54. Asthma and Respiratory Pharmacology (HT) Flashcards
What is asthma?
- Asthma is a syndrome of recurrent, reversible airway obstruction.
- Most patients recognize asthma as a series of acute attacks of breathlessness and wheezing.
What are the symptoms of an acute asthma attack?
- 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
What is the trigger for acute asthma attacks?
- 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
What is a common exacerbating factor for asthma attacks?
- 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
Is asthma an acute or chronic condition?
- 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.
Describe the pH changes that occur during an asthma attack.
[EXTRA?]
- 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
What is airway obstruction in mild to moderate asthma caused by?
- Oedema of the airway walls
- Mucus in the airway
How does blood oxygen change during an asthma attack?
[EXTRA]
- 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
What drives breathlessness and increased ventilation during an asthma attack?
- 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
What are some different ways of classifying asthma?
- 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
What can be said about patients with extrinsic asthma?
[EXTRA]
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
What is the difference between eosinophilic and non-eosinophilic asthma? Why is it important?
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.
How does mature-onset asthma differ from normal asthma?
- Responds less well to drugs
- Association with nasal polyps
- Often a high eosinophil count, despite no obvious association with allergy
Describe how acute and chronic inflammation are involved in asthma.
- 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
Which cells are present in high numbers in asthmatic inflammation?
Eosinophils
What makes the inflammation in asthma unusual?
- Characterised by high eosinophil counts
- Eosinophils are fragile and degranulate easily
How are eosinophils involved in the pathophysiology of asthma?
- 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.
Describe the pathophysiology of a typical asthma.
- 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
What are some triggers for acute asthma attacks?
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.
What are the two types of drugs for treating asthma?
- Symptomatic -> Aim to just treat the acute attacks
- Disease-modifying -> Aim to treat the underlying condition
Describe the main symptomatic treatments for asthma attacks.
[IMPORTANT]
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
What is aminophylline?
[IMPORTANT]
- 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.
What is ipratropium?
[IMPORTANT]
- A cholinceptor antagonist that is used in treatment of asthma attacks.
- It is usually used when there the sympathetic treatments are ineffective, etc.
What are the side effects of using bronchodilators in treating asthma?
[IMPORTANT]
Systemic beta-adrenergic side effects, including cardiac rhythm disturbances, tremor and feelings of anxiety.
Describe the main disease-modifying treatments for asthma.
They mostly work by immunosuppression:
- Steroids
- Leukotriene antagonists [EXTRA]
- Monoclonal antibodies for the cytokines that activate eosinophils [EXTRA]
What are the two main routes of adminstration of steroids for asthma?
- Inhaled (e.g., beclomethasone), for mild to moderate asthma
- Oral, for severe asthma
What are some side effects of steroid use in treating asthma?
[IMPORTANT]
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
Give an example of a steroid used in treatment of asthma.
Beclomethasone
Describe how steroids help to treat asthma.
[IMPORTANT]
- 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.
How can you measure how effective a therapeutic response to asthma is?
[IMPORTANT]
- 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)
What body systems might general anaesthesia affect?
- Cardiovascular system
- Respiratory system
- Body temperature control
What are the effects of general anaesthetics on the cardiovascular system?
- Reduced cardiac output
- Arterial and venous vasodilation
In other words, there is cardiovascular depression.
What are some potential sites of action for how general anaesthetics can cause cardiovascular depression?
- 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.
How is this Guyton curve changed by general anaesthetic use?
- 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.
What are the two effects that general anaesthetics can have on the heart?
- Reduce conduction
- Reduce contractility
Describe how low doses of halothane (a general anaesthetic) might affect a patient’s ECG.
- Increases RR interval -> Due to slowing of conduction through the SAN
- Increases PR interval -> Due to slowing conduction through the AVN
Describe how high doses of halothane (a general anaesthetic) might affect a patient’s ECG.
They may cause complete heart block, where the P waves do not trigger QRS complexes, and all QRS complexes are triggered in the ventricles.
What causes general anaesthetics to have an effect on cardiac conduction?
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.
What causes general anaesthetics to have an effect on cardiac contractility?
- 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
Why do general anaesthetics cause vasodilation?
They can act as calcium channel blockers, just like nifedipine in this diagram.
How do anaesthetic reduce sympathetic outflow?
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.
How can this cardiovascular depression due to general anaesthetic be managed?
- 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.
What parts of the respiratory system might be affected by general anaesthetic use?
- Effects on control of ventilation
- Effects on airway obstruction
- Effects on V/Q mismatching
How do general anaesthetics affect ventilation?
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.
Describe how general anaesthetics may cause decreased sensitivity of the peripheral chemoreceptors to oxygen.
- 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
How do general anaesthetics affect the airways?
- 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
Draw a graph of V/Q’s in the lungs, under normal conditions and under anaesthesia.
Under anaesthesia, the distribution is broadened, so there is more V/Q mismatch.
How do general anaesthetics affect V/Q matching?
- 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
Summarise the unwanted effects of volatile and IV general anaesthetics.
Is anaesthesia more like coma or sleep?
Coma, because it is relatively easy to rouse someone from sleep.
What are the stages of anaesthesia?
[EXTRA]
Note: These are rarely useful in modern medicine since they are too unpredictable and inconsistent.
How can the depth of anaesthesia be monitored?
Basic parameters such as heart rate are a good indication. For example, if the heart rate increases, then the anaesthesia is becoming too light.
What are the main components of anaesthesia and why are they important?
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.
What are the two main classes of general anaesthetic?
- Intravenous
- Inhalational (a.k.a. volatile/gaseous)
What are some examples of intravenous general anaesthetics that are mentioned in the spec?
Propofol
What are some examples of inhalational (gaseous) general anaesthetics that are mentioned in the spec?
Isoflurance, Sevoflurane
What is general anaesthetic efficacy classically correlated with?
Oil:water partition coefficient
What does MAC stand for?
Minimum alveolar concentration
What is minimum alveolar concentration (MAC) and what is it used for?
[IMPORTANT]
- 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.
For inhalational (gaseous) general anaesthetics, what determines the rate of onset of action?
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
What is the mechanism of action of general anaesthetics?
[EXTRA]
It is debated. See essay!
Describe the mode of action of nitrous oxide.
[EXTRA]
What are some commonly used modern general anaesthetics?
- Halothane
- Isoflurane
- Enflurane
- Desflurane
- Sevoflurane
- Ketamine
- Propofol
What are some advantages of inhalational and intravenous general anaesthesia? When is each used?
[IMPORTANT]
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
Name some properties of thiopental and ketamine (intravenous general anaesthetics).
[EXTRA]
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
What are some problems with the use of ketamine as a general anaesthetic?
[EXTRA]
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
Name some properties of propofol.
- 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
What are some classes of drugs used in adjunct therapy with general anaesthesia?
- Anxiolytics
- Neuromuscular blocking agents
- Muscarinic antagonists
- Cholinesterase inhibitors
- Local anaesthetics
- NSAIDs
- Opiate analgesics
- Drugs for the reversal of opiates
- Antiemetics
Why might anxiolytic drugs be used as an adjuvant drug in general anaesthesia? Give an example.
- They can be used to calm the patient before the operation
- e.g. Temazepam
Why might neuromuscular blocking drugs be used as an adjuvant drug in general anaesthesia? Give an example.
- They are used to induce a more reliable paralysis and also assist in intubation
- e.g. Vecuronium, Suxamethonium
Why might antimuscarinic drugs be used as an adjuvant drug in general anaesthesia? Give an example.
- They prevent bradycardia and hypotension that is associated with general anaesthetic use. Also prevent excess glandular secretions.
- e.g. Atropine
Why might cholinesterase inhibitors be used as an adjuvant drug in general anaesthesia? Give an example.
- They are used to reverse neuromuscular block at the end of the operation
- e.g. Neostigmine
Why might local anaesthetics be used as an adjuvant drug in general anaesthesia? Give an example.
- They can be used for post-operative pain relief
- e.g. Lidocaine, Bupivacaine
Why might NSAIDs be used as an adjuvant drug in general anaesthesia? Give an example.
- They can be used for post-operative pain relief. They also reduce the likelihood of inflammation and infection.
- e.g. Ibuprofen
Why might opioids and opioid reversing drugs be used as an adjuvant drug in general anaesthesia? Give an example.
- Opioids are used to provide analgesia during surgery (and after surgery too).
- e.g. Morphine
- These are reversed using naloxone.
Why might antiemetics be used as an adjuvant drug in general anaesthesia? Give an example.
- Decreased the likelihood of vomiting during stage 2 of anaesthesia.
- e.g. Ondansetron
Compare asthma and COPD.
[IMPORTANT]
- 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.
How does general anaesthesia affect body temperature regulation?
- 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.
