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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
Due to the two phases to an asthma attack, the FEV1 changes over time, but in what ways?
FEV1- decreases after initial reaction (immediate) FEV1- recovers after the immediate reaction FEV1- deteriorates again during delayed reaction FEv1- recovers fully
26
How does atopic asthma differ from non-aptopic asthma in relation to immune system activation?
Non- atopic- low level TH1 response which mediates IgG and macrophages Atopic- strong TH2 response that is an antibody mediated immune response involving IgE
27
What are TH0 cells?
Precursors | They differentiate to either TH1 or TH2 cells
28
In the development of allergic asthma describe the induction phase
- 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
29
in the development of allergic asthma describe the effector phase
- 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
30
What are the two phases to the development of allergic asthma?
1. Induction phase | 2. Effector phase
31
How do mast cells become activated in allergic asthma?
Antigens combine with IgE antibodies on the surface of mast cells
32
What happens during mast cell activation in allergic asthma?
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
33
What happens when mast cells release chemotaxis and chemokine during allergic asthma?
- 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
What are the two main types of drugs that are used in asthma and which drug classes are used for each?
Relievers- bronchodilators 1. SABAs 2. LABAs 3. CysLT1 receptors antagonists Controllers/preventors- anti- inflammatory 1. Glucocorticoids 2. Cromoglicate 3. Humanised monoclonal IgE antibodies
35
Why are LABAs never given as mono therapy?
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
During stage 3 of asthma treatment, what happens if there is no response to the added LABA?
Dose of ICS is increased | And, if required trail of other therapies such as CysLT1 receptor antagonist or theophylline is used
37
What are the three classes of B2-adrenoceptor agonists?
1. SABAs 2. LABAs 3. Ultra LABAs
38
Why are SABAs administered by inhalation?
This reduces the dose required and therefore the systemic effects experienced
39
What are some of the potential side effects to SABAs?
- Tachycardia - Cardiac dysrhythmias - Hypokalaemia
40
What 3 things do SABAs achieve?
- Bronchodilation - Increased mucus clearance - Decreased mediator release of mast cells and monocytes
41
LABAs are always co-administered with a _____________
Glucocorticoid
42
What is the benefit that LABAs have over SABAs?
They can be used for nocturnal asthma
43
What is isoprenaline and why is it not frequently used?
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
Name a non-selective B2 adrenoceptor agonist
Isoprenaline
45
Why is the use of propranolol dangerous in patients requiring bronchodilation therapy?
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
What happens when phospholipase A2 acts on activated mast cells?
Intracellular release of arachidonic acid occurs
47
After arachidonic acid is released intracellularly in mast cells, what happens when the mast cells are stimulated by 5-lipoxygenase(FLAP)?
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
LTB4 has what effects in the airways?
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
What happens in the airways to LTC4?
It is metabolised to LTD4 and LTE4 | LTD4 can also metabolise to LTE4
50
Which leukotrienes will act on the CysLT1 receptor?
- LTD4 - LTE4 - CysLT1
51
Activation of the CysLT1 receptor will lead to what?
Contraction of bronchial smooth muscle | and later, inflammation
52
In the USA, which drug is used to block stimulation is mast cells by 5-lipoxygenase ?
Zileuton
53
What are two of the main CysLT1 antagonists?
- Monterlukast | - Zafirlukast
54
Why are CysLT1 receptor antagonists not recommended for relief of severe acute asthma?
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
How are CysLT1 receptor antagonists administered?
Orally
56
What are the two main methylxathines?
1. Theophylline | 2. Aminophylline
57
What are the two main actions methylxanthines take to counteract asthma symptoms ?
1. Bronchodilator action | 2. Anti-inflammatory action
58
Describe the bronchodilator action of methylxanthines
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
How is diaphragmatic contractility affected by the use of methylxanthines?
It is increased | This can reduce fatigue and improve ventilation
60
Describe the anti- inflammatory action of methylxanthines
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
Why does HDAC increase the strength of bonds between histones and DNA backbone?
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
Why are methylxanthines not high on the list for the treatment of asthma?
They have serious side effects and very narrow therapeutic window - seizures - Hypotension, dysrhythmias - GI tract issues- vomoting, discomfort - Kidney problems
63
How can methylxathines negatively impact drug metabolism?
They can interfere with enzyme involved in drug metabolism such as cytochrome P450s
64
What is the adrenal cortex?
The outer layer of the adrenal gland
65
Name the layers of the adrenal cortex from most superficial to deep
1. Glomerulosa 2. Fasciculata 3. Reticularis
66
The different layers of the adrenal cortex can synthesise different ______
steroids
67
The adrenal cortex synthesises which two major classes of steroid hormone?
1. Glucocorticoids- synthesised in zona fasiciculata | 2. Mineralocorticoids- synthesised in zona glomerulosa
68
Are steroid hormones pre-sorted in vesicles or are they synthesised on demand by hormones from the anterior pituitary ?
Synthesised on demand by the anterior pituitary gland
69
What is the main glucocorticosteriod produced in humans?
Cortisol
70
What is the main mineralocorticoid in humans and what are its main effects?
Aldosterone | Regulates the retention of water and salt by the kidneys
71
Of the two, what are more useful for asthma treatment, corticosteroids or mineralocorticoids , and why?
Corticosteriods | They have anti- inflammatory action and they dampen down the immunological response
72
In basic terms , how is a cortisol synthetically altered to allow it to be a suitable asthma treatment?
Cortisol has both corticoid and mineralocorticoid properties The mineralocorticoid properties are edited out so only the corticoid properties have influence
73
Give three examples of glucocoticosteroids that are synthetic derivatives of cortisol?
1. Beclometasone 2. Budesonide 3. Fluticasone
74
Why should glucocorticoids never be administered alone?
They have no (direct) effect on bronchospasm and will not relive it
75
Why should glucocorticoids be administered by inhalation?
To avoid systemic effects
76
Where are glucocorticoid receptors in cells?
Cytoplasm (or nucleus) | activation leads to effects in nucleus
77
How do glucocorticoids enter the nucleus?
By diffusion into the cytoplasm | they are hydrophobic agents- so their receptor will be intracellular
78
What is the glucocorticoid receptor called?
GRa
79
The GRa receptor is normally bound to by ____ ____ ______, specifically ____ and when the glucocorticoid binds to the receptor ____ will dissociate
Heat shock proteins HSP90 HSP90
80
Upon glucocorticoid binding to Gr , what occurs initially ?
The receptor/agonist complex can move to the nucleus aided by specific karyopherins called importins

Respiratory (12 decks)

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