Week 4 Flashcards
What is a receptor? Definition and properties
A receiving molecule (glycoprotein) that sends specific messages into cells once the appropriate ligand has been bound
N terminal generally the one being bound (in extracellular environment)
What is amplification?
Receptors amplify signals
They work at very low concentrations
Time scales different dependent on drug/receptor - from ms to days
Ligand-gated receptor/channel complexes - definition and example
Five subunits with pore in the middle, look like a flower from above
Each subunit has a binding site for a drug
Example: Nicotinic receptor
G-protein-coupled receptors - definition and example
one single protein that spans 7 transmembrane regions
N-terminal - ligand-binding site
C-terminal G-protein binding region
Examples: Muscarinic receptors
What is a G protein?
Guanine nucleotide (GTP/ GDP) binding proteins
3 subunits - alpha, beta, gamma
A G protein attached to GTP is active, or “on,” while a G protein that’s bound to GDP is inactive, or “off.”
What are the subtypes of alpha G-protein subunits?
Gs (stimulate), Gi (inhibit), Gq
Tyrosine kinase receptors - discussion and example
Ligand (such as insulin) binds to receptor which essentially allow glucose into fat cells to be stored / processed
Process - ligand binds, two channels move together, phosphate is added to the tyrosine on the receptor which allows the channel to open
1 protein subunit, 1 transmembrane
domain
Example - insulin
Intracellular (or nuclear) receptors
Found within the cell
Example - cortisol hormone receptor
What are other drug binding targets (other than receptors)? (3)
proteins, such as receptors, enzymes, transporters, ion channels or genetic material, such as DNA.
Why do we need to regulate level of breathing?
Adjusted to meet demand for O2 and production of CO2
In what circumstances does O2 requirements or Co2 production increase? 4 examples
Exercise, infection, injury, metabolic dysfunction
How do you increase amount of O2 transported?
Both ventilation AND increased cardiac output
Physiological process of breathing
Nerve signals sent from CNS to respiratory muscles (which are skeletal muscles) to tell them to relax and contract
Key respiratory muscles for inspiration and expiration
Inspiration - Diaphragm, external Intercostal muscles, pectorals, sterocleidomastoid, scalene
Expiration - elastic recoil of diaphragm, internal intercostals, abdominals
How does the brainstem dictate the basic breathing pattern?
Complex series of nueronal connections that interpret and determine the body’s need for oxygen
What factors determine the rate and depth of breathing?
Receptors in muscles and joints (direct rather than waiting for CO2 levels to go up)
Stretch receptors in lungs
Chemoreceptors
Central chemoreceptors - where, function, overview of mechanism
In medulla
Monitors changes in arterial CO2
Responds to changes in H in CSF but does NOT directly respond to changes in blood pH
Do not respond to changes in O2 levels
MECHANISM - negative feedback loop
Peripheral chemoreceptors - where, function, overview of mechanism
In carotid and aortic bodies
Activated by O2 levels, CO2 levels, and acidaemia (low pH)
Sends signal to respiratory centres in medulla via sensory nerves to increase ventilation
Negative feedback loop
What is the hypercapnic drive?
Predominant stimulus underlying urge to breathe
Ventilation is generally proportional to PaCO2 (because of the importance of pH to homeostsis)
What is hypoxic drive?
Occurs at VERY low PaO2
Low PaO2 stimulates increased ventilation (buth this drive only kicks in only at very low PaO2)
What steps are required for the initiation of breathing?
CNS sends message to inspiratory muscles to start breathing
Breathing feedback mechanisms overview (4 outlined)
Central chemoreceptors
Peripheral chemoreceptors
Muscles
Emotional stimuli
Irritant and stretch receptors in lungs
What is sleep apnoea?
Temporary cessation of breathing during sleep
More than 5 episodes per hour lasting more than 10 seconds
Causes tiredness, cardiovascular complications, obesity/diabetes
What test is used to diagnose sleep apnoea?
Polysomnography EOG EEG ECG MANY TESTS
What are the two types of sleep apnoea? (Two types with general causes)
Obstructive - airways blocked
Can be caused by obesity, alcohol/sedatives, smokers
Central - dysfunction in process that initiates breathing
Stroke, drugs such as opiods can suppress neuronal activity, altitude, neonates, central hypoventilation syndrome
What is cheyne-stokes respiration?
Cheyne–Stokes respiration is an abnormal pattern of breathing characterized by progressively deeper, and sometimes faster, breathing followed by a gradual decrease that results in temporary apnea.
Often happens at high altitudes
Back and forth between peripheral and central chemoreceptors
Peripheral increase breathing in response to low O2
Central decrease breathing to respond to low pH
What is consent? (three legal principles)
Voluntary agreement to treatment, examination
Permission to examine, investigate, treat
Waiving of right to bodily integrity
What are the key legal issues that doctors have? (three)
Battery, negligence (both civil) and assault/battery (criminal)
What are the three aspects of VALID consent?
Information, voluntariness, competence
Patients must also know they can change their mind
What are the four features of competence? (re consent)
- understand relevant information
- retain relevant information
- weight up relevant information
- communication decision
What information should you give when getting consent?
PARQ Procedure Alternatives Risks Questions
How much information is adequate? (three different legal models)
Professional practice standard - what complies with the practice standard?
Reasonable / prudent person standard - what does a hypothetical reasonable person want to know?
Subjective standard - what does this person want to know?
What is the significance of the Montgomery negligence case?
Diabetic woman had vaginal delivery and son had significant disabilities. She claimed she had not been fully informed of risks. Won £5 million
How did the law evolve following the Montgomery case?
Move away from the Bolam test to a model where they doctor is responsible to ensure the patients are aware of any material risks and alternatives - based either on a hypothetical reasonable patient or if possible, the patient themselves (if known well enough)
What is asthma?
a respiratory condition marked by attacks of spasm in the bronchi of the lungs, causing difficulty in breathing
Additional mucus caused by immune response
Common symptoms: wheeze, cough, dyspnoea (breathlessness)
What is the general mechanism of asthma? (5 steps)
CAUSE: allergen inhalation / exercise Immune system response Airway inflammation Impaired airway function RESULT: symptoms
What is the general mechanism of asthma? (5 steps)
CAUSE: allergen inhalation / exercise Immune system response Airway inflammation Impaired airway function RESULT: symptoms
What is the relationship between the radius of the airway and the resistance and airflow?
As airway radius DECREASES, resistance INCREASES and airflow DECREASES
What is the impact of asthma on the airway? Four factors
- contraction of smooth muscle
- excess mucus secretion
- oedema / swelling
- irritation of sensory neurons (cough)
What is normal vs asthmatic airflow?
Normal airflow - laminar flow
Asthmatic - Turbulent flow (produces wheezing)
Simple description of allergic response (two stages)
Sensitisation - allergen exposure - allergen processed by immune system - antibodies generated, immune system 'primed' Response - allergen exposure (same allergen) - allergen binds to antibodies w/ immune cell activation, inflammatory response - Symptoms
Simple description of allergic asthma response (two stages)
Sensitisation - allergen exposure - allergen processed by immune system - antibodies generated, immune system 'primed' Response - allergen exposure (same allergen) - allergen binds to antibodies w/ immune cell activation, inflammatory response - Symptoms
Describe the sensitisation process of allergy-induced asthma (6 steps)
- Allergen inhaled and enters airway tissue
- Antigen is engulfed by antigen-presenting cell (dendritic cell)
- Antigen presented to naive helper T cell
- T cell is activated and becomes Th2 cell
- The Th2 cell coordinates with other immune cells via cytokines (Eosinophils and B cells)
- B cells produce antibodies which bind to mast cells
List the cell types responsible in allergy-induced asthma response - name, role, inflammatory mediators involved
B cells - produce antibodies and IgE
Th2 cells - recruit eosinophils, activate B cells
Mast cells - Degranulate to cause inflammation, contraction, mucus
Eosinophils - Degranulate to cause inflammation, contraction, mucus
What happens during allergy-induced asthmatic response? (2 phases possible)
Primary
- Allergen enters airway and enters airway tissue
- Allergen binds receptor on mast cell, which degranulates
- Eosionphil degranulates
- Inflammation causes symptoms
Reoccurrence can be causes T CELL RESPONSE / LATE RESPONSE
What is the long-term impact of asthma?
Ongoing, recurrent response to inflammatory mediator release Tissue damage (chronic = airway remodelling)
What are other cells that have recently been found to be involved in allergic asthma response? (two)
airway epithelial cells
group 2 innate lymphoid cells
Paranasal sinuses (four)
Frontal, maxillary, thymoid, sphenoid
Pharynx divisions (three)
Nasopharynx, oropharynx, laryngopharynx
Function of the larynx (four)
Allow crossing over of the digestive / respiratory passages
Prevent food from entering the trachea
Contribute to voice production
Permit coughing by ‘fixing’ the thorax
Where does the hyoid bone sit (vertebral level)
CIII-CIV
Where does the cricoid bone sit (vertebral level)
CV-CVI
Where does the trachea bifurcate?
The carina
How do the right and left main bronchi differ?
Left - angled, longer, narrower (angled due to position of heart)
Right - more upright, shorter, wider - more like to inhale objects into this lung
Describe position of the muscles of the thorax (9)
Pectoralis major Pectoralis minor Subclavius Serratus anterior (Latissimus dorsi) Diaphragm External intercostals Internal intercostals Innermost intercostals Scalenes
Describe respiratory movements
Diaphragm movement during inspiration and expiration
Movement of sternum and ribs (pump handle and bucket handle)
What cells make up the trachea and its cartilage
Lined with ciliated respiratory epithelium
Goblet cells (secret mucus)
Cilia and microvilli cover surface
Hyaline cartilage anterior, smooth muscle posterior
How big are the pleural cavities in reference to the lungs?
The cavities extend about 2 ribs lower than the lungs to allow for expansion
How do receptors work? (simple process with 5 steps)
Chemical signal (drug) ENTERS the body It BINDS to receptor There is a CHANGE in receptor protein conformation SIGNAL transduction Cellular RESPONSE
What are the immune cells involved in asthma sensitisation and response (4)? What is their role in asthma?
Th2 cells - During sensitisation - induce B cells to produce IgG
During response - coordinate immune response via cytokine release
B cells - produce allergen specific IgE
Mast cells - allergen induced degranulation which releases inflammatory mediators
Eosinophils - cytokine-induced degranulation which releases inflammatory mediators
What is descriptive epidemiology?
The first stage of epidemiological investigation - focuses on describing disease distribution by place/ time / person
Describe the findings of the ISAAC study
The International Study of Asthma and Allergies in Childhood
The ISAAC findings have shown that these diseases are increasing in developing countries and that they have little to do with allergy, especially in the developing world.
Define ‘ecological study’
Study of a population or community (rather than individual)
Value of geographical studies
Measuring exposure and disease rates helps to see changes/differences within populations (where other causal factors may be consistent)
Impact of migration on studying geographical variation
Are differences in disease risk associated with adult environment or genes and early environment?
Describe the findings of migration studies in asthma
People moving from low to high risk countries, they reach asthma levels of new high country
Sometime full effect not felt until second gen
What are the pitfalls of geographic studies? (4) and how do you overcome them?
Differences between countries: Ascertainment (ability to seek medical care) Diagnosis Recording (of info) Population structure (age, sex)
What is the ecological fallacy?
Assuming that the findings of an ecological study apply to an individual
Pitfalls of migration studies (3)
Selection bias
Information bias
Potential influence of stress of migration
What is a period effect vs a cohort affect?
Period effect - recent cause of marked change in disease rate
Cohort effect - an early life cause of marked change in disease rate
Potential pitfalls in studying time trends
Changes in ascertainment
Changes in diagnosis
Changes in recording of information
Changes in population structure
Is breathing in or out more work?
In - inspiration is an active process
Expiration is passive
What muscles are needed for forced inspiration and forced expiration?
Forced inspiration - diaphragm, muscles of the neck, including the scalenes, contract and lift the thoracic wall, increasing lung volume.
Forced expiration - abdominal, internal intercostal - (bucket handle, water pump)
During injury, at what level would your breathing be affected?
Above C5/6
What stimulates breathing?
When CO2 is too high, you breathe faster
Neurogenic factors to increase breathing (5)
Impulses - limb receptors during exercise
Pulmonary receptors sensitive to stretch
Juxtapulmonary receptors stimulated by congestion
Impulses from receptors in muscles / joints of chest wall
Conscious changes
Chemical stimuli to increase breathing (3) - which one is strongest?
Rise in CO2 (strongest)
Rise in H+ ions
Reduced pO2
What defines respiratory failure?
pO2 less than 8kPa
Type 1 - hypoxic (pCO2 less than 6.5)
Types 2 - hypercapnic (pCO2 more than 6.5)
What do hypoxic and hypercapnic mean?
Hypoxic - not enough oxygen
Hypercapnic - too much CO2 (not able to breathe it off)
What characterises type 1 respiratory failure? And examples (2 types)
V/Q mismatch
Increased resp rate (which leads to fall in pCO2)
Alveolar unit failure (stuff in lungs prevent air getting to alveoli OR collapse)
Pulmonary oedema / pneumonia / collapse / fibrosis
Pulmonary vasculature failure (blood isn’t getting to lungs properly)
embolism / hypertension
What characterises type 2 respiratory failure? And examples (3)
Ventilation failure - insufficient excretion of CO2 building up in lungs
hypoventilation
Examples - nervous system or neuromuscular failure
Airway failure (obstruction or dysfunction)
Chest wall or pleural space failure
Asthma, COPD, obesity
What is the ventilation-perfusion match? What kind of respiratory failure does this cause?
Lack of air or blood to lungs
Type 1 failure
How can you calculate pH?
pH is proportional to bicarbonate / pCO2
Henderson-Hasselbach equation
H + HCO3– H2CO3 – H2O + CO2
What occurs during metabolic acidosis? What about respiratory acidosis?
Metabolic acidosis - Increased production of acids (H+)
Respiratory acidosis - Reduced ventilation leading to raised pCO2
What occurs during metabolic alkalosis? what about respiratory alkalosis?
Metabolic alkalosis - Loss of acids
Repiratory alkalosis - Increased ventilation leading to low pCO2
What is the aetiology of asthma? (3)
Genetics
Immunology
Environment
How do you make an asthma diagnosis? (3)
- Classic symptoms and signs (two or more) - cough, wheeze (only caused by asthma, COPD), dyspnoea, chest tightness, sputum production, reduction in exercise tolerance
- Tests for variability
- Tests for eosinophilic inflammation or atopy (FeNO, blood eosinophls, skin prick test)
What are the clinical features of asthma?
Cough, wheeze (only caused by asthma, COPD), dyspnoea, chest tightness, sputum production, reduction in exercise tolerance
- Variable
- worse at night / early AM
- Triggers
Examination of asthma
Exam can be completely normal
Expiratory wheeze may be heard
Silent chest is life threatening asthma
Describe challenge tests for asthma
Mathacholine,histamine,acetylcholine challenge is a lung irritant to produce fall in FEV1 (asthma if dose provoking 20% fall is less than 16mg/mL
What are the non-pharmacological management techniques for asthma? (4)
- allergen avoidance
- smoking cessation
- weight loss
- breathing technique training
What is an asthma action plan? (4)
Peak flow values and action required (3 levels)
Details about asthma - peak flow, meds
How to tell when asthma control is poor
What you should do if control is poor
What to do in emergency
Of your best peak flow values:
less than 80% - ICS
less than 60% - start oral steriods, doctor within 24 hours
less than 50% - present to A&E
How to you review asthma patients? (three first steps)
Make sure they have asthma
Make sure they are taking their inhaler
Make sure they are using it properly
Questions to assess level of asthma control (7, 3 key)
Does the patient have: Daytime symptoms Night time wakening * Need for rescue medication * Asthma attacks Limitations on activity * Normal lung function Side effects from meds
Overview of immediate and subsequent management
Oxygen B2 bronchodilator (salbutamol) via O2 nebuliser Ipratropium bromide via nebuliser Prednisolone or IV hydrocortisone NO sedatives
If improving, continue all
If not improving, regular doses of b2 bronchodilator and ipratropium
If still not improving, refer on
When do you discharge patients following acute asthma?
xxx
People often need similar time for recovery to previous hospital stay with acute asthma
Why does asthma still kill?
Because many patients are still on beta2-agonist but aren’t using longer term drug (?)
Severe can progress very quickly
Describe: Moderate acute asthma (3)
Increasing symptoms
PEF > 50-75% of best or predicted
No features of severe asthma
Describe: Acute severe asthma (4)
Any of the following: PEF > 33-50% of best or predicted RR > 25/min HR > 110/min Inability to complete sentences in one breath
Describe: Life-threatening asthma (clinical 7 and measurements 4)
Any one of these in patients with severe asthma:
Altered conscious level exhaustion arrhythmia hypotension cyanosis silent chest poor respiratory effort PEF > 33% of best or predicted SpO2 <92% PaO2 <8kPa normal PaCO2 (4.6-6)
Describe: Near-fatal asthma
Raised PaCO2 and / or requiring mechanical ventilation
DR (of DR DEAC PIMP) of asthma
Definition - a respiratory condition marked by attacks of spasm in the bronchi of the lungs, causing difficulty in breathing. It is usually connected to allergic reaction or other forms of hypersensitivity
Various types include adult-onset, allergic, asthma-COPD overlap, exercise-induced bronchoconstriction, noallergic, occupational
Risk factors Family history Viral respiratory infections in infancy/childhood Allergies Occupational exposure Smoking Air pollution Obesity
Main parameters of spirometry? How is it performed? What are the main flow rates examined?
Common test to measure how well your lungs are working by measuring how much you inhale / exhale and how quickly. Can be used for diagnosis or to check status / response to treatment
Forced vital capacity (FVC).This is the largest amount of air that you can forcefully exhale after breathing in as deeply as you can. A lower than normal FVC reading indicates restricted breathing.
Forced expiratory volume (FEV).This is how much air you can force from your lungs in one second. This reading helps your doctor assess the severity of your breathing problems. Lower FEV-1 readings indicate more significant obstruction.
Relationship between FVC and FEV
Relationship between them called the Tiffeneau-Pinelli index - FEV1/FVC
In obstructive lung disease (difficulty exhaling completely), the ratio goes DOWN
In restrictive lung disease (difficulty fully expanding lungs), ratio may be the same but both values will drop
How should x-rays be examined?
Airways Bones / breathing Cardiac Diaphragm Everything else - fluid, soft tissues, medical implements, etc.
Different colours of sputum and what it suggests. What are the different colours suggestive of?
Phlegm = mucus in your chest
When you cough up phlegm = sputum
Green / yellow - generally indicates infection
Brown - brown colour generally caused by old blood
White - viral infections, GERD, COPD, heart failure
Black - Inhalation of something black (coal, tar) or fungal infection
Clear - viruses, allergies
Red/pink - Indicates blood
What are potential causes of chest tightness in adults?
Many potential causes including muscle strain, anxiety, pneumonia, GERD (gastroesophageal reflux disease), asthma, ulcers, hernia, rib fracture and many others
Describe the anatomy of the bronchiole
Lumen, epithelium, basement membrane, lamina propia, smooth muscle, glands, cartilage
MICA for B2 agonists - and examples
M (2)
I (3)
C (3)
A (6)
B2 agonists - SHORT (Salbutamol, terbutaline) or LONG (salmeterol, formoterol) indacaterol
M: B2 receptors in smooth muscle of bronchi, gut, uterus, blood vessels
G protein couples receptor is stimulated, leading to smooth muscle relaxation
Also stimulate Na/K pumps causing shift of K from ECF to ICF
I: Asthma
COPD
Hyperkalaemia
C: B-blockers may reduce effectiveness, use alongside corticosteroids can lead to hypokalaemia
Cardiac conditions in general
A: Tachycardia, palpitations, anxiety, tremor, muscle cramps, high serum glucose levels
MICA for corticosteriods - inhaled
M
I (2)
C (3)
A (4)
M: Interact with cytoplasm receptors
Activated receptor moves into nucleus, modifies transcription of genes to downregulate pro-inflammatory genes and up-regulate anti-inflammatory ones
Reduces exacerbations and symptoms
I: Asthma
COPD
C: TB, pneumonia, suppress growth in children (at very high doses)
A: Oral candidiasis (thrush)
Hoarse voice
May increase risk of pneumonia
Only causes systemic side effects in very high doses
MICA for corticosteriods - systemic
M
I (4)
C (4)
A (5)
Prednisolone
M: Interact with cytoplasm receptors
Activated receptor moves into nucleus, modifies transcription of genes to downregulate pro-inflammatory genes and up-regulate anti-inflammatory ones
Direct action on suppression of monocytes / eosinophils
I: Allergic / inflammatory disorders (anaphylaxis, asthma)
Autoimmune diseases
Cancer (reduce tumour associated swelling)
Hormone replacement in adrenal insufficiency and hypopituitarism
C: Cytochrome P450 inducers- may make them less effective
NSAIDs- increase risk of peptic ulcers and GI bleeding
B2-agonists- increase hypokalaemia risk
Wide angle glaucoma
A: Immunosuppression = higher chance of infection
Metabolic side effects including diabetes mellitus, osteoporosis
Mood / behavioural changes
Hypertension / hypokalaemia
Adrenal atrophy
MICA for antimuscarinics, bronchodilators
M
I (2)
C (3)
A (5)
(SHORT e.g. Ipratropium or LONG e.g. aclidnium)
M: Competitive inhibitor of acetyl choline (which normally binds to muscarinic receptor)
Bind to muscarinic receptor - blocks the action of the neurotransmitter acetylcholine
Block parasympathetic activity, reduce smooth muscle tone, increase heart rate, reduce gland secretions in GI and respiratory tracts
I: Asthma
COPD
C: Patients with: angle-closure glaucoma, arrhythmias, urinary retention
A: - Irritation of respiratory tract - GI disturbance - Urinary retention - Blurred vision Headaches
Give an overview of the potential treatments for asthma
B2 agonists
Corticosteriods (inhaled or systemic)
Antimuscarinics / bronchodilators
Aminophylline / theophylline
Both B2 agonists and antimscarinics have short and long acting versions
