ila Flashcards
5 stages of atherosclerosis
fatty streak intermediate lesion fibrous cap covered plaque rupture plaque erosion
endothelial barrier damaged by what
lipids - LDL cholesterol smoking toxins - free radical - CO - nicotine hypertension
atherosclerosis occurs where in the vessel
intima of arteries
what attracts monocytes to the fatty streak
LDL cholesterol is oxidised and modified which send cytokines out
what are foam cells
lipid laden macrophages (full of LDL cholesterol) that die full
what cells are in a fatty streak
t cells
foam cells
LDL cholesterol
what cells are in an intermediate lesion
t cells foam cells LDL cholesterol platelets smooth muscle cells pools of extracellular lipid
where do smooth muscle cells migrate from into intermediate lesion of atherosclerotic plaque
tunica media
what is the positive feedback loop in athergenesis
foam cells release cytokines (interleukin 1, 6, CRP) to attract more monocytes (that become macrophage foam cells) and T cells
what is the fibrous cap of plaque made of and where does it come from
smooth muscle cells secrete collagen and elastin
what do smooth muscle cells produce in atherogenesis
collagen
elastin
– these for fibrous cap
calcium
– stiffens plaque
and what stage in atherogenesis does angiogenesis occur
fibrous cap covered stage
what makes up the fibrous cap stage of atheroma
t cells foam cells LDL cholesterol / pools of extracellular lipid calcium platelets smooth muscle cells angiogenesis connective tissue : elastin and collagen necrotic core (as it gets big!)
race associated with atherosclerosis
south asian
white
gender associated with atherosclerosis
male
name a condition that increases risk of atherosclerosis
diabetes (type 2>1)
hypertension
hyperlipidema
obesity
why does high glucose increase risk of atherosclerosis
blood slowed
increase in free radicals
LDL modified –> inflammation
diabetes
why does high cholesterol increase risk of atherosclerosis
damages endothelium
more LDL into intima
pro inflammatory when oxidised in fatty streak
hypercoagulation
why does smoking increase risk of atherosclerosis
CO, nictotine, free radicals are toxins that damage the endothelium
increases LDL
hypercoagulation
why is low activity arisk factor for atheroma
slows blood
more LDL in HDL/LDL balance
higher BP
higher fat
endartectomy =
plaque removal
angioplasty
stent
atheroma pharmocological treatment
statins- reduce cholest
antihypertensives
anticoagulants/antiplatelets
diabetes medication
how does allergen cause mast cell activation
immunological: allergen interacts with B cells b cells --> antibodies igE ig E attaches to mast cells/ basophils mast cells activated
non-immunological:
antigen on trigger cell binds directly to mast cell
mast cell activated
what are the mediators of allergic response / allergen attack
mast cells
what happens when mast cells activated
mast cells release cytokines and inflammatory mediators
so..
wbc recruited histamine released (from mast cells/basophils)
histamine effect
bronchial smooth muscle contraction
vasodilation
vascular permability rises – liquid leaks from vessels
mast cells vs basophils
mast cells = mature basophils
proteolytic trigger for anaphylaxis =
allergen can cross skin and mucosal barriers
aerodynamic trigger for anaphylaxis=
trigger can get into nasal and broncial mucosa
during anaphylaxis, what causes inflammatory cells to infilatrate
neutrophil and eosinophil chemotactic factors
which of the anaphylaxis mediators are preformed vs newly formed
preformed = HENS
histamine,
eosinophil and neutrophil chemotactic factors
serotonin
newly formed: PT
prostaglandins and thromboxanes
what is the role of prostaglandins and thromboxanes
platelet activator factor
what causes the sob, wheeze, shallow breaths of anaphylaxis?
histamine
- bronchoconstriction of smooth muscle
- vasodilation and vascular permeability –> swelling of throat and tongue
what causes the low BP and light headed , confusion, collapsing symptoms of anaphylaxis
histamine
-vasodilation and leaky vessels (increase permeability)
what causes the rash in anaphylaxis
histamine
- redness due to vasodilation
what causes the tachycardia /arrythmia in anaphylaxis
histamine
- due to vasodilation and increased vascualr permability, reduced perfusion –> abdominal cramps, vomiting
- heart works harder to compensate for reduced perfusion – baroreceptors
- histamine increases heart rate
if a patient with anaphylaxis is having breathing problems, how should they be positioned
sat upright
if a patient with anaphylaxis is unconcious, how should they be postioned
recovery position
if a patient with anaphylaxis has low bP how should they be
lying flat - feet raised
after ABCDE, patient positioning and trigger removal what is the next key step for anaphylaxis treatment
and how much
adrenaline
IM 500 μg microgrmas
repear dose every 5 mins if shock persists
action of adrenaline
on alpha adrenoreceptor
(how does this affect heart)
- peripheral vasoconstriction, vascular resistance
- BP increases
- coronary perfusion increases
action of adrenaline on beta 2 adrenoreceptors
- dilates airways
- reduces oedema (less leaky vessels
action of adrenaline on beta 1 adrenoreceptors
- increases HR (chonotropic)
- increases force of contraction (inotropic)
general action of adrenaline with both beta adrenoreceptors
suppresses histamine and other inflammatory mediator release
other treatment of anaphylaxis
antihistamine
steroids
oxygen (may be hypoxic)
IV fluid (may be hypotensive)
name an antihistamine
chlorfemine
how do steroids act against anaphylaxis (by doing what specifically)
suppress immune response: suppress prostaglandin and leukotryin mediators
how can you confirm the patient’s condition is anaphylaxis
blood test
- rapid increase in tryptase = enzyme released from mast cells in any immune response)
- too early/ late may give false negative
- histamine levels
- take multiple samples, spread by few hours (and compare to baseline)
antibody associated with anaphylaxis
igE
histamine effect on liver
stimulates glycogenolysis
histamine effect on fat
triggers lipolysis
protein binding property of a drug=
allows drug to be carried by a protein (eg albumin) in blood to destination
- so lower plasma/unbound conc
- there is competition for binding
effect of having high unbound conc of drug?
effect increases, potentially can be toxic
does bound or unbound drug cross the membrane
unbound
lipid soluble property of a drug =
high lipophlicity = more lipid soluble
- drug can be absorbed in gut more easily
- drug can cross biphosphate lipid membrane from blood into cells/tissues mostly passively
- so more potent and more fast-acting
what kind of drug molecules are able to cross the blood brain barrier
unbound
lipid soluble
unionised
distribution of a drug
low distribution = high proportion at the effect site (and little elsewhere)
how does a drug distribute around the body (order)
and how does this relate to why an additional booster of drug may be given
first to highly perfused areas (brain, lungs, liver). then gradually to less perfused areas too (muscle). this lowers the plasma concetration and so concentration distrubuted to highly perfused areas decreases (inc brain- which is where we want for anaesthetic for eg)
- so booster given to boost brain amount- to keep patient asleep
agonist
binds to receptor to activate / stimulate it to obtain a response
inverse agonist
something that biinds to a receptor to activate it but has the opposite action/effect of the agonist
antagonist
reduced the effect of an agonist by reducing/removing stimulus and thus response
- competitive and non-competitive antagonists
competitive antagonist
binds to the same (orthosteric) site as agonist does. this means the agonist is unable to bind.
can be reversible (surmountable) or irreversible (insurmountable)
non competitive antagonist
binds to a different (allosteric) site as the agonist does. this causes a shape change that means the agonist can no longer bind.
only irreversible (insurmountable)
orthosteric vs allosteric binding sites
same vs different binding sites
described compet/noncompet inhibitors to an agonist
different targets of drugs
receptors
- ligand gated ion channels( ligand binds to ion channel to open it)
- g protein couples receptors (ligand binds to recptor on cell surface to activate g protein on inside –> signally cascade)
- kinase linked receptors (ligand in active site causes conformational change that allows enzme activity inside target cell)
- cytosolic/nuclear receptors (ligand enters cell (imported) and binds to DNA, switching on transcription for a specific gene)
enzymes
transporters
ion channels
enzyme drug targets
drug binds to enzyme to decrease its activity
receptor drug targets
lignad binds to recpetors to cause response within target cell
bioavailability
fraction of drug absorbed into blood/ systemic circulation
bioavailability of morphone IV/ IM/ oral
100% IV
nearly 100% IM – goes from muscle directly to blood
50% oral
why is the bioavailability of oral drugs what it is?
first pass :
(gut)
liver:
elimination
first pass effect on bioavailability
not all oral drug absorbed due to:
intestine lumen - digestive enzymes metabolise drugs + colonic bacteria
intestinal wall - contains enzymes that transport drugs back to lumen
surgery may reduce surface area of absorption sites
so some drug excreted in faeces
sometimes liver is counted within this (another flashcard)
elimination(liver) effect on bioavailability
gut absorption –> blood –> portal vein –> liver –> metabolised aka eliminated (splanchnic circulation)
IV: drug passes elsewhere before reaching liver
converting IV dose to oral (morphine)
2x
to compensate
effect of reduced renal function on morphine
kidney cant excrete so more in system
- more potent
- smaller dose given for renal patients
name 5 ideal qualities in a drug
- low protein binding
- high ionising proporion
- lipophilic
- no side effects
- cheap
- long lasting shelf life
- stable in solution
- rapid clearance and no active metabolites (= cant cause damage once metabolised, so less renal failure)
name 3 signs and 3 symptomson arterial thrombosis
- perishingly cold
- pulselessness
- pallor
- paralysis
- pain - in muscle (+ cramps)
- paraethesia numbness/tingling -
venous thrombosis signs/symptoms
red hot swollen increased pulse pain, cramps stiffness (looks like inflammation)
virchows triad
= 3 factors that contribute to thrombus development (pathologically)
- stasis of blood
- endothelial damage/injury
- hypercoagulability
name 3 causes of blood stasis
- AF (blood in atria)
- pregnancy
- low mobility
- sickle cell anaemia
- venous insufficiency - valves not working
name 3 causes of endothelial injury
- smoking
- hyperlipidimia
- hypertension
(same as atherosclerosis causes) - atherosclerosis?
name 5 causes of hypercoaguability and state whether they are inherited or aquired
inherited:
- haemophilia = unable to make coagulation factors 8 or 9
- coagulation factor deficiecy
aquired:
- malignancy/cancer
- dehydration
- oral contraceptive pill / post pregnancy / HRT (increase in prothrombin/ fibrinogen)
- infection
- heparin-induced thromocytopenia (isnt this the opposite of thrombogenesis?)
also have since thought - polycythaemia (inc but not only rubra vera), DIC
undisturbed healthy endothelium prevents thrombus formation by:
producing prostacyclin
- vasodilation
- inhibits platelet activation
producing NO
- vasodilation
- inhibits platelet aggregation
what in the endothelium is exposed with endothelial injury
what part do these play
what is released from damaged endothelium
collagen and von willebrand factor
collagen: releases endothelin 1 –> vasoconstriction
von Willebrand: platelets bind to vW at glycoprotein 1b
also – tissue factor is released
platelets release what 3 things, and what is their effect
how do they release them
ATP and ADP - platelet amplification
thrombin- platelet activation
each have positive feedback loops
released in secretory vesicles (Exocytosis)
what is activated platelet called
pseudopodia.
it is spiculated
it has more gcoprotein receptors exposed
fibrinogen binds to what
effect
glycoprotein receptors on activated platelets
effect= platelet aggregation (clump together)
what do platelets release after platelet aggregation
effect
thromboxin A2
-> vasoconstriction and platelet activation (pos feedback)
tissue factor effect
extrinsic pathway of coagulation cascade : tissue factor causes
prothrombin –> thrombin. thrombin causes fibrinogen to fibrin.
fibrin = insoluble
what is clot made of
insoluble fibrin + aggregated activated platelets
which gender is at higher risk of thrombosis
men
well’s score =
likelihood of getting a DVT (/PE) based on symptoms / risk factors - calf/whole leg swelling - superficial veins present - pitting oedema - local tenderness - paresis - paralysis - cancer - immobilisation/surgery - previous DVT - other diagnoses unlikely
test for DVT
D dimer elevation
- this is a degradation product of fibrin (degraded by plasmin)
positive result (elevation) isnt definitive (not specific - malignancy, pregnancy, operations)
but negative result (no elevation) can rule DVT out!!
ultrasound
DVT treatment
+ explain action
heparin
- indirect thrombin inhibitor (binds to antithrombin which binds to factor 10a and prevents thrombin functioning in the cascade)
- increases prothrombin time
warfarin
- antagonist to vitamin k so stops blood clotting factors (1972) as these are activated by vit k
- increases prothrombin time
what is heparin reversed by
protamine
what is warfarin reversed by
vitamin k
warfarin half life
36h = long
so is hard to reverse (Wait for half life + wait for vit k to activate factors again before they can work)
INR
stands for
what is normal
international normalized ratio
measure of blood clotting
usually between 2 and 3
measure of blood clotting
INR prothrombin time (differs place to place)
DVT complications
- PE
- sudden, severe
- post thrombotic syndrome
- long term affects due to scarring and damage to veins/valves or due to some blockage remaining. causes impaired venous return
name 5 PE symtpoms
1 SOB/ trouble breathing/ 2 rapid breathing 3 chest pain 4 coughing, maybe blood 5 fainting/light headed 6 sweating/clammy 7 tachy 8 blueish 9 anxiety/restless
name 5 sympyoms of post thrombotic syndrome
1 pain /ache/ cramping 2 heaviness 3 swelling, oedema 4 parasthesia - itching/pins needles 5 redness /discoluration 6 ulcers 7 mobilisation is a releiving factor
what is chronic venous insufficiency
the name fro post thrombotic syndrome when there has never been a DVT
AKI diagnosis criteria
increase in serum creatinine of 26+ μmol/L within 48h
increase in serum creatinine of 1.5+ xbaseline from within past 7d
urine volume less than 0.5mL/kg/h for 6h
AKI severity staging
stage 1 : 1.5-1.9 xbaseline serum creatinine
stage 2 : 2.2.9 xbaseline serum creatinine
stage 3 : 3+ x baseline serum creatinine or renal replacement therapy
if you have 1 kidney can you still have normal kidney function?
yes
prerenal causes of AKI pathophysiology
decrease in effective blood flow to kidney to decreased GFR
kidneys recieve 20-25% of cardiac output so any failure of circulating blood volume / intra renal circulation has profound effect on renal perfusion
prerenal causes list
volume depletion- hypovolemia
- haemorrhage
- severe vom/diar
- burns
- over diuresis (renal fluid loss)
- peritonitis
edematous states
- HF
- hypotension
CV
- HF
- hypotension
- cardiogenic shock
- MI
- PE
systemic vasodilation
- liver cirrhosis
- ACE i / antihypertensives
- anaphylaxis
increased cascular resistance
- NSAIDs
- renal vasoconstriction / thrombosis / stensosi
- surgery
- anasthesia
severe infections/ sepsis
intrinsic AKI causes - glomerulus
- glomerulonephritis = inflammation of glomeruli / small vesselss causing them damage
intrinsic AKI causes!!!! - tubules
list
ISCHAEMIC - reduced blood flow so less oxygen/ nutrients/ ATP
- shock
- haemorrhage
- trauma
- bacteraemia
- pregnancy
- pancreatitis
NEPROTOXIC exogenous - antibiotics - contrast media - anasthetic - heavy metals - organic solvents - antineoplastic drugs endogenous - rhabdomyolysis = break down of damaged skeletal muscle = toxic to kidney - myoglobin - haemoglobin - uric acid
ATN- acute tubular necrosis = tubules damaged (normally by pre-renal damage)
intrinsic AKI causes - vascular pathophysiology
injury to intra renal vessels . this decreases renal perfusion and diminishes GFR
intrinsic AKI causes- vascular
list
large vessels
- renal artery stenosis/ thrombosis (bilateral)
small vessels
- vasculitis (inflammation + scarring to blood vessels –> stiff, weak, narrow)
- hypertension
- atherosclerotic/thrombotic emboli
intrinsic AKI causes -
interstitum
infections (bacterial/viral)
medications (antibiotics, diuretics, NSAIDs)
AIN - acute intersitial nephritis = inflammation of kidneys as allergic to certain drugs( eg NSAIDs) or an infection
post renal AKI causes pathophysiology
disease states downstream of kidney, often obstruction.
this increases tubular pressure and so decreases GFR. May also lead to impaired renal blood flow and inflammatory process (decreases GFR)
post renal AKI causes list
EXTRA RENAL OBSTRUCTION prostate hypertrophy (BPH/cancer) imporperly placed catheter bladder cancer cervical cancer retroperitoneal fibrosis
INTRA RENAL OBSTRUCION kidney stone (nephrolithilasis) obstructed urinary catheter bladder stones blood clots ureter cancer (bilateral)
nephrotic vs nephritic
NEPHROTIC (kideny disease) loss of protein - big proteinuria (but no blood) hypoalbuminemia peripheral oedema hyperlipidiaemia
NEPHRITIC (glomeruli inflammation)
loss of blood - haematuria - cola coloured urine
little proteinuria
oligurai
decreased blood volume causes what (RAAS)
kidney cells produce renin. this converts angiotensinogen to angiotensin 1. this is converted to angiotensin 2 by ACE (from lungs). angiotensin 2 causes
1) vasoconstriction
2) aldosterone production (adrenal cortex) - so tubules reabsorb more Na and water into blood
3) ADH (from hypothalamus) - so thirst increases and water is reabsorbed in kidney tubules and collecting duct (aqua porin 2)
increase in BP effect on HR
detected by baroreceptors (carotid sinus, aortic arch) –>
HR decreases
NSAID effect on kidneys
NSAIDS are toxic to kidneys, can induce AKI
NSAIDs inhibit COX enzyme
COX enxyme synthesises prostaglandins
prostaglandins cause afferent arteriolar vasodialtion (and diminished vascular resisitance)
so NSAIDs –> afferent arteriole vasoconstriction, higher vascualr resistance, reduced renal perfusion, slower GFR,
AKI ECG
hyperkalemia so tall tented T waves loss of P waves - flatteneed pathological Q wave wide QRS may then cause bradycardia
K normal range
3.5-5.4
how to correct for hyperkalemia
insulin
- drives K into cells using sodium- potassium ATPases
- insulin also drives glucose into cells
SO
need to give dextrose (glucose) with it to counter this
how much dextrose given per insulin
10 units of insulin in 50 ml of 50% dextrose over 10-15 mins
TIA vs stroke
TIA symptoms resolves spontaneously, within 24h
this is because the clot dissolves/moves on on its own
amaurosis fugax
- =
- cause
fleeting sudden onset loss of vision in one or both eyes. painless.
lots of causes but for TIA/stroke is atherosclerosis or thromboembolism in
- -internal carotid artery
- -opthalmic artery
- -retinal artery
- leading to temporary retinal hypoxia
what is the name for transient visual disturbance of loss in one or both eyes
amaurosis fugax
stroke relation to AF
atrial fibrillation –> rapid, irregular palpitations , uncoordinated atrial contraction
–> blood collects and pools –> stasis–> clot formation –> stroke
stroke affecting lower limb is clot where?
anterior cerebral artery
stroke affecting upper limb/ face is clot where?
middle cerebral artery
cause of increased intracranial pressure in haemorrhagic stroke (2)
blood itself –> takes up space –> increased ICP
+
blood comes into contact with cerebral neurons → inflammatory response→ swelling and oedema → increased intracranial pressure
cause of increased intracranial pressure in ischaemic stroke
ischaemic/ necrosing tissue → inflammatory response → swelling and oedema → increased intracranial pressure
total anterior circulations stroke (TACS)
- where
- which arteries
- criteria
Large stroke in cortex
anterior or middle cerebral arteries
Criteria: all of the following Unilateral weakness and/or sensory deficit of face/limbs Homonymous hemianopia (losing same side of vision in both eyes) Higher cerebral dysfunction
Partial anterior circulation stroke (PACS)
- where
- which arteries
- criteria
In cortex
Anterior or middle cerebral arteries
Criteria: 2 or the following Unilateral weakness and/or sensory deficit of face/limbs Homonymous hemianopia (losing same side of vision in both eyes) Higher cerebral dysfunction
Lacunar stroke (LACS)
- where
- which arteries
- criteria
Subcortical
In small deep perforating arteries – internal capsule, midbrain
Criteria
Pure motor, sensory or sensorimotor (2 of face, arm, leg)
Ataxic hemiparesis (weakness + clumsiness + lack of control - affects leg more than arm)
Posterior circulation stroke (POCS)
- where
- which arteries
- criteria
Posterior cerebral artery (Cortical), basilar artery + branches (cerebellum) vertebral artery (brainstem)
Criteria:
Cerebellar or brainstem syndrome
Loss of consciousness
Isolated homonymous hemianopia
what is the affect of increased intracranial pressure
CSF, venous system, arteries == squashed!!
Cerebral perfusion pressure in the arteries is not high enough to perfuse the brain properly
ICP> mean arterial blood pressure (perfusion pressure)… arteriole compresses
Brain not perfused → brain more ischaemic
what symptoms do you see with increased intracranial pressure?
what is this reflex called?
hypertension
bradycardia
irregular breathing (dyspnea–> apnea)
= cushings reflex
and papilloedema
what is the explanation between the symptoms of increased intracranial pressure
cerebral ischemia → sympathetic (fight/flight)
- Stimulatees alpha 1 adrenergic receptors = vasoconstriction → hypertension
- -Stimulates beta 1 receptors→ increased heart rate (Tachy)
hypertension –> Stimulates baroreceptor in aortic arch → parasympathetic → decrease heart rate (brady) via m2 receptors
Hypertension → presses on respiratory centre on brain stem→ irregular breathing
when you see cushing reflex , what does this indicate
increased intracranial pressure
this is an acute emergency
brain herniation/ death is imminent
