Respiratory Pharmacology

Question 1

What is Asthma?

Answer 1

Reversible airflow obstruction increases in airway resistance involving bronchoconstriction + inflammation

Decreases in FEV₁ (forced expiration volume in first second)

Value of < 70% means increased airway resistance

If asthma, then reversed using Beta₂-agonist

Question 2

What is COPD?

Answer 2

Airflow limitation that is not fully reversible

Both chronic bronchitis + emphysema

Loss of lung function

80-90% deaths related smoking

Diseases of late onset in life (elderly)

High energy demand + difficulty eating, e.g. use inhaler before meal, leading to weight loss

Question 3

Describe the phases of asthmatic attack

Answer 3

Question 4

What are the two categories for asthma therapy?

Answer 4

1) relief of symptoms (bronchodilators) - block early phase if asthma attack caused by bronchoconstriction
2) prevention of attack (anti-inflammatory agents) - prevents late phase caused by release of cytokines

Question 5

What are bronchodilators?

Answer 5

Reverse bronchospasm + rapid relief

Beta₂ adrenoceptor agonists e.g. salbutamol

• 1^st choice
• Increase FEV₁
• Given by inhalation

Longer acting agents (salmeterol) given for long-term prevention

Question 6

Where are Beta₂-adrenoceptors + function?

Answer 6

On smooth muscle and mast cell

Increase in cAMP prevents release of histamine

Affects on mucus secretion

Question 7

What is Desensitisation?

Answer 7

Caused by long-term use of Beta-adrenoceptor agonists which leads to tolerance/desensitisation

Due to internalisation of the receptor

Prevented by steroids

Question 8

Examples of Long-acting beta-adrenoceptor agonist

Answer 8

Salmetorol

Formoterol

Indacaterol

Dont know why they are long acting

Current theory = absorbed into lipid bilayer of cells - slowly released over time to activate

Question 9

Adverse effects of beta₂-adrenoceptor agonists

Answer 9

Tremor

Palpitations

Hypokalaemia

Due to high doses of drugs e.g. nebulisers

Question 10

Example of Phosphodiesterase inhibitor

Answer 10

Roflumilast (PDE4) inhibitor (DAXAS)

For COPD

Reduces inflammation

Can enhance Beta-adrenoceptor effects

Question 11

Function of Muscarinic M-receptor antagonist

Answer 11

Block parasympathetic bronchoconstriction

e.g. ipratropium (non-selective antagonist)

Inhaled (fewer systemic effects)

Inhibits mucous secretion

Tiotropium = long-acting, due to slow dissociation from receptor

Aclidinium = long-acting but newer

Question 12

What are the side effects of Muscarininc M-receptor?

Answer 12

They are non-selective so they block muscarinic receptors all over body

Dry mouth

Nausea/headache

Constipation

Urinary retention

Blurred vision

Atrial fibrillation + Tachycardia + Palpitation

Question 13

What are Xanthines + example?

Answer 13

Bronchodilators (not as good as b2-adrenoceptor agonist)

E.g. theophylline

2^nd line use

Orally inhaled (or IV aminophylline in emergencies)

Question 14

What is Aminophylline?

Answer 14

Mix of theophylline + ethylenediamine (2:1 ratio)

Improves solubility

Measure plasma theophylline 4-6 hrs after infusion (iv)

Monitor plasma levels - toxicity

Question 15

What are the side effects of Theophylline?

Answer 15

Tremor

Palpitations

Nausea

CNS stimulations

Drug interactions:

• inhibit of metabolism increases toxicity (cimetidine)
• induce metabolism reduces plasma levels

Question 16

What are anti-inflammatory agents?

Answer 16

Preventative - do not reverse an attack

Target late phase of asthma response

e.g. Corticosteroids

Question 17

What receptors do steroids act on?

Answer 17

Act at intracellular or glucocorticoid receptor

Question 18

Examples of Inhaled steroids

Answer 18

Beclometasone

Bidesonide

Ciclesonide

Fluticasone

Mometasone

Question 19

Example of an oral steroid

Answer 19

Prednisolone

e.g. acute asthma attack

Question 20

Example of an IV steroid

Answer 20

Hydrocortisone

e.g. life threatening asthma

Question 21

What genes are switched on/activated by glucocorticoids when steroid has bounded?

Answer 21

Annexin A1

Beta₂-adrenoceptors

IkB (Inhibitor of NF-kB)

MKP1 (inhibits MAP kinase)

Anti-inflammatory cytokines e.g. IL-10, 1L-12

Question 22

What genes are switched off/repressed by glucocorticoids when crosslinked with steroid?

Answer 22

Inflammatory cytokines - e.g. IL-2, IL-3, IL-6, TNFα

Chemokines

Inflammatory enzymes - e.g. iNOS, COX-2

Inflammatory peptides - e.g. endothelin-1

Question 23

How can genes be repressed when steroid binds to glucocorticoid receptor?

Answer 23

Question 24

What is Annexin A1?

Answer 24

Involved in the up-regulation of anti-inflammatory genes

Act through formyl peptide receptors (FPR)

• inhibits histamine release from mast cells
• inhibits cPLA2 - PGs

Question 25

How do steroids affect Beta₂-adrenoceptor?

Answer 25

**Increase transcription of B₂-AR** Protect against **downregulation** of B₂-ADR after **long term use (desensitisation)** Benefits of co-administration

Question 26

What are the side effects of corticosteroids?

Answer 26

**Throat infections/oral candidiasis** with inhaled steroids **Osteoporosis** **Adrenal suppression** in children * use **lowest** effect dose of steroid * monitor height Indigestion **Chicken** **pox** severe (avoid contact) - immune response **Withdrawal** effect (reduce oral steroids gradually if more than **3** weeks)

Question 27

Patients with severe asthma + COPD have poor response to steroids (Steroid resistance) What are the reasons for the resistance?

Answer 27

Genetics GR receptor modification Decreased nuclear translocation of GR Increases efflux of steroids

Question 28

How are leukotrienes made?

Answer 28

Question 29

Function of Leukotriene mediator

Answer 29

They have a role in inflammation + asthma Stimulate mucus secretion Cause bronchoconstriction Role in airway remodelling Linked to hyperresponsiveness Link with exercise-induced asthma

Question 30

Function of Cysteinylleukotriene receptor antagonist

Answer 30

Block LT receptors - block inflammatory actions of cystLTs e.g. montelukast Leukotriene receptor antagonist block production of leukotrienes + LTB4 Antagonist block bronchoconstriction Zileuton = Suppressor of leukotriene synthesis + LTB4

Question 31

What are the side effects of CystLT receptor antagonist?

Answer 31

Headache Rash Nausea Jaundice Mood disorders/suicidal thoughts (from montelukast)

Question 32

What is Omalizumab?

Answer 32

Used for severe allergic asthma that **cannot** be controlled by steroids It's a **monoclonal antibody against free IgE** - Prevents IgE from **binding to immune cells** preventing a**llergen-induced mediator release** (e.g. histamine) S.C. Injection every 2-4 weeks

Question 33

How can drug-induced asthma occur?

Answer 33

Affects 15% of asthmatics Drugs involved are NSAIDS, Beta-AR + drug allergies **NSAIDS inhibit COX** * more arachidonic acid leukotriene production * leads to inflammation/spasm + bronchoconstriction **B-adrenoceptor antagonist** * non-selective (**propranolol**) * selective (**atenolol**) **Drug allergy** (e.g. penicillins, cephalosporins, dipyridamole, tramadol)

Question 34

Example of a cromone

Answer 34

**e.g. sodium cromoglicate** **Preventative** (mast cell stabilisers) * Prevent + relieve swelling of the airways * buildup of mucus + asthma Benefit in **exercise-induced** asthma Given by **Inhalation**

Question 35

Function of **mucolytics**

Answer 35

**Break up thick mucus** e.g. carbocysteine, erdosteine, mecysteine, dornase alfa Act as an **antioxidants** Used in **COPD** Dornase alfa (recombinant deoxyribonuclease) **breaks down extracellular DNA** from dying **neutrophils** * used in **CF** to reduce mucus **viscosity**

Question 36

What is a Cough?

Answer 36

Question 37

What are Anti-tussive agents?

Answer 37

Stops coughing e.g. Codeine (opioid) + dextromethorphan (non-opioid) * act in cough centre * little bit better than placebo * codeine is avoided in children under 18 years * dextromethorphan avoided in children under 6 years e.g. Levodropropizine * inhibit release of sensory neuropeptides * compared to Codeine + dextromethorphan

Question 38

What is Cystic Fibrosis?

Answer 38

**Inherited disorder of ion transport in epithelial cells** Affects respiratory, hepatobiliary, gastrointestinal, reproductive tracts, pancreas Defect in **chloride transporter** leading to **reduced Na⁺** and **H₂0 transport** * Thicker secretions w/obstruction + destruction of exocrine glandular ducts * recurrent infections

Question 39

Discuss the disease characteristics of CF

Answer 39

**Pancreatic exocrine insufficiency** * reduced/absent secretions Patients living **longer** - but developing other complications: * diabetes * liver disease * osteoporosis

Question 40

How can we manage CF?

Answer 40

**Aim is to clear viscous mucus from airways to treat respiratory infections, improving respiratory function** Physiotherapy Antibiotics Corticosteroids Bronchodilators Dornase Alfa administered using Nebuliser * **synthetic** version of enzyme which **cleaves extracellular DNA** * ‘Digests’ extracellular **DNA** released from **dying** neutrophils in the airway which contributes to **increased mucus viscosity**