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Unit 13 > Pharmacology of Asthma and COPD > Flashcards

Pharmacology of Asthma and COPD Flashcards

1
Q

What is meany by chronic asthma?

A

A common chronic inflammatory conditions of the airways
Key features - airway hyperresponsiveness and variable airflow obstruction.
Most frequent symptoms are cough, wheeze, chest tightness and breathlessness.
Long term management of asthma

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2
Q

What is meant by acute asthma?

A

The progressive worsening of asthma symptoms, including breathlessness, wheeze, cough and chest tightness.
An acute excaberation characterised by a reduction in pulmonary function particularly FEV1 and PEFR.
Asthma attack

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3
Q

What is the main pharamcological treatment pathway in asthma patients as recommended by NICE?

A

Newly diagnosed - SABA as reliever, may be sufficient in patients with short lived, infrequent symptoms with normal lung function.
Maintenance therapy (frequency or uncontrolled) offer ICS as first line treatment, particularly if use inhlaer more than 3 times a weeks.
If ICS fails offer an additional LTRA then a LABA (with or without LTRA).
Consider a combination inhaler (MART regime).
May then consider additional drugs if needed, ICS dose should be lowest effective dose may increase to medium dose in ineffective.
Then refer to specialist care.

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4
Q

What are the two main pathophysiological stages in asthma?

A

Immediate - bronchospasm - revserible air flow obstruction due to smooth muscle contraction, often caused by genetic predispotion (hyperresponsiveness) or environmental triggers such as allergens causing IgE, histamine, leukotrine release

Later phase - inflammation, causes reversible airflow obstruction due to mucus, odema, exudate and swelling, caused by inflammatory cells and mediates produced in immediate phase, self perpetuating. T cells, eosinophils,

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5
Q

How do the two stages of asthma normally present?

A

Exposre to allergen - acute phase within 1-2 hours in most people.
Make relatively quick recovery
Late phase - around 5-6 hours, rapid decline in lung function, worse than immediate phase and slower to recover. This decline can be life threatening and often requires treatment.

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6
Q

What long term changes tend to occur in the airways of chronic asthmatic?

A

Increased mucus production
Goblet cells hyperplasia and submucosal glands increased
Thickening of the basement membrane with increased subendothelial collagen deposition (fibrosis)
Increased tissue-resident immune cells - mainly macrophages (cellular infiltrate)
Smooth muscle thickening
Theses changes are mainly the responses of chronic inflammation resulting in increased smooth muscle tone, growth factor release and increased mucus demand.

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7
Q

What changes tend to occur in the airways of acute asthma attack?

A

Increased mucus production
Bronchoconstriction of the airway
Damage to epithelial surface - indirectly through inflammation and mediators released from eosinophils and basophils.

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8
Q

What cytokines are released by Th2 to encourage B cell to produce IgE?

A

IL-4 and IL-13 d

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9
Q

What cytokines encourage a naive T cell to become a Th2?

A

IL-4 and IL2

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10
Q

What cytokines encourage the recuitment and activation of eosinophils?

A

IL-5 released from Th2
IL3, IL5 and GM-CSF from mast cell.
IgE also recruits Eosinophils and basophils.

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11
Q

What are the three key features of the early response in asthma?

A

Bronchospasm
Edema
Airflow obstruction
(Degranulation of mast cells)

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12
Q

What are the three key features of the late response in asthma?

A

Airway inflammation
Airflow obstruction
Airway hyperresponsiveness with increased mucus production
(mediate by immune cells, Th2, eosinophils and masts)

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13
Q

What anti-asthmatic drugs are considered bronchodilators?
When are these most useful?

A

B2 agonists
Theophyliline
LTRA
Anti-muscarinics
In early stage of asthma for symptomatic relief of acute symptoms

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14
Q

What anti-asthmatic drugs are considered anti-inflammatory?
When are these most useful?

A

Glucorticoids
Targeted biologics
Target the transition from the immediate to late phasem and the late phase. Prevent the development of chronic asthma and airway remodelling. Reduce inflammation in the airway.

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15
Q

What naming stems indicate a SABA?

A

Note also have salbutamols.

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16
Q

What is the clinical use of salbutamol?

A

Airway obstructive disease (Asthma/COPD)
Premature labour (tocolytic) - prevent uterine contractions
Performance enhancing.

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17
Q

What is the mechanism of salbutamol in the treatment of airway obstructive disease?

A

Class - SABA
Chem - is a small molecule, structural analogue of adrenaline
Pharmacology - beta 2 adrenoreceptor partial agonist (note still some effect at beta 1)
Physiology - binds to Beta 2 on smooth muscle, GPCR, Gs activates adenylyl cyclase - causing increased cAMP and increased PKA activation -> smooth muscle relaxation
Also binds to beta 2 on mast cells - here increased cAMP prevents degranulation of mast cells.
Physiology: bronchodilator, reduce inflammation, enhance mucocilliary clearance and inhibit microvascular leakage.

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18
Q

What are the potential risks of salbutamol?
What are the theories behind this?

A

Over dose - beta agonist - increase heart rate and force of contraction through effect at beta 1
Can cause vasodilation in vascular beds in skeletal muscle (hypotension)
Is anabolic - stimulates muscle hypertrophy - dose is monitored in professional sports

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19
Q

Suggest why most asthmatic drugs are inhaled.
Why is this still problematic?

A

Aims to increase concentration of drugs at the lungs rather than in systemic circulation.
However often absorbed through oral mucosa into blood stream, drains quickly into heart as does blood from lungs - can still cause cardiovascular effects.

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20
Q

What is the signalling process of adenylyl cyclase in cardiac muscle?

A

Ligand binds to beta adrenergic receptor (beta 1)
Gas is activated, activates adenylyl cyclase
Increases conversion of ATP to cAMP
cAMP activates HCN - increases funny currents to increase heart rate.
cAMP activates PKA, which phosphorylated VGCa2+C - more responsive - increase intracellular calcium - inc force of contraction.

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21
Q

What is the signalling process surrounding adenylyl cyclase in smooth muscle?

A

Beta 2 adrenergic receptor - activated by ligand - Gas
Activates adenylyl cyclase - increase conversion of ATP to cAMP.
Activates PKA which phosphorylates MLCK so becomes inactive as decreased interaction with calcium-calmoduline complex
Also activates MLCP
This prevents the phosphorylation of the MLC, hence inhibits smooth muscle contraction.

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22
Q

What receptors can inhibit adenylyl cyclase?

A

M2 and alpha 2 receptors - found in smooth muscle

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23
Q

What is the effect of activation of M3 and alpha 1 receptors?

A

M3 - Ach binding.
Alpha 1 adrenergic (post synaptic) - adrenaline binding.
Are GPCRs
Activates Gaq.
Activates PLC beta
Increases IP3 and DAG
Results in increased calcium ion concentration
Calcium calmoduline complex - increase MLCK activity
Increase smooth muscle contraction via affect at MLC.

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24
Q

What is the clinical use of budesonide?

A

Anti-inflammatory
Immunsuppressive

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25
Q

What is the mechanism of action of budesonide in asthma?

A

Class - inhaled corticosteroid
Chem - synthetic glucocorticoid
Pharm - bind to cytosolic glucocorticoid receptor.
Cause dissociation from heat shock (chaperone) proteins and heterodimerisation
Active receptor translocates to the nucleus and acts as a transcription factor
Binds to glucocorticoid response element-specific sequences on DNA.
It brings about physiological effects by modifying gene expression
Physiology - effects transcription machinery, transrepression to reduce pro-inflammatory mediators (IL-4,5,13) that are normally transcibed related to NFkB
transactivation - increase anti-inflammatory mediators (IL-10, TGFbeta)
Reduced immune cell migration, reduce inflammation, prevent tissue damage, reduce mucus production and alleviate symptoms.

26
Q

What naming system indicates leukotriene receptor antagonist?

A

-lukast suffix.

27
Q

What is the clinical use of montelukast?

A

Prophylaxis of asthma

28
Q

What is the mechanism of action of montelukast in the treatment of asthma?

A

Is a leukotriene receptor antagonist.
Chem - synthetic analogue of leukotrienes
Pharm - competitive antagonist at CysLT1 receptors (GPCRs)
Phyiology: prevents activation of PLCbeta and prevents inhibition of Adenylyl cyclase overall inhibits bronchospasm and vasospasm.

29
Q

What is the normal effect of leukotrienes in the airways?

A

Leukotrienes include LTC4, LTD4, LTE4
Binds to CysLT1
Causes inhibition of adenylyl cyclase - reduced cAMP - reduced inhibition of MLCK - enables smooth muscle contraction
Activates PLCbeta -> activates IP3 and DAG -> inc Ca2+ -> cause smooth muscle contraction.

Smooth muscle contraction
Vascular permeability
Leukocyte activation.

30
Q

What is the process of leukotrienes production?

A

Membrane phospholipids are acted on by phospholipase A2, this produces arachidonic acid
Then acted on by 5-LOX to convert to leukotriene A4 (LTA4)
Addition of gluthione and further enzymes can be modified down the pathway of LTC4, LTD4 and LTE4 - these three are considered cysteinyl leukotrienes.

31
Q

What are the different types of lipoxygenase enzyme?

A

5-LOX (leukotrine synthesis)
12-LOX
15-LOX

32
Q

Explain why the use of aspirin can be problematic in asthmatic individuals.

A

Aspirin is an NSAID - inhibits COX enzyme, prevents the conversion of arachidonic acid into Prostaglandin G2.
This increases the conc of arachidonic acid (substrate) for the 5-LOX enzyme - this increases the leukotriene synthesis
THis promotes inflammation and exacerbates asthma symptoms in the airway via - activation of leukocytes, bronchoconstriction, vasoconstriction and increased vascular permeability.
Hence aspirin has caution/contra-indicated in asthma.

33
Q

What are some of the targeted biologics available for asthma?

A

Benralizumab
Mepolizumab
Resilizumab
Omalizumab
Dupilumab
Tezepelumab

34
Q

What is the role of benralizumab as a treatment for asthma?

A

Is a targeted biologic - humanized monoclonal antibody
Blocks/depletes IL-5R found on immune cells
Prevents interaction with IL-5, this stops the activation/recruitement of eosinophils and basophils.
Inhibits proliferation of B cells
Activates eosinophil apoptosis.

35
Q

What is the role of mepolizumab and reslizumab as a treatment for asthma?

A

Is a targeted biologic - humanized monolconal antibody
Neturalises/blocks IL-5, by binding ti OL-5 with high affinity, this prevents the interaction with its receptor.
Inhibits the growth, differentiation, recruitment and survival of eosinophils
Decreased eosinophil levels in the blood, leads to decreased airway inflammation and improved asthma control.
Inhibits B cell proliferation
Used in severe refractory eosinophilic asthma.

36
Q

What is the mechanism of action of omalizumab?

A

Class: targeted biologic
Chem: humanised recombinant monoclonal antibody
Pharmacology: Neutralises/ blocks unbound heavy chain constant region on circulating IgE.
Physiology: Prevents IgE binding to Fc receptor on the mast cell
Prevents allergen-induced degranulation - prevents inflammatory mediator release
Prevents tissue infiltration with eosinophils
Clinical: Prophylaxis of severe allergic asthma, prevent wheezing, SOB and coughing.
Reduce airway hypersensitivity.
Mainly used for patients with perennial allergen

37
Q

What is the mechanism of action of dupilumab?

A

Is a human monoclonal antibody - targeted biologic
Neutralises/blocks IL-4 receptor ligand binding subunit (IL4 receptor antagonist)
Reduces activity of IL-4 and IL-13, prevents Beta cell activation, eosinophil recruitement, Th2 survival and differentiation and IgE production.
Treatment for severe asthma.
Awaiting NICE approval to be used for patients with a raissed FeNO in asthma
Already approved for use in asthma.

38
Q

What is the mechanism of action for tezepelumab?

A

Targeted biologic - Human monoclonal antibody
Neutralises/blocks TSLP, prevents the release of T cell attracting chemokines (aka reduces IL-5 and IL-13)
Used to treat severe asthma (not just eosinophilic)

39
Q

What is the clinical indication of theophylline?

A

To treat chronic asthma. - is a second line drug
Can also be used as a diuretic, inc HR and force, CNS stimulant.

40
Q

What is the mechanism of theophylline in the treatment of chronic asthma?

A

Class: methylxantine
Chem: small molecule
Pharmacology and physio:
Competitive inhibitor of phosphodiesterase - causes bronchodilation
Competitive antagonist at adenosine receptors, is non selective but has greatest affect as A2A
Adenosine 1 receptor - norm pro-inflammatory, activates Gai, decrease cAMP - cause bronchoconstriction - this process is inhibited by drug
Adenosine 2 receptor - anti-inflammatory, activates Gas, increase cAMP, cause bronchodilation (drug action here does not have such as great physiological effect).

41
Q

What naming indicates a long-acting muscarininc antagonist? (LAMA)

A

trop somewhere in the name

42
Q

What is the clinical indication of tiotropium?

A

Is a LAMA
Used in the treatment of severe asthma and COPD.

43
Q

What is the mechanism of action of tiotropium in asthma?

A

Class: is a long acting mucarininc antagonist
Chem: synthetic analogue of atropine.
Pharm: competitive antagonist at M3 receptors. Is non selective so also effects M2 and M1
Physio:
Normally ACh - binds to M3 - Gaq activated - PLC inc calcium ion conc - bronchoconstriction and mucus secretion
Norm - ACh binds to M2 - Gai - decrease cAMP - bronchoconstriction.
Therefore antagonism of the M3 and M2 receptors reduces bronchospasm and mucus secretion

44
Q

What is the overall effect of anti-muscarinics in the asthmatics airway?

A

Inhibits parasympathetic action
Leads to decreased smooth muscle contraction, reduced blood vessel permeability and reduced mucous gland secretions.

45
Q

What is the reason why cigarettes use to be recommended for asthmatics?

A

Stramonium leaves in cigarettes
Contain tropane alkaloids such as atropine
Act as anti-muscarinics
Would prevent bronchoconstriction and mucus secretion
However outweighed by harmful effect of allergens in smoke.

46
Q

What are the key pathological features of COPD?

A

Is most common in smokers, smoke activates alveolar macrophages, releases neutrophil attracting chemokines.
Inflammatory reaction.
Neutrophil releases proteases such as elastase and MMPs
Impaires normal lung defences - resulting in recurrent infections of airways (bronchititis) and alveoli (pneumonia)
Alveolar wall destruction leads to emphysema.
Mucus hypersecretion - chronic bronchitis

47
Q

How does smoking and stopping smoking affect lung health?

A

Lung capacity (FEV1) declines in everyone from age 25yrs
Declines at a faster rate in smokers
Stopping smoking - decline rate returns back to that of non-smoker
However, existing damage is not reversed.
This continued decline but a slower rate, is why ex-smokers can still be at a higher risk of conditions at an earlier age.

48
Q

What are the two key elements of COPD?

A

Bronchitis and emphysema

49
Q

What are the different progressive stages of asthma?

A

Acute inflammation
Chronic inflammation
Airway remodelling
Each stage is less reversible than the previous.

50
Q

What is the main therapeutic goal of asthma?

A

Relief - reverse bronchospasm and prevent severe attacks of mucus secretion and airway odema

Prophylaxis - prevent bronchospams, airway remodelling and chronic inflammation.

51
Q

What is the main therapuetic goal of COPD?

A

Relief - increase airway patency, control recurrent infections
Prophylaxis - to prevent chronic inflammation and control mucus secretion.

52
Q

What therapies tend to be used as relief therapies from asthma?

A

Bronchodilators such as beta agonsits (LABA and SABA), muscarininc antagonists and theophylline.

53
Q

What therapies tend to be used as prophylaxis treatment in asthma?

A

Bronchodilators - LA B2 agonists, theophyline and montelukast
Glucorticoids (inhalred or oral)
Anti-IGE therapies
Anti0 IL5 therapies.

54
Q

What is the clinical indication of a SABA referring to activation times?

A

Salbutamol (SABA)
Rapid onset within 30 mins (norm within 5 mins)
lasts for 3-5hrs
Hals life of 2.5 to 5.5 hours
Use 3-4 times a day
Symptomatic control in asthma

55
Q

What is the clinical indication of a LABA referring to activation times?

A

Formoteral (LABA)
Rapid onset within minutes
LAsts for 8-12 hours
Half life 2-3hrs or 5hrs
Use twice a day
Prophylatic use as an adjective therapy in those whose asthma is not adequately controlled by glucorticoids.
Long acting prevent bronchospasm in those require long term bronchodilator therapy.

56
Q

What is the clinical indication of a ultra-LABA referring to activation times?

A

Indacterol is an ultra LABA
Effect lasts for more than 24 hours
Haslf life of 40-52 hrs
Use once a day
Prophylatic use
Used in COPD.

57
Q

What is the mechanism allowing LABAs to have a longer duration than SABAs?

A

Lipophilic tail in LABA can be inserted into membrane.
Interacts with exosite on receptor - enables activation of beta 2 receptor
Attachment to membrane reduces diffusion of drug away from site of action, increases duration of effect.
Very complex PD and PK factors influence it.

58
Q

What is the non pharmacological fundamentals of COPD care?

A

Help to stop smoking
Pneumococcal and influenza vaccine
Offer pulmonary rehab if needed
Co-develop a personalized self-management plan
Optimise treatment for comorbidities.

59
Q

What is the guidance around pharmacological treatment in COPD?

A

Only offer inhlaed therapies after non-pharmacological has failed and patient has been trained on how to use inhalers.
Offer SABA or SAMA as needed
If asthmatic features and likely to respond to steroids offer LABA + ICS
If no asthmatic features offer LABA and LAMA
If patient has day to day symptoms that impact quality of life or has 1/2 severe/moderate attacks a year offer all three LABA, LAMA and ICS (if addition of ICS makes no difference then remove).

60
Q

Compare and contrast the overall process of asthma and COPD.

A

Both - chronic inflammatory and airway obstruction

Asthma - bronchospasm (affect smooth muscle), airway hyperreactivity and inflammation with eosinophils and Th2, drug treatments are more effective

COPD - bronchitis and alveolar breakdown (emphysema), bmucus hypersecretion and mucosal infiltrate most effective treatment is stopping smoking.

61
Q

Compare and contrast the changes to the airway on a cellular level in COPD and asthma.

A

COPD - large amounts of peribronchiolar fibrosis, inc neutrophils, Th1 and Cytotoxic T cell dominated, alveolar disruption

Asthma - increased smooth muscle cell, basement membrane, inc airway vessels, mast cells, eosinophils, Th2 dominanayed, shed epithelium.

Both increase goblet cells and have immune cell infiltrate.

62
Q

How is salbutamol normally given to an asthmatic?

A

Reliver inhlaer
Pressured metered-dose inhaler normally with a spacer - easier to use and improve delivery to lungs
In acute and prolonged attacks salbutamol is given via nebuliser which deliver the medication as a mist for those with severe difficulty unable to inhlale effectively.

Unit 13 (22 decks)

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