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YEAR 2 - Applied Physiology & Pharmacology > 54. Asthma and Respiratory Pharmacology (HT) > Flashcards

54. Asthma and Respiratory Pharmacology (HT) Flashcards

1
Q

What is asthma?

A
  • Asthma is a syndrome of recurrent, reversible airway obstruction.
  • Most patients recognize asthma as a series of acute attacks of breathlessness and wheezing.
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2
Q

What are the symptoms of an acute asthma attack?

A
  • Dyspnoea (feeling of breathlessness)
  • Wheeze, particularly on exhalation

Additional signs and symptoms that may occur:

  • Cough – usually dry, but sometimes productive of thin mucous threads towards the end of an attack
  • Palpitation or tachycardia
  • Light-headedness or feeling faint

In moderate to severe asthma:

  • Tiredness or drowsiness
  • Cyanosis
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3
Q

What is the trigger for acute asthma attacks?

A
  • Classical trigger is exposure to a particular allergen (e.g. grass pollen) and the attack finishes when the allergen is removed
  • In others, there is no obvious single allergen, but the attack can be brought on by:
    • Inhaling irritants -> Smog and smoke (note how these are processed as irritants rather than allergens)
    • Inhaling cold air
    • Physical exercise
    • Anxiety + Emotional stress
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4
Q

What is a common exacerbating factor for asthma attacks?

A
  • Chest infections can exacerbate asthma be making attacks more frequent and more severe
  • Asthma also makes the individual more susceptible to chest infections, so this can be a vicious cycle
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5
Q

Is asthma an acute or chronic condition?

A
  • For some people, there may be normal physiology between attacks
  • But for most asthmatics, asthma is a chronic disease with acute exacerbations. In between attacks the immune system and inflammation is not normal.
  • There may also be chronic damage to the airways that predisposes to further asthma attacks.
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6
Q

Describe the pH changes that occur during an asthma attack.

[EXTRA?]

A
  • In severe asthma, the airways can become so blocked that CO2 is retained and therefore there is acidaemia
  • In mild to moderate asthma:
    • In the early stages of the attack, the CO2 can dissolve in the watery mucous and there is hyperventilation -> This leads to alkalaemia
    • In the later stages of the attack, the mucous becomes less watery due to sympathetic stimulation and dehydration, so less CO2 dissolves -> This leads to acidaemia
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7
Q

What is airway obstruction in mild to moderate asthma caused by?

A
  • Oedema of the airway walls
  • Mucus in the airway
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8
Q

How does blood oxygen change during an asthma attack?

[EXTRA]

A
  • Although the patient feels breathless from the start of the attack, the patient is unlikely to be hypoxaemic since oxygen can still reach the alveoli
  • In later stages of the attack in severe asthma, when the mucus becomes more viscous, the patient may become hypoxaemic
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9
Q

What drives breathlessness and increased ventilation during an asthma attack?

A
  • Inflammatory oedema of the airway walls leads is detected receptors in the lungs that detect the distortion of pulmonary tissue -> These signal to the CNS, resulting in increased ventilation.
  • Later in the attack, there may be hypoxaemia and hypercapnia, which lead to increased ventilation also
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10
Q

What are some different ways of classifying asthma?

A
  • Intrinsic vs Extrinsic:
    • Intrinsic -> Not due to an external trigger, but due to exercise, stress, etc.
    • Extrinsic -> Due to an external allergen
  • Eosinophilic vs Non-eosinophilic [IMPORTANT]
    • Eosinophilic -> Have persistently elevated eosinophil counts
    • Non-eosinophilic -> Do not have persistently elevated eosinophil counts
  • Bronchoconstrictor vs Inflammatory asthma
    • Bronchoconstrictor -> People who are diagnosed as “asthmatic” because of episodes of wheezing, without the severe breathlessness of classical asthma, and often without a clear allergic history
    • Inflammatory asthma -> Asthma which is characterised by inflammation
  • Classical vs Mature-onset asthma
    • Classical asthma -> Usually diagnosed early in life
    • Mature-onset asthma -> Diagnosed in later life
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11
Q

What can be said about patients with extrinsic asthma?

[EXTRA]

A

They commonly have a history of other allergic or auto-immune diseases, often pre-dating the asthma: hay fever, eczema and psoriasis are well-known examples

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12
Q

What is the difference between eosinophilic and non-eosinophilic asthma? Why is it important?

A

Patients with eosinophilic asthma have persistently elevated eosinophil counts, which is important in anti-eosinophil therapies that are being developed to control the development of asthma.

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13
Q

How does mature-onset asthma differ from normal asthma?

A
  • Responds less well to drugs
  • Association with nasal polyps
  • Often a high eosinophil count, despite no obvious association with allergy
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14
Q

Describe how acute and chronic inflammation are involved in asthma.

A
  • Asthma is a chronic condition with a background process of chronic inflammation (although it is not what is typically called chronic inflammation)
  • There are recurrent episodes of acute inflammation superimposed on this
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15
Q

Which cells are present in high numbers in asthmatic inflammation?

A

Eosinophils

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16
Q

What makes the inflammation in asthma unusual?

A
  • Characterised by high eosinophil counts
  • Eosinophils are fragile and degranulate easily
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17
Q

How are eosinophils involved in the pathophysiology of asthma?

A
  • They are activated by cytokines such as IL-5 and IL-13
  • They are present in high numbers near the lungs
  • The eosinophils release proteases and perforins, which cause damage to the bronchial epithelium
  • The eosinophils are very fragile and degranulate easily, so a smaller stimulus is required for this than in most people.
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18
Q

Describe the pathophysiology of a typical asthma.

A
  • Inflammatory response is initiated in a variety of ways (see other flashcard)
  • This leads to release of cytokines (e.g. IL-5 and IL-13) that recruit other immune cells, particularly eosinophils
  • Acute inflammation leads to:
    • Oedema
    • Mucus secretion
    • Bronchoconstriction -> This is perhaps initiated by the bronchial plexus responding to inflammatory cytokines
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19
Q

What are some triggers for acute asthma attacks?

A

The trigger differs between different types of asthma. Some examples:

  • Hypersensitivity reaction -> Allergen binds to IgE, which leads to mast cell activation and histamine release. This starts the acute inflammatory process.
  • Bronchial plexus -> Some forms of “intrinsic” asthma might be initiated by the bronchial plexus.
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20
Q

What are the two types of drugs for treating asthma?

A
  • Symptomatic -> Aim to just treat the acute attacks
  • Disease-modifying -> Aim to treat the underlying condition
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21
Q

Describe the main symptomatic treatments for asthma attacks.

[IMPORTANT]

A

They are also bronchodilators:

  • β2-adrenoceptor agonists -> e.g. Salbutamol, Adrenaline
  • Methylxanthines -> e.g. Aminophylline (inhibit the degradation of cAMP, so they strengthen the effects of beta stimulation)
  • Cholinoceptor antagonists (antimuscarinics) -> e.g. Ipratropium
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22
Q

What is aminophylline?

[IMPORTANT]

A
  • A methylxanthine that is useful in the treatment of asthma attacks.
  • It is given in hospitals via IV in the case of a severe asthma attack that salbutamol is insufficient in.
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23
Q

What is ipratropium?

[IMPORTANT]

A
  • A cholinceptor antagonist that is used in treatment of asthma attacks.
  • It is usually used when there the sympathetic treatments are ineffective, etc.
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24
Q

What are the side effects of using bronchodilators in treating asthma?

[IMPORTANT]

A

Systemic beta-adrenergic side effects, including cardiac rhythm disturbances, tremor and feelings of anxiety.

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25
Q

Describe the main disease-modifying treatments for asthma.

A

They mostly work by immunosuppression:

  • Steroids
  • Leukotriene antagonists [EXTRA]
  • Monoclonal antibodies for the cytokines that activate eosinophils [EXTRA]
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26
Q

What are the two main routes of adminstration of steroids for asthma?

A
  • Inhaled (e.g., beclomethasone), for mild to moderate asthma
  • Oral, for severe asthma
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27
Q

What are some side effects of steroid use in treating asthma?

[IMPORTANT]

A

Side-effects of steroids include:

  • Increased susceptibility to infection

Systemic (oral) administration of steroids may also be associated with:

  • Altered metabolism, including hyperglycaemia
  • Mood swings
  • Fluid retention
  • Hypertension
  • Thrombosis
  • Osteoporosis
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28
Q

Give an example of a steroid used in treatment of asthma.

A

Beclomethasone

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29
Q

Describe how steroids help to treat asthma.

[IMPORTANT]

A
  • Corticosteroids inhibit the synthesis and action of the enzyme phospholipase A2 which is required for the synthesis of both prostaglandins and leukotrienes.
  • They also suppress transcription of many cytokines.
  • Thus, the corticosteroids inhibit acute inflammation.
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30
Q

How can you measure how effective a therapeutic response to asthma is?

[IMPORTANT]

A
  • Symptom review (a discussion with the patient to establish how the asthma is affecting their quality of life)
  • Lung function monitoring (the patient can measure their own peak flow and FEV-1 with a meter at home)
  • Degree of dependence on acute bronchodilators (for example, increasingly frequent use of salbutamol may indicate that the dose of steroids is no longer adequate)
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31
Q
A
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32
Q

What body systems might general anaesthesia affect?

A
  • Cardiovascular system
  • Respiratory system
  • Body temperature control
33
Q

What are the effects of general anaesthetics on the cardiovascular system?

A
  • Reduced cardiac output
  • Arterial and venous vasodilation

In other words, there is cardiovascular depression.

34
Q

What are some potential sites of action for how general anaesthetics can cause cardiovascular depression?

A
  • Myocardium itself (acting on conduction or contractility)
  • Vessels themselves
  • Sympathetic control of myocardium and vessels

These lead to reduced cardiac output and arterial and venous vasodilation.

35
Q

How is this Guyton curve changed by general anaesthetic use?

A
  • The venous line gradient increses due to venous vasodilation
  • This means the Pmcf shifts to the left
  • The arterial line gradient also increases due to arterial vasodilation
  • The Frank-Starling curve shifts down due to decreased contractility

Therefore, the arterial pressure, venous pressure and cardiac output all fall.

36
Q

What are the two effects that general anaesthetics can have on the heart?

A
  • Reduce conduction
  • Reduce contractility
37
Q

Describe how low doses of halothane (a general anaesthetic) might affect a patient’s ECG.

A
  • Increases RR interval -> Due to slowing of conduction through the SAN
  • Increases PR interval -> Due to slowing conduction through the AVN
38
Q

Describe how high doses of halothane (a general anaesthetic) might affect a patient’s ECG.

A

They may cause complete heart block, where the P waves do not trigger QRS complexes, and all QRS complexes are triggered in the ventricles.

39
Q

What causes general anaesthetics to have an effect on cardiac conduction?

A

At the concentration they are used at (where the line is almost vertical), general anaesthetics block a small fraction of calcium channels, which are involved in SAN and AVN depolarisation.

40
Q

What causes general anaesthetics to have an effect on cardiac contractility?

A
  • Reduce calcium influx into cardiac myocytes -> Due to inhibiting L-type calcium channels
  • Reduce release/uptake of calcium by the SR
  • Reduces calcium activation of contractile proteins -> Only a very minor effect in a few general anaesthetics
41
Q

Why do general anaesthetics cause vasodilation?

A

They can act as calcium channel blockers, just like nifedipine in this diagram.

42
Q

How do anaesthetic reduce sympathetic outflow?

A

If anaesthetics knock-out higher cortical centres, it’s a reasonable guess that they will have a parallel effect on the sympathetic nervous system in the brainstem.

43
Q

How can this cardiovascular depression due to general anaesthetic be managed?

A
  • IV fluids -> Shift Pmcf to the right
  • Vasoconstrictors (ephedrine, metaraminol, noradrenaline) -> Decrease the gradient of the arterial and venous lines
  • Inotropes (ephedrine, adrenaline) -> Shift the Frank-Starling curve upwards

Antimuscarinics are also used not only to dry up secretions, but also to protect against bradycardia caused by the dominance of the vagus on the heart.

44
Q

What parts of the respiratory system might be affected by general anaesthetic use?

A
  • Effects on control of ventilation
  • Effects on airway obstruction
  • Effects on V/Q mismatching
45
Q

How do general anaesthetics affect ventilation?

A

Volatile anaesthetics:

  • Reduce ventilation by reducing the sensitivity of the (mostly peripheral) chemoreceptors, so that stimulation of ventilation is reduced and therefore there is hypoventilation.

Intravenous anaesthetics:

  • Reduce ventilation by affecting the respiratory centres in the brain, so that, although the chemoreceptor feedback loops are still intact, there is still some hypoventilation.
46
Q

Describe how general anaesthetics may cause decreased sensitivity of the peripheral chemoreceptors to oxygen.

A
  • Normally, TASK channels underlie the firing of the chemoreceptors upon hypoxia
  • At high oxygen leves, ROS are created, which inhibit the TASK channels
  • General anaesthetics can create ROS of their own, which reduces chemoreceptor firing
47
Q

How do general anaesthetics affect the airways?

A
  • They cause airway obstruction
  • Normally, part of the chemoreceptor response is pharyngeal dilation to prevent airway collapse upon inhalation
  • However, since the general anaesthetics reduce the sensitivity of the chemoreceptors (see earlier flashcard), airway narrowing and collapse is more likely
48
Q

Draw a graph of V/Q’s in the lungs, under normal conditions and under anaesthesia.

A

Under anaesthesia, the distribution is broadened, so there is more V/Q mismatch.

49
Q

How do general anaesthetics affect V/Q matching?

A
  • They lead to more V/Q mismatch
  • This is because they create ROS that inhibit TASK channels in chemoreceptors -> This reduces their sensitivity to oxygen
50
Q

Summarise the unwanted effects of volatile and IV general anaesthetics.

A
51
Q

Is anaesthesia more like coma or sleep?

A

Coma, because it is relatively easy to rouse someone from sleep.

52
Q

What are the stages of anaesthesia?

[EXTRA]

A

Note: These are rarely useful in modern medicine since they are too unpredictable and inconsistent.

53
Q

How can the depth of anaesthesia be monitored?

A

Basic parameters such as heart rate are a good indication. For example, if the heart rate increases, then the anaesthesia is becoming too light.

54
Q

What are the main components of anaesthesia and why are they important?

A

They are important because very few agents will produce all 3 effects, meaning that agents often have to be paired in order to achieve the whole triad.

55
Q

What are the two main classes of general anaesthetic?

A
  • Intravenous
  • Inhalational (a.k.a. volatile/gaseous)
56
Q

What are some examples of intravenous general anaesthetics that are mentioned in the spec?

A

Propofol

57
Q

What are some examples of inhalational (gaseous) general anaesthetics that are mentioned in the spec?

A

Isoflurance, Sevoflurane

58
Q

What is general anaesthetic efficacy classically correlated with?

A

Oil:water partition coefficient

59
Q

What does MAC stand for?

A

Minimum alveolar concentration

60
Q

What is minimum alveolar concentration (MAC) and what is it used for?

[IMPORTANT]

A
  • It is a measure used to compare the potency of inhalational general anaesthetics
  • It is defined as the concentration of the vapour in the lungs that is needed to prevent movement in 50% of subjects in response to surgical (pain) stimulus.
  • More than 90% of all patients become anaesthetised following the administration of 1.3 MAC and presumably, 1.5 to 2.0 MAC is required to ensure anaesthesia in all patients. MAC is additive.
61
Q

For inhalational (gaseous) general anaesthetics, what determines the rate of onset of action?

A

Blood-gas partition co-efficient:

  • The LOWER the solubility in blood, the more rapid the onset of action is
  • This may seem counter-intuitive, but it is because the general anaesthetic is more willing to pass into the tissues from the blood
62
Q

What is the mechanism of action of general anaesthetics?

[EXTRA]

A

It is debated. See essay!

63
Q

Describe the mode of action of nitrous oxide.

[EXTRA]

A
64
Q

What are some commonly used modern general anaesthetics?

A
  • Halothane
  • Isoflurane
  • Enflurane
  • Desflurane
  • Sevoflurane
  • Ketamine
  • Propofol
65
Q

What are some advantages of inhalational and intravenous general anaesthesia? When is each used?

[IMPORTANT]

A

Intravenous general anaesthetics:

  • Used for INDUCTION of anaesthesia -> Faster onset of action with less time in stage 2

Inhalational general anaesthetics:

  • Used for MAINTENANCE of anaesthesia -> Easy to control depth of anaesthesia
66
Q

Name some properties of thiopental and ketamine (intravenous general anaesthetics).

[EXTRA]

A

Thiopental:

  • Barbiturate, highly lipid soluble
  • Rapid onset (20 sec)
  • Slowly metabolised
  • No analgesia
  • Causes cardiovascular depression

Ketamine:

  • Analogue of phencyclidine
  • Relatively slow onset (2-5 minutes)
  • Amnesic with reduced pain perception (dissociative anaesthesia)
  • Used mainly in children (minor proc)
  • Non-competitive antagonist NMDAR – ketamine to block responses requires that NMDAR ion channels open - deep active site - long lasting effect
67
Q

What are some problems with the use of ketamine as a general anaesthetic?

[EXTRA]

A

It also targets:

  • Negative allosteric modulator nACh receptors
  • Weak agonist of the μ-opioid and κ-opioid receptors and very weak agonist of the δ-opioid receptor
  • Agonist of the D2 receptor
  • Inhibitor of the reuptake of serotonin, dopamine, and norepinephrine
  • Voltage-gated sodium channel and L-type calcium channel blocker, and HCN1 cation channel blocker.
  • Inhibitor of nitric oxide synthase
  • σ receptor 1 and 2 agonist (μM affinities)
  • Activation of AMPA receptors? Ketamine indirectly enhances AMPAR-mediated excitatory synaptic function in frontal cortex
68
Q

Name some properties of propofol.

A
  • Propofol is the most important intravenous general anesthetic in current clinical use
  • Acts by potentiating GABAA (γ-aminobutyric acid type A) receptors
  • The binding site is located within the β subunit at the interface between the transmembrane domains and the extracellular domain and lies close to known determinants of anaesthetic sensitivity
  • Target controlled infusion (TCI) systems are used to administer TIVA in the UK and Ireland. Avoidance of Accidental Awareness during general Anaesthesia (AAGA).
  • Propofol is principally a hypnotic
  • Short acting
  • Used with opioid or muscle relaxant
69
Q

What are some classes of drugs used in adjunct therapy with general anaesthesia?

A
  • Anxiolytics
  • Neuromuscular blocking agents
  • Muscarinic antagonists
  • Cholinesterase inhibitors
  • Local anaesthetics
  • NSAIDs
  • Opiate analgesics
  • Drugs for the reversal of opiates
  • Antiemetics
70
Q

Why might anxiolytic drugs be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • They can be used to calm the patient before the operation
  • e.g. Temazepam
71
Q

Why might neuromuscular blocking drugs be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • They are used to induce a more reliable paralysis and also assist in intubation
  • e.g. Vecuronium, Suxamethonium
72
Q

Why might antimuscarinic drugs be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • They prevent bradycardia and hypotension that is associated with general anaesthetic use. Also prevent excess glandular secretions.
  • e.g. Atropine
73
Q

Why might cholinesterase inhibitors be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • They are used to reverse neuromuscular block at the end of the operation
  • e.g. Neostigmine
74
Q

Why might local anaesthetics be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • They can be used for post-operative pain relief
  • e.g. Lidocaine, Bupivacaine
75
Q

Why might NSAIDs be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • They can be used for post-operative pain relief. They also reduce the likelihood of inflammation and infection.
  • e.g. Ibuprofen
76
Q

Why might opioids and opioid reversing drugs be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • Opioids are used to provide analgesia during surgery (and after surgery too).
  • e.g. Morphine
  • These are reversed using naloxone.
77
Q

Why might antiemetics be used as an adjuvant drug in general anaesthesia? Give an example.

A
  • Decreased the likelihood of vomiting during stage 2 of anaesthesia.
  • e.g. Ondansetron
78
Q

Compare asthma and COPD.

[IMPORTANT]

A
  • Classically, asthma is thought to be reversible, while COPD is irreversible
  • However, it has now been realised that chronic inflammation underlies both diseases.
  • The nature of the inflammation differs, as well as the response to anti-inflammatory medications.
79
Q

How does general anaesthesia affect body temperature regulation?

A
  • General anesthesia eliminates behavioral thermoregulatory compensations, leaving only autonomic defenses to offset environmental perturbations.
  • Anaesthesia inhibits thermoregulatory control and this inhibition is dose-dependent. It impairs the vasoconstriction threshold about three times as much as the sweating threshold.

YEAR 2 - Applied Physiology & Pharmacology (11 decks)

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