Lecture 10 - Bronchodilators

Question 1

Side effects of corticosteroids

Answer 1

• not common when using less than 1000 ug/day
• oropharyngeal thrush
• dysphonia
• immunosuppression, adrenal suppression in response to stress, osteroporosis, muscle wasting, hyperglycemia, cataracts, brusing, moon face, hyperextension, buffalo hump

Question 2

Corticosteroids improve lung function: study

Answer 2

• it takes several weeks for the treatment to start having an effect
• the key is to combine a short acting with a long acting reliever
• comes back at normal after 8 weeks - but patients have to keep going
• low values are generally in the morning, low values in the evening

Question 3

Corticosteroids MOA

Answer 3

• Nuclear receptors have to cross into cells or ligand activated transcription factors
• not found in membranes
• regulate gene transcription - steroid and thyroid hormones
• can both increase and decrease gene transcription
• increase: Annexin-1, b adrenergic receptor
• decreases- cytokines (inflammtation(

Question 4

Low dose corticosteroid MOA

Answer 4

• repress gene transcription by trans-repression.
• binds the glucocorticoid receptor then binds to CBP and then interact with HDAC2 -> winds up the genes and shuts down transcription of inflammatory genes

Question 5

High dose corticosteroid MOA

Answer 5

• cis repression: negative GRE
• trans activation: GRE, anti-inflammatory
• forms homodimer which migrates to nucleus

Question 6

Corticosteroid resistance

Answer 6

• asthmatic people are more likely to smoke
• non-smokers: improvement with use of glucocorticosteroids
• in smokers: increase free radicalproduction and inflammation leads to no benefits from glucocorticosteroids

Question 7

Mechanism of smoking and decrease effectiveness of glucocorticosteroids

Answer 7

• cigarette smoke and inflammation leads to increase free radical and NO which combine to form Peroxynitrite, which activates PI3Kdelta
• this phosphorylates and inactivates HDAC2 -> winds up and represses transcription of inflammatory genes
• low dose might be a powerful antioxydant

Question 8

Diagnosis of asthma

Answer 8

• history
• physical examination
• Consider other diagnoses
• documenting variable airflow limitation

Question 9

Drug target ASM and/or inflammation

Answer 9

• Smooth muscle has a b2 adrenoceptor on it - for people with asthma, number of most cells in smooth muscle - increases contraction via histamine
• epithelium - other target for b2 receptors - mucocilliary transport very weak - more obstruction

Question 10

ANS control

Answer 10

• sympathetic NS: open up airway via activation of adrenal glands and release of adrenaline - acts on b2
• Parasympathetic NS: via vagus nerve
• short post ganglionic nerve fiber in airway - releases Ach which binds M3AChR - release of calcium in cells in smooth muscle - contraction
• IgE in mast cel when cross link cause increase calcium in mast cells - release of Histamine - bing H1R on smooth muscle cell - contraction

Question 11

SNS - special ganglia in the adrenal medulla

Answer 11

• sympathetic activation leads to Ach release from presynaptic nerve which act on nicotinic ACh receptors of chromaffin cells in medulla to cause release of noradrenaline and adrenaline

Question 12

B adrenoceptor agonist

Answer 12

• SABA: adrenaline, salbutamol, albuerol, fenoterol, terbutaline sulphate
• LABA: salmeterol, formoterol
• UltraLABA: indacaterol, vilanterol

Question 13

Anti-cholinergic drigs

Answer 13

• SAMA: ipratropium bromide

- LAMA: tiotropium bromide

Question 14

Antileukotrienes

Answer 14

• act on cysLT1 antagonists - promote contraction nearly equally effective as corticosteroids

Question 15

Phosphodiesterase inhibitors

Answer 15

• increase cAMP t1/2
• intracellular mediator that helps reduce calcium
• selctive PDE4: roflumilast: COPD

Question 16

Net contraction = contraction - relaxation

Answer 16

1) Contraction pathway
- Hist - H1R
- AChh - M3AchR
- LT - CysLT1
- all constitituve active and activate By - activate PLC which produces DAG + IP3 increases calcium

2) Relaxation pathway
- Adrenaline receptor constitutively active - Activates Gas - increase CAMP which inhibits MLCKCyt - decrease calcium, decrease contraction

Question 17

Summary of b2 adrenoceptor activation

Answer 17

• smooth muscle relaxation (inhibition of contraction)
• increased ciliary beat frequency
• inhibition of mast cell activation: decrease mediator release, desensitization

Question 18

Effects of salbutamol

Answer 18

• prevents asthma attack before exercise
• decrease airway resistance via b2
• increase b1 activation - increase HR

Question 19

Asthma attack classification

Answer 19

• Mild - speak in whole sentences
• Severe: speech not in full sentences, O2 saturation (90-94%)
• life threatening (

Question 20

Adverse effects of b2 agonists

Answer 20

• tremor
• increased HR palpitations (b1)
• SK vasoduilation and relex tachycardia
• tolerance of b2 adrenergic agonist
• masking of signs and symptoms of asthma
• increase muscle mass

Question 21

Acute effect of b2 agonists

Answer 21

• Hyperglycemia (B3)
• Hypokalaemia
• Hypomagnesemia - cramping

Question 22

Study on SABA and LABA

Answer 22

• SABA use alone increases airflow variability indicating poor asthma control and promotes unstable airway function leading to precipitate a severe asthma attach
• need to combine with LABA
• regular short acting agonist therapy should not be used to treat asthma

Question 23

COPD

Answer 23

• small airway disease
• alveolar destruction
• comorbidities

Question 24

COPD bronchodilators

Answer 24

• short acting reliever meds: SABA or SAMA
• symptom relief: LAMA and/or LABA
• exacerbation prevention
• for severe COPD also consider low dose theophylline
• Newer treatment includes ultraLABA/LAMA