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.
-Downstream effects ultimately cause reduced calcium influx into cell, reduced calcium release from SR and increased calcium storage.
-Smooth muscle relaxation (bronchodilation)
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.
(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 C4 leukotriene synthase, 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
