1
Q
A
2
Q
Name and describe 4 kinds of hypoxia
A
- Arterial (or hypoxic) hypoxia: in which the partial pressure of oxygen in arterial blood (PaO2) is low
- Anaemic hypoxia: in which the oxygen carrying capacity of the blood is reduced
- Ischaemic hypoxia: in which the cardiac output or local blood flow is inadequate
- Histotoxic hypoxia: in which the ability of the tissues to take up and use oxygen is impaired
3
Q
How does a doctor most often recognise asthma? What are the common symptoms?
A
He or she recognizes bronchial asthma as being recurrent episodes of airflow limitation that are usually reversible.
- The symptoms consist of
- breathlessness
- wheezing
- chest tightness
- cough
- sometimes productive of sputum.
While these symptoms may be reversible spontaneously, more often they respond quickly to bronchodilators, in particular inhaled Beta-adrenergic agonists
4
Q
Which parts of the lungs does asthma affect?
A
Anatomically, asthma affects both the central and more distal airways
5
Q
What is the measurement of lung function used for in asthmatic patients? (2)
What is notable about the lung function of asthmatics over time, and how do you tend to measure lung function?
A
- Lung function tests are used in asthma diagnosis. For FEV1, for example, an improvement of 15-20 per cent in response to an inhaled Beta-adrenergic agoist is considered significant enough to support a diagnosis of asthma.
- Lung function tests are used to look for airway obstruction which gives an indication of the severity of asthma. The presence or absence of airways obstruction itself is not an important factor in the diagnosis of asthma.
- Regular peak flow measurements has shown that asthmatics may have an excessive diurnal variation of airflow obstruction, usually in the early morning, as often characterized by the early morning wheeze.
6
Q
What is the measurement of lung function used for in asthmatic patients? (2)
What is notable about the lung function of asthmatics over time, and how do you tend to measure lung function?
A
- Lung function tests are used to look for airway obstruction. The presence or absence of airways obstruction itself is not an important factor in the diagnosis of asthma, although it provides an index of the severity of asthma in a diagnosed patient.
- Regular peak flow measurements has shown that asthmatics may have an excessive diurnal variation of airflow obstruction, usually in the early morning, as often characterized by the early morning wheeze.
7
Q
What does the current best definition of asthma now include? (4)
A
- clinical symptoms (intermittent wheeze, cough and shortness of breath);
- lung function tests showing variability of airflow obstruction (peak expiratory flow rate diurnal variability with asthma exacerbation);
- bronchial hyperresponsiveness
- airway inflammation with bronchial mucosal infiltration with inflammatory cells, such as eosinophils and T cells
8
Q
What is bronchial hyperresponsiveness?
A
Bronchial hyperresponsiveness: abnormal response of the airways to a provoking bronchoconstrictor stimulus, such as
- -inhaled methacholine
- -histamine
- -exercise.
The asthmatic individual shows a greater degree of responsiveness than the non-asthmatic individual:
A smaller amount of bronchoconstrictor agent causes a SIMILAR degree of bronchoconstriction, or of the maximal degree of worsening of lung function.
9
Q
- What disease other than asthma shows bronchial hyperresponsiveness?
- What does the presence of BHR in the absence of other symptoms show?
- What do some consider the degree of BHR to show?
- What causes BHR?
A
- Chronic obstructive pulmonary disease shares bronchial hyperresponsiveness (BHR), but the degree of BHR is usually mild.
- The presence of BHR in the absence of symptoms is not considered to be asthma, although this is a predisposing factor to the onset of asthma.
- Some workers consider the degree of BHR as indicative of the severity of asthma.
- The causes of BHR are not known, but may include airway wall thickening, airway inflammation and/or abnormal airway smooth muscle contractility.
10
Q
- What is airway inflammation? What is it characterised by?
- What is it often seen with?
- What does airway inflammation separate asthma from?
A
- the airways submucosa of patients with asthma is chronically inflamed with a cellular infiltrate characterized by eosinophils and T cells, together with epithelial damage and fragility.
- Often, there is subepithelial flbrosis characterized by an increased thickness of the ‘basement membrane’.
- This characteristic inflammatory response could be used to separate asthma from other airway conditions, such as chronic obstructive pulmonary disease and emphysema, which often cause diagnostic confusion with asthma.
11
Q
Can airway obstruction be reversed in asthma?
A
- reversibility of airflow obstruction, spontaneously or by pharmacological means, is an important component of asthma.
- However, airflow obstruction is not always totally reversible: over time there may be total loss of reversibility of airways obstruction resulting from the chronic inflammatory process.
12
Q
What are the characteristic features if you were to examine an asthmatic lung? (6)
A
Characteristic features:
- presence in the airway of inflammatory cells,
- plasma exudation,
- oedema,
- smooth muscle hypertrophy (thickening),
- mucus plugging
- shedding of the epithelium
13
Q
In which countries is asthma most common?
A
The prevalence is:
- highest in the affluent English-speaking countries,
- intermediate in western Europe, Latin America, Africa and South-East Asia, and
- lowest in India, China, eastern Europe and the former Soviet Union.
There is a correlation between the rates of asthma with those of rhinoconjunctivitis.
14
Q
Where in Europe is asthma most common?
What do asthma numbers in European countries strongly relate to?
A
- the highest prevalence in the UK and in some centres in France
- the lowest prevalence in East Germany and Spain.
- The geographical variation in atopic sensitization corresponded closely to the geographical variation of asthma
15
Q
How do incidence of asthma vary between different areas of the UK?
A
There is little variation in asthma prevalence among children or adults throughout the UK
16
Q
How many people in the uk have asthma?
A
1 out of every 7 children and 1 out of every 25 adults - have asthma symptoms requiring treatment. One worrying feature about the prevalence of asthma is the increase over recent decades.
17
Q
How is the overall severity of an asthma condition measured? (6)
A
The severity of asthma can be defined in many ways, including:
- The frequency of daily symptoms;
- The need for medical consultations, either at the surgery or attendance in casualty departments;
- Time taken off work or school
- Poor quality of life characterized by non-participation in communal activities such as sports.
Other parameters that can define the severity of asthma include: the number of admissions to hospital for treatment of acute severe asthma episodes; the variability in peak flow measurements and lung function tests.
18
Q
What are the risk factors for deaths from asthma? (7)
A
- age (for those over 40 years),
- cigarette smoking,
- a past history of severe or life-threatening attacks,
- previous hospital admissions and emergency room visits
- discontinuity of physician care.
A fatal outcome was also associated with inadequate assessment and inappropriate treatment of severe asthma, with overreliance on high doses of bronchodilator therapy and insufficient use of corticosteroids
19
Q
How has the number of deaths from asthma been changing in the UK and why? (5 reasons)
A
The gradual reduction in mortality in the UK over the past decade may have been due to a combination of factors, including:
- increased use of inhaled corticosteroids,
- reduced reliance on potent Beta2 adrenergic agonist,
- better education of patients (and doctors) regarding asthma management,
- adherence to national management guidelines by health carers,
- recognition of severe asthma and of patients at risk of dying as the result of asthma.
Asthma deaths have continued to fall over the past 5 years.
20
Q
- At what age is the incidence of asthma highest?
- What tends to happen in asthma up to the age of 6?
- What will you tend to find in those who have wheezing at 6 years old?
A
- The incidence of asthma is highest in early childhood, decreasing throughout later childhood and adolescence.
- The majority of wheezers at 3 will have remitted by 6.
- The persistent wheezers at age 6 more often have a family history of asthma (particularly maternal), elevated immunoglobulin E (IgE) levels in infancy and at age 6 years, and had decreased lung function at age 6.
21
Q
What happens in the evolution from childhood asthma to adulthood? (3)
A
- Between 30 and 70 per cent of children with asthma become markedly improved or symptom-free by early adulthood
- Significant asthma symptoms persist in about 30 per cent.
- Some may have asymptomatic periods before developing wheeze again as adults.
22
Q
- What types of sensitisation do you often find in patients admitted to hospital with asthma?
- What factor in childhood asthma is an indication of future adult asthma?
A
- Sensitization and exposure to house dust mite (and cockroaches, as found in some inner cities in the US) is very common amongst children and young adults attending emergency rooms for treatment of severe asthma episodes.
- Children with mild asthma are likely to have a good prognosis, but children with moderate or severe asthma will likely continue to have some degree of airway hyperresponsiveness and will be at risk from the long-term effects of asthma throughout life
23
Q
What causes are there for asthma which begins in adulthood? (2)
A
- Sometimes this may be in response to sensitizing agents in the workplace leading to occupational asthma, or from the development of atopy later in life.
- Often, there is a history of an upper respiratory tract viral infection with the first exacerbation.
24
Q
What are the 3 Medullary Centers Controlling Respiration?
A
1) The medullary respiratory centres
2) The apneustic centre
3) The pneumotaxic center
25
What do the medullary respiratory centres do?
What is reciprocal inhibition of the medullary respiratory centres?
* Sometimes called the "medullary rhythmicity" centers, as they are believed to set the baseline rhythm for respiration.
* In the normal resting state, respiration is due to the inspiratory center and when these nerves shut off, there is passive exhalation. The expiration center is only required when activity and requirements are increased.
* When your ventilation requirements are increased, as during exercise, your inspiratory center can suppress activity of the expiratory center while you inhale, and the expiratory center can suppress activity of the inspiratory center while you exhale. This is reciprocal inhibition.
26
What does the apneustic centre do?
Apneusis refers to an inspiratory gasp.
The apneustic center facilitates inspiration... for example, the apneustic center may prolong inspiration when your oxygen requirements become elevated, as during exercise. In this sense, the apneustic center helps to control depth of respiration.
27
What does the pneumotaxic center do?
This area controls the other 2 centers (respiratory and apneustic) and cuts off inspiration at a certain point to make sure that inspiration does not continue too long. In this sense, the pneumotaxic center helps to control rate of respiration.
For example, let's say you were exercising really strenuously and your inspiratory center was so hyperstimulated that it was still trying to make you inhale when your lungs were already fully inflated; you need the pneumotaxic center to shut off the inspiratory center in such a case so that you can keep ventilating the lungs!
28
Where are the central chemoreceptors located, and what are they sensitive to?
Central Chemoreceptors are located on both sides of the medulla where cranial nerves 9 (glossopharyngeal nerves) and 10 (vagal nerves) leave the brain. These chemoreceptors are primarily sensitive to pCO2 and the pH of blood
29
What substance do the pH chemoreceptors detect? How is this produced in the blood from Co2?
H+!
30
If co2 levels in the blood fall too low, the person faints. Why is this?
This is primarily because of the important role of carbon dioxide in maintaining peripheral blood pressure. Carbon dioxide strongly stimulates constriction of arterioles. When carbon dioxide levels drop with hyperventilation, blood vessels relax, peripheral blood pressure falls, and less blood and oxygen are delivered to the brain.
31
* Where are the peripheral respiratory chemoreceptors located?
* What are they sensitive to?
* What do they stimulate?
* How common is it for these receptors to be active?
* Peripheral Chemoreceptors known as the Aortic Bodies in the aortic arch and the Carotid Bodies (by the carotid baroceptors) at the bifurcation of the carotid arteries in the neck monitor pO2.
* These pO2 receptors send nerve impulses to the medulla to increase respiration when pO2 falls. These centers are actually sensitive to both PO2 and pH.
* pO2 in arterial circulation would have to fall to levels as low as pO2 normally seen in venous circulation before the peripheral chemoreceptors stimulate the medulla, so they do not play a role in normal respiratory control.
32
What is the mode of action of salbutamol.
Salbutamol is a beta 2 adrenergic agonist. These receptors are found in the airway and in smooth muscle.
33
What does beta receptor activation cause to happen?
It causes the bronchial smooth muscle to relax and the rate and force of contraction of cardiac muscle to increase.
34
Which adrenergic receptors do adrenaline and noradrenaline each stimulate?
* There are at least two adrenergic receptor sites (alpha or beta).
* Norepinephrine activates primarily alpha receptors
* Epinephrine activates primarily beta receptors, although it may also activate alpha receptors
35
What does the stimulation of alpha adrenergic receptors do?
constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract
36
What is the MOA of beclometasone diproprionate? (General answer and specific answer)
* Beclometasone dipropionate is a prodrug of the free form, beclometasone
* Beclometasone is a glucocorticoid steriod. It binds to the glucocorticoid receptor in the cytoplasm of epithelial cells, which in turn up-regulates the expression of anti-inflammatory proteins in the nucleus and represses the expression of pro-inflammatory proteins.
* (SPECIFICALLY: The antiinflammatory actions of corticosteroids are thought to involve lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes
* This also inhibits leukocyte infiltration at the site of inflammation
* Corticosteroids also act as vasoconstrictors which decreases airway edema and mucus secretion)
37
What are the potential side effects of beclometasone used as asthma prophylaxis?
* Oral candidiasis (thrush) which may appear as a white coating possibly with irritation. This may usually be prevented by rinsing th mouth out with water after using the inhaler.
* Unpleasant taste/smell
* Hoarsness
38
Treatment with beclometasone diproprionate decreases the amount of some inflammatory cytokines at the bronchial epithelium. Which cytokines are reduced, and what is the effect of their reduction?
* The cytokines which reduce are Il-8, GM-CSF and RANTES.
* The reduction in these cytokines significantly decreases the number of activated eosinophils in the bronchial epithelium, and decreases bronchial hyperresponsiveness.
39
What is COPD?
Chronic obstructive pulmonary disease (COPD):
The co-occurrence of chronic bronchitis and emphysema, a pair of commonly co-existing diseases of the lungs in which the airways become narrowed. This leads to a limitation of the flow of air to and from the lungs, causing shortness of breath (dyspnea).
40
In clinical practise, how is COPD defined/diagnosed?
In clinical practice, COPD is defined by its characteristically low airflow on lung function tests. In contrast to asthma, this limitation is poorly reversible and usually gets progressively worse over time.
41
What is COPD caused by?
COPD is caused by noxious particles or gas, most commonly from tobacco smoking, which triggers an abnormal inflammatory response in the lung.
Worldwide, COPD ranked as the sixth leading cause of death in 1990
42
How is COPD treated/managed? (5)
Important management strategies are smoking cessation, vaccinations and drug therapy (often using inhalers). Some patients go on to require long-term oxygen therapy or lung transplantation.
43
What is pneumonia? What are the main symptoms? What is it caused by?
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs (alveoli)—associated with
* fever,
* chest symptoms - cough, difficulty breathing
* and a lack of air space (consolidation) on a chest X-ray.
Pneumonia is typically caused by an infection but there are a number of other causes. Infectious agents include: bacteria, viruses, fungi, and parasites
44
What are the symptoms of pneumonia? (4) How is it diagnosed and treated?
Typical symptoms include cough, chest pain, fever, and difficulty breathing. Diagnostic tools include x-rays and examination of the sputum. Vaccines to prevent certain types of pneumonia are available. Treatment depends on the underlying cause. Presumed bacterial pneumonia is treated with antibiotics.
45
What is emphysema? What is the main symptom? What is the basic physiology of the disease and what causes it?
Emphysema is a long-term, progressive disease of the lungs that primarily causes
* shortness of breath.
In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. Emphysema is called an obstructive lung disease because the destruction of lung tissue around smaller sacs, called alveoli, makes these air sacs unable to hold their functional shape upon exhalation. It is often caused by long-term exposure to air pollution or smoking
46
Which bacteria most commonly causes pneumonia?
S. pneumoniae (Streptococcus pneumoniae) - about 2 thirds of cases are caused by S. pneumoniae
47
What are the risk factors for bacterial pneumonia? (6)
1. Influenza infection — Influenza infection greatly predisposes to secondary pneumococcal pneumonia
2. Alcohol abuse - both current and former abusers
3. Smoking
4. COPD and asthma
5. Hyposplenism or splenectomy
6. Immunocompromise
48
What is bronchitis, and what types can it be divided into?
Bronchitis is inflammation of the mucous membranes of the bronchi, the airways that carry airflow from the trachea into the lungs. Bronchitis can be divided into two categories, acute and chronic, each of which has distinct etiologies, pathologies, and therapies.
49
What is acute bronchitis characterised by? (2) What causes bronchitis?
Acute bronchitis is characterized by the
* development of a cough,
* with or without the production of sputum, mucus that is expectorated (coughed up) from the respiratory tract.
Acute bronchitis often occurs during the course of an acute viral illness such as the common cold or influenza. Viruses cause about 90% of cases of acute bronchitis, whereas bacteria account for fewer than 10%.
50
What is chronic bronchitis? What is it characterised by?
Chronic bronchitis, a part of COPD, is characterized by the presence of a productive cough that lasts for three months or more per year for at least two years. Chronic bronchitis most often develops due to recurrent injury to the airways caused by inhaled irritants. Cigarette smoking is the most common cause, followed by air pollution and occupational exposure to irritants
51
What is mesothelioma?
Mesothelioma (or, more precisely, malignant mesothelioma) is a rare form of cancer that develops from transformed cells originating in the mesothelium, the protective lining that covers many of the internal organs of the body. It is usually caused by exposure to asbestos.
52
What causes pain in asthma?
Epithelial loss exposes nerve terminals to inhaled irritants
53
Describe the first, short term stage of the immune response in atopic asthma
* there are lots of T-cells in asthmatic lungs
* When T cells are presented with an antigen, they stimulate B cells to produce specific IgE
* This IgE binds to receptors on mast cells
* When an allergen binds to the IgE on the mast cells, the mast cells release granules of histamine and prostaglandin
* These products produce bronchoconstriction, vasodilation, mucus secretion and tissue destruction (asthma symptoms)
54
Decribe the second, long term stage of the immune response in atopic asthma
* The activated T cells recruit and activate eosinophils
* IgE also binds to the eosinophils
* When an allergen binds to the IgE on the eosinophils they release major basic protein which destroys epithelium (epithelial disquamation)
55
What is efficacy? What has no efficacy?
Efficacy is the full effect that a drug can have. An antagonist has no efficacy.
56
What is an antagonist? What is a competitive antagonist?
* An antagonist is something that reduces responses to an agonist but doesn’t do anything on its own.
* A competitive antagonist binds to a receptor but does not activate the receptor. The antagonist will compete with an available agonist for the same binding sites.
* Antagonist activity can be reversible or irreversible
57
What is affinity? What is it measured by?
Affinity is how tightly something binds to a receptor.
* it is measured by Kd, the dissociation constant. This is the concentration of drug which results in 50% of the maximum number of binding sites becoming occupied.
58
What is the potency of an antagonist defined by?
* The potency of an antogonist is defined by its EC50 value - this is the concentration of an antagonist needed to elicit half-inhibition of the maximum biological response of an agonist.
* The lower the EC50 value, the greater the potency of teh antagonist and the lower the concentration of the drug needed to inhibit the maximum biological response.
59
What does the affinity of an antagonist for its binding site determine?
The affinity of an antagonist for its binding site (Kd) determines the duration of inhibition of agonist activity.
60
What does low Kd and what does high Kd signify?
Lower Kd signifies higher affinity, and higher Kd signifies lower affinity - which makes sense when you consider that Kd is drug the concentration required to fill half the binding sites - if you need only a low concentration, the affinity fir the binding sites must be pretty high.
61
What affect does a competitive antagonist have on an agonist dose-response curve?
A competitive antagonist will shift an agonist dose-response curve to the right, but will have NO EFFECT on the maximum response to the agonist - ie, if you add enough agonist the maximum response can still be acheived.
62
In asthmatic lungs, which immune cells are in high numbers?
At the cellular level, asthmatic patients show a marked lung infiltration of proinflammatory cells, especially eosinophils and T lymphocytes and neutrophils
63
What is atopic asthma? How common is it?
Atopic asthma, found in some 66% to 75% of asthma patients, is a type of asthma that is caused in part by a predisposition to atopy, which is the hypersensitivity to certain antigens called allergens.
64
In patients with atopic asthma, what type of receptor do they display more of in the lung tissues?
Atopic individuals produce abnormally high levels of the antibody IgE in response to these allergens, express more high affinity IgE receptors than normal individuals, and have more of these receptors occupied by IgE. Atopic asthma is also accompanied by the characteristic inflammatory components that are present in all forms of asthma
