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Respiratory > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Stimulation of the post-ganglionic non-cholinergic fibres causes what?

A

Bronchial smooth muscle relaxation mediated by nitric oxide and vasoactive intestinal peptide

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2
Q

Stimulation of pastganglionic cholinergic fibres causes what?

A

Bronchial smooth muscle contraction mediated by M3 muscarinic ACh receptors on ASM cells and increased mucus secretion mediated by M3 muscarinic ACh receptors on goblet cells

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3
Q

Where are the cell bodies of the preganglionic fibres located?

A

In the brainstem

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4
Q

Where are the cell bodies of the postganglionic fibres located?

A

Embedded in the walls of the bronchi and bronchioles

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5
Q

What activates GPCR (g protein coupled receptor)

A

Transmitter or hormone

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6
Q

How do actin and myosin filaments generate contraction?

A

By sliding over each other to generate force

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7
Q

Contraction of smooth muscle results from what?

A

Phosphorylation of the regulatory myosin light chain in the presence of elevated intracellular Ca2+ (and ATP)

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8
Q

Relaxation of smooth muscle results from what?

A

Dephosphorylation of MLC by myosin phosphatase which has constitutive activity

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9
Q

Describe what happens to the rate of phosphorylation and de-phosphorylation in the presence of elevated Ca2+

A

The rate of phosphorylation exceeds the rate of de-phosphorylation

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10
Q

What molecule degrades cAMP?

A

Phosphodiesterase

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11
Q

What reveals hyper-responsiveness in asthma?

A

Provocation tests with inhaled bronchoconstrictors (spasmogens) such as histamine or methacholine

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12
Q

Describe immediate and delayed phases of asthma attack

A
  • immediate is mainly bronchospasm

- delayed is mainly inflammatory reactions

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13
Q

What initiates an adaptive immune response in allergic asthma?

A

Initial presentation of an antigen eg. dust mite protein or pollen

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14
Q

Describe the effector phase of the development of allergic asthma

A
  • eosinophils differentiate and activate in response to IL-5 released from TH2 cells
  • mast cells in airway tissue express IgE receptors in response to IL-4 and IL-13 released from TH2 cells
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15
Q

Describe the subsequent presentation of antigen in the development of allergic asthma

A
  • cross links IgE receptors stimulates calcium entry into mast cell and release of calcium from intracellular stores
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16
Q

What does the release of Ca2+ from intracellular stores and calcium entry into mast cells evoke?

A
  • release of secretory granules containing preformed histamine and the production and release of other agents (eg. leukotrienes LTC4 and LTD4) that cause airway smooth muscle contraction
  • release of substance eg. LTB4 and platelet-activating factors and prostaglandins that attract cells causing inflammation eg. mononuclear cell and eosinophils into the area
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17
Q

What are the two classes of drugs used in the treatment of asthma?

A
  • relievers

- controllers/ preventers

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18
Q

What do relievers do and name some examples?

A
  • they act as bronchodilators
  • short acting beta 2 adrenoceptor agonists (SABAs)
  • long acting beta 2 adrenoceptor agonists (LABA)
  • cysLT1 receptor antagonists
  • methylxanthines
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19
Q

What do controllers and preventers do and name some examples?

A
  • act as anti-inflammatory agents that reduce airway inflammation
  • glucocorticoids
  • cromoglicate
  • humanised monoclonal IgE antibodies
  • methylxanthines
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20
Q

Describe aerosol dosing of drugs

A
  • slow absorption from lung surface and rapid systemic clearance
  • low dose delivered rapidly to target
  • low systemic concentration of drug
  • low incidence of adverse effects
  • distribution of drug is reduced in severe airway disease
  • difficult for small children and infirm people
  • effective in mild to moderate disease
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21
Q

Describe oral dosing of medication

A
  • good oral absorption and slow systemic clearance
  • high systemic dose necessary to achieve an appropriate concentration in the lung
  • high systemic concentration of drug
  • high incidence of adverse effects
  • distribution unaffected by airway disease
  • good compliance
  • easy administration
  • effectiveness good even in severe disease
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22
Q

What do beta 2 adrenoceptor agonists act as?

A

Physiological antagonists of all spasmogens

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23
Q

Describe short acting agents eg. salbutamol, albuterol, terbutaline

A
  • first line of treatment for mild, intermittent asthma
  • taken as needed
  • usually administered by inhalation
  • acts rapidly to relax bronchial smooth muscle, maximal effect within 30 minutes, relaxation for 3 to 5 hours
  • increase mucus clearance and decrease mediator release from mast cells and monocytes
  • have few adverse effects (due to unwanted systemic absorption) when administered by the inhalation route, fine tremor being the most common. However tachycardia, cardiac dysrhythmia and hypokalaemia can occur
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24
Q

Describe long acting agents eg. salmeterol, formoterol

A
  • not recommended for acute relief of bronchospasm
  • are useful for nocturnal asthma ( act for approximately 8 hours)
  • should not be used as monotherapy, but can be used as add-on therapy if asthma inadequately controlled by other drugs
  • LABAs must always be co-administered with a glucocorticoid
  • for this purpose, combination inhalers such as Symbicort and seratide are available but costly
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25
Q

Describe cysteinyl leukotriene (CysLT1) receptor antagonists

A
  • act competitively at the Cys LT1 receptor
  • derived from mast cells and infiltrating inflammatory cells cause smooth muscle contraction, mucus secretion and oedema
  • effective as add on therapy against early and late bronchospasm in mild persistent asthma
  • effective against antigen-induced and exercise induced bronchospasm
  • relax bronchial smooth muscle
  • administered orally
  • generally well tolerated
  • eg, montelukast, zafirlukast
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26
Q

Describe methylxanthines

A
  • have an uncertain molecular mechanism of action

- might involve inhibition of isoforms of phosphodiesterases that inactivate cAMP and cGMP

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27
Q

At high doses, what does theophylline do?

A

Inhibits PDE3 inhibiting the action the cAMP in ASM

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28
Q

Describe corticosteroids

A
  • adrenal cortex synthesises two major classes of steroid hormone that are released into the circulation, glucocorticoids and mineralocorticoids. Not pre-sorted by synthesised and released on demand
  • glucocorticoids the main hormone is cortisol regulates numerous essential processes such as
  • inflammatory responses decreased
  • immunological responses decreased
  • liver glycogen deposition increased
  • glucogenesis is increased
  • glucose output from liver increased
  • glucose utilisation decreased
  • protein catabolism increased
  • bone catabolism increased
  • gastric acid and pepsin secretion increased
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29
Q

What is the function of mineralocorticoids

A

Regulate the retentions of salt and water by the kidney

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30
Q

Describe the actions of endogenous steroids

A

May possess both glucocorticoid and mineral corticoid actions

The latter are unwanted in the treatment of inflammatory conditions

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31
Q

Glucocorticoids signal via what receptors?

A

Nuclear receptors, specifically GR alpha

32
Q

What type of molecule are glucocorticoids?

A

Lipophilic molecules

33
Q

What is the effect of glucocorticoids on the transcription of genes encoding anti-inflammatory proteins?

A

They increase the transcription of these genes

34
Q

Glucocorticoids recruit what to activated genes and switch off gene transcription?

A

Histone deacetylases (HDACs)

35
Q

Name the function of glucocorticoids

A

Decrease formation of TH2 cytokines (eg. IL-4 and IL-5) and cause apoptosis

36
Q

What is the clinical use of glucocorticoids in asthma?

A

Prevent inflammation and resolve established inflammation

37
Q

Describe short term and long term effects of glucocorticoids in asthma

A

Short term they do not alleviate early stage bronchospasm caused by allergens or exercise. However long term treatment is effective (particularly in combination with long-acting beta 2 adrenoceptor agonist LABA

38
Q

Describe glucocorticoid use in mild/moderate asthma

A

Glucocorticoids (often beclomethasone, budenosine orfluticasone) are given by inhalation from a metered dose inhaler (to minimise any unwanted systemic effects)
Efficacy develops over several days

39
Q

What are the most common adverse effects of the use of glucocorticoids in asthma?

A
  • dysphonia (hoarse and weak force)
  • oropharyngeal candidiasis
  • this is due to the deposition of steroid in the oropharynx
40
Q

What are cromones?

A

Second line drugs now infrequently used prophylactically in the treatment of allergic asthma (particularly in children)

41
Q

What is the proposed mechanism of cromones?

A

Mast cell stabilisers

42
Q

Describe the use of sodium cromoglicate

A
  • cromone
  • delivered by inhalation - little systemic absorption
  • can reduce both phases of an asthma attack, but efficacy may take several weeks to develop to block late-phase reaction, requires frequent dosing
  • is more effective in young children and young adults as opposed to older patients
43
Q

Give an example of a monoclonal antibody direct against IgE

A

Omalizumab

44
Q

Describe monoclonal antibodies directed against IgE

A
  • binds IgE via fc to prevent attachment to Fce receptors- supresses mast cell response to allergens
  • reduces expression on Fce receptors on various inflammatory cells
  • expensive treatment
  • requires IV administration
45
Q

Name a monoclonal antibody directed against IL-5

A

Mepolizumab

46
Q

Describe the effects of chronic bronchitis

A
  • inflammation of bronchi and bronchioles
  • cough
  • clear mucoid sputum
  • infections with purulent sputum
  • increasing breathlessness
47
Q

Describe the effects of emphysema

A
  • distension and damage to alveoli
  • destruction of acinial pouching in alveolar sacs
  • loss of elastic recoil
48
Q

What is COPD characterised by?

A

Increased resistance to air flow during expiration

49
Q

How many isoforms of muscarinic receptors are there?

A

5

50
Q

Describe M1 receptors

A
  • ganglia
  • facilitate neurotransmission mediated by Ach acting on nicotinic receptors
  • M1 receptors mediate a slow e.p.s.p that increases action potential frequency resulting from nicotinic receptor stimulation
51
Q

Describe M2 receptors

A
  • postganglionic neurone terminals

- act as inhibitory auto-receptors reducing release of Ach (their blockade increases the release of Ach)

52
Q

Describe M3 receptors

A
  • airway smooth muscle

- mediate contraction of Ach (also present on mucus - secreting cells evoking increased secretion)

53
Q

Name some muscarinic receptor antagonists currently licensed in the UK

A
  • ipratropium (SAMA)
  • glycopyrronium (LAMA)
  • aclidinium (LAMA)
  • umeclidinium (LAMA)
54
Q

Describe muscarinic receptor antagonists

A
  • have a delayed onset of bronchodilation
  • reduce bronchospasm caused by irritant stimuli and also block Ach mediated basal tone
  • decrease mucus secretion
  • have little effect on the progression of COPD, their family is mainly palliative
  • have very few adverse effects (little systemic absorption due to the progression of the quaternary ammonium group)
  • ipratropium is a non-selective blocker or M1, M2 and M3 receptors, preferred agents with some selectivity for M3 are available
55
Q

Describe the vago-vagal reflex

A

Muscarinic antagonists block transmission by Ach acting on ASM M3 receptors. Irritant stimulus initiates a vagal reflex.

56
Q

Why are M3 selective blockers superior to ipratropium

A
  • the functional selectivity of relatively selective M3 blockers over ipratropium is achieved by differences in rate of association and dissociation from the M3 receptor
  • block of the M3 and M1 is desirable, but block of M2 is not because release of Ach from parasympathetic post-ganglionic neurones is increased by autoreceptor antagonism
57
Q

What is the basic logic of beta 2 agonist muscarinic antagonist combinations?

A
  • muscarinic antagonists block activation by Ach, prevents contraction
  • activation by a beta 2 agonist causes relaxation
58
Q

Name some examples of a beta 2 agonist / muscarinic antagonist combinations

A
  • ipratropium (SAMA) and salbutamol (SABA)
  • aclidinium bromide (LAMA) and formoterol (LABA)
  • glycopyrronium (LAMA) and indacaterol (LABA)
  • tiotropium (LAMA) an olodaterol (LABA)
  • umeclidinium (LAMA) and vilanterol (LABA)
59
Q

Describe rofumilast in the treatment of COPD

A
  • selective PDE4 inhibitor, supresses inflammation and emphysema
  • approved as oral treatment for severe COPD accompanied by chronic bronchitis, but has limiting adverse gastrointestinal effects
60
Q

When do glucocorticoids benefit COPD patients?

A

Benefit patients who develop frequent and severe exacerbations when given with a LABA

61
Q

Why might glucocorticoid unresponsiveness occur in COPD?

A

Due to oxidative / nitrative stress (associated with chronic inhalation of tobacco smoke). HDAC2 is reduced in COPD

62
Q

Describe rhinitis

A
  • common and often debilitating disease involving acute or chronic inflammation of the nasal mucosa
  • may be allergic, non-allergic or mixed
63
Q

What is rhinitis characterised by?

A
  • rhinorrhoea
  • sneezing
  • itching
  • nasal congestion and obstruction (swelling of nasal mucosa largely due to dilated blood vessels - particularly in cavernous sinusoids)
64
Q

Describe allergic rhinitis

A
  • can be classififed as seasonal, perennial or episodic (SAR, PAR, EAR)
  • has many similarities to allergic asthma (two are strongly linked)
65
Q

What causes allergic rhinitis?

A
  • inhalation of allergen increases specific IgE levels -IgE binds to receptors on mast cells and basophils
  • re-exposure to allergen causes mast cell and basophil degranulation, release of mediators including histamine, cysLTs, tryptase and prostaglandins causing acute itching, sneezing rhinorrhoea and nasal congestion
  • delayed response caused by recruitment of lymphocytes and eosinophils to nasal mucosa contributes to congestion and obstruction
66
Q

Describe non-allergic and occupational rhinitis

A
  • non allergic; any rhinitis, acute or chronic, that does not involve IgE dependant events
  • occupational rhinitis; may involve both allergic and non-allergic components
67
Q

Name some causes of non-allergic rhinitis

A
  • infection; infectious rhinitis (largely viral)
  • hormonal imbalance; hormonal rhinitis (eg. pregnancy)
  • vasomotor disturbances; vasomotor rhinitis
  • non allergic rhinitis with eosinophilia syndrome (NARES)
  • medications; drug induced rhinitis (eg. aspirin)
68
Q

What are the targets in the treatment of rhinitis and rhinorrhoea?

A
  • anti-inflammatory
  • mediator receptor blockade
  • nasal blood flow
  • anti-allergic
69
Q

Name some drugs used in the treatment of rhinitis and rhinorrhoea

A
  • anti-inflammatory; glucocorticoids
  • mediator receptor blockade; H1 receptor antagonists, CysLT1 receptor antagonists
  • nasal blood flow; vasoconstrictors
  • anti-allergic; sodium cromoglicate
70
Q

What is the overall mechanism of glucocorticoids?

A

Reduce vascular permeability, recruitment and activity of inflammatory cells and the release of cytokines and mediators

71
Q

Name some examples of glucocorticoids that are used in the treatment of rhinitis

A
  • beclomethasone
  • fluticasone
  • prednisolone
72
Q

What is the mechanism of anti-histamines (H1 receptor antagonists) ?

A

Competitive antagonists that reduce effects of mast cell derived histamine including;

  1. vasodilation and increased capillary permeability
  2. activation of sensory nerves
  3. mucus secretion from submucosal glands
73
Q

Describe the mechanism of CysTL1 receptor antagonist in rhinitis treatment

A

CysLT1 receptor antagonists reduce the effects of CysLT upon the nasal mucosa

74
Q

Name an example of a CysTL1 receptor antagonist

A

Montelukast

75
Q

What drugs are given to target eosinophilic inflammation?

A
  • anti inflammatory medication
  • corticosteroids
  • cromones
  • theophylline
76
Q

Describe the actions of a spacer device

A
  • avoids coordination problems
  • reduces oropharyngeal and laryngeal side effects
  • reduces systemic absorption from swallowed fraction
  • acts as a holding chamber for aerosol
  • reduces particle size and velocity
  • improves lung deposition
77
Q

Summarise the treatment of acute COPD

A
  • nebulised high dose salbutamol and ipratropium
  • oral prednisolone
  • antibiotic (amoxicillin / doxycycline) if infection
  • physio to aid sputum expectoration
  • non-invasive ventilation to allow higher FiO2
  • ITU intubated assisted ventilation only if reversible component (eg. pneumonia)

Respiratory (7 decks)

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