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Pharmacology (Respiratory) Flashcards

1
Q

What does stimulation of parasympathetic nerve fibres in the airways cause and by which receptor does it work?

A

Causes contraction of bronchiole smooth muscle and increased mucus secretion, M3 muscarinic receptors.

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2
Q

How can the parasympathetic nervous system do the opposite to its normal effect on the airways?

A

By using different transmitters e.g. NO, VIP. This is called nitrergic transmission.

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3
Q

How does the sympathetic nervous system affect airways?

A

Stimulation causes bronchial smooth muscle relaxation, decreased mucus secretion and increases mucociliary clearance by adrenaline released from the adrenal gland binding to B2 adrenoceptors. Also causes contraction of vascular smooth muscle mediated by A1 adrenoceptors.

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4
Q

How is smooth muscle contraction stimulated by GPCRs?

A

GPCR activated -> Gq protein activates phospholipase C -> converts PIP2 into IP3 -> binds to receptor in sarcoplasmic reticulum (calcium channel) -> calcium enters cytoplasm -> leads to contraction

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5
Q

How is smooth muscle contraction stimulated by depolarisation of the membrane?

A

Voltage-gated calcium channels activated -> calcium binds to ryanodine receptor (calcium activated calcium channel) on sarcoplasmic reticulum -> calcium enters cytoplasm -> leads to contraction

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6
Q

How does calcium in the cytoplasm cause contraction of smooth muscle?

A

Calcium binds to calmodulin -> produces calcium calmodulin complex (regulatory protein) -> activates myosin light chain kinase (MLCK) -> phophorylates myosin light chain which can then bind actin -> filaments slide over each other

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7
Q

What results from the dephosphorylation of MLC by myosin phosphatase and when does the rate of phosphorylation of MLC exceed dephosphorylation?

A

The relaxation of smooth muscle. When there is elevated intracellular calcium.

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8
Q

How is intracellular calcium gotten rid of for relaxation?

A

Primary and secondary active transport.

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9
Q

How is relaxation of bronchial smooth muscle controlled by signalling molecules?

A

Adrenaline binds to B2 adrenoceptor -> activates Gs protein -> activates adenylyl cyclase which converts ATP to cAMP -> allows activation of protein kinase A (PKA) -> causes inhibition of MLCK and stimulation of myosin phosphatase -> results in relaxation of bronchial smooth muscle

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10
Q

How is the pathway for smooth muscle contraction switched off?

A

When cAMP is degraded to 5’AMP by PDE (phosphodiesterase).

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11
Q

What are some causes of asthma attacks?

A

Allergens, exercise, respiratory infections, environmental pollutants.

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12
Q

What are the pathological changes to the bronchioles that result from long standing inflammation?

A
  1. increased mass of smooth muscle (hyperplasia and hypertrophy) 2. accumulation of intersitial fluid (oedema) 3. increased mucus secretion 4. epithelial damage (exposing sensory nerve endings) 5. sub-epithelial fibrosis
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13
Q

How is bronchial hyper-responsiveness caused in asthma?

A

Epithelial damage exposing sensory nerve endings (C-fibres, irritant receptors) contributes to increases sensitivity of airways to bronchoconstrictor influences.

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14
Q

What are the 2 components of hyper-responsiveness and how are they measured?

A

Hypersensitivity and hyper-reactivity. Measured by inducing bronchoconstriction with inhaled bronchoconstrictors and the fall in FEV1 is plotted against the log concentration of inhaled bronchoconstrictor. The less drug required to cause constriction, the more hypersensitive. Greater the fall in FEV1, the more hyperreactive.

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15
Q

What are the immediate and delayed phases of an asthma attack?

A

Immediate - bronchospasm and acute inflammation (type 1 hypersensitivity reaction). Delayed - inflammatory reaction (type IV).

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16
Q

What is the body’s response to an allergen in a non-atopic individual?

A

Allergen -> phagocytosis by dendritic cell -> low level Th1 response (cell-mediated immune response involving IgG and macrophages)

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17
Q

What is the body’s response to an allergen in an atopic individual?

A

Allergen -> phagocytosis by dendritic cell -> strong Th2 response (antibody-mediated immune response involving IgE).

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18
Q

In allergic asthma, describe how the B cell maturation is caused.

A

CD4+ T cells mature to Th0 cells -> mature to Th2 cells (produce cytokine environment to inhibit production of Th1 cells) -> Th2 activate B cells by binding and IL-4 production -> B cells mature into IgE secreting P cells

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19
Q

What does IgE bind to?

A

IgE receptors on mast cells in airway tissue (receptors expressed in response to IL-4 and 13 released from Th2 cells) and receptors on eosinophils (causes differentiation and activation).

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20
Q

What causes the cross linking of IgE receptors on mast cells and what does this then stimulate?

A

Antigen presentation. Stimulates calcium entry into mast cells and release of Ca2+ from intracellular stores which causes release of secretory granules containing histamine and production and release of other agents e.g. leukotrienes LTC4 and LTD4).

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21
Q

What substances are released from mast cells after cross linking of IgE receptors that attract cells causing inflammation e.g. mononuclear cells and eosinophils?

A

LTB4, platelet activating factor (PAF) and protsoglandins (PGD2).

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22
Q

What are the key events in the late phase of asthma?

A

Chemotaxins and chemokines released from mast cells causing infiltration of cytokine releasing Th2 and monocytes. This activates inflammatory cells, particularly eosinophils. These then release mediators (CysLTs and others) which cause airway inflammation, airway hyperresponsiveness, bronchospasm, wheezing, mucus over secretion and cough. Release of eosinophil major basic and cationic proteins also causes epithelial damage.

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23
Q

Give some examples of relievers.

A

Short acting B2 adrenoceptor agonists (SABAs), long acting B2 adrenoceptor agonists (LABAs), CysLT1 receptor antagonists.

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24
Q

What are controllers/ preventers and what are some examples of them?

A

Anti-inflammatory agents that reduce airway inflammation, used to prevent and requires long term usage e.g. glucocorticoids (corticosteroids), cromoglicate, humanised monoclonal IgE antibodies.

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25
Q

Why are drugs for asthma best when inhaled and when may the oral route have to be used?

A

Only a low dose is needed so it reduces adverse effects. When inhalation is difficult e.g. severe airway disease, for children or infirm people.

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26
Q

How do B2 adrenoceptor agonists work?

A

Act as physiological antagonists of all spasmogens. Reduce intracellular calcium concentration. Also cause opening of particular types of potassium channel which allows potassium to flow out of the cell causing hyperpolarisation (further from reaching threshold depolarisation).

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27
Q

Give 2 examples of short acting B2 agonists (SABAs).

A

Salbutamol and terbutaline.

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28
Q

What are SABAs the first line treatment for?

A

Mild, intermittent asthma.

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29
Q

What are the usual times of effect of SABAs?

A

Act within 5 mins, max effect within 30 mins, effective for 3-5 hours.

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30
Q

What is the effect of SABAs on mucus clearance and on mast cells and monocytes?

A

Increases mucus clearance, decreases mediator release from mast cells and monocytes.

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31
Q

What are the adverse effects of SABAs?

A

Common: fine tremor. Uncommon: tachycardia, cardiac dysrhythmia and hypokalaemia (decreased concentration of calcium ions). These occur due to loss of selectivity as the concentration increases.

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32
Q

Give 2 examples of LABAs.

A

Salmeterol, formoterol.

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33
Q

When are LABAs useful?

A

For nocturnal asthma, as an add-on therapy in asthma inadequately controlled by other drugs e.g. glucocorticoids.

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34
Q

Why is it bad to use non-selective beta-agonists?

A

Can cause harmful stimulation of cardiac B1 adrenoceptors.

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35
Q

Describe the process by which leukotrienes produce cellular effects.

A

Mast cell activated -> intracellular release of arachidonic acid by phospholipase A2 -> stimulation of mast cell 5-lipoxygenase by FLAP -> activates LTA4 -> becomes either LTB4 or LTC4 -> crosses membrane -> produces cellular effects

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36
Q

What cellular effects can leukotrienes produce?

A

LTB4: infiltration of inflammatory cells releasing CysLTs, LTC4: becomes either LTD4 or LTE4 which can both bind to CysLT1 receptor. CysLT1 receptor activation causes bronchoconstriction and inflammation.

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37
Q

Give 2 examples of CysLT1 receptor antagonists.

A

Montelukast, zafirlukast.

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38
Q

When are CysLT1 receptor antagonists useful?

A

As add on therapy against early and late bronchospasm in mild persistent asthma and in combo with other medications. Are effective against antigen-induced and exercise-induced bronchospasm.

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39
Q

How are CysLT1 receptor antagonists administered and why are they not recommended for relief of acute severe asthma?

A

The oral route. Their bronchodilator activity is worse than salbutamol.

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40
Q

What are the possible side effects of CysLT1 receptor antagonists?

A

Generally well tolerated but some reports of headache and GI distress.

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41
Q

Give 2 examples of methylxanthine.

A

Theophylline and aminophylline.

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42
Q

What is a possible mechanism of action for methylxanthines?

A

Inhibition of phosphodiesterases (PDE3 and 4) that inactivate cAMP and cGMP (second messengers that relax smooth muscle).

43
Q

What are the main effects of methylxanthines?

A

Bronchodilator (at high doses) and anti-inflammatory actions, inhibit mediator release from mast cells and increase mucous clearance.

44
Q

What effects do methylxanthines have on the diaphragm?

A

Increase diaphragmatic contractility and reduce fatigue (may improve lung ventilation).

45
Q

How may methylxanthines potentiate (increase) the anti-inflammatory action of glucocorticoids?

A

It activates histone deacetylase.

46
Q

How are methylxanthines administered?

A

By the oral route as sustained release preparations.

47
Q

What is the problem with methylxanthines and what are their side effects?

A

They have a very narrow therapeutic window and have numerous drug interactions. Supra-therapeutic conc: actions involvin the CNS, CVS, GI tract and kidneys. Therapeutic conc: nausea, vomiting, abdominal discomfort and headache.

48
Q

What 2 major classes of steroid hormone are synthesised by the adrenal cortex and where?

A

Glucocorticoids (zona fasciculata) and mineralocorticoids (zona glomerulosa).

49
Q

What is the main naturally occurring glucocorticoid and what does it regulate?

A

Cortisol and a lot of essential processes including decreasing inflammatory and immunological responses.

50
Q

What are the synthetic derivatives of cortisol with little/no mineralocorticoid activity?

A

Beclomethasone, budesonide and fluticasone.

51
Q

Do glucocorticoids have direct bronchodilator action?

A

No.

52
Q

What is the molecular mechanism of action of glucocorticoid?

A

Combine with nuclear receptor GR alpha in the cytoplasm producing dissociation of inhibitory heat shock proteins. Activated receptor translocates to nucleus aided by importins. In nucleus they assemble into homodimers and bind to glucocorticoid response elements (GRE) in the promoter region of specific genes. Transcription switched on or off to alter mRNA levels and rate of synthesis of mediator proteins.

53
Q

What are the 2 ways that genes are regulated by glucocorticoids?

A
  1. Glucocorticoids acting at GREs 2. Modifying the structure of chromatic (DNA and histones) via deacetylation of histones.
54
Q

What is the expression of inflammatory genes associated with?

A

Acetylation of histones by histone acetyltransferases (HATs). Acetylation unwinds DNA from histones allowing transcription.

55
Q

How to glucocorticoids cause deacetylation of histones?

A

They recruit histone deacetylases to activated genes and switch off gene transcription.

56
Q

What are the effects of glucocorticoids?

A
  1. Prevent allergen-induced influx of eosinophils into the lung and causes apoptosis. 2. Decrease formation of Th2 cytokines and cause apoptosis. 3. Prevent production of IgE antibodies. 4. Reduce number of mast cells and decreases Fc epsilon expression.
57
Q

What are the effects of glucocorticoids on structural cells?

A

Decreases cytokines and mediators released from epithelial cells, less leak in endothelial cells, increased B2 adrenoceptors and decreased cytokine production in airway smooth muscle, decreases mucus secretion in mucous glands.

58
Q

What are cromones described as?

A

Mast cell stabilisers (agents that supress histamine from mast cells) but is not the basis of their effectiveness in the treatment of asthma.

59
Q

Other than mast cell stabilisation, what are the other effects of Cromones?

A

No direct effect on bronchial smooth muscle. Uncertain mechanism of action. Weak anti-inflammatory effect. Decreases sensitivity of irritant receptors associated with sensory C-fibres that trigger exaggerated reflexes and reduction of cytokine release are potential mechanisms.

60
Q

Give an example of a cromone and some details about it.

A

Sodium cromoglicate: delivered by inhalation, can reduce both phases of asthma attack but takes several weeks to develop to block late-phase reactions so requires frequent dosing. Is more effective in children and young adults.

61
Q

How do humanised monoclonal IgE antibodies treat asthma?

A

Bind to IgE via Fc to prevent attachment to Fc epsilon receptors which suppresses mast cell response to allergens. Also reduces expression of Fc epsilon receptors on various inflammatory cells. Very expensive and IV administration required.

62
Q

What else can antibodies be directed against and what is this a recently introduced treatment for?

A

Interleukin 5 - Asthma associated with severe eosinophilia.

63
Q

Describe how smoking can cause COPD.

A

Smoking -> stimulation of resident macrophages -> cytokine production -> activation of neutrophils, CD8+ T cells, increased macrophage numbers -> release of metalloproteinases e.g. elastase, free radicals -> leads to chronic bronchitis and emphysema.

64
Q

Describe chronic bronchitis.

A

Inflammation of bronchi and bronchioles, cough, clear mucoid sputum, infections with purulent sputum, increasing breathlessness.

65
Q

Describe emphysema.

A

Distension and damage to alveoli, destruction of acinial pouching in alveolal sac, loss of elastic recoil.

66
Q

What are the symptoms of rhinitis?

A

Rhinorrhoea (runny nose), sneezing, itching, nasal congestion and obstruction (dilated blood vessels particularly in cavernous sinusoids).

67
Q

What are the 3 types of rhinitis?

A

Allergic, non-allergic or mixed.

68
Q

What can allergic rhinitis be classified as?

A

Seasonal (SAR), perennial (PAR), episodic (EAR).

69
Q

What other disease does allergic rhinitis have similarities with?

A

Allergic asthma.

70
Q

Is the molecular process of rhinorrhea basically the same as asthma?

A

Yes.

71
Q

What is the delayed response caused by and what is it?

A

Recruitment of lymphocytes and eosinophils to nasal mucosa, contributes to congestion and obstruction.

72
Q

What is non-allergic rhinitis defined as?

A

Any rhinitis, acute or chronic, that does not involve IgE-dependent events.

73
Q

Describe the types of non-allergic rhinitis.

A

Infection rhinitis (largely viral), hormonal rhinitis (e.g. pregnancy), vasomotor rhinitis (cause unknown), non-allergic rhinitis with eosinophilia syndrome (NARES), drug induced rhinitis e.g. aspirin.

74
Q

May occupational rhinitis involve both allergic and non-allergic components?

A

Yes.

75
Q

What increases the volume of the nasal mucosa and causes difficulty breathing in in rhinitis?

A

Increased mucosal blood flow, increased blood vessel permeability or both.

76
Q

Give examples of target and treatment of rhinitis.

A

Anti-inflammatory - glucocorticoids. Mediator receptor blockade - H1 receptor antagonists, CysLT1 receptor antagonists), nasal blood flow (vasoconstrictors), anti-allergic (sodium cromoglicate).

77
Q

What is the mechanism of glucocorticoids in rhinitis?

A

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

78
Q

What types of rhinitis may glucocorticoids be useful in?

A

Mainstay of therapy for SAR and PAR and are of value in NARES and vasomotor rhinitis.

79
Q

How are glucocorticoids applied in rhinitis and are they effective as a monotherapy?

A

Topically as a spray to the nasal mucosa, and yes.

80
Q

What may glucocorticoids be combined with in moderate to severe rhinitis?

A

Antihistamines.

81
Q

When may glucocorticoids be given orally with rhinitis?

A

In very severe intractable cases.

82
Q

What are the mechanisms of anti-histamines (H1 receptor antagonists)?

A

Competitive antagonists that reduce effects of mast cell derived histamine. Reduces vasodilation and capillary permeability, activation of sensory nerves and mucus secretion from submucosal glands.

83
Q

What types of rhinitis are anti-histamines effective in?

A

SAR, PAR and EAR, less so in non-allergic rhinitis.

84
Q

What symptom do anti-histamines affect the least?

A

Congestion.

85
Q

How are anti-histamines administered in rhinitis?

A

Orally or as an intranasal spray (azelastine).

86
Q

Are first or second generation agents of anti-histamines preferred and why?

A

Second: reduced sedation as don’t cross blood brain barrier and lack of anti-cholinergic effects.

87
Q

Give examples of 2nd generation anti-histamines.

A

Loratidine, fexofenadine, cetirizine (also has mild anti-inflammatory action).

88
Q

What is the mechanism of action of anti-cholinergic drugs in rhintis?

A

ACh release from post-ganglionic parasympathetic fibres activates muscarinic receptors on nasal glands causing a watery secretion that contributes to rhinorrheoa - blocked by anti-cholinergics.

89
Q

What type of rhinitis are anti-cholinergic drugs used in?

A

PAR and SAR.

90
Q

What symptoms do anti-cholinergic drugs help to suppress?

A

Reduces rhinorrhoea (no influence on itching, sneezing and congestion).

91
Q

How are anti-cholinergic drugs administered?

A

Intranasally.

92
Q

What is the only side effect of anti-cholinergic drugs?

A

Dryness of the nasal membranes.

93
Q

What is the name of the anti-cholinergic drug used in rhinitis?

A

Ipratropium.

94
Q

What is the time of onset of action of sodium cromoglicate?

A

4 to 7 days, weeks may be required for full effect.

95
Q

How is sodium cromoglicate administered?

A

Intranasally (less effective than corticosteroids).

96
Q

What are CysLT1 receptor antagonists equi-effective with?

A

H1 receptor antagonists, effect may be additive.

97
Q

What types of allergic rhinitis are CysLT1 receptor antagonists used in?

A

PAR and SAR.

98
Q

How are CysLT1 receptor antagonists administered?

A

Orally.

99
Q

In what patients would CysLT1 receptor antagonists be considered?

A

Patients with allergic rhinitis and asthma.

100
Q

What is the name of the CysLT1 receptor antagonist used in rhinitis?

A

Montelukast.

101
Q

What is the mechanism of action of vasoconstrictors in rhinitis?

A

Act directly or indirectly to mimic the effect of noradrenaline. Produce vasoconstriction via activation of alpha-1 adrenoceptors to decrease swelling in vascular mucosa.

102
Q

What is the name of the vasoconstrictor used in rhinitis?

A

Oxymetazoline (administered intranasally).

103
Q

Why is nasal administration of oxymetazoline not recommended for more than a few days?

A

Due to development of a rebound increase in nasal congestion upon discontinuation (rhinitis medicasmentosa). Occurs due to receptor desensitisation and downregulation.

Respiratory (30 decks)

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