Slater Flashcards
Explain how histamine causes bronchoconstriction and vasodilation
Bronchoconstriction:
-Histamine binds to H1 receptors on the bronchial smooth muscle.
-This is a GPCR, activation of which increases activity of phospholipase C signaling pathway.
-This increases inositol triphosphate (IP3) activity
-Stimulates calcium release from sarcoplasmic reticulum to cause contraction.
Vasodilation
-Histamine binds to H1 receptors on the endothelial cells which line vessels.
-Stimulates the endothelial cells to release nitric oxide
-Nitric oxide increases activity of guanylyl cyclase which increases cGMP.
-cGMP activates protein kinase G which reduces availability of intracellular calcium by reducing calcium influx and increasing calcium storage.
- the result is loss of vasoconstriction -> vasodilation -> increased vascular permeability.
List 5 things that mast cells release upon degranulaton
- Histamine - bronchoconstriction, vasodilation, increased vascular permeability, mucous production.
- Prostaglandin D2 - vasodilation, bronchocontriction
- Leukotrienes C4,D4,E4 - same as histamine
- Cytokines TNF, IL4, IL5 - augment immune response
- Chemotactic factors - ECF (eosinophil), NCF (neutrophil).
What criteria must be met to make a diagnosis of asthma?
- Presence of recurrent respiratory symptoms which are characteristic of asthma which vary over time and in intensity. These are typically worse either early in morning or late at night: Wheeze, chest tightness, cough, dypnea.
- Objective evidence of obstructive disease pattern which shows reversibility with bronchodilators: spirometry, PEFR, bronchial provocation test.
5 complications of severe asthma attack
- aspiration pneumonia
- pneumothorax
- Respiratory failure/arrest
- Cardiac arrest
- Hypoxic brain injury
What class of drug is Formeterol? What is its MOA?
Formoterol is a B2 adrenoreceptor agonist which has a quick onset and long lasting duration (12 hours) (LABA)
-Inhaled formoterol binds to B2 receptors of bronchial smooth muscle
-This is a Gs PCR, activation of which causes the alpha subunit to enhance activity of adenylyl cyclase thereby increasing cAMP which increases Protein Kinase A.
-PKA can then phosphorylates mediators of calcium availability and myosin light chain kinase (inactivating it).
-There is reduced calcium influx
-Can also hyperpolarise the SMC by coupling with calcium-activated K+ channels
-Downstream effects ultimately cause reduced calcium influx into cell, reduced calcium release from SR and increased calcium storage.
-Smooth muscle relaxation (bronchodilation)
Beta 2 receptor is a Gs PCR
describe the main features of olfactory epithelium
- Olfactory epithelium is a specialized type of epithelium that lines the superior conchae at the roof of the nasal cavity.
- It is composed of pseudostratified columnar epithelium
- It is composed of 3 main cell types
(1) Basal cells which are spherical in shape and sit at the basement membrane: these are stem cells which give rise to the other 2 cell types.
(2) Supporting cells: Columnar cells which project fluid-bathed microvilli which contain ion channels which function in normal olfaction. These cells also function in metabolic + structural support.
(3) Olfactory neurons: These are bipolar neurons which contain chemoreceptors within non-motile cilia in the apical dendrite. These respond to odiferous agents and signal propogates through axons which pass through cribiform plate and converge on olfactory bulb of CN1.
- Bowmann’s glands reside in the lamina propria and secrete mucous, lysozymes and amylase onto the mucosal surface. The mucous contains IgA antibodies and mucopolysaccharides.
-Goblet cells are absent in oflactory epithelium
-Cilia are present but not visible.
What is meant by “compensated alkalosis?”
This means that the kidneys have successfully returned the blood pH levels to normal (having previously been elevated), however HCO3- remains low indicating continued compensatory efforts from the kidneys because the causative factor is still ongoing, i.e. hypocapnia caused by hyperventilation.
reference values for:
(i) pH
(ii) pO2
(iii) pCO2
(iv) HCO3-
pH (7.35-7.45)
pO2 (10-14 kPa)
pCO2 (4.8-6.1 kPa)
HCO3- (22-26 mmol/L)
describe the synthesis of leukotrienes
Arachidonic acid is cleaved from membrane phospholipids by Phospholipase A2
AA -> 5-HpETE (hydroperoxide) by 5-lipooxyegnase
5-HpETE -> Leukotriene A4 (LTA4) by 5-LOX
LTA4 -> LTB4 by LTA4 Hydrolase
LTA4 to cysteinyl leukotrienes C4, D4, E4 by leukotriene C4 synthase, gamma-glutamyl leuokotrienase, and dipeptidase respectively.
Describe the process by which smooth muscle contracts
(i) Acetylcholine binds to muscarinic receptor (M3 in bronchial smooth muscle)
(ii) Activation of Gq protein which increases phospholipase C activity
(iii) Increased inositol triposphate (IP3)
(iv) Increased Diacylglycerol (DAG)
(v) opening of VG calcium channels/release of calcium from SR
(vi) calcium binds to calmodulin -> activation of myosin light chain kinase
(vii) MLCK phosphorylates myosin light chain allowing for actin-myosin cross bridge cycling -> contraction
(viii) Myosin light chain phosphatase dephosphorylates myosin light chain causing it to detach from actin.
Describe the mechanism of action of Omalizumab in asthma control
Omalizumab is a IgG-type monoclonal antibody directed again circulating IgE.
By binding to IgE, it prevents IgE from binding to its high affinity receptors found on mast cells, eosinophils and basophils.
It also causes reduced expression of these high-affinity receptors.
This prevents IgE-mediated mast cell degranulation as well as eosinophil infiltration into the airways thereby reducing the allergy-mediated inflammatory response in the airways.
Clinical features of an acute severe asthma exacerbation
(i) PEFR 33-50% of best/predicted
(ii) HR >/= 110bpm
(iii) RR >/= 25 per min
(iv) Cant complete sentence in one breath
(v) Accessory muscle use
Clinical features of status asthmaticus
(i) PEFR < 33% best or predicted
(ii) Pa02 < 8kPa
(iii) PaCo2 normal or increased
(iv) Silent chest
(v) cyanosis
(vi) Poor respiratory effort
define and describe the pathophysiology behind pulsus paradoxus
- Pulsus paradoxus is defined as a drop in systolic blood pressure by >10mmHg during inspiration.
- Pulsus paradoxus occurs in a severe asthma attack due to large negative intrathoracic pressure swings needed to overcome increased airway resistance.
- This increased negative pressure enhances venous return to the right side of the heart, causing right ventricular filling to increase significantly.
- At the same time, lung hyperinflation raises pulmonary vascular resistance, which can reduce blood flow to the left side of the heart.
- The enlarged right ventricle pushes the interventricular septum leftward, further reducing left ventricular filling and preload.
- The net effect is a decreased stroke volume and a marked drop in systolic blood pressure during inspiration, which is characteristic of pulsus paradoxus
Describe the pathogenesis of atopic asthma
Introduction of an allergen is processed by antigen-presenting cells (e.g., dendritic cells) and presented to naive TH0 cells on MHC-II molecules.
In predisposed individuals, TH0 cells differentiate into Th2 cells.
Th2 cells secrete key cytokines:
IL-4: Promotes B-cell class switching to produce IgE antibodies against the allergen.
IL-5: Activates eosinophils and enhances their recruitment and survival.
IL-13: Stimulates mucus production, goblet cell hyperplasia, and subepithelial fibrosis.
On allergen re-exposure, IgE (bound to sensitized mast cells via Fcε receptors) cross-links with the allergen, triggering mast cell degranulation.
Mast cell mediators include:
Cysteinyl leukotrienes (C4, D4, E4): Cause bronchoconstriction, vasodilation, and increased vascular permeability.
Histamine: Similar effects to leukotrienes.
Prostaglandin D2: Vasodialation and bronchoconstriction
Chemotactic factors: Attract eosinophils which release tissue damaging peroxidases.
Chronic inflammation leads to airway remodeling, perpetuating airway hyper-responsiveness. Features include:
Hyperplasia/hypertrophy of smooth muscle, mucus, and goblet cells.
Subepithelial fibrosis, basement membrane thickening, mucosal edema, and increased vascularity.
Sloughing of epithelial cells, loss of microvilli, and occasional squamous metaplasia.
These changes result in maladaptive responses to stimuli, with excessive and prolonged bronchoconstriction contributing to symptoms of asthma.
Why should NSAIDs be avoided in asthmatics?
- NSAID’s inhibit cyclo-oxygenase enzymes which is involved in the production of prostaglandin E2 from arachidonic acid. Prostaglandin E2 is known to inhibit leukotrienes.
- Blockade of the COX pathway may force more AA metabolism down the leukotriene pathway
Describe the pathophysiology of cyanosis in a patient with a severe asthma attack
During a severe asthma attack, increased airway resistance due to bronchoconstriction and mucus plugging leads to reduced ventilation in a large portion of the alveoli.
The inflammation throughout the respiratory tree is often patchy, meaning some alveoli may be adequately ventilated, while others are under-ventilated or poorly ventilated.
This causes a ventilation/perfusion (V/Q) mismatch:
Blood perfusing under-ventilated alveoli receives insufficient oxygen, leading to hypoxemia. These areas contribute to a low V/Q ratio.
Although some blood is perfusing well-ventilated areas and oxygenated, this is insufficient to fully offset the hypoxia in under-ventilated regions. The oxygen dissociation curve is flattened at high oxygen levels, meaning hemoglobin saturation cannot increase further to compensate.
Hypoxic vasoconstriction attempts to redirect blood flow to well-ventilated areas, but this may not be enough to counteract the widespread hypoxemia.
As a result, physiological shunting may occur, where blood flows through poorly ventilated alveoli without proper oxygenation.
Cyanosis is observed because of the increased levels of deoxygenated hemoglobin circulating in the blood. This causes a bluish coloration in the skin and mucous membranes, particularly when oxygen saturation drops below 85-90%.
As the patient becomes hypercapnic, contributing to respiratory acidosis, the Bohr effect leads to a reduced affinity of hemoglobin for oxygen. This promotes the release of the small amounts of oxygen that remain in the blood to the hypoxic tissues. However, this also further contributes to cyanosis by increasing the concentration of deoxygenated hemoglobin in the blood, which gives a bluish tint to the skin and mucous membranes
Why might an asthmatic with low blood oxygen levels not show signs of central cyanosis?
An asthmatic with low blood oxygen levels may not show signs of central cyanosis due to the compensatory state of respiratory alkalosis. During an asthma attack, hyperventilation occurs as the body attempts to compensate for low oxygen levels. Hyperventilation leads to CO₂ being “blown off” — meaning CO₂ levels drop and blood pH increases, resulting in respiratory alkalosis.
The drop in CO₂ reduces the concentration of H⁺ ions (due to the carbonic anhydrase reaction), which shifts the carbonic acid-bicarbonate equilibrium to the left. This results in a higher pH and lower CO₂ levels in the blood.
Alkalosis and low Co2 shifts the dissociation curve to the left, increasing hemoglobin’s affinity for oxygen. This means that despite low oxygen levels, the hemoglobin will bind oxygen more readily, maintaining higher oxygen saturation in the blood.
As a result, even though oxygen levels may still be low, the blood is still relatively well-oxygenated, which offsets the development of cyanosis, a condition caused by increased deoxygenated hemoglobin.
Mechanism of action of Dupilumab
Dupilumab is an antibody which inhibits IL4 and IL13 signalling.
It binds to Type 1 (IL4) and Type 2 (both) receptors which prevents downstream activation of Janus kinase and STAT pathways.
By blocking these IL4 and IL13 signalling pathways, it decreases key mediators of inflammation including IgE.
MOA of Mepolizumab, Reslizumab and Benralizumab
These are IL5 antibodies.
Mepolizumab and Reslizumab
- Binds to IL5 and prevents it from binding to its receptors on eosinophils
-This reduces production, survival and migration of eosinophils.
Benralizumab
-Binds to IL5 receptor on eosinophils and basophils causing apoptosis
What spirometry findings are suggestive of asthma
- Obstructive lung disease pattern
- FEV1 < 80% best or predicted
- Reduced FVC (but to a lesser extent than FEV1)
- FEV1/FVC ratio <0.7 - Reversibility
- increase of 12% and 200ml with bronchodilator
- increase of 15% and 400ml with bronchodilator
What PEFR findings are suggestive of asthma
3 measurements taken, highest one used
Increase PEFR >20% after bronchodilator
What suggests hyperresponsiveness in metacholine test?
Methacholine, an M3 receptor agonist, is given via nebuliser, with the dose being increased gradually. Spirometry or PEFR is done after each increase in dose.
DROP in FEV1 >20% after a standard dose of methacholine is suggestive of asthma
Moderate sensitivity but low specificity for asthma
–> it is good at demonstrating a hyper-responsiveness and so those who get a negative result can more or less rule out asthma, however a postive result could mean: asthma, COPD, cystic fibrosis, allergic rhinitis.
Name the type of respiratory epithelium
Describe 2 differences between respiratory and olfactory epithelium
Respiratory epithelium: Pseudostratified ciliated columnar with goblet cells
Differences:
(1) Cell types
*Olfactory does not have goblet cells, respiratory does.
*Olfactory contains an abundance of olfactory and sustentacular cells, the respiratory mucosa does not
(2) Mucosal thickness
*Olfactory mucosa is thick, respiratory mucosa is thin
Name 2 classes of drugs that can trigger an asthma exacerbation
NSAIDs
*NSAIDs blocks the cyclo-oxygenase site which prevents binding of arachidonic acid for further production to prostanoids.
*This therefore inhibits PGE2 production which is a key inhibitor of leukotrienes.
*Leukotriene activity can therefore increase and cause bronchoconstriction.
*Reduced COX metabolism of AA may also direct more AA down the leukotriene pathway.
Beta Blockers
*Beta blockers, particularly non-selective beta blockers can inhibit Beta 2 receptors in the bronchial smooth muscle.
*Beta 2 receptors in bronchial smooth muscle are responsible for mediating bronchodilation and are agonised with certain asthmatic interventions.
*Therefore by binding to and blocking beta 2 receptors, the bronchodilator response is blocked which can result in bronchoconstriction.
Cardioselective Beta 1 blockers - Atenolol, bisopoprolol
List 2 clinical features of nasal problems associated with asthma
1.Sneezing and running nose (rhinorhea)- allergic rhinitis
2.Reduced sense of smell/mouth breathing – nasal polyps causing obstruction
Criteria for discharge (GINA)
Significant symptom improvement
PEFR 60-80% of best or predicted
o2 sats > 94% on room air
Continue oral prednisolone usually for 1 week
Check inhaler technique
MOA of glucocorticoids
-Travel in blood bound to steroid binding globulin- active.
-Some travels in plasma, unbound - active
-It is lipophilic and so diffuses into cell.
-Binds the intracellular receptor which is bound by a
heat shock protein
-Binding the receptor results in dissociation of HSP
-Translocates to nucleus
-Alters gene expression
- Upregulates anti-inflammatory genes (trans-activation):
(i)Anexin-1 activation
—> Activation of anexin 1 leads to inhibition of phospholipase A2-alpha.
—>This blocks release of arachidonic acid from cell membranes
—> This inhibits production of ecosanoids i.e. prostaglandins + leukotrienes.
(ii) MAPK phosphatase 1 activation
—> leads to dephosphorylation and inhibition of MAPK family of proteins
—> decreased intracellular signalling
—> inhibition of phospholipase A2-alpha
—> blocks release of arachidonic acid
- Downregulates pro-inflammatory genes (transrepression): NFkB, Activator protein 1
(i) NFkB: normally binds DNA to promote transcription of inflammatory mediators + COX-2 enzymes
(ii) Activator Protein 1: Normally acts in the transcription of inflammatory mediators.
- Increases anti-inflammatory cytokines IL-10, IL-1ra
- Also causes non-genomic changes
List 5 physiological effects of glucocorticoids
(1) Immunosuppression –> Reduced T cells, reduced eosinophils, reduced macrophages, reduced vascular permeability and adhesion molecules means leukocytes can’t get to site of infection
(2) Myopathy: increased protein breakdown and decreased protein synthesis in skeletal muscle
(3) Hyperglycemia: Decreased glucose uptake and increased gluconeogenesis
(4) Hypertension: alpha-1 adrenergic affects
(5) Menstrual irregularities due to disruption of HPA axis.
(6) Avascular necrosis and bone fracture
Describe how the metacholine causes bronchoconstriction
- binds to M3 receptor of bronchial smooth muscle
- This is a Gq protein coupled receptor
- Activates phospholipase C
- Increased activity of inositol triphosphate
- increased diacylglycerol
- Increased influx of calcium
- binds to calmodulin which activates myosin light chain kinase etc
Describe type I hypersensitivity reaction
Type 1
- “First and Fast”
- involves IgE, mast cell and allergen.
*First phase (within minute)
-> antigen cross-links IgE on mast cell leading to immediate degranulation and release of histamine, tryptase , leukotrienes
*Second phase (hours)
-> mast cell releases chemokines + other inflammatory mediators which attract eosinphils
-> leads to further inflammation and tissue damage.
Example: anaphylaxis/ allergic asthma
