Tutorial 5 - Respiratory Disease

Question 1

Label the letters A-H as shown on the diagram with either the neurotransmitter or hormone released from each site or the receptor which is stimulated at each site.

Answer 1

A = Acetylcholine (ACh)
B = Nicotinic ACh receptor
C = ACh
D = Muscarinic receptor
E = ACh
F = Nicotinic ACh receptor
G = Adrenaline
H = Beta-adrenergic receptor

Question 2

In which parts of the autonomic nervous system is the neurotransmitter Acetyl Choline (ACh) found?

Answer 2

Released from:

• all preganglionic nerve terminals, both sympathetic and parasympathetic.
• all parasympathetic postganglionic nerve terminals.
• postganglionic sympathetic nerve terminals in sweat glands.
• sympathetic fibres innervating adrenal medulla (as if the adrenal medulla were a ganglion).

(Also released at NMJ, although this is not part of the ANS and hence not required for this question).

Question 3

What type of receptors does ACh activate?

Answer 3

Muscarinic (Subdivided into classes 1-3)

Nicotinic (subdivided into two classes – ganglionic and NMJ)

Question 4

What are the effects of ACh transient?

Answer 4

It is rapidly metabolised and thus inactivated by acetylcholinesterase in the synaptic cleft.

Question 5

The action of ACh in the respiratory tract mimics the stimulation of which nerve?

Answer 5

Vagus (X cranial)

Question 6

What is airway resistance and what factors contribute to airway resistance in man?

Answer 6

Resistance is the amount of pressure required to deliver a given flow of gas and is expressed in terms of a change in pressure divided by flow.

The standard units of resistance are cm H20/L/second and the normal value for an adult is very low (~ 0.5 – 1.5 cm H20/L/sec) and arises from recoil and pressure in the normal anatomy (airway diameter and length).

In contrast, in disease this value may be 100.0 cm H20/L/sec or higher. Anything which reduces the airway lumen will increase the resistance, so in disease states this could be mucus plugs, bronchoconstriction, a reduction in lung volumes or lung fibrosis (because the lungs collapse down/ lose elasticity and put pressure on the airways, squashing those which lack cartilage to keep them open) or inhaled foreign bodies.

There are other factors (laminar vs turbulent air flow, density of inspired gas etc but these are relatively minor under most circumstances). Intubating a patient will increase their airway length so will also increase resistance. The later stages of pregnancy also increase resistance as the growing foetus pushes abdominal contents upwards and compresses the thorax.

Question 7

CASE 1

Answer 7

Mr MacKenzie

65 year old gentleman

50 year history of smoking

Following a recent diagnosis of chronic obstructive pulmonary disease (COPD), he has cut down his cigarette smoking, but not given up completely.

His GP thinks that an antimuscarinic agent might alleviate some of Mr MacKenzie’s feeling of breathlessness, particularly when he smokes. What is the rationale for this?

Question 8

His GP thinks that an antimuscarinic agent might alleviate some of Mr MacKenzie’s feeling of breathlessness, particularly when he smokes. What is the rationale for this?

CASE 1

Answer 8

The irritant effect of cigarette smoke activates a variety of receptors and can provoke a vagal response.

Parasympathetic NS possess constrictor actions on the airway smooth muscle and would thus act to increase airway resistance via increased contraction of the airway smooth muscle.

Giving a muscarinic antagonist may counteract some of this.

Question 9

Describe what a semi-log plot showing the effect of an increasing dose of metacholine on airways resistance, would look like. How would you label the axes? In the classroom, draw a labelled semi-log plot.

CASE 1

Answer 9

The semi-log plot would have methacholine concentration on the x-axis and resistance on the y-axis. It would have a sigmoidal appearance

Question 10

What would you predict that prior administration of a muscarinic antagonist would do to the position of this semi-log plot and why?

CASE 1

Answer 10

Depending on the relative concentrations and change in resistance we are looking for, it should prevent the increase in resistance since it would physically occupy the muscarinic receptors and hence block the constrictor actions of acetylcholine on the airway smooth muscle. If we gave a high enough dose of metacholine, we could overcome the blockade but clinically, we have no clinical reason for making it harder for someone to breath.

Question 11

What side effects might Mr MacKenzie experience after treatment with an oral muscarinic antagonist?

CASE 1

Answer 11

Main ANS effects:

• tachycardia
• relaxation of smooth muscle (gut, bronchi, biliary tract, bladder)
• inhibition of secretions (salivary, lacrimal, bronchial, sweat, gastric acid)

Main CNS effects:

depends on drug

• atropine is excitatory
• hyoscine causes sedation in low doses
• anti-emetic
• anti-extrapyramidal
• so useful in Parkinson’s disease)

Question 12

This range of side effects would severely limit the therapeutic value of a muscarinic antagonist. How have these problems been overcome to produce a therapeutically useful drug?

CASE 1

Answer 12

Administer drug topically to reduce dose required and the drugs used such as Ipratropium bromide do not readily cross into the bloodstream.

Question 13

CASE 2, PART 1

Answer 13

Gemma suffers from mild asthma. One of her friends who is a medical student told her that histamine can exacerbate asthma, so she purchased a course of over the counter antihistamine tablets in the hope that it would prevent her asthma symptoms. However, it didn’t work.

Question 14

Why did the anti-histamines not work?

CASE 2

Answer 14

Histamine is only one of many bronchoconstrictors in the airways – the percentage contribution of histamine to the overall bronchoconstriction is too small for its blockade to give a clinically useful bronchodilator effect.

Question 15

What other endogenous mediators may contribute to the bronchoconstriction observed in patients with asthma?

CASE 2

Answer 15

Prostanoids, leukotrienes, bradykinin are examples covered elsewhere in the curriculum.

Question 16

Despite her medical condition, Gemma is a keen hockey player, who plays for her university team and is determined not to let her respiratory condition hold her back. What simple precautions would you advise her to take before playing hockey?

CASE 2

Answer 16

Take her normal bronchodilator before exercising and do a proper war m up. The doctor may prescribe a long- acting bronchodilator such as salmeterol to build up a good level of “cover”

Question 17

CASE 2, PART 2

Answer 17

Over the next three months, there were two occasions where Gemma had to withdraw from the field during a match due to breathing difficulties, despite having carried out her normal pre-match preparations. On the first occasion, Gemma had caught a cold so had dosed herself with the strongest over the counter preparation she could find to relieve her symptoms. On the second occasion, Gemma wanted to play despite suffering from a pulled muscle in her shoulder. Just prior to the match, one of her team mates had given her some cream which she had found useful for a similar problem.

Question 18

What class of drug to you think was a common factor in both cases? Why did it exacerbate Gemma’s asthma? Should the different routes of administration of the two treatments influence the severity of the bronchoconstriction?

CASE 2, PART 2

Answer 18

NSAIDS – The inclusion of aspirin or ibruprofen in her OTC cold/flu medication. NSAIDs reduce the production of protective bronchodilator prostanoids by blocking COX activity and thus making more arachidonic acid precursor available for the increased production of bronchoconstrictor leukotrienes. As above, the inclusion of aspirin or ibruprofen in the cream reduced the production of protective bronchodilator prostanoids by blocking COX activity and thus making more arachidonic acid precursor available for the increased production of bronchoconstrictor leukotrienes.

It is quite possible for either the trans-dermal application and the oral application to induce bronchoconstriction. Concepts to discuss:

Dosing – in the end, it is the dose and subsequent concentration that reaches the systemic circulation that will determine the degree of bronchoconstriction. We do not know how much drug from either preparation reached the systemic circulation.

Lipid solubility – this will massively increase the bioavailability of the trans-dermal preparation

Ionisation/first pass metabolism – this will massively influence absorption from the gut and the amount of drug that escapes into the systemic circulation.

Students may discuss the following in relation to the effect of viruses on asthma – It is possible that the viruses which cause upper respiratory tract infections such as colds and flu can exacerbate asthma in their own right. Respiratory viruses interact with host factors to promote recurrent virus-induced wheezing and the development of asthma via a number of mechanisms including increased recruitment of inflammatory cells, promotion of cytokine production, enhancement of allergic inflammation, and augmented airways hyperresponsiveness. In addition, the body’s response to the infection can cause bronchial hyperresponsiveness, increased mucus secretion and inflammatory mediator release. These mediators can cause the exacerbation of symptoms.

Question 19

Not wishing to have a repeat of this problem, Gemma went to see her GP – what advice do you think he gave her?

CASE 2, PART 2

Answer 19

Not all patients with asthma as aspirin sensitive, but there is no foolproof way of identifying those who are, so avoiding products containing NSAIDS is wise for all asthmatics.

The pathogenesis of AIA has implicated both the lipoxygenase (LO) and the cyclooxygenase (COX) pathways. By inhibiting the COX pathway, aspirin diverts arachidonic acid metabolites to the LO pathway. This also leads to a decrease in the levels of prostaglandin (PG) E2, the anti-inflammatory PG, along with an increase in the synthesis of cysteinyl leukotrienes (LTs). Evidence suggests that patients with AIA have increased activity of LTC4 synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, in their bronchial biopsy specimens, thereby tilting the balance in favor of inflammation. The initial event in AIA appears to be the interruption of the synthesis of PGE2. PGE2 has profound regulatory effects on other inflammatory systems. It reduces LT synthesis by inhibiting 5-LO, inhibits cholinergic transmission, prevents mediator release from mast cells, and prevents ASA-precipitated bronchoconstriction.

Question 20

As well as giving her some advice, the doctor also suggested Gemma had a trial of an additional medication called montelukast. This is a leukotriene antagonist. What is the rationale for using such a drug in asthma and why do you think the doctor is trying it in Gemma’s case?

CASE 2, PART 2

Answer 20

The bronchoconstriction of asthma is caused by a soup of different mediators, the exact composition of which is unique to each individual patient (and also various in response to environmental factors, like infections – see above). The fact that aspirin caused Gemma to suffer an increase in symptoms suggests that leukotrienes might be significant contributors to her bronchoconstriction so a leukotriene antagonist is worth a try.

Some asthma phenotypes seem particularly sensitive to montelukast, such as asthma predominantly induced by exercise or asthma associated with allergic rhinitis.

It is important to note that whilst LT antagonists have an important role to play in asthma management, the current guidelines recommend inhaled corticosteroids as the first step preventer for most people most of the time and that’s largely because they will give blanket reduction of bronchoconstrictor mediators so they are a safe bet.

Question 21

What 4 main categories are drugs for respiratory diseases divided into?

Answer 21

1. Drugs which modulate the autonomic regulation (including those affecting second messenger systems)
2. Anti-inflammatory drugs
3. Anti-microbial drugs
4. Drugs used to treat cancer.

Question 22

What nerves control the tone of bronchial muscle?

Answer 22

Autonomic nerves

Question 23

How does the arrangement of bronchial muscle affect airway resistance?

Answer 23

the bronchial muscle is arranged in a circular fashion around the bronchi, the degree of tone has a significant effect on airway resistance.

Question 24

What actions of bronchial muscle change airway resistance?

Answer 24

Bronchi dilatation in a normal individual decreases resistance by 25%

Bronchoconstriction increases airway resistance

Question 25

How are airway resistance and airway radius linked?

Answer 25

The resistance to airflow is inversely proportional to the fourth power of the airway radius

So a small change in airway diameter can have a large effect on resistance and hence on the difficulty of breathing.

Question 26

What are the common types of condition that can reduce airway diameter and increase airway resistance?

Answer 26

ASTHMA

• mucus plugs
• bronchoconstriction

FIBROTIC LUNG CONDITIONS

• reduce lung volumes
• put pressure on the airways

​INHALED FOREIGN BODIES

• especially in children