Drugs in Respiration - Pharmacology - Ashtma, COPD Flashcards
the CNS goes via the vagus nerve to….
Trachea and conducting bronchi
The trachea and conducting bronchi branch into what?
- Submucosal gland - M1/M3
- Blood vessel - M3
- Airway smooth muscle - M3 - post-ganglionic fibres
Innervation of human airway smooth muscle
no sympathetic innervation
only of glands and blood vessels
Asthma inflammatory cell
eosinophils
COPD inflammatory cell
neutrophils
Immediate phase of asthma
Trigger: allergen ↓ mast cells/mononucellar cells ↓ spasmogens e.g. leukotrienes C4, D4, Histamine, PGD2 ↓ Bronchospasm
Immediate phase of asthma - mast cell branch
mast cells/mononucelear cells ↓ Chemotaxins Chemokines ↓ Late phase
Late phase of asthma starting at chemotaxins and chemokines
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
Selective B2-receptor agonists
examples
Advanatages
Disavantages
Salbuatmol, terbutaline, salmeterol
Advantages: Rapid airway relaxation
Decreased systemic effects
Disadvantages Receptor desensitization Receptor down-regulation Refractory bronchoconstriction Asthma-related death
Pharmacology of B2-receptor agonists
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)
What does SERCA stand for
Sarcoplasmic/Endoplasmic Reticulum Calcium Atpase
What does PMCA stand for
Plasma-membrance Ca2+ ATPase
Advantages of B2-agonists
- administered via inhalation; mostly well-tolerated, minimises adverse effects
- rapid onset (minutes), SABAs last 3-6hours
- Long acting forms last 8-12 hours
Disadvantages of B2-agonists
- 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
Phosphodiesterase inhibitors
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
Methylxanthines
drugs
-caffeine, theophylline, theobromine
Advantages of methylxanthines
↑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
How Bronchodilator M3 receptor antagonists work
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
advantages of antimuscarinic bronchodilators
- reduces mucus secretion
- may be useful as add-on in life-threatening acute asthma
- may alleviate acute asthma unresponsive to standard therapy
disadvantaages of antimuscarinic bronchodilators
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
Contraindiciations of antimuscarinic bronchodilators
benign prostatic hyperplasia, bladder outflow obstruction, narrow angle glaucoma
Allergic asthma - role of T lymphocytes
Corticosteroid action
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
Corticosteroids indication
effective in asthma and possibly in COPD
reduces airway inflammation
reduce oedema by increasing membrane permeability
-reduce mucous secretion
Corticosteroids
Beclometasone dipropionate 100-400ug
Fluticasone propionate 50-200ug
Each twice daily
Other drugs used for asthma
-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
COPD mechanism
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
MMPs
-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
Roflumilast
PDE4 inhibitor used in conjunction with SABA
Main PDE in macrophages, eosinophils, neutrophils
Roflumilast enhancese SABA/LABA effects and improves FEV1
Roflumilast side effects
Diarrhoea Nausea Abdominal pain Headache Unexplained weight loss
Analeptics
respiratory stimulants
Doxapram
Doxapram action pharmacology
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
Doxapram action
stimulates medullary respiratory centres
- transiently ↑volume and rate of respiration
- requires IV administration- short duration of 8-10min
Doxapram indications
- 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
Doxapram safety
narrow margin of safety
May cause convulsions (mechanical ventilation preferred)
