination formulations are available for inhaled corticosteroids (ICS)?

Answer 20

ICS/LABA combination formulations available

• Seretide® & Cipla® = Fluticasone propionate and salmeterol
• Symbicort® & DuoResp Spiromax® = Budesonide and formoterol
• Flutiform® = Fluticasone propionate and formoterol
• Breo Ellipta®* = Fluticasone furoate and vilanterol only

Breo Elipta* = only suitable for patients who require moderate to a high dose of inhaled corticosteroid in combination with LABA (fluticasone furoate 5 times more potent than fluticasone propionate –> one inhalation once daily)

Question 21

Is some ICSs safer than other types? Is fluticasone furoate less or more potent than fluticasone propionate? How to do the dosing?

Answer 21

• No evidence one ICS is safer than anothe
• Fluticasone furoate is more potent than fluticasone propionate - can be given once daily

Dose

• Dose equivalence: 100mcg beclomethasone = 200mcg budesonide = 80mcg ciclesonide = 100mcg fluticasone propionate = 20mcg fluticasone furoate
• Generally, start with a low dose and adjust according to response
• USE LOWEST DOSE POSSIBLE

Question 22

For oral corticosteroids;

A) What is it indicated for?

B) What type and dose to use in adults and adolescents?

C) What type and dose to use in children?

Answer 22

A)

• Indicated for the management of asthma flares

B)

All patients should be given oral corticosteroids within the first hour (oral route preferred) of an asthma flare

• Prednisolone 37.5mg to 50mg daily continue for 5 to 10 days
• Hydrocortisone IV 100mg every 6 hours

C)

Oral prednisolone recommended within the first hour if asthma does not respond to initial inhaled bronchodilator (oral preferred)

• Prednisolone 2mg/kg (up to 50mg) as an initial dose then 1mg/kg on subsequent days
• IV hydrocortisone or IV methylprednisolone can be used if oral route not available

Question 23

For Adverse effects of ICS;

A) What are the common ones (>1%)

B) What are the rare ones (<0.1%)

C) Potential systemic adverse effects? –> depends on dosage, duration of treatment and the delivery system

Answer 23

A)

• dysphonia, oropharyngeal candidiasis, bruising, facial skin irritation following nebulisation

B)

• allergic reactions, including bronchospasm, rash, urticaria and angioedema

C)

• Adrenal suppression
• Bone density loss
• Pneumonia (in COPD patients)
• Glaucoma, cataract
• Skin thinning and bruising
• Impaired growth

Question 24

For adverse effects with regular systemic corticosteroids;

A) What should be monitored if oral therapy is required for maintenance?

B) What are the long term effects?

Answer 24

A)

• If oral therapy is required for maintenance therapy bone density should be monitored

B)

Long term effects include:

• acne,
• adrenal suppression,
• bruising,
• cataracts,
• depression and psychiatric effects,
• diabetes,
• dyslipidaemia,
• dyspepsia,
• facial flushing,
• gastric ulceration,
• hirsutism,
• hypertension,
• impaired wound healing,
• increased appetite,
• menstrual irregularities,
• oedema,
• osteoporosis & fractures,
• proximal myopathy,
• skin atrophy,
• sodium and water retention,
• truncal obesity,
• weight gain

Question 25

For cromones (anti-inflammatory agent);

A) What are the two types of drugs?

B) What is the MOA

C) Indication? Why is it rarely used now?

D) Adverse effects

Answer 25

A)

• cromoglygate and nedocromil

B)

Mechanism of action not fully understood

• “Mast cell stabiliser” prevents histamine release BUT this is not how it works in asthma because other compounds that prevent release of histamine from mast cells are ineffective in asthma
• Depresses exaggerated neuronal reflexes
• May inhibit the release of T-cell cytokines

C)

• Maintenance treatment of asthma, prevention of exercise-induced bronchoconstriction – rarely used now
• Rarely used because of 3-4x daily dosing, unpleasant taste and inhaler becomes blocked easily

D)

• Cough, throat irritation, bitter taste, transient bronchospasm

Question 26

For Anti-IgE drugs (anti-inflammatory agent);

A) MOA?

B) Example of a drug in this class

C) Indication for drug in answer B

D) Dose for part B

E) Adverse effects

F) Rare adverse events

Answer 26

A)

• Anti-IgE drugs are antibodies that block IgE activation of receptors on mast cells and other anti-inflammatory cells
• ↓ serum free IgE – dose-dependent (↓84 to 99% of baseline)

B)

• Omalizumab - Recombinant humanised monoclonal antibody directed against IgE

> Reduces the immune system’s response to allergen exposure

C)

• Maintenance treatment of moderate-to-severe allergic asthma in patients treated with inhaled corticosteroids and with raised serum IgE levels
• Not all patients respond

D)

• SC injection every 2 to 4 weeks

E)

• Injection site reactions, rash, headache, upper respiratory tract infections weight increase, fatigue, arm swelling, nausea, pharyngitis, musculoskeletal pain, upper abdominal pain

F)

• Anaphylaxis (usually occurs within 2 hours but can be delayed to >24 hours), angioedema, urticaria, serum sickness-like syndrome (onset 1 to 5 days), Churg-Strauss syndrome (causal relationship not established)

Question 27

For other monoclonal antibodies (anti-inflammatory agents);

A) Provide TWO examples of the type of drugs found in this calss

B) MOA

C) Indication

Answer 27

A)

• mepolizumab and benralizumab

B)

• Antibodies that block IL-5 (mepolizumab) or its receptor (benralizumab) and markedly reduce eosinophil production and survival

C)

• Maintenance therapy for severe, refractory asthma (add-on therapy)
• BUT – new drugs with limited clinical experience

Question 28

Summary for Asthma

Answer 28

There are two classes of drugs used in the treatment of asthma

• Preventers – to control underlying inflammation
• Relievers – to provide relief of symptoms

There are a variety of drugs used to treat asthma but the mainstay of therapy is

• Beta2 agonists used “when required” for relief of symptoms (reliever)
• Regular inhaled corticosteroids (required in most patients) (preventer)