Integrative Summary questions Flashcards
explain how the hypothalamus corrects raised plasma osmolality
osmoreceptors in OVLT and subfornical organ detect raised osmolality
they stimulate posterior pituitary which releases ADH
ADH acts on the collecting duct of the kidney nephron to increase its permeability to H20 via the insertion of AQP-2 channels on the apical membrane, so more H20 is reabsorbed, correcting plasma osmolality and producing concentrated urine.
how are AQP-2 channels inserted into apical membrane during ADH release?
ADH binds to V2 receptors (Gs GPCRs) on BL memebrane on late DCT and CD
activates adenylate cyclase
increases cAMP
activates protein kinase A
increase number of channels and inserts more
how is CD made impermeable to H20 following ADH removal?
AQP-2 channels endocytosed from apical membrane
in addition to osmoreceptor stimulation in the OVLT due to increased plasma osmolality, how else is ADH release stimulated?
Ang II acts on subfornical organ
baroreceptors detect decrease in BP when plasma vol reduced, causing increased osmolality, and stimulate ADH release from post pituitary
which hormone limits ECF volume expansion promoted by ADH?
ANP- released from atrial walls when ECF volume high.
Promotes Na+ excretion (and inhibits Na+ reabsorption along nephron), but main role is promoting excretion: vasodilates afferent arteriole via activation of guanyly cyclase, increase cGMP, stimulate protein kinase G, reduce Ca2+ causing relaxation of vascular smooth muscle, hence dilation, which increases GFR as increased renal b.flow, so more Na+ excreted.
functions of ADH other than increaseing permeability of CD to H20?
increases H20 permeability of late DT
stimulates NaCL reabsorption at thick ascending limb of LOH, DT and cortical part of CD. This may help to maintain hyperosmotic medullary interstitium necessary for H20 reabsorption from medullary part of CD.
increases permeability of medullary CD to urea
K+ secretion in cortical CD
vasoconstriction at the glomerulus to reduce the effective filtering SA
what proportion of H20 filtered by the kidney is reabsorbed in the early part of the DCT?
none!
where does ADH act to regulate urea reabsorption when H20 must be conserved?
medullary CD
urea will concentrate medullat interstitium to allow more H20 reabsorption by thin descending limb of LOH
what 3 factors control renin release?
reduced NaCl delivery to DCT- as reduced GFR will reduce NaCl filtration.
reduced perfusion pressure- detected by baroreceptors in afferent arteriole
SNS stimulation- NA acts on beta 2 adrenoceptors on granular cells.
why do ACEIs have SE of a cough?
stop ACE breaking down bradykinin- a potent vasodilator and can cause coughing
what is the main danger with acidaemia, and how does this come about?
hyperkalaemia- H+ moves out of ECF into ICF, and K+ moves in opposite direction into ECF.
AND kidneys: H+ is secreted by a H+-K+ ATPase in the alpha intercalated cells of the DCT and CD and so if there is more H+ in the ECF, more will be secreted across the apical memebrane, which results in more K+ being reabsorbed.
why is a H+-K+ ATPase used to expel H+ into the urine in the DCT and CD, rather than a transporter coupled to Na+ movement?
most Na+ has been reabsorbed by this point, so insufficient Na+ gradient to provide energy to move H+ against its concentration gradient.
how does aldosterone affect Na+ and K+ concentrations in the body?
increases Na+- increasing BP, by increasing expression of Na+ pump on BL membrane of principal cells in cortical CD (and DCT), and ENaC expression on apical membrane.
reduces K+ as increase Na+ pump expression, and ROMK channel expression on apical membrane, and ENaC. Na+ pump brings K+ into principal cell from ECF, creating a chemical gradient for diffusion into filtrate, and ENaC bring Na+ into cell from filtrate, creating a +ve lumen potential that promotes a favourable electrical gradient for K+ diffusion out into the filtrate via the ROMK channels.
What stimulates increased secretion of aldosterone from the zona glomerulosa of the adrenal cortex in the body?
hyperkalaemia
AngII- RAAS activation if decrease in BP (decrease in mean by about 30mmHg) or low blood volume
contrast the effects of acute and chronic increases in aldosterone secretion
acute: Na+ pump stimulated but secretion of K+ not increased as increased Na+ and H20 reabsorption reduces tubular flow so there is less K+ wash out to maintain gradient for K+ secretion by principal cells of cortical CD. BUT chronic secretion, ECF expands with Na+ reabsorption, so tubular flow returned to normal and K+ secretion enhanced?
why does alkalosis become life-threatening more quickly than acidosis?
alkalosis reduces solubility of Ca2+ in plasma, so it binds to plasma proteins and gets uptaken into bone, causing hypocalcaemia which produces tetany and paraesthesia as low Ca2+ in ECF increases Na+ permeability of neuronal membranes causing a progressive depolarisation that increases the chance of AP firing.
Hypokalaemia also occurs but this change is less dangerous.
2 treatment’s for Conn’s syndrome?
aldosterone antagonist e.g. spironolactone
remove tumour
blood results show low [HCO3-], low pCO2 and a relatively normal pH. What is this acid base state, and what may have caused it?
1 of 2: compensated respiratory alkalosis, or compensated metabolic acidosis. the 1st occurs acutely with hyperventilation following anxiety or panic attacks, or more LT with type 1 respiratory failure. If no resp disease present, unlikely to be alkalosis. To determine if metabolic acidosis, check anion gap. If increased, indicates metabolic acidosis e.g. lactic acidosis.
why does diabetic ketoacidosis occur?
in diabetes, low insulin:anti-insulin ration coupled to high rates of beta oxidation of FA promotes ketone production as an alternative energy source as glucose unable to be uptake by tissues for metabolism ,and ketones are capable of crossing BB barrier to provide energy to the brain.
blood results show high pCO2, high [HCO3-] and relatively normal pH. What is this acid base state, and what may have caused it?
compensated respiratory acidosis e.g. type 2 resp failure e.g. COPD, asthma, myasthenia gravis, kyphosis, respiratory depression caused by opiates e.g. morphine.
although results also suggest compensated metabolic alkalosis, this can’t occur as pH won’t be fully compensated for as would have to reduce breathing rate to increase pCO2 but this wouldn’t provided body with sufficient O2 to function normally.
factors promoting K+ uptake into cells?
insulin aldosterone catecholamines alkalosis increased [K+] in ECF
factors promoting K+ shift out of cells?
exercise cell lysis e.g. rhabdomyolysis- myoglobin appears in urine* acidosis reduced [K+] in ECF increase in ECF osomolarity
why is it difficult for kidneys to correct a metabolic alkalosis caused by vomiting?
patient will be dehydrated, reduced blood volume and BP, stimulating RAAS ( if mean BP decrease by 30mmHg), which results in Na+ and H20 reabsorption by kidney tubules, and HCO3- reabsorbed with Na+, so worsens alkalosis.
ALSO, Cl- lost in vomit, so kidneys want to reabsorb more H+ to correct acidosis but H+ reabsorbed via cotransporter which moves Cl- out and there is insufficient Cl- to move out, so H+ can’t be moved in to ECF.
what is the atrial kick?
the additional blood flow into the ventricles during atrial systole (remember, most filling of ventricles occurs in diastole.)
what might a higher intensity than normal 2nd heart sound indicate?
systemic or pulmonary hypertension causing abnormally high aortic or pulmonary pressure.
how is the first heart sound produced?
at onset of ventricular systole, AV valves forced shut as ventricular pressure becomes > atrial pressure. On closing, impact of valve leaflets induces oscillations in a variety of structures so these vibrate, producing sound. Louder and longer duration than S2.
how is the second heart sound produced?
closure of outflow valves (aortic and pulmonary) at end of ventricular systole when pressure on vessel exceeds pressure in ventricle. Lower intensity, shorter duration and higher pitch than S1.
what is the gap between the 1st and 2nd heart sounds?
280 ms at rest between 1st and 2nd (approx. length of systole). S2 to S1 =700ms.
when might a third heart sound be heard?
early in diastole due to rapid ventricular filling.
when might a fourth heart sound be heard?
in atrial systole, rarely heard unless high EDP
what is the dicrotic notch in the cardiac cycle?
increase in aortic pressure following aortic valve closure as brief backflow of blood into L ventricle allows aortic valve to close so now blood can’t move back into heart from aorta.
why does atrial pressure briefly increase following the onset of ventricular systole?
as ventricle contracts, ventricular pressure increases rapidly, causing AV valves to bulge into the atria, which causes increase in atrial pressure.
define preload and afterload
preload= filling pressure of heart afterload= pressure heart has to pump against
approximate cardiac output at rest?
5L/min
symptoms and signs of left sided HF?
dyspnoea- exertional, orthopnoea, paroxysmal nocturnal dyspnoea
chest pain resulting from dyspnoea
fatigue
ankle swelling- peripheral oedema
heart murmur- mitral regurge- systolic murmur
anorexia
dizziness
basal crackles- fluid overload, pulmonary oedema as fluid backs up from L heart, airways forced shut during expiration as compressed by fluid in pulmonary interstitium, crackles produced as airways forced shut reopen during inspiration- ‘pop’ open.
symptoms and signs of right sided HF?
raised JVP
peripheral oedema- pitting ankle oedema
pleural effusion
ascites
why are ACEIs best avoided in patient with HF who also has known/suspected renovascular disease e.g. severe bilateral renal artery stenosis?
cause significant reduction/abolishment of GFR, causing severe and progressive renal failure as ACEIs stop AngII from preferentially constricting the efferent arteriole to increase GFR when blood flow to kidney limited e.g. renal artery stenosis.
most common cause of HF?
IHD
what SE may you have to warn a patient about when treating HF with an ACEI?
cough- due to bradykinin increase as not broken down by ACE
define systolic heart failure
impaired ventricular contraction resulting in inadequate pumping of heart to meet the metabolic needs of the body.
ejection fraction <45%.
define diastolic heart failure
impaired ventricular filling during diastole, so heart not pumping out adequate blood supply to meet metabolic needs of body as not able to fill with sufficient blood.
why might hypertension be responsible for diastolic heart failure?
hypertension results in increased afterload on heart, so heart must work harder to pump blood out into the systemic circulation, so in an attempt to generate more focre may hypertrophy- cardiac myocytes grow larger and ventricular wall thickness increases, but thicker ventricle less compliant so ability to fill is reduced, contributing to diastolic failure.
what structural heart changes occur in systolic HF?
increased LV capacity as heart dilation occurs. Myocardial wall thins- mycoardial fibres replaced by fibrous tissue, and undergo necrosis, matrix proteinases function in cardiac remodelling, changing the overall structure of collagen so contractility is lost.
mitral valve becomes incompetent as valve leaflets unable to come together fully when valve closes due to ventricle dilation.
neuro-hormonal activation causes failing heart to work harder, causing energy defecit, dysfunction of ATP dependent transporters and subsequent Ca2+ overload, which impairs relaxation and causes AP lengthening- long QT syndrome, and arrhythmia generation- major cause of sudden death- VF.
what ventricular remodelling occurs after an MI?
myocytes= permanent cells, can’t regenerate, so ischameic necrosis occurs and fibrous tissue is laid down with scar formation, so loss of contractile myocardium. Heart remodels around scar to reduce risk of scar rupturing, so heart subsequently dilates.
what features may indicate HF on a chest X-ray?
increased cardiac:thoracic, >50% on a PA view )heart would be enlarged if AP view as situated anteriorly in chest)
bat’s wing shadowing= bilateral perihilar shadowing that may occur with pulmonary oedema, shows as increased lung markings
upper zone blood vessel enlargement- due to pulmonary venous hypertension
septal (Kerley) B lines- horizontal lines reaching lung edge, fluid accumulating between secondary lobules of lung due to pulmonary oedema
pleural effusions= homogeneous white opacification, meniscus sign
why is there a rise in resting heart rate with increasing age?
progressive decrease in vagal tone, so sympathetic influence on heart rate becomes more dominant
example of a +ve inotropic drug?
digoxin
adrenaline
how does the SNS contribute to progressive decline in myocardial function in chronic heart failure?
Ca2+ overload in myocytes, excessive Ca2+ uptake by SR and mitochondria
why can lactic acidosis occur with heart failure and why in this condition is it even more problematic?
poor perfusion so inadequate O2 for aerobic respiration, so proceeds anaerobically producing lactate= acidic.
Acidosis is -vly inotropic as interferes with actions of Ca2+, so cardiac fiunction will be depressed further.
how does the PNS slow HR?
ACh acts on M2 receptors: Gi GPCRs- inhibited cAMP production so depolarisation slowed and increase K+ channel opening, causing hyperpolarisation. This makes pacemaker action potential shallower, so increases the time between beats.
how does ANP act to support CO in HF?
vasodilates afferent arteriole, and constricts efferent arteriole, so increasing GFR and hence increasing Na excretion, so less Na+ and H20 retained by body, so reduce afterload so less pressure that the heart has to pump against so reduce w.load of heart.
acts through guanylyl cyclase stimulation- increase cGMP, PKG stimulation, reduce IC Ca2+ so smooth muscle relaxation in afferent arteriole.
define hypersensitivity
antigen-specific immune responses that are inappropriate or excessive and result in harm to host.
examples of extrinsic antigens triggering hypersensitivity?
non infectious substances e.g. peanuts
infectious microbes
drugs e.g. Penicillin
can control these
examples of intrinsic antigens triggering hypersensitivity?
infectious microbes e.g. Strep. pyogenes
self-antigens- AI diseases- women more susceptible, genetic susceptibility- HLA classes run in families, link to environ factors, cause of most endocrine diseases.
why might a patient suffering from a sore throat later develop rheumatic heart disease following an AI response?
sore throat caused by strep pyogenes and the microbial antigens of this organism are very similar to host antigens in cardiac muscle so when MHC molecules present the microbial antigen to T cells, the immune response may also be targeted against cardiac muscle as the antigens displayed are similar.
what virus is linked to the development of type 1 diabetes due to its antigens being similar to those displayed by beta cells of islets of Langerhans in the pancreas?
coxsackie
describe the common feature of hypersensitivity reactions in terms of how they come about
2 phases: sensitization and effector
sensitization: 1st encounter wiht antigen, host recognises antigen and immune response occurs but no tissue damage results
effector: clinical pathology on re-exposure to the same antigen, so tissue damage occurs.
how do types I, II and III hypersensitivity reactions differ from type IV?
I-III are antibody dependent:
I=IgE
II and III= IgG and IgM
timings of type I hypersensitivity?
immediate response=<30min, to non-infectious environmental antigens.
describe the immune mechanism of type I hypersensitivity
on 1st exposure to the allergen, antigen-specific IgE binds to mast cells but there are no symptoms.
2nd exposure is required, on which the allergen cross-links antigen-specific IgE molecules on mast cells causing mast cell activation and histmaine release.
Histamine causes vasodilation, increased vascular permeability through endothelial cell contraction and bronchial constriction.
effects mediated via histamine release in type I hypersensitivity reactions?
vasodilation
increased vascular permeability
bronchial constriction
how are type I hypersensitivity reactions diagnosed?
clinical history: atopy, allergens, seasonality, route of exposure
measure blood/serum levels of mast cell products e.g. mast cell tryptase, serum allergen specific IgE.
skin prick test- apply liquid allergen extract to determine which type of allergen causing hypersensitivity. Wheal (raised swelling) and flare (red as increased b.flow) reaction, >3mm, patient mustn’t be on antihistamines. BUT risk of anaphylaxis in those highly sensitive and requires trained personnel. Targets mast cells in
epidermis.
food and drug allergy challenge tests
what is urticaria and why might it occur with type I hypersensitivity reactions?
itchy rash that occurs with activation of mast cells in the epidermis.
what happens with mast cell activation in the deep dermis in type I hypersensitivity reactions?
angioedema= non-itchy swelling e.g. of lips, eyes, tongue and upper respiratory airways, may be a medical emergency- airway blockage.
describe the mechanism behind hereditary angioedema
complement component deficiency: lack C1 inhibitor, so complement system remains activated, if airways involvement in attack can be fatal as oedema blocks airways- unable to breathe.
tment of type I hypersensitivity reactions?
AVOID ALLERGEN
Epipen- IM adrenaline 0.5mg- vasoconstriction, IV fluids- increase BP as vasodilation can cause hypotension on systemic activation of mast cells.
Antihistamine (IM or slow IV)
Hydrocortisone (corticosteroid-anti-inflammatory- inhibits gene expression, transrepression and transactivation functions)- IM or slow IV
allergen desensitisation in patients at high risk of systemic attacks
carry medical alert bracelet
result of systemic activation of mast cells in type I hypersensitivity reactions?
hypotension
angioedema
generalised urticaria
wheezing as a result of bronchial constriction
clinical examples of type I hypersensitivity reactions?
asthma hayfever (allergic rhinitis) food allergies e.g. peanuts, fish, milk acute urticaria systemic anaphylaxis
what is lost in vomiting?
H2O, H+ and Cl-
severe vomiting- loss of K+ and Na+
describe the mechanism of type II hypersensitivity reactions
antibody-mediated- IgG or IgM, bind to antigens on cell surface to disrupt function, binding to other cellular components causes tissue damage. Antibody bound to antigen activates complement, and antibody dependent cellular toxicity. Phagocytes may also have a role. May be self-antigen or exogenous chemicals.
Describe hypersensitivity reaction in Grave’s disease
Type 2: antibody-mediated to change function. Anti-thyroid stimulating hormone receptor antibody, bind to TSH receptors on follicular cells of thyroid and chronically stimulate them, most common cause of hyperthyroidism, more common in females, only cause of hyperthyroidism that produces exopthalmos.
Describe hypersensitivity reaction in Myasthenia Gravis
type 2, anti-ACh receptor antibody. Skeletal muscle weakness, ptosis.
Tensilon test= diagnostic test where drug given which inhibits ACh breakdown.
Can treat with neostigmine= ACh esterase inhibitor so more ACh around.
Describe hypersensitivity reaction in pernicious anemia
type 2: anti-intrinsic factor antibody, intrinsic factor necessary for Vit B12 absorption from at the terminal ileum. Deficiency can cause paraesthesia, numbness, cognitive or visual disturbance, angular chelitis, macroglossia. Megaloblastic anaemia.
Schilling test= diagnostic. Radio-labelled Vit B12 given to see if can be absorbed.
how does good pasture’s syndrome occur?
type II hypersensitivity reaction causing tissue damage, mediated by anti-glomerular basement membrane antibody= tye of IgG= against type IV collagen in glomerular BM and also expression on alveolar BM so causes pulmonary haemorrhage, and haemoptysis.
Rapidly progressive glomerulonephritis- all glomeruli can be lost within 48 hrs of onset. Acute onset of nephritic syndrome: high BP, haematuria, feel very unwell.
Tment= immunosuppression and plasmaphoresis
Diagnostic test= IgG deposition on renal biopsy, and ELISA to detect antibodies against alpha 3 chain of type IV collagen
