trigger 2 - ischaemia Flashcards
central nervous system - CNS
brain and spinal cord
peripheral nervous system - PNS
all the nerves
split into somatic and autonomic
protection of the brain
1 - skull
2 - meninges (3 membranes)
3 - cerebrospinal fluid (CSF)
somatic nervous system
voluntary control
relationship with external environment
autonomic
involuntary
regulate vital internal functions
split into sympathetic and parasympathetic
grey matter
consists of:
- neurons cells bodies and their dense network of dendrites
- centre of spinal cord
- thin outer layer of cereal hemispheres (cerebral cortex)
white matter
myelin sheath
brain stem
responsible for a variety of automatic functions, such as control of respiration, heart rate, and blood pressure, wakefullness, arousal and attention.
cerebrum structure
divided into a right and a left hemisphere
4 lobes:
frontal, parietal, temporal, and occipital
stroke involving cerebellum
may result in a lack of coordination, clumsiness, shaking, or other muscular difficulties
important to diagnose early, since swelling may cause brainstem compression or hydrocephalus.
blood supply to the brain
right/left common carotid arteries
right/left vertebral arteries.
external carotid arteries
supply face and scalp with blood
vertebro-basilar arterial system
back of brain
supplies vital brain structures (brain stem, occipital lobes, cerebellum) with blood, oxygen and nutrients
Circle of Willis
found central base of brain
a circle of communicating arteries - carotid and verterbrobasilar
other arteries arise from this and travel to all parts of the brain
anterior cerebral artery (ACA)
extends upward and forward from the internal carotid artery
supplies the frontal lobes (logic, personality, and voluntary movement, especially of the legs)
what happens if there is stroke in one or both of the ACAs
weakness in the leg on the opposite side
if both ACAs are affected - mental symptoms e.g. akinetic mutism
middle cerebral artery (MCA)
largest branch of internal carotid artery
supplies parts of frontal/parietal/temporal lobes
often most obstructed artery in strokes
posterior cerebral artery (PCA)
stem from basilar artery (mostly)
supply temporal and occipital lobes
visual defects common if infarction occurs
lenticulostriate arteries
small, deep penetrating arteries - arise from anterior part of Circle of Willis(by MCA) and affect basal ganglia
lacunar strokes
arise when small lenticuloistriate arteries are occluded
v common - high incidence in patients with chronic hypertension
zymogen
an inactive substance which is converted into an enzyme when activated by another enzyme
e.g. all enzymes present in plasma of clotting cascade found in this form
final step of clotting cascade
thrombin causes fibrinogen to convert to fibrin
fibrin aggregates strengthen the platelet plug
common pathway
clotting cascade
thrombin formation
excitotoxicity
glutamate becomes toxic and causes damage to neurones due to over excitability
- intracellular calcium ion overload
- activation of NDMA receptors
calcium ion sinks
mitochondria
endoplasmic reticulum
overloading of sinks reduces ATP synthesis
formation of reactive oxygen species (ROS)
danger point reached
positive feedback exaggerates process
problems caused by raised calcium ion conc.
- increased glutamate release from nerve terminals
- activation of proteases and lipases (membrane damage)
- activation of nitric oxide synthase
- arachidonic acid release
activation of reactive oxygen species
generate free radicals
- damage membrane lipids, proteins and DNA
oxidative stress
over production of ROS which produce free radicals
- the body’s inability to detoxify them
- neurons susceptible to excitotoxic damage
e.g. hypoxia
kainic acid
glutamate receptor agonist(activator)
arachidonic acid
increases free radical production
inhibits glutamate uptake
reducing excitotoxicity
glutamate antagonists
calcium channel blocking drugs
free radical scavengers
ischaemia and excitotoxicity
ischaemia causes depolarisation of neurones and lots of glutamate release
NMDA receptors activated and Calcium accumulation occurs
alteplase
stroke drug
recombinant tissue plasminogen activator
helps restore blood flow by dispersing thrombus
given within 3 hours
2 types of stroke
ischaemic - lack of blood flow (atherosclerosis)
hemorrhagic - weakened blood vessel ruptures (less common)
Hypoxia Inducible Factor (HIF)
transcription factors that respond to decreases in available oxygen in the cellular environment
stent
small mesh tube used to treat narrow/weak arteries
stent surgery procedure
percutaneous coronary intervention (PCI)or angioplasty
restores blood flow in blocked arteries
supports inner wall of artery
drug-eluting stents can prevent arteries from becoming blocked again
hypertension
high blood pressure
140/90 mmHg
VCAM-1
vascular cell adhesion molecule
produced by endothelial cells after damage has occurred
cause monocytes and T-lymphocytes to adhere(using cytokines) to endothelium as part of inflammatory response
oxidation of LDLs
occurs due to exposure to nitric oxide, macrophages, and some enzymes e.g. lipoxygenase
macrophages take them up and become foam cells
fatty streaks
the first signs of atherosclerosis that are visible without magnification
consist of lipid-containing foam cells in the arterial wall just beneath the endothelium
commonly occur in aorta/coronary arteries of 20/30yr olds
can form atherosclerotic plaques
T-lymphocytes in the intima
secrete cytokines
- induce smooth muscle cells to migrate from the media to the intima
smooth muscle cells proliferate due to growth factors and accumulate in intima
ruptured plaques
trigger acute thrombosis (activate platelets and clotting cascade)
blood gas test
tests oxygen levels in your blood
tests your blood pH - too acidic = acidosis or too alkaline/basic =alkalosis
sample collecting for blood gas test
arterial blood used
Allen test checks enough wrist circulation for sample
where is the respiratory centre found
brain stem (medulla oblongata and pons)
function of respiratory centre
control the rate and depth of respiratory movements of the diaphragm and other respiratory muscles
what chemoreceptors are involved with the respiratory centre
central chemoreceptors:
- found on the ventrolateral surface of medulla oblongata - detect changes in the pH of spinal fluid
what can desensitise the central chemoreceptors
chronic hypoxia (oxygen deficiency) and increased carbon dioxide
oedema
excess fluid retention tissues/cavities
can cause swollen ankles
importance of circle of willis
provides multiple paths for oxygenated blood to supply the brain
allows brain function to continue if one supplier is constricted
myocardial infarction (MI)
heart attack
where are the subunits of HIF-1 found
HIF-a in cytoplasm - gets hydroxylated in normoxia
HIF-B in nucleus
dimerisation of HIF-a and HIF- causes transcription
atheroma
accumulation of atherosclerotic plaque
4 steps of plaque formation
1 - endothelial dysfunction - formation of foam cells
2 - stable plaque formation - fibrous cap formation
3- T-cell activation - pro-inflammatory cytokines produced
4 - thrombus formation - extrinsic clotting cascade
step 1 of plaque formation
endothelial dysfunction
- monocytes attach to endothelium via VCAM-1 receptors
- monocytes converted to macrophages in intima
- uptake of modified LDLs
- macrophages oxidise LDLs and become foam cells
- foam cells are what cause the fatty streaks
step 2 - stable plaque formation
- foam cells accumulate in intima
- vascular smooth muscle cells migrate from the intima to epithelium
- produce collagen and proliferate to form fibrous cap
T cell activation in atherosclerotic plaque formation
Th1 and Th2 recruited to break down fibrous cap
MMPs produced by foam cells
pro inflammatory cytokines produced
4th step of plaque formation
- thrombus formation
fibrous cap broken down endothelium becomes exposed tissue factor released - extrinsic clotting cascade binds to factor VII factor VIIa
3 cardiac biomarkers
cardiac troponins (Tni and Tnt)
creatine kinase MB
myoglobin
cardiac troponins
cardiac biomarker i and t correlate to severity of infarction detected after 12hours of symptoms long persistence - up to 12 days high specificity high sensitivity
creatine kinase MB
cardiac biomarker enzyme peaks 24 hours after symptoms lower sensitivty than troponins only used when troponin not available
myoglobin
cardiac biomarker
released quickly after onset of symptoms
not specific
high levels seen when any muscle tissue is damaged
CRP used to predict thrombotic events
found in serum or plasma as a result of inflammatory response
ischaemic stroke
when a blood blot blocks a blood vessel in the brain
narrowing/stenosis of brain blood vessel
most common type of stroke
causes oxygen deprivation and reduced blood flow
2 types of ischaemic stroke
thrombotic
embolic
embolic stroke
type of ischaemic stroke
blood clot develops elsewhere then travels in the blood to the brain
important risk factor for ischaemic stroke
high blood pressure
insoluble protein fibres that cause blood clot
fibrin
process of primary homeostasis
platelets forming network
endothelium of blood vessel damaged
connective tissue exposed
platelets adhere to and form a plug
seal reinforced by fibrin clot
clotting factors
proteins in the blood that control bleeding
respond in clotting cascade and strengthen platelet plug
where do clotting factors come from
platelets
damaged cells
plasma
tPA
tissue plasminogen activator
enzyme catalyses conversion of plasminogen to plasmin
used to treat embolic or thrombic stroke
what releases tPA
endothelium
junctions important in BBB
tight junctions
excitotoxicity
when neurons are damaged or killed by over-stimulation of glutamate receptors
why does hypoxia causes increased H+ conc
anaerobic respiration
lactic acid production
effect of reduced ATP on calcium storage
SERCA pump requires ATP
calcium can no longer be stored in ER
deleterous Ca2+ effects of excitotoxicity
NOS/ROS production - damage cell membrane and DNA
hydroxyl free radicals
how does excitotoxcity activate apoptosis
glutamate release causes increased intracellular Ca2+ conc
production of ROS/NOS
activation of caspases
apoptosis
ischaemic cascade
biochemical reactions in aerobic tissue induced by hypoxia following ischaemia
can ischaemic cascade continue even when blood flow returns
yes
effect of decreased blood supply to tissue
decreased oxygen
decreased ATP
anaerobic metabolism
effects of anaerobic metabolism in ischaemic cascade
lactic acidosis
disruption of acid-base balance
failure of neural system - regional brain dysfunction
which pumps break in ischaemic cascade
Na+ and Ca2+ pumps
overview of ischaemic cascade
blood supply reduced
anaerobic metabolism
pumps broken - intracelluar Na and Ca conc increased
damage
effects of increased intracellular Na+ conc. in ischaemic cascade
H2O influx
swelling
cytotoxic oedema
necrotic cell death
effects of increased Ca2+ conc in ischaemic cascade
production of free radicals and ROS - mitochondrial injury - release of apoptotic factors
excitotoxicity - glutamate accumulation
degrading enzymes - proteases/lipases - necrotic cell death
reperfusion injury
tissue damage caused when blood flow is restored following ischaemia/hypoxia
effects of return of blood supply
increased oxygen and ATP
reactivation of dysfunctional Na+ and Ca2+ pumps
production of ROS and free radicals
why does mitochondrial permeability increase in reperfusion injury
ROS/free radicals cause damage to plasma membrane macromolecules and ER
mitochondrial pore
why does intracellular Ca2+ increase in reperfusion injury
ROS causes damage to ER membrane
Ca2+ released
damage caused by Ca2+ in reperfusion injury
activation of degradative enzyme
endothelial injury - clots
pro-inflammtory cytokine release
apoptosis
brain stem connects
spinal cord and cerebellum
order of brain stem from top to bottom
thalamus
midbrain
pons
medulla
role of midbrain
regulates autonomic functions e.g. HR, BR
relays visual and auditory signals
where in the brain stem controls eye movements
midbrain
role of pons
transmission of signals from cerebrum to cerebellum
controls balance and posture
regulation of breathing
regulation of deep sleep
role of medulla
involuntary reflexes e..g sneezing, coughing, vomiting
autonomic centres e..g control of BP
how many cranial nerves come from the brainstem
10 out of 12
where is respiratory centre found
pons and medulla oblongata
input to respiratory centre
neural, chemical and hormonal signals
e..g peripheral chemoreceptors and central chemoreceptors
function of respiratory centre
control rate and depth of respiratory movements of diaphragm and other respiratory muscles
what is known as the pacemaker of the lungs
respiratory centre in the pons and medulla
3 effects of the respiratory centre
1 - altered inspiration-expiration rhythm
2 - altered magnitude of ventilation
3 - modified respiratory activity e.g. coughing/speech
increased arterial PCO2 causes
decreased blood pH
what recognsies blood pH
peripheral chemoreceptors
effect of ventilation on blood PCO2
increased ventilation means more CO2 exhaled
blood pH increases
peripheral chemoreceptors
sensory extensions of peripheral nervous system into blood vessels
detect changes in chemical concentrattions
where are peripheral chemoreceptors found
blood
carotid bodies
aortic bodies
function of peripheral chemoreceptors
detect chemical changes and send info to respiratory centre:
- decrease in PO2
- increase in PCO2
- decrease in arterial blood pH
what do peripheral chemoreceptors detect
- decrease in blood PO2
- increase in blood PCO2
- decrease in arterial blood pH
how do signals detected from peripheral chemoreceptors in aortic arch get to RC
via vagus nerve
how do signals detected in carotid bodies get to RC
via glossopharyngeal nerve
where are central chemoreceptors found
ventrolateral medullary surfaces near the respiratory centre
in the brainstem
between cranial nerves 9 and 10
function of central chemoreceptors
detect pH of CSF
decreased pH means too much CO2
can H+ diffuse across BBB
no
when CO2 crosses BBB
converted into H+ and HCO3-
decreases pH of csf
detected by medullary chemoreceptor
communicates to inspiratory respiratory centre
2 types of respiratory centre
dorsal inspiratory
ventral expiratory
dorsal expiratory respiratory centre
always active
ventral expiratory centre
active breathing
acid-base balance
regulation of blood pH to maintain pH between 7.35 and 7.45
acidosis
when blood pH<7.35
causes depression of CNS, coma
alkalosis
blood pH<7.45
over-excitability of CNS causes neurons to fire without stimuli
how does the kidney regulate acid-base balance
addition or secretion of bicarbonate ions (HCO3-)
where is HCO3- reabsorbed
at the PCT along with H+ at the Na+/H+ pump
overview effect of hypoxia
activates angiogenic switch to icnrease blood supply by increasing HIF-1a
role of HIF-1a in hypoxia
activates transcription of genes involved in VEGF
HIF-1a mechanism in hypoxia
no O2 so no hydroxylation
HIF-1a not degraded so translocates to nucleus
HIF-1a forms a dimer with HIF-beta
binds to HRE to cause transcription
HIF-1a mechanism in normoxia
prolyl hydroxylase enzymes add -OH group to HIF-1a
attracts E3 ub ligase of polyubiquitin tail
ub targets HIF to proteosome
degraded
HRE
hypoxia response elements
arterial blood gas analysis
shows imbalance of O2, CO2 or pH in the blood
O2 saturation can also be calculated
blood O2 saturation
amount of O2 bound to haemaglobin
normal blood pH
7.35-7.45
normal blood PO2
80-100 mmHg
normal blood PCO2
35-45 mmHg
normal blood O2 saturation
95-100%
normal blood bicarbonate conc
22-26
where do you take blood samples for arterial blood gas analysis
from the radial artery in the wrist
why is the wrist radial artery good for sample collection
easily accessible
blood flow easily controlled
where does 70% of bicarbonate reabsorption take place
PCT
desribe how bicarbonate is reabsorbed from the PCT into the blood
Na+/H+ exchnage pump
