Drugs in Respiration - Pharmacology - Ashtma, COPD

Question 1

the CNS goes via the vagus nerve to….

Answer 1

Trachea and conducting bronchi

Question 2

The trachea and conducting bronchi branch into what?

Answer 2

• Submucosal gland - M1/M3
• Blood vessel - M3
• Airway smooth muscle - M3 - post-ganglionic fibres

Question 3

Innervation of human airway smooth muscle

Answer 3

no sympathetic innervation

only of glands and blood vessels

Question 4

Asthma inflammatory cell

Answer 4

eosinophils

Question 5

COPD inflammatory cell

Answer 5

neutrophils

Question 6

Immediate phase of asthma

Answer 6

Trigger: allergen 
↓
mast cells/mononucellar cells 
↓
spasmogens e.g. leukotrienes C4, D4, Histamine, PGD2
↓
Bronchospasm

Question 7

Immediate phase of asthma - mast cell branch

Answer 7

mast cells/mononucelear cells
↓
Chemotaxins 
Chemokines
↓
Late phase

Question 8

Late phase of asthma starting at chemotaxins and chemokines

Answer 8

chemotaxins
Chemokines
↓
Infiltration of cytokine-released Th2 cells and monocytes; activation of inflammatory cells (especially eosinophils)
↓
-mediators e.g. cysLTs→airway inflammation and airway hyper-reactivity
-eosinophil major basic protein, eosinophil cationic protein→epithelial damage→airway hyper-reactivity

Airway hyper-activity and airway inflammation
↓
bronchospasm, wheezing, coughing

Question 9

Selective B2-receptor agonists
examples
Advanatages
Disavantages

Answer 9

Salbuatmol, terbutaline, salmeterol
Advantages: Rapid airway relaxation
Decreased systemic effects

Disadvantages
Receptor desensitization 
Receptor down-regulation 
Refractory bronchoconstriction 
Asthma-related death

Question 10

Pharmacology of B2-receptor agonists

Answer 10

Gs-GTP activates adenylyl cyclase and that produces cAMP
This cAMP does 3 things:
1) Increases SERCA
2) Increases PMCA
3) Decreases C2+ entry via channels
These three things decrease the intracellular concentration of Ca2+
Which in turn causes myosin-p to convert to myosin
This causes relaxation
(MLCK causes contraction)

Question 11

What does SERCA stand for

Answer 11

Sarcoplasmic/Endoplasmic Reticulum Calcium Atpase

Question 12

What does PMCA stand for

Answer 12

Plasma-membrance Ca2+ ATPase

Question 13

Advantages of B2-agonists

Answer 13

• administered via inhalation; mostly well-tolerated, minimises adverse effects
• rapid onset (minutes), SABAs last 3-6hours
• Long acting forms last 8-12 hours

Question 14

Disadvantages of B2-agonists

Answer 14

• May stimulate B1 receptors -ADRS in liver, heart and skeletal muscle
• increased risk of asthma-related death (unusal genotype) - hypoxia
• even when inhaled, only 10% goes to airways as rest swallowed
• Tachcardia, ↑release of glucose from liver, tremor, ↑contracility of heart

Question 15

Phosphodiesterase inhibitors

Answer 15

inhibits phosphodiesterase, preventing breakdown of phospholipase, increasing cAMP and hence ↑protein kinase A, ↑SERCA, ↑PMCA
all of these increases cause lower intracellular calcium and hence smooth muscle relaxation

Question 16

Methylxanthines

drugs

Answer 16

-caffeine, theophylline, theobromine

Question 17

Advantages of methylxanthines

Answer 17

↑endogenous cAMP
enhance B2-agonist effects
↑cAMP can inhibit some inflammatory processes
Antagonists at adenosine receptors
Cheap, may work in COPD and severe, unresponsive asthma

Question 18

How Bronchodilator M3 receptor antagonists work

Answer 18

2 mechanisms: things it blocks

• Rhok inhibits MLCPP which means contraction is blocked
• PLC→IP3→increase in intracellular ca2+ to activate MLCK which increases phosphorlyation of myosin, causing contraction

Question 19

advantages of antimuscarinic bronchodilators

Answer 19

• reduces mucus secretion
• may be useful as add-on in life-threatening acute asthma
• may alleviate acute asthma unresponsive to standard therapy

Question 20

disadvantaages of antimuscarinic bronchodilators

Answer 20

numerous adverse effects
constipation, dry mouth, nausea, cough, headache, dizziness
Less common side effects:
vomiting, palpitation, tachycardia, urinary retention, throat irritation,
blurred vision, mydriasis, raised intra-ocular pressure, angle-closure glaucoma

Question 21

Contraindiciations of antimuscarinic bronchodilators

Answer 21

benign prostatic hyperplasia, bladder outflow obstruction, narrow angle glaucoma

Question 22

Allergic asthma - role of T lymphocytes

Corticosteroid action

Answer 22

Glucocorticoids inhibit transcription of genes for interleukins
-drug binds to intracellular protein (receptor) and then they both enter the nucleus
Binds to DNA and changes gene expression
Inhibits transcription of genes for COX2, iNOS, cytokies,interleukins and cell adhesion molecules
-stimulate synthesis and release of annexin-1

Question 23

Corticosteroids indication

Answer 23

effective in asthma and possibly in COPD
reduces airway inflammation
reduce oedema by increasing membrane permeability
-reduce mucous secretion

Question 24

Corticosteroids

Answer 24

Beclometasone dipropionate 100-400ug
Fluticasone propionate 50-200ug

Each twice daily

Question 25

Other drugs used for asthma

Answer 25

-Omalizumab (monoclonal antibody - binds to IgE and prevents it from attaching to mast cells) - side effect is analphalactic shock
-mast cell stabilisers - mechanism unclear
sodium cromoglicate, nedocromil - more effective in 6-12 year olds

Question 26

COPD mechanism

Answer 26

epithelial cells/macrophages→TGF-B→fibrosis and remodelling of airways

smoke, irritants cause secretion of chemotactic factors - attract monocytes (become macrophages) and neutrophils
↓
proteases e.g.:
-metalloproteinase 9 - breaks down basement membrane and causes mucous hypersecretion, acts in alveolar wall too
-elastase
Both proteases cause alveolar wall destruction (emphysema)
Reduces surface area for gas exchange

Question 27

MMPs

Answer 27

-matrix melloproteinases (neutrophil-derived proteases)
destroy elastin fibres in the lung parenchyma
Cause proteolytic degradation of extracellular matrix (ECM)
PDE4 inhibitors help reduce MMP production

Question 28

Roflumilast

Answer 28

PDE4 inhibitor used in conjunction with SABA
Main PDE in macrophages, eosinophils, neutrophils
Roflumilast enhancese SABA/LABA effects and improves FEV1

Question 29

Roflumilast side effects

Answer 29

Diarrhoea 
Nausea 
Abdominal pain 
Headache 
Unexplained weight loss

Question 30

Analeptics

Answer 30

respiratory stimulants

Doxapram

Question 31

Doxapram action pharmacology

Answer 31

1-Carotid chemoreceptors→Inhibition of Task1/Task 3 K+ leak channels
2-Brainstem respiratory control centres→respiratory motor neurones→increase frequency and depth of breathing by acting on diaphragm
3-Aortic chemoreceptors→inhibition of Task1/Task3 K+ leak channels

Question 32

Doxapram action

Answer 32

stimulates medullary respiratory centres

• transiently ↑volume and rate of respiration
• requires IV administration- short duration of 8-10min

Question 33

Doxapram indications

Answer 33

• post operative respiratory depression
• complication of opioid analgesic therapy
• overdose of CNS depressant drugs
• ventilatory failure in COPD
• reduces frequency of apnoea in premature neonates but caffeien preferred alternative

Question 34

Doxapram safety

Answer 34

narrow margin of safety

May cause convulsions (mechanical ventilation preferred)