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Respiratory > Pharmocology > Flashcards

Pharmocology Flashcards

1
Q

What does the stimulation of postganglionic cholinergic neutrons cause?

A
  1. Bronchial smooth muscle contraction (M3 receptors)

2. Increased muscle secretion (M3 receptors on goblet cells)

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2
Q

What does the stimulation of postganglionic parasympathetic non-cholinergic neutrons cause?

A

Bronchial smooth muscle relaxation

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3
Q

In which four ways does the sympathetic system affect the airways?

A
  1. Bronchial smooth muscle
  2. Mucous secretion
  3. Mucociliary clearance
  4. Vascular smooth muscle contraction
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4
Q

Bronchial smooth muscle is not innervated by sympathetic neurones- how does the sympathetic system influence the bronchi?

A

There is no postganglionic neurone, so innervation of the adrenal gland allows it to act as this neurone, by releasing adrenaline which can cause bronchial smooth muscle by binding to B2 adrenoceptors

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5
Q

What are the receptors associated with the sympathetic system in submucosal glands and what is their activated effect?

A 
B2 adrenoceptors (act on goblet cells and epithelium)
Reduces mucus secretion and increases clearance (mucociliary elevator)
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6
Q

Which receptor mediated vascular smooth muscle contraction?

A

A1 adrenoceptors

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7
Q

What is the sarcoplasmic reticulum?

A

Type of endoplasmic reticulum that regulates calcium ion concentration in skeletal muscle

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8
Q

During motor neurone conduction in skeletal muscle, what type of receptor is activated after hormone or neurotransmitter release ?

A

G protein couples receptor (Gq and phospholipase)

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9
Q

How is IP3 produced during skeletal muscle contraction?

A

Produced from PIP2 (phosphatidylinositol (4,5) )biphosphate after Gq subunit binds to phospholipase

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10
Q

What is the function of IP3 in skeletal muscle contraction?

A

Produced IP3 acts as a substrate for the IP3 receptor (transmembrane) which, when bound, allows efflux of calcium ions out of the sarcoplasmic reticulum and into the cytoplasm. Contraction is now viable

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11
Q

Describe how calcium can aid the pathway of smooth muscle contraction.

A

When the impulse arrives, voltage gated calcium channels open an influx of calcium flows into the cytoplasm. Calcium can then activate ryodine receptors (calcium activated channels). This allows for calcium efflux out of the sarcoplasmic reticulum.

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12
Q

Which two main things must be available for muscle contraction to occur?

A
  1. ATP

2. Calcium

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13
Q

Why is calcium required for muscle contraction?

A

Calcium combines with calmodulin which creates a complex that activates MLCK

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14
Q

What does activated MLCK allow for?

A

Activated MLCK breaks down ATP allowing inactive myosin cross-bridges to enter the cocked position and able to bind with actin filaments

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15
Q

What causes smooth muscle relaxation?

A

Dephosphorylation of MLC by MLC phosphatase

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16
Q

When levels of calcium are high in smooth muscle cells, the rate of phosphorylation will be much higher than dephospho rylation, so for relaxation to occur, what must happen to the levels of calcium?

A

Calcium level must be reduced

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17
Q

What effect does adrenaline have when binding to B2 adrenoceptors in smooth muscle?

A
  • G protein coupled receptors active (Gs)
  • Complex activates adenylyl cyclase which boosts cAMP levels
  • cAMP combines to PKA
  • PKA facilitates smooth muscle relaxation
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18
Q

In what 2 ways does PKA stimulate smooth muscle relaxation?

A
  1. Phosphorylating and inhibiting MLCK which inhibits contraction
  2. Phosphorylating and stimulating myosin phosphatase which facilitates relaxation
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19
Q

Chronic asthma can have many negative effects, what are some of these?

A
  • increase smooth muscle reducing the bronchiole diameter
  • inflammation causes a build up of oedema
  • increased mucus secretion into the lungs causing a partial obstruction
  • epithelial lining becomes damaged and cells are shed which exposes sensory nerve endings causing irritability
  • sub-epithelia fibrosis- epithelial cells deposit excess collagen reducing space further in the airways
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20
Q

What causes bronchial hyper-responsiveness in asthma?

A

Epithelial damage leads to C-fibre (irritation receptor) exposure causing increased sensitivity to bronchoconstricotor influences

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21
Q

As a result of epithelial damage in asthma, neurogenic inflammation occurs- what are the consequences of this?

A

Various peptides are released from these nerve endings

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22
Q

Which two components contribute to the severity of asthma?

A
  1. Hyper-sensitivity- concentration of bronchoconstrictor influences that will evoke asthmatic response
  2. Hyper- reactivity- The severity of the response experienced
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23
Q

What composes the immediate reaction in an asthma attack?

A

Initial bronchospasm and acute inflammation

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24
Q

What composes the delayed reaction of asthma?

A

Continued bronchospasm and delayed inflammation

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25
Q

Due to the two phases to an asthma attack, the FEV1 changes over time, but in what ways?

A

FEV1- decreases after initial reaction (immediate)

FEV1- recovers after the immediate reaction

FEV1- deteriorates again during delayed reaction

FEv1- recovers fully

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26
Q

How does atopic asthma differ from non-aptopic asthma in relation to immune system activation?

A

Non- atopic- low level TH1 response which mediates IgG and macrophages

Atopic- strong TH2 response that is an antibody mediated immune response involving IgE

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27
Q

What are TH0 cells?

A

Precursors

They differentiate to either TH1 or TH2 cells

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28
Q

In the development of allergic asthma describe the induction phase

A
  • The allergen is processed by dendrite cells
  • It is presented to CD4+ cells which become activated
  • TH0 cells are activated
  • Those which differentiate to TH2 activates B cells by physical contact or release of cytokines such as IL-4
  • B cells proliferate and differentiate to plasma cells
  • Antibodies are produced
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29
Q

in the development of allergic asthma describe the effector phase

A
  • Plasma cells secrete IgE antibodies due to interleukin 4 action
  • Interleukin 5 is released from TH2 cells which activates eosinophils
  • Mast cells express IgE receptors and become activated due to release of IL-4 and IL-13
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30
Q

What are the two phases to the development of allergic asthma?

A
  1. Induction phase

2. Effector phase

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31
Q

How do mast cells become activated in allergic asthma?

A

Antigens combine with IgE antibodies on the surface of mast cells

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32
Q

What happens during mast cell activation in allergic asthma?

A

Calcium enters via calcium channels and it is released from intracellular stores

  • mast cell secrete histamine, leukotrienes (LTC4, LTD4)- causes contraction of airways
  • mast cells release substances (chemokine/chemotaxins) that attack inflammation causing cells to the area

This explains the primary and secondary responses to an asthma attack

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33
Q

What happens when mast cells release chemotaxis and chemokine during allergic asthma?

A
  • TH2 cells infiltrate the area with monocytes (TH1 may also be involved)
  • Inflammatory cells such as eosinophils become activated
  • Eosinophils cause damage to epithelium
34
Q

What are the two main types of drugs that are used in asthma and which drug classes are used for each?

A

Relievers- bronchodilators

  1. SABAs
  2. LABAs
  3. CysLT1 receptors antagonists

Controllers/preventors- anti- inflammatory

  1. Glucocorticoids
  2. Cromoglicate
  3. Humanised monoclonal IgE antibodies
35
Q

Why are LABAs never given as mono therapy?

A

Monotherapy of LABAs can be harmful
Receptors can lose sensitivity and pharmacological effect over time decreases
This can cause a long-term decrease in the amount of B2 adrenoceptors as they are withdrawn from the surface of cells and potentially broken down by lysomes

36
Q

During stage 3 of asthma treatment, what happens if there is no response to the added LABA?

A

Dose of ICS is increased

And, if required trail of other therapies such as CysLT1 receptor antagonist or theophylline is used

37
Q

What are the three classes of B2-adrenoceptor agonists?

A
  1. SABAs
  2. LABAs
  3. Ultra LABAs
38
Q

Why are SABAs administered by inhalation?

A

This reduces the dose required and therefore the systemic effects experienced

39
Q

What are some of the potential side effects to SABAs?

A
  • Tachycardia
  • Cardiac dysrhythmias
  • Hypokalaemia
40
Q

What 3 things do SABAs achieve?

A
  • Bronchodilation
  • Increased mucus clearance
  • Decreased mediator release of mast cells and monocytes
41
Q

LABAs are always co-administered with a _____________

A

Glucocorticoid

42
Q

What is the benefit that LABAs have over SABAs?

A

They can be used for nocturnal asthma

43
Q

What is isoprenaline and why is it not frequently used?

A

It is a non-selective beta agonist (works on both B1 and B2 adrenoceptors)
It will stimulate cardiac muscle as well as causing bronchodilation
Selective B2 agonists are preferred for bronchodilation

44
Q

Name a non-selective B2 adrenoceptor agonist

A

Isoprenaline

45
Q

Why is the use of propranolol dangerous in patients requiring bronchodilation therapy?

A

Propranolol is a non-selective B adrenoceptor antagonist
It blocks both B1 and B2 adrenoceptors
Adrenaline is required to bind to B2 adrenoceptors in the airways to ensure a relatively relaxed state is maintained
Upon propranolol administration, this cannot occur and there is a risk of bronchospam

46
Q

What happens when phospholipase A2 acts on activated mast cells?

A

Intracellular release of arachidonic acid occurs

47
Q

After arachidonic acid is released intracellularly in mast cells, what happens when the mast cells are stimulated by 5-lipoxygenase(FLAP)?

A

Arachidonic acid is metabolised to leukotriene A4 (LTA4) and then subsequently into LTB4 and LTC4 which are both secreted into the extracellular space by transport proteins

48
Q

LTB4 has what effects in the airways?

A

Causes infiltration of other inflammatory cells causing the production and release of other leukotrienes including CysLT1 (cysteinyl leukotriene)
LTB4 will also act as a chemokine attracting this leukotriene into the airway cells

49
Q

What happens in the airways to LTC4?

A

It is metabolised to LTD4 and LTE4

LTD4 can also metabolise to LTE4

50
Q

Which leukotrienes will act on the CysLT1 receptor?

A
  • LTD4
  • LTE4
  • CysLT1
51
Q

Activation of the CysLT1 receptor will lead to what?

A

Contraction of bronchial smooth muscle

and later, inflammation

52
Q

In the USA, which drug is used to block stimulation is mast cells by 5-lipoxygenase ?

A

Zileuton

53
Q

What are two of the main CysLT1 antagonists?

A
  • Monterlukast

- Zafirlukast

54
Q

Why are CysLT1 receptor antagonists not recommended for relief of severe acute asthma?

A

Their bronchodilator activity is less than salbutamol
They are not effective against all contractile stimuli
Salbutamol is effective against any provoking stimulus due to acting in a physiological manner- cAMP pathway

55
Q

How are CysLT1 receptor antagonists administered?

A

Orally

56
Q

What are the two main methylxathines?

A
  1. Theophylline

2. Aminophylline

57
Q

What are the two main actions methylxanthines take to counteract asthma symptoms ?

A
  1. Bronchodilator action

2. Anti-inflammatory action

58
Q

Describe the bronchodilator action of methylxanthines

A

Normally cAMP is broken down to 5’AMP by phosphodiesterase enzymes
This prevents smooth muscle relaxation
Methylxanthines (at high dose) inhibit phosphodiesterase (3/4) and allow for smooth muscle relaxation
Levels of cAMP can activate protein kinase A which can phosphorylate and inhibit MLCK, or phosphorylate and stimulate myosin phosphatase - preventing contraction/allowing for relaxation

59
Q

How is diaphragmatic contractility affected by the use of methylxanthines?

A

It is increased

This can reduce fatigue and improve ventilation

60
Q

Describe the anti- inflammatory action of methylxanthines

A

At high dose, pro-inflammatory mediator release from mast cells is inhibited and mucociliary clearance is reduced
Methylxanthines can induce intra-cellular effects- they can activate histone deacetylase (HDAC) in the nucleus
HDAC removes acetyl groups (in histone proteins), increasing the +ve charge of histone tails and increasing bond strength between histones and DNA
This means transcription of inflammatory genes occurs less frequently

61
Q

Why does HDAC increase the strength of bonds between histones and DNA backbone?

A

Normally acetylation occurs in histone proteins converting amines to amides which neutralises +ve changes
This reduces the amount of +ve charges from the histone proteins bonded to the -ve DNA backbone
This weakens the attraction and promotes the transcription of genes (inflammatory in the case of pharmacology) as chromatin expands
HDAC prevents this acetylation occurring ensuring strong bonds remain between histones and DNA

62
Q

Why are methylxanthines not high on the list for the treatment of asthma?

A

They have serious side effects and very narrow therapeutic window

  • seizures
  • Hypotension, dysrhythmias
  • GI tract issues- vomoting, discomfort
  • Kidney problems
63
Q

How can methylxathines negatively impact drug metabolism?

A

They can interfere with enzyme involved in drug metabolism such as cytochrome P450s

64
Q

What is the adrenal cortex?

A

The outer layer of the adrenal gland

65
Q

Name the layers of the adrenal cortex from most superficial to deep

A
  1. Glomerulosa
  2. Fasciculata
  3. Reticularis
66
Q

The different layers of the adrenal cortex can synthesise different ______

A

steroids

67
Q

The adrenal cortex synthesises which two major classes of steroid hormone?

A
  1. Glucocorticoids- synthesised in zona fasiciculata

2. Mineralocorticoids- synthesised in zona glomerulosa

68
Q

Are steroid hormones pre-sorted in vesicles or are they synthesised on demand by hormones from the anterior pituitary ?

A

Synthesised on demand by the anterior pituitary gland

69
Q

What is the main glucocorticosteriod produced in humans?

A

Cortisol

70
Q

What is the main mineralocorticoid in humans and what are its main effects?

A

Aldosterone

Regulates the retention of water and salt by the kidneys

71
Q

Of the two, what are more useful for asthma treatment, corticosteroids or mineralocorticoids , and why?

A

Corticosteriods

They have anti- inflammatory action and they dampen down the immunological response

72
Q

In basic terms , how is a cortisol synthetically altered to allow it to be a suitable asthma treatment?

A

Cortisol has both corticoid and mineralocorticoid properties
The mineralocorticoid properties are edited out so only the corticoid properties have influence

73
Q

Give three examples of glucocoticosteroids that are synthetic derivatives of cortisol?

A
  1. Beclometasone
  2. Budesonide
  3. Fluticasone
74
Q

Why should glucocorticoids never be administered alone?

A

They have no (direct) effect on bronchospasm and will not relive it

75
Q

Why should glucocorticoids be administered by inhalation?

A

To avoid systemic effects

76
Q

Where are glucocorticoid receptors in cells?

A

Cytoplasm (or nucleus)

activation leads to effects in nucleus

77
Q

How do glucocorticoids enter the nucleus?

A

By diffusion into the cytoplasm

they are hydrophobic agents- so their receptor will be intracellular

78
Q

What is the glucocorticoid receptor called?

A

GRa

79
Q

The GRa receptor is normally bound to by ____ ____ ______, specifically ____ and when the glucocorticoid binds to the receptor ____ will dissociate

A

Heat shock proteins
HSP90
HSP90

80
Q

Upon glucocorticoid binding to Gr , what occurs initially ?

A

The receptor/agonist complex can move to the nucleus aided by specific karyopherins called importins

Respiratory (12 decks)

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