Overview Flashcards
EG. FLASHCARDS FOR NO LECTURE EDRF Effect of NO on smooth muscle Colour of nitrous acid Nitrous acid - formula Nitric oxide - formula Entonox - what is this and it's use? What is formed when NO is oxidised How does NO differ from nitrogen dioxide (it is a free radical)HAPE
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Define endothelium
Thin (single) layer of simple squamous epithelium
Composed of endothelial cells
Define EDRF
Endothelium derived relaxing factor aka. NO
Causes vascular smooth muscle to relax
Function of NO in blood vessels
Causes vascular smooth muscle to relax - vasodilation
Appearance of nitrous acid (HNO2)
This is colourless (this is NOT NO)
Nitrous oxide vs. nitric oxide - chemical formula
Nitrous oxide - N2O
Nitric oxide - NO
Define Entonox
Anaesthesia gas
Composed of 50% NO and 50% O2
Use of entonox
Pre-hospital care
Childbirth
Emergency medicine
Define free radical
Molecule with an unpaired electron in it’s outer valence/reactive shell
Free radicals - oxidising or reducing agents?
Free radicals look to take electrons - oxidising agents
Effect of NO being free radical?
NO is very unstable (but much more stable than other free radicals)
When is NO stable?
In body tissues where the PO2 is lower than 50mmHg
Reaction of NO with hydroxyl (OH) radical
NO + OH –> HNO2
Enzyme that synthesises NO?
Nitric oxide synthase (NOS)
Function of NOS
L-arginine + 1/2 O2 –> citrulline + NO (+ H+ + e-)
Three isoforms of NOS
1 - bNOS - brain
2 - iNOS - induced (not calcium dependent)
3 - eNOS - endothelial
Location of bNOS
Central and peripheral neuronal cells
Calcium dependent
Location of iNOS
Found in macrophages (also most nucleated cells)
Induced - not calcium dependent
Location of eNOS
Vascular endothelial cells
Calcium dependent
What can induce production of iNOS?
Inducible in the presence of inflammatory cytokines
How is NO synthesis regulated in the vascular endothelium?
Main regulation is via movement of blood past the endothelial wall - sheer stress opens calcium channels - calcium enters the endothelial cells - production of eNOS
Also via binding of ACh to the ACh recepors on the endothelium allows the entry of calcium
Pathway of eNOS activation in the vascular endothelium
Calcium - activates calmodulin
Calmodulin activates eNOS
Three cofactors required for synthesis of eNOS
Biopterin H4
FMN
FAD
Composition responsible for the production of activated eNOS from inactivated eNOS
Ca2+ + calmodulin
What does NO activate in smooth muscle cells?
Guanylate cyclase
What is the mechanism of action of guanylate cyclase?
Conversion of guanosine triphosphate in the smooth muscle to cyclic guanosine monophosphate (cGMP)
Effect of cGMP on the vascular smooth muscle?
cGMP - relaxation of vascular smooth muscle - vasodilation
Mechanism of action of NO causing smooth muscle relaxation
NO diffuses from endothelium to smooth muscle cells
NO activates guanylate cyclase
Guanylate cyclase converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP)
cGMP causes smooth muscle relaxation
Effect of vasodilation?
Vasodilation increases local blood flow
This maintains low peripheral vascular resistance and a normal blood pressure
Effect of whole body inhibition of eNOS by drug?
This causes increased blood pressure esp. pulmonary arterial pressure
Two antagonisers of NO i.e. vasoconstrictors of the blood vessels?
Noradrenaline
Angiotensin
Damage to the NO system results in what complication?
Hypertension
Effect on blood flow to exercising muscles?
Blood flow increases over ten fold
Effect on blood flow to heart during exercise
Blood flow increases up to three fold
Effect on blood flow to kidney during exercise
Blood flow decreases by nearly half
Effect on blood flow to skin during exercise
Blood flow increases nearly four fold
Effect on blood flow to brain during exercise
Blood flow to the brain does not change
Receptors causing vasoconstriction of arterioles
Alpha-1 receptors
What causes the vasodilation to exercising muscles?
Chemical factors - NO and adenosine
Effect of sympathetic nervous system on arterioles
Vasoconstriction - NO and adenosine overcome this
How is NO production increased during exercise?
Increased local blood flow - increased sheering forces and opening of calcium channels - increased activation of eNOS - increased production of NO
How is NO produced in anaerobic metabolism?
Depletion of ATP produces lactate which lowers pH
Lowered pH produces nitrous acid HNO2 - can form NO
Two effects of exercise on the coronary arterioles and cause
Diameter of the coronary arterioles increases
Number of open arterioles (collaterals) increases
Caused by NO
Cause of angina during exercise
If atheromatous plaque is present - vessel cannot dilate - ischaemia and angina
Usage of NO for treatment of angina is given in the form of?
GTN - glycerin trinitrate
Two areas where NO has an effect?
Smooth muscle (around blood vessels) In the blood
Effect of NO in RBCs
NO reacts with oxyhaemoglobin to produce nitrosohaemoglobin
Effect of nitrosohaemoglobin
This displaces oxygen - increases delivery of oxygen to hypoxic tissue
Why does local hypoxia occur during exercise?
Occurs in muscles at the start of exercise
More ATP used than produced
Define persistent pulmonary hypertension of the newborn (PPHN)
Reduced pulmonary arterial resistance with the first breath does not occur - lungs are not properly perfused
Addition of NO to the inspired gas
Effect of low ventilation on NO levels and why?
Low ventilation causes low NO production because O2 is required for the production
SO low ventilation equates to low perfusion
Effect of exercise on the pulmonary circulation
Exercise causes increased CO - causes increased blood flow - the pulmonary arterial resistance decreases to maintain the BP
Receptors causing relaxation of bronchial smooth muscle
Beta 2 receptors
Effect of reduced NO in the brain
Reduced NO - reduces the cerebral blood flow
Resting blood flow through the brain
50ml/min/100gm
Blood loss causing reversible brain damage
Blood flow falls to half of normal - around 25
Blood loss causing irreversible brain damage
Blood flow falls to one quarter of normal - around 10-15
Function of basal release of NO
Prevention of leucocytes (anti-inflammatory) and platelets (anti-thrombotic) from adhering to the surface of the endothelium
Four functions of NO
Direct vasodilation
Anti-thrombotic effect
Anti-inflammatory effect
Anti-proliferative effect
How can iNOS lead to shock?
Overproduction of NO from macrophages can result in septic shock - uncontrollable vasodilation
Equation for blood pressure
BP = CO x SVR
Define cardiac output
Blood flow produced by the heart per minute
Define systolic BP
Maximum BP during ventricular contraction
Define diastolic BP
Minimum level of BP measured between the contractions of the heart
Eight components that can effect BP
Activity Temperature Diet Emotional state Posture Physical state Medication usage Ethnic background
Normal BP
120/80
Hypotension level
<90/60
Define postural hypotension
When the systolic decreases by 20 or the diastolic decreases by 10 when standing
Three causes of postural hypertension
Old age
Diabetes
Drugs
CNS effects of hypotension x4
Dizziness
Impaired cognition
Lethargy and fatigue
Visual disturbances (hypoperfusion of brain)
Muscle effects of hypotension x2
Paracervical backache (upper back) General fatigue
Boundary for hypertension
140/90 persistently
Range of prehypertensio
130-139/85-89
Range of prehypertensio
130-139/85-89
Are prehypertensives candidates for drug therapy?
No - lifestyle modification
Isolated systolic hypertension
Systolic: >140
Diastolic: <90
Three lifestyle modifications to reduced BP
Weight loss
Increased physical activity
Limited alcohol consumption
What should be avoided prior to blood pressure measurements (x3) and for how long?
Caffeine
Exercise
Smoking
At least 30 minutes
Which BP increases with age?
Systolic
Four adverse effects of hypertension
Stroke
Coronary heart disease
Renal impairment
Peripheral vascular disease
Each 20/10mmHg increase in BP increases the risk of mortality by what rate? What age group is this prevalent in?
Doubles the risk
40-69 years
What is HOTT?
Hypertension Optimal Treatment Trial
What is HOTT?
Hypertension Optimal Treatment Trial
Results of HOTT - what did it tell us?
Lowest incidence of CV events when DBP maintained at 83
and maintained at <80 in diabetics
SO especially important to control hypertension in diabetics
Concentric hypertrophy
Thickened wall of the left ventricle
Decreased lumen diameter
Must increase the HR to maintain CO
Eccentric hypertrophy
Whole ventricle enlarges - enlarged heart is weaker
Effect of chronic hypertension on the heart
Results in concentric hypertrophy
SO then the HR increases
Effect of chronic hypertension on the eyes x3
Chronic hypertension damages the retina
Cotton wool spots
Silver wiring
Severe cases: swelling of the optic disc i.e. papilledema
Define pailledema
This is swelling of the optic disc of the eye
Primary hypertension cause
Idiopathic - genetic
90-95% of cases
Secondary hypertension cause x5
5% of cases
Renal disease Endocrine disease Coarctation of the aorta Iagtrogenic i.e. hormonal/oral contraception, NSAIDs Thyroid - hyper or hypo
Two systems to control BP
Neuronal - baroreceptors
Hormonal - RAAS
Location of baroreceptros
Carotid artery - carotid sinus
Aortic arch
These are mechanoreceptors
Timescale of the RAAS system to maintain BP
Maintenance of steady, long term pressure
Timescale of the RAAS system to maintain BP
Maintenance of steady, long term pressure
RAAS pathway
Angiotensinogen to angiotensin I via renin
Angiotensin I to angiotensin II via ACE
Effects of angiotensin II x3
Increased sympathetic action
Release of aldosterone
Increased secretion of ADH
Increased levels of what may be present in patients with hypertension? x2
Increased renin
Increased angiotensin II
Effect of hypertension on salt and water and why?
Excess salt retention - raised water levels causes change in osmotic pressure
Retention of water - raised ADH
Two key treatments in hypertension (non-pharmacological)
Dietary salt restriction
Diuretics
Normal sodium levels
Between 135 and 145mmol/L
Hyponatremia
Sodium levels <135mmol/L
Three symptoms of mild hyponatraemia
Loss of energy and fatigue
Confusion
Muscle weakness
Six symptoms of severe hyponatraemia
Nausea and vomiting Headache Spasms Restlessness and irritability Seizures Coma
Prevalence of hypertension in type II diabetics at age 45
40%
Prevalence fo hypertension in type II diabetics age 75
60%
BMI for obesity
> 30
Five factors that are raised in obese patients that can result in the onset of hypertension
Increased renal renin release
Increased angiotensin formation
Increased sodium retention
High levels of leptin - increased sympathetic vasoconstriction
Hyperinsulaemia - insulin induced hyperkalaemia
First line treatment for hypertension
Lifestyle changes - exercise, increased fruit and veg and decreased salt, reduced weight if obese
First line pharmacological treatment for hypertension
Thiazide diuretic
Name of thiazide diuretic used in the treatment of hypertension
Bendroflumethazide
Second and third line treatment of hypertension
Thiazide + beta blocker or ACE inhibitor
Angiotensin receptor blocker
Fourth line treatment of hypertension
Calcium channel blocker
Final line treatment of hypertension
Alpha blocker
First line pharmacological treatment for hypertensive diabetics
ACE inhibitors or angiotensin receptor blockers
Most important first line treatment for obese hypertensives
Exercise and try to lose weight
Therapeutic target for hypertensives
<140/85 in clinic
<130/80 at home
Therapeutic target for diabetic hypertensives
<140/80 in clinic
<130/75 at home
Define erythropoesis
Production of red blood cells
Sites of erythropoesis prior to brith
1-3 week - yolk sac and mesothelial layers of the placenta
6 week - liver and spleen
3 month - bone marrow as the bones form
0-5 years - site of erythropoiesis
Bone marrow of all bones
5-20/25 years site of erythropoiesis
Bone marrow of the long bones
25 years + site of erythropoesis
Bone marrow of membranous bones - vertebrae, sternum, ribs, cranial bones, ileum
Name the 5 membranous bones
Verterbae Sternum Cranium Ribs Ileum
Define myeloid tissue
Bone marrow
Red bone marrow function
Site of erythropoiesis
Yellow bone marrow function
Contains large amounts of fat droplets and cells
Stages of production of an erythrocyte
Haematopoetic stem cell Common myeloid progenitor cell (committed at this stage) Proerythroblast Early erythroblast Late erythroblast Erythroblast Normoblast Reticulocyte Erythrocyte
Cytoplasm of what cell stains blue?
Proerythroblast
How to recognise proerythroblast?
Bright blue rim of cytoplasm around blue nucleus
How to recognise early erythroblast?
Polychromatic i.e. many coloured nucleus
Cells that contain ribosomal RNA in them are?
Reticulocytes
Define diapedesis
Passing of the erythrocytes through pores in the capillary membranes from the bone marrow into the blood
Diameter of erythrocytes
7.8um
Volume of erythrocyte
90cu mm
Volume of RBC in microcytic anaemia
<79/80fl
Volume of RBC in macrocytic anaemia
> 100fl
Normal RBC count - general
Around 5 million per microlitre
Normal lifespan of RBC
120 days (+/- 30 days)
RBC count in men
5.2 x0.3x10^6
RBC count in women
4.7 x0.3x10^6
Component that controls erythropoiesis is?
EPO - erythropoietin
Production site of EPO
Fibroblasts in the kidney - at the proximal convoluted tubule
Glomus cells of the carotid body
Why is EPO only produced in these specific locations?
Oxygen levels here are not affected by exercises or BP changes - steady usage of oxygen
What are EPO secreting cells sensitive to?
Hypoxia
Hypoxia stimulates increased EPO release
Anaemia caused by kidney damage and why?
Kidney damage - reduced EPO production
This can cause microcytic anaemia
Charge on erythrocytes
Outside negative surface charge due to presence of glycoproteins - causes them to repel and not stick to each other
Define rouleaux
Clumping of erythrocytes caused by reduced charge on their surface
Cause of rouleaux x2
Inflammatory reactions Bacteria in the blood
Define ESR
Erythrocyte sedimentary rate
Significance of raised ERS
Non-specific marker for infection in the blood (due to formation of rouleaux)
Two reasons RBCs need ATP
Sodium pumps in the membrane
GLUT1 transporters to consume glucose
Metabolism of RBCs
Anaerobic glycolysis (and pentose phosphate pathway)
Name the four myeloid cells
M M Me Megacaryocyte Mast Cell Myeoblast Erythrocyte
Cells and site of removal of RBCs from the body
Removed via macrophages when passing through the spleen
Three signals indicating need for removal of RBCs
Cell surface antigens of old cells differ to that of young cells
Increased levels of methaemoglobin
RBCs become more rigid and trapped in splenic capillaries
Breakdown of haem via what enzymes
Haem to biliverdin via haemoxygenase
Biliverdin to bilirubin via biliverdin reductase
Colour of biliverdin
Green
Globin proteins are broken down into what?
Amino acids
Unconjugated bilirubin
When bilirubin is bound to albumin in the splenic macrophages and released into the blood
Conjugated bilirubin
Occurs in the liver
Bilirubin attaches to glucoronic acid via hepatocytes and is now more soluble
How is conjugated bilirubin excreted?
Converted to urobilnogen in the small intestine - passes out in faeces (10% in urine)
Site of haemoglobin to biliverdin
Spleen
Site of biliverdin to bilirubin
Liver
Site of bilirubin to urobilnogen
Small intestine
Acid that binds to bilirubin to form conjugated bilirubin
Glucoronic acid
Stercobilin
10% of urobilnogen converted to this - excreted in the urine
Define arteriosclerosis
Thickening of an arterial wall which then loses elasticity
Sclerosis - hardening
Most common form of ateriosclerosis
Athersclerosis
Three stages of atherosclerosis
Endothelial damage (and activation)
Uptake of modified LDLs, adhesion and infiltration of macrophages
Smooth muscle proliferation and formation of fibrous cap
Four functions of the endothelium
Vasomotor tone
Thrombosis - antithrombotic properties
Production of inflammatory factors
Production of cellular adhesion molecules (CAMs) - receptors for monocytes
Four causes of endothelial damage
Shear stress e.g. turbulent blood flow
Toxic damage e.g. free radicals
High levels of lipids
Viral or bacterial infection
Function of lipoproteins
Transportation of fat in the blood
Five types of lipoproteins
Chylomicrons VLDL LDL IDL HDL
LDL vs. HDL
LDL - bad - composed of mainly cholesterol
HDL - good - composed of mainly protein
Two ways in which LDLs can become modified
Oxidation
Glycation
Glycation of LDLs is prevalent in?
Diabetes mellitus - high glucose levels
Effect of oxidised LDL?
This can act to cause endothelial damage itself
Infiltration of macrophages occurs as?
Increased monocytes bind to CAM - crosses endothelium and transformed into macrophages
Define foam cells
Lipid laden macrophages
How are foam cells formed?
Macrophages pick up excess levels of modified LDL via scavenger receptor and grow larger and larger
LDL apolipoprotein B100
Apoliprotein B100 present on?
VLDL
IDL
LDL
Apoliprotein present on chylomicrons?
B48
Fatty streak of atheroma occurs in which layer of the artery?
Occurs in the tunica intima
Component causing smooth muscle proliferation in arteriosclerosis?
Platelet derived growth factor (PDGF)
Two cell types that release PDGF?
Endothelial cells
Macrophages
What are the two types of smooth muscle?
Resting - contractile
Proliferating - secretion of extracellular materials
What is broken down by the proliferating smooth muscles?
Internal elastic lamina
How is a thrombus formed by the smooth muscle cells?
Proliferating smooth muscle cells
Secretion of extracellular materials e.g. collagen
Collagen - platelets will stick to this and form a thrombus
Four common sites of atheroma formation
Carotid bifurcation
Aortic bifurcation
Lateral walls of the common iliac arteries
Coronary arteries
Unmodifiable risk factors for atheroma formation x3
Age
Sex
Family history
Modifiable risk factors for atheroma formation x5
Dyslipidaemia Smoking Hypertension DM Physical activity
Define dyslipidaemia
Elevated LDL/cholesterol levels
Desirable total cholesterol levels in adults
<200mg/dl
Desirable LDL and HDL levels in adults
LDL - <130
HDL - <40
Three emerging risk factors for the onset of atherosclerosis
Homocysteinaemia
Lipoprotein a
Infection
Three treatment options for atheroma formation
Modifiable risk factors
Plasma lipid reduction - statins
Polypill usage
What is contained in the polypill? x5
Statin
Three BP lowering drugs - thiazide, beta blocker, ACE inhibitor
Folic acid
Aspirin
Complications from atheroma formation x5
Coronary artery disease - MI/angina Peripheral vascular disease Stroke Aneurysm Renal artery stenosis
Surgical interventions for atherosclerosis x3
CABG
PCI
Stent
Arterial stent generally done in which artery?
Generally done via radial artery rather than the femoral artery
Two types of angina and causes
Stable - coronary artery disease
Unstable - acute myocardial infarction
Typical history of stable angina (from the patient)
Central chest pain comes on following exertion
Stops when exertion is ceased
Two main causes of angina
Decreased myocardial oxygen supply
Increased myocardial oxygen demand
Two causes of reduced myocardial oxygen supply
Coronary heart disease
Severe anaemia
Three causes of increased myocardial oxygen demand
Left ventricular hypertrophy
Right ventricular hypertrophy
Rapid tachyarrythrmias
Five indications for cardiac referral of a patient
New onset angina
Exclusion of angina in high risk individuals with atypical symptoms
Worsening angina in patient with previously stable symptoms
New or recurrent angina in patient with history of e.g. MI
Assessment of occupational fitness eg. airline pilots
Four methods for diagnosis of angina
Clinical assesment
Electropcardiography
LV wall motion analysis
Perfusion imaging
Diagnostic features for assessment of angina x6
HISTORY Character - tight Location - chest central Radiation - arms, throat, jaw Duration - 5-10 minutes at the most Provocation - exertion
ECG results of patient stable angina - resting vs. exercise ECG
Resting ECG - can be normal
Exercise ECG - abnormal
Exercise ECG - stable angina appearance
Planar or down-sloping ST depression
ST depression is indicative of what?
ST depression - indicates ischaemia
Main non-invasive investigation for angina
Exercise ECG
Functional imaging investigations for angina x3
Isotope perfusion imaging
MR perfusion imaging
Dobutamine stress echo
Drugs to increase O2 delivery for angina x4
Nitrates
Calcium channel blockers
Nicorandil
Revasc
Drugs to reduced oxygen demand in angina
Beta blockers Nitrates Nicorandil Calcium channel blockers Trimetazidine Ivabridine
Secondary prevention of angina
Aspirin and statins primarily
Also ACE inhibitors
Surgical interventions for the management of angina
CABG
PCI
Diagnostic criteria for MI
Change in the troponin levels (increase) PLUS at least one of:
Symptoms of ischaemia
New ST segment/T wave changes
Pathological Q waves
Imaging evidence of lack of wall motility
Presence of thrombus on angiograph
Increased troponin levels indicate?
MI - cardiac muscle damage
Where is troponin found?
Found only in cardiac myocytes
Change on ECG required for MI?
Not for NSTEMI
YES for STEMI - ECG is diagnostic for STEMI
Two types of MI
NSTEMI - non-ST elevation myocardial infarction
STEMI - ST elevation myocardial infarction
STEMI vs. NSTEMI
STEMI - ruptured coronary plaque and occlusive thrombus
NSTEMI - ruptured coronary plaque and subocclusive thrombus
Type 1 AMI and cause
Spontaneous AMI
Plaque rupturing
Five cardiac signs of AMI
Chest pain 4th heart sound Low grade fever Leucocytosis and raised inflammatory markers Troponin leak (increased levels)
Three autonomic symptoms of AMI
Tachycardia
Sweating
Vomiting
Five traits that may result in a delay for calling for help when experiencing an AMI
Older people Women Nocturnal or weekend pain No previous AMI People with diabetes
What percentage of people who die from an AMI do so before reaching the hospital?
33%
What is the mortality rate after one year of an AMI?
40%
Major cause of morbidity in AMI patients?
Cardiogenic shock - left ventricular failure
Treatment for STEMI
Reduction of the size of the infarct via thrombolytic drugs
and reperfusion therapy
Two main types of thrombolytic drugs
Streptokinase
Tissue plasminogen activator (tPA)
What are thrombolytic drugs?
These work to dissolve the blood clots
Action of streptokinase
Lysis of fibrin in the thrombus
Action of tPA
Converts plasminogen to plasmin –> this lysis the fibrin in the thrombus
Main method for reperfusion therapy?
Primary PCI
What should be provided prior to primary PCI?
Anti-platelet drugs i.e. aspirin/heparin
Prevention treatment for AMI following discharge?
Lifestyle - smoking, diet, exercise
Prevention durgs - aspirin, statin, beta blocker, ACE-inhibitor , tricagrelor
Prevention devices e.g. ICD
Should tricagrelor be given for life treatment?
No
How many patients with AMI are smokers?
20%
How many patients with AMI under 60 years are smokers?
50%
What percentage of AMI sufferers quit smoking?
33%
Volume of RBCs in the body
24x10^12
RBC lifespan
120 days - about 4 months
RBCs make up what proportion of all body cells?
1/3
RBC approximate death rate
2x10^11
Average diet contains how much iron per day?
15mg
What is the total quantity of body iron?
3-5mg
Most iron in the body is in what form?
Circulating haemoglobin - 2mg
Where is the majority of iron absorbed in the body?
Duodenum
Cells that absorb iron are? Location?
Enterocytes in the duodenal lining
Two forms in which iron can be absorbed
Free iron in the ferrous form Fe2+
Protein e.g. haem
Ferrous iron formula
Fe2+
Ferric iron formula
Fe3+
Function of ferric reductase on iron
Ferric reductase reduces Fe3+ to Fe2+ (for absorption)
What component regulates the level of free iron in the plasma?
Transferrins
What component transports iron from the bone marrow into the blood?
Transferrins
How many iron atoms can transferrins hold and in what form?
Can hold two iron atoms in the ferric (Fe3+) form
Location of transferring receptor
Erythroblast
Release of iron from transferring occurs where?
Within the cell i.e. erythroblast via endocytosis
Free iron in the erythroblast is taken up by?
Ferritin
How is iron stored in cells?
Bound to ferritin
How is iron released from ferritin?
Controlled fashion - when needed
Common diagnostic test for iron deficiency anaemia
Serum ferritin levels - indirect marker of stored iron
Define anaemia
Low hb. level <13.5g/dl male and <11.5g/dl female
Most common blood disorder of patients
Anaemia
Anaemia hb. level in child 6 months to 6 years
<11g/dl
Anaemia hb. level in child 6 years to 14 years
<12 g/dl
Three variables that alter normal hb. level
Age (decreases with age)
Sex
Racial background
Five further tests if hb. is low
History and examination Full blood count and blood film Serum 12, folate, ferritin Renal and liver function tests ESR
Symptoms of anaemia x5
Tiredness Fainting Shortness of breath Worsening angina/claudication Palpitations
Signs of anaemia x6
Pallor Rapid heart rate Bounding pulse Systolic flow murmur Cardiac failure Retinal haemorrhages
Causes of reduced production of RBCs leading to anaemia x6
Iron deficiency B12/folate deficiency Marrow infiltration e.g. cancer Chronic disease Infections e.g. HIV/parvovirus
Causes of increased destruction of RBCs leading to anaemia x1
Haemolytic anaemia
Causes of increased loss of RBCs leading to anaemia x1
Bleeding
Two most common causes of anaemia
Iron deficiency and B12/folate deficiency
MCV of microcytic anaemia
<76fl
MCV of macrocytic anaemia
> 96fl
Volume of normocytic anaemia
76-96fl
Two main microcytic anaemias
Iron deficiency anaemia
Thalassaemia
1ml of blood contains how many mg of iron?
0.5mg
Major source of haem iron is?
Food of animal origin
Factors that can enhance iron absorption x6
Haem iron - meat Ferrous salts - Fe2+ Acidic pH Iron deficiency Pregnancy Hypoxia
Factors that can impair iron absorption x5
Non-haem iron i.e. veg Ferric salts - Fe3+ Alkaline pH Iron overload Inflammatory disorders
Common drug that can decrease iron absorption
Protein pump inhibitors for acid reflux/indigestion
Causes of iron deficiency anaemia x10
Menorrhagia Varices Ulcer Inflammatory bowel cancer Coeliac Atrophic gastritis Growth spurts Pregnancy Elderly Vegans Hookworm
Histological cell which signifies iron deficiency anaemia is?
Pencil cell
Tablets given to treat iron deficiency anaemia?
Ferrous sulphate
Four causes of normocytic anaemia
Acute blood loss
Chronic disease
Cancer
Haemolysis
Three causes of macrocytic anaemia
B12/folate deficiency
Alochol/liver disease
Myelodysplasia
Specific function of B12/folate
Conversion of homocysteine to methionine (DNA synthesis)
B12 and folate deficiency result in what type of anaemia?
Macrocytic - cells fail to divide
B12/folate - which is destroyed by cooking?
Folate
How long is B12 stored for in the body?
Three years
How long is Folate stored for in the body?
Four months
Where is B12 absorbed?
Ileum - bound to IF
Where is folate absorbed?
Duodenum and jejunum
What is B12 bound to in the body?
Intrinsic factor
Cells that produce IF are?
Parietal cells of gastric mucosa
Lack of IF results in?
Pernicious anaemia
Histological appearance of B12/folate deficiency?
Hypersegmented neutrophils
Two main causes of B12 deficiency
Nutritional - lack in diet
Malabsorption - gastric i.e. IF or intestinal e.g. chron’s disease
Pernicious anaemia?
Lack of IF
Autoimmune disorder - action of autoantibody
Autoantibody in pernicious anaemia attacks what? x2
Gastric mucosa
IF
Five signs of pernicious anaemia
Insidious - gradual onset Anaemia Glossitis Mild jaundice Neurological symptoms
Treatment for pernicious anaemia
Intramuscular B12 once every three months for life
Four signs of folate deficiency
Insidious
Anaemia
Glossitis
Mild jaundice
NO neurological signs!
Treatment for folate deficiency
Oral folic acid
Define haemolytic anaemia
Lifespan of RBC <120 days
Three signs of haemolytic anaemia
Jaundice
Increased LDH levels
Spherocytosis
Three signs of haemolytic anaemia - explain
Jaundice - increased release of bilirubin (can lead to gallstones)
Increased levels of LDH - released from the cells
Spherocyte formation
Four haemolytic anaemias
Hereditary spherocytosis
Sickle cell disease
Thalassaemia
Glucose-6-phosphate dehydrogenase deficiency
Signs of haemolytic anaemia x4
Pallor and anaemia
Jaundice
Gallstones
Splenomegaly
Inheritance pattern of hereditary spherocytosis
Autosomal dominant
G6PD function
Prevents/reverses the oxidation of Hb. membrane SO prolongs the lifespan of RBC
Inheritance of G6PD deficiency
X-linked
Immunoglobulin involved in autoimmune haemolytic anaemia
IgG
Investigation for autoimmune haemolytic anaemia
Direct Coombs test/Direct antiglobulin test
Define stroke
Interruption of cerebral blood flow causing ischaemia and hypoxia
Two causes of stroke
Infarction - blockage of artery
Haemorrhage - rupture of aneurysm
Two divisions of haemorrhagic stroke
Parenchymal - into the brain tissue
Subarachnoid - into the subarachnoid space
Stroke is the ____ most common cause of death in the UK? After what?
Third most common
Heart disease
Cancer
Direct Coombs test/direct antiglobulin test is used for?
Investigation of autoimmune haemolytic anaemia
Stroke symptoms are quick or gradual?
QUICK
Symptoms of stroke
Sudden numbness/weakness of face/limbs
Sudden confusion
Sudden trouble with vision
Sudden severe headache
FAST pneumonic for symptoms
Face
Arms
Speech
Time
Stroke golden hour
Interventions in the first hour following stroke make significant difference to outcome
Four types of stroke
TIA
Thrombotic - ischaemic
Embolic - ischaemic
Haemorragic
Maximum length of a TIA
24 hours - clinically this is only for 85% of patients
Typical length of a TIA
<1 hour
Cause of TIA
Release of small emboli from a thrombus
Temporary downstream blockage of vessel
What is thrombotic stroke?
Development of atheroma in a cerebral vessel - ruptures and forms local clot
What is embolic stroke?
Embolism occurs from an original thrombus
Original thrombus in this case is not in cerebral arteries
Main feature of embolic stroke?
Rapid development of neurological signs
Thrombotic and embolic strokes make up what percentage of all strokes?
85%
Source of embolism in embolic stroke is usually where?
Left side of heart
Key feature of haemorrhagic stroke is? x2
Severe headache
Stupor/coma that may progress with time
Cause of haemorrhagic stroke
Rupture of blood vessel
Define lacunar stroke
Occlusion of artery supplying deep structures rather than cortex
Basal ganglia, thalamus, pons, cerebellum
Presence of cortical infarct signs in lacunar stroke?
Absent
Three forms of lacunar stroke?
Motor hemiparesis with dysarthria
Ataxia and hemiparesis
Dysarthria and clumsy hand
Define dysarthria
Difficult or unclear articulation of speech due to poor articulation of the muscles of speech
Define ataxia
Loss of full control of bodily movements
Main feature of embolic stroke?
Rapid development of neurological signs
Thrombotic and embolic strokes make up what percentage of all strokes?
85%
Source of embolism in embolic stroke is usually where?
Left side of heart
Key feature of haemorrhagic stroke is? x2
Severe headache
Stupor/coma that may progress with time
Cause of haemorrhagic stroke
Rupture of blood vessel
Define lacunar stroke
Occlusion of artery supplying deep structures rather than cortex
Basal ganglia, thalamus, pons, cerebellum
Presence of cortical infarct signs in lacunar stroke?
Absent
Three forms of lacunar stroke?
Motor hemiparesis with dysarthria
Ataxia and hemiparesis
Dysarthria and clumsy hand
Define dysarthria
Difficult or unclear articulation of speech
Define ataxia
Loss of full control of bodily movments
Motor hemiparesis with dysarthria where is the lesion?
Infarct in the posterior limb of the internal capsule
Ataxia and hemiparesis where is the lesion?
Infarct in the posterior limb of the internal capsule
Dysarthria and clumsy hand where is the lesion?
Infarct in the anterior limb of the internal capsule
Impaired function of cerebral sodium pump results in? x2
Swelling of the brain nerve cells (increased leakage of Na+ and hence water into the cell)
This swelling results in increased ICP
Why do cerebral nerve cells require a very high level of sodium pumps?
Have a very large surfaced-area to volume ration - increased sodium leakage
Hypertension accounts for what percentage of stroke risk?
35-50%
Those with AF have what percentage risk of stroke per year?
5%
Name five lesser risk factors for stroke
Hypercholestrolaemia Migraine Obstructive sleep apnoea Diet low in potassium Thiazide and loop diuretics
Most common artery for stroke
Middle cerebral artery
Why is MCA prone to aneurysms and stroke?
Highly tortuous artery
Lenticulostriate arteries - supply and origin
Arteries to the basal ganglia and the internal capsule
Leave MCA at 90 degree angle
Function of internal capsule
Motor commands from motor cortex to brainstem and sinal cord
Function of cerebral sodium pump x2
Maintains the membrane potential
Maintains the nerve cell size and shape
Impaired function of cerebral sodium pump results in? x2
Swelling of the brain nerve cells (lack of movement of Na+ and water out of the cell)
This swelling results in increased ICP
Why do brain cells have the highest consumption of ATP?
Most of the ATP is required to fuel the sodium pump
Three main treatment strategies for stroke
Restore blood flow
Combat excitotoxicity
Combat free radical damage
How can blood flow be restored following stroke?
Introduce tissue plasminogen activators - to burst the clots
Which cells remove potassium from the extracellular space of the brain?
Glial cells - take up the potassium
Hypoxic brain - effect on potassium levels?
In a hypoxic brain, the glial cells do not take up the potassium - increased extracellular potassium levels
Superoxide dismutase
Free radical scavenging enzymes against ROS
Cause of exocitotoxicity in hypoxic brain
Excess release of nuerotransmitters
Two main glutamate receptors
AMPA
NDMA
Consequence of excitotoxicity in the brain
Increased influx of calcium in the cell - this increases the metabolic demand - formation of free radicals
Define penumbra
Middle region around a stroke focus - the neurones are damaged by they can survive if intervention occurs
Three main treatment strategies for stroke
Restore blood flow
Combat excitotoxicity
Combat free radical damage
Three drugs to combat the excitotoxicity
NMDA antagonists
AMP antagonist e.g. NBQX
Lithium
Three methods to reduce free radial damage of the brain
Antioxidants e.g. vitamin C and E
Enzymes - superoxide dismutase
Cool down the brain
Superoxide dismutase
Free radical scavenging enzymes against ROS
Define clinical shock
Acute circulatory failure with inadequate or inappropriately distributed tissue perfusion resulting in cellular hypoxia
Two components of shock syndrome
Hypotension
End organ injury
Normal CO
5l/min
Normal MAP
100mmHg
MAP of shock
MAP <60mmHg
Equation for BP
COxSVR
Equation for CO
CO = HR x SV
Two hormones that act to maintain SVR and their receptors
Noradrenaline - alpha-1 receptors
Angiotensin 2 - angiotensin AT1 receptor
These are vasoconstrictors
What is the most common cause of low CO
Generally due to low SV
HR tends to be compensation
Starling’s law of the heart
The force of contraction increases as the end diastolic volume increases
SO the greater the preload, the greater the force of contraction so the greater the stroke volume
Location of alpha-1 receptors and angiotensin receptors
Alpha adrenoreceptor - on the outside
Angiotensin receptor - lumen
Three factors that can increase myocardial contractility
Sympathetic NS
Catecholamines i.e. adrenaline/noradrenaline
Ionotrope drugs
Receptor for ionotropoic drugs
Beta-1 receptor
Four factors leading to reduced myocardial contractility
Cardiac disease
Hypoxia/hypercapnia
pH/electrolyte disturbance
Drugs e.g. BBs or CCBs
How is SVR maintained?
Constriction of arterioles in end organs
Two hormones that act to maintain SVR and their receptors
Noradrenaline - alpha-1 receptors
Angiotensin 2 - angiotensin receptor
These are vasoconstrictors
Two local vasodilators
No
Prostacyclin
Local vasoconstrictor
Endothelin
Cells that produce prostacyclin
Endothelial cells
Prostacyclin is produced from what?
Arachidonic acid
Two functions of prostacyclin
Inhibits platelet activation
Local vasodilator - reduces calcium entry into smooth muscle
Hormone that antagonises the effects of prostacyclin is?
Thromboxane
Compensated shock
Initial stage of shock
Decompensated shock
Later stage of shock - organs cannot be perfused and start to fail
Four main classes of shock
Obstructive shock
Distributive shock
Hypovolaemic shock
Cardiogenic shock
Obstructive shock and example
Physical obstruction causing failure of cardiac output e.g. pulmonary embolism
Main sign of septic shock
Fever
Hypovolaemic shock and eg
where you have bled and lost too much blood so there is not enough circulating blood so that even if you were to increase the heart rate, preload cannot increase e.g. haemorrhage
Cardiogenic shock and eg
Failure of the heart to pump efficiently and supply blood to the body e.g. myocardial infarction/heart failure
Classic presentation of hypovolaemic shock
Low BP High HR Confusion Anxiety Greyish pallor Oligouria
Effect of breath sounds on obstructive shock
Breath sounds are absent on the affected hemiothorax
Volume of blood loss that is life threatening
> 40% - >2litres
At whcih stage of hypovolaemic shock will treatment be required
Stage 3 - prior to this can be compensated for
Immediate compensation to shock
Increased sympathetic - HR and contractility via baroreceptors
Release of ADH vasopressin
Longterm compensation to shock
Renin, aldosterone release, increased thirst sensation, increased EPO production
Name of cells that produce EPO
Peritubular fibroblasts
Four stages of hypovolaemic shock
1 - <15% loss of blood
2 - <30% loss of blood
3 - >30% loss of blood
4 - >40% loss of blood
Septic shock is a form of which type of shock?
Distributive
Composition of feotal hb
Two alpha
Two gamma
Composition of adult Hb. (HbA)
Two alpha and two beta
Genes for alpha subunit - chromosome?
Alpha subunit - 2 genes on chromosome 16
Genes for beta subunit - chromosome?
Beta subunit - 5 genes on chromosome 11
Five genes for beta subunit
Gamma A Gamma G Epsilon Delta Beta
HbF compared to HbA
HbF can bind O2 more efficiently than HbA
Hb. Gower-1 and composition
Very first form of Hb - first six weeks
Two zeta
Two epsilon
Composition of HbA2
Two alpha
Two delta
Beta thalassaemia cause
Mutation on chromosome 11
Alpha thalassaemia
Deleted/faulty genes on chromosome 16
Beta thalassaemia
Deleted/faulty genes on chromosome 11
Four forms of alpha thalassaemia and cause
Minima - one gene defective - silent carrier
Minor - two genes defective
Hb H disease - three genes defective
Hydrops fetalis - four genes defective - incompatible with life
Hydrops fetalis stillborn infant cause
Four defective genes on chromoome 16
Beta thalassaemia cause
Point mutation on chromosome 11
MCV of haemolyic anaemia
6-8g/dL
Two forms of beta thalassaemia
Heterozygous - minor
Homozygous - major
Consequence of beta thalassaemia major
Cannot produce sufficient levels of HbA either
HbE
Hb with single point mutation in Beta chain
Mitral valve prolapse
> 2mm systolic prolapse of one or both valve leaflets into the LA
Cause of SCA
Mutant form of beta subunit
Mutation of glutamic acid to valine (GAG to GTG) at codon 6 of chromosome 11
HbC
Hb with abnormal beta subynit
HbE
Hb with single point mutation in Beta chain
Most common valve lesion
Mitral valve prolapse
Symptoms of mitral valve prolapse
Asymptomatic
Signs of mitral valve prolapse
Ejection click and late systolic murmur
Treatment of mitral valve prolapse
Usually none necessary
Symptoms of aortic stenosis x5
Dyspnoea Angina Syncope LVF Sudden death
