Blood Pressure & Hypertension Flashcards
How does blood pressure change across the vascular tree (general terms) - Aorta to Vena Cava?
PP = Pulse pressure
What are the main short, medium and long term mechanisms that control blood pressure?
Short term - Neural reflexes - baro- and chemo-receptors
Medium term - Renin-angiotensin and capillary changes
Longer term - fluid retention blood pressure control – controlled by kidneys
What is the definition of hypertension? Why is it important?
Blood Pressure (BP) that is too high.
Blood pressure includes systolic (SBP) and diastolic (DBP) quoted as SBP/DBP and measured in mmHg e.g. 140/90
Why is it important?
- Link between high blood pressure and adverse cardiovascular outcomes - cerebrovascular disease, CHD, etc.
- Link with other health conditions - e.g. diabetes, Alzheimer’s, etc.
Note - that blood pressure fluctuates throughout the day - sleep (lower), recumbent (lower), white coat effect (higher), etc.
How should someone go about taking their blood pressure?
- Relax 5min
- Take at least three blood pressure readings over a few mins (first time measuring - use both arms)
What are the main arterial diseases of interest?
- Coronary heart disease (CHD) & Myocardial infarctions - also angina, sudden cardiac death, heart failure
- Cerebrovascular diseases & cerebrovascular accident - stroke, transient ischaemic attacks, multi-infarct dementia
- Also other arterial disease
- Peripheral vascular disease
- Renal impairment, renal artery stenosis
- Abdominal aortic aneurysms
- Retinopathy, papilloedema
What are the risk factors for cardiovascular disease?
Note - these risk factors are used in online risk calculators (QRisk3) in order to predict the likelihood of a cardiovascular event
How can we define hypertension? What do the NICE guidelines say?
BP level above which investigation and treatment do more good than harm
NICE (2019) Diagnosis of Hypertension requires: BOTH
1. Conventional (Clinic) BP ≥ 140/90
AND
2. ABPM/Home BP ≥ 135/85
What are the different gradings for hypertension?
Grade 1 - more than 140/90 - less than 160/100
Grade 2 - more than 160/100 - less than 180/120
Grade 3 (severe) - more than 180/120
What is white coat hypertension?
White coat effect - People’s blood pressure being higher in clinic by more than 20/10 when compared to the home BP measurments
What organs are typically damaged by hypertension?
Signs of hypertensive tissue damage:
1. Kidneys - Kidney disease
2. Heart - hypertrophy + blood vessel damage/lesions
3. Retina - hypertensive retinopathy
Who receives treatment for hypertension?
- Target people with Highest Sustained BP
- Grade II HT +/or Target organ damage
- Basically below grade II - treatment only if really needed - nuance - People with a high absolute risk, e.g.
a) Already with CVD – previous MI, CVA, with angina
b) With diabetes, chronic kidney disease (CKD)
c) With 10-yr CVD risk >10% (age, lipids, smoking, etc.)
Best to prioritise treatment to high risk groups – as here is where most lives saved
What is the treatment pathway for hypertension? What are the exceptions to blood pressure targets?
- Everyone with hypertension
a) Lifestyle advise - ideal weight range, limit salt intake, regular exercise etc.
b) BP kept under review (may be just x1-2/year if mild)
c) May require drug treatment if the patient remains hypertensive
d) Aim to reduce blood pressure below 140/90 - no longer hypertensive - High-risk groups quickly start anti-hypertensive drug treatment aiming for target BP no longer hypertensive
- Grade 2-3 hypertension
- Grade 1 hypertension+Risk - CVD, organ damage, vulnerbale (diabetes, kidney disease), high CVD risk
Note - Blood pressure exception targets
- Target less than 130/80 – Chronic kidney disease+ diabetes +/or alb/creat >70:Group (iv)[above]
- Target less than 150/90 - if lowering may pose a higher risk - above the age of 80
- Relax BP goals – if frailty/multimorbidity making higher risk to BP lowering - e.g. falls
What types of investigations are used to diagnose/investigate hypertension?
-
History & examination
Past BP levels
CVD and CVD risk factors -
Blood pressure – GP/clinic/hospital
AND home or ambulatory - Blood tests: urea, electrolyte, eGFR, lipids, HbA1c/glucose, liver function test with GGT, urate
- Urinalysis – protein, glucose, blood..
- ECG - when available
-
Target organ damage: if BP particularly high (eg new grade II HT)
review urinalysis (+eGFR), ECG, fundoscopy, symptoms
What are examples of common anti-hypertensive drugs?
Class A, B, C and D drugs
ACE inhibitors - enalapril, lisinopril, ramipril
ANG-II receptor blockers - losartan, candesartan
Calcium channel blockers - nifedipine, amlodipine [+ rate limiting: verapamil, diltiazem]
Diuretics - bendroflumethiazide, [chlortalidone/indapamide]
Beta-blockers - atenolol, metoprolol, bisoprolol
Used in resistant hypertension
- Mineralocorticoid-Blockers - spironolactone, eplerenone
- Alpha-Blockers - doxazosin
What does the treatment timeline for hypertension look like?
- BP diagnosis
- Lifestyle management
- Begin anti-HT treatment
- Adjsut anti-HT treatment if needed
- Resistant HT - Poor BP despite 3 Drug
treatments (stacking) - specialist referral, futher treatment?, secondary causes?
What is the mechanism of action and side effects of ACE inhibitors and AngII receptor blockers? What are the contra-indications/cautions?
ACE inhibitors - inhibit ACE, block RAAS, increase bradykinin - dilate arteries (and veins),
AngII receptor blockers- similar (no BK effect)
Side effects
- ACE inhibitors - cough, rise in/high K+, renal dysfunction
- Angiotensin receptor blockers – few, rise in/high K+, renal dysfunction
Cautions
- Pregnancy
What is the mechanism of action and side effects of calcium channel blockers? What are the contra-indications/cautions?
Calcium channel blockers - typically used in older patients
Block voltage-operated calcium channels, dilate arteries (± heart rate reduction)
Side effects:
Headaches, flushing, ankle swelling and tachycardia
Contra-indications
- Heart block
- Heart failure
What is the mechanism of action and side effects for thiazides (diuretics)? What are the contra-indications/cautions?
Thiazides - typically used in older patients
Inhibit Na+-Cl- symport, distal tubular natriuresis, dilate arteries and veins
Side effects of diuretic use:
Impotence, rashes, biochemical – low Na+, low K+, raised glucose (risk of diabetes), high urate (risk of gout)
Contradincations:
1. Gout
2. Low K+
What is the mechanism of action and side effects for beta-blockers? What are the contra-indications/cautions?
MOA - Block beta-adrenoceptors, reduce cardiac rate and output, block RAAS, initial vasoconstriction (ultimately vasodilate)
Side effects:
Wheeze [caution with asthma/COPD], cold peripheries, lassitude, exercise intolerance, impotence, bradycardia, heart block, raised glucose
Contradindications
1. Heart block
2. Asthma/COPD
What is the mechanism of action and side effects for mineralocorticoid blockers? What are the contra-indications/cautions?
Mineralocorticoid blockers (diuretic blocking aldosterone action) – block mineralocorticoid receptors, distal nephron natriuresis/limit potassium loss
Mineralocorticoid blockers - rise in/high K+, gynaecomastia (just spironolactone)
Contraindications
1. High K+
2. Low mineralocorticoid (aldosterone)
What is the mechanism of action and side effects for alpha-blockers? What are the contraindications/cautions?
Alpha-blockers – block alpha1-adrenoceptors, dilate arteries and veins.
Side effects:
Dizziness (especially on standing), urinary symptoms, tachycardia, oedema [caution with heart failure]
Contraindications
1. Impaired urine continence
2. Postural hypotension
3. Heart failure
What are the main reasons for hypertension treatment failure?
- Poor adherence (extremely common)
- Ineffective combinations (common)
- Other drugs (e.g. NSAIDs; common)
- Inappropriately low doses (common)
- Secondary causes (uncommon: less than 5%)
What are the two main groups of hypertension (based on cause)?
- Primary hypertension - 95% - no known cause
- Secondary hypertension - 5% - cause can be identified
Note - One of the suspect reason for primary hypertension – long term malfunction of corrective measures - kidney failure to control blood volume
What are the environmental and genetic factors that predipose someone to hypertension?
Underlying problem (thought) - Impairment in the kidney regulation of body salt balance in all Hypertension
Environmental
1. Body weight – obesity
2. Physical inactivity
3. Excess calorie intake
4. Salt – high salt/sodium, low potassium low, magnesium
5. Excess Alcohol Stress
Genes (30-50% contribution)
- Recently, large GWAS study found >1000 genetic loci of modest/small effect together just explaining ~5.7% genetic variance in blood pressure.
What are some endocrine, medical and renal/vascular causes of hypertension?
Endocrine - primary Aldosteronism, phaeochromocytoma /paraganglioma (nerve cells regulating blood pressure)
Medical - Oestrogen oral contraceptives, Non-steroidal anti-inflammatory drugs (NSAIDs) and Alcohol
Renal/vascular - Renal artery stenosis (atheroma/fibromuscular) and Glomerulonephritis/pyelonephritis/vasculitis (inflammation of the kidney)
What forces dictate the movement of fluid in capillaries/capillary fluid equilibrium?
Blood pressure gradients
a) Oncotic pressure - moves fluid into capillaries
b) Hydrostatic pressure - moves fluid out into the tissue
Balance of these forces dictate whether fluid moves in/out of the capillaries
Arterial end - fluid moves out of the capillaries
Venous end - fluid moves back into the capillaries
What two main variables does the cradiovascular system need to control? What challenges does the system need to adapt to?
Blood pressure - must be maintained to provide perfusion of all the body organs
Blood volume- must be maintained to provide the venous return necessary for adequate cardiac output and blood pressure generation
Challenges
1. Fluid deprivation
2. Fluid overload
3. Fluid depletion
4. Meals
5. Exercise
6. Temperature changes
7. Postural changes
8. Zero gravity/acceleration
What mechanisms exist to regulate blood pressure? (sensors, effectors, effector organs and response time)
Sensing - arterial baroreceptors
Effectors
NS - Symapthetic & parasympathetic
Hormones - RAAS, adrenaline and vasopressin
Local factors - NO, endothelin, kinins, prostaglandins, renin-angiotensin
Effector organs
1. heart
2. arterioles
Response time - seconds/minutes
What mechanisms exist to regulate blood volume? (sensors, effectors, effector organs and response time)
How can you calculate arterial blood pressure using cardiac output and systemic vascular resistance?
ARTERIAL BLOOD PRESSURE (ABP) measured in mmHg - typical brachial ABP in a young adult ~ 120/80 mmHg
ABP = CO x SVR
CARDIAC OUTPUT (CO) - output from ventricle in 1 minute
CO = stroke volume (~70 mL) x heart rate (60-80/min)
cardiac output ~ 5 L/min
SYSTEMIC VASCULAR RESISTANCE (SVR) - majority of vascular resistance is provided by arterioles - note significantly effected by blood vessel radius
Conclusion: arterial blood pressure will be dependent on heart rate, cardiac contractility and arteriolar tone
What factors increase and decrease heart rate? What factors increase cardiac contractility?
What neural, circulating, and local factors influence blood vessel tone?
More research
What is the Baroreceptor reflex?
Baroreceptor reflex - defense of blood pressure and cerebral blood flow
Blood pressure sensed by baroreceptors – carotid arteries and in aortic arch – stretch allows the body to gain information of the blood pressure state
Signal send to vasomotor centre of the brain
If blood pressure drops…
1. Sympathetic NS activation (Alpha 1 and beta 1) - effects on the heart, blood vessels, adrenals and kidney
- Note both the arteriolar and venous system constrict upon sympathetic NS activaion, to ensure that blood doesn’t pool in one system
2. Parasympathetic NS activation - heart - bradycardia (muscarinic receptr)
Note - as we age we tend to lose our baroreflex
What are the three major compartments that store fluid in the body? What is the major determinant of blood volume?
70kg man:
Blood (intravascular) volume - 4 L
Extracellular (interstitial) fluid - 12 L
Intracellular fluid - 32 L
Blood volume is dependent on the overall hydration of the body which is regulated by the kidney (level of reabsorption/excretion)
Why is blood volume important to regulate? How is it regulated?
Blood volume is required to maintain venous return to the heart to enable it to produce an adequate cardiac output
Sensors
1. Kidneys - juxtaglomerular cells sense low Na+ delivery and urine flow
2. Heart - low pressure stretch receptors in atria
Efferent signals
1. Renin-angiotensin system
2. Sympathetic nerves
3. Other mechanisms
Outline how the renin-angiotensin system works to regulate blood volume.
- Blood volume sensed by juxtaglomerular cells in the kidney
- Release renin
- Renin converts angiotensinogen into angiotensin I
- Angiotensin converting enzymes converts angiotensin I into angiotensin II
- Angiotensin II - wide range of impacts
a) Increases efferent arteriolar constriction - increasing GF
b) Arteriole vasoconstriction - increasing blood pressure
c) Stimulate posterior pituatary - thirst and vasopressin (increase H20 reabsoprtion)
d) Aldosterone release - increase Na+ reasborption - increase H20 absorption
What are the immediate consequences/responses to acute haemorrhage?
- Decrease in intravascular volume
- Decreased return to heart
- Decreased ventricular filling
- Cardiac output decreases
- Blood pressure decreases
- Renal perfusion decreases
- Decrease capillary hydrostatic pressure
What are the sensors that would be activated in response to acute haemorrhage?
Blood volume and blood pressure receptors
What are the sympathetic responses that arise in response to acute haemorrhage?
What symptoms do we see when someone goes into hypovolaemic shock?
Treatment - Intravenous fluid infusion and blood transfusion
What are the risk factors for cardiovascular disease?
What damaging cycle do we see in chronic heart failure?
Basically the systems that normally correct for decrease blood pressure/volume are activated during heart failure leading to extra stress that can overwhelm the heart
What are the key problems identified in cardiovascular disease? What are drugs that can be used to counteract these issues?
What are the different systems/variables that can be manipulated in order to changes stroke volume and heart rates, thus influencing arterial blood pressure?
What are angiotensin-converting enzyme (ACE) inhibitors? How do they work? What are their indications and contra-indications?
What are angiotensin receptor antagonists
inhibitors? How do they work? What are their indications and contra-indications?
Work further down on the angiotensin system – blocking at the receptor level – actions and indications are similar
Usually used for people on ACE inhibitors that develop and dry cough
What are calcium channel blockers? How do they work? What are their indications and contra-indications?
What are thiazide diuretics? How do they work? What are their indications and contra-indications?
Reducing the reabsorption of sodium and chloride
What are potassium sparing diuretics? How do they work? What are their indications and contra-indications?
Aldosterone receptor antagonists - decrease in Na+/K+ exchanger - less re-absorption
Sodium channel blockers - block sodium channels in luminal membrane
What are beta-blockers? How do they work? What are their indications and contra-indications?
Decreased activation of B1 - inhibits cAMP formation and PKA activation - leading to a variety of downstream effects - decreased contractility of muscle cell, decreased calcium availability, etc.
- Vasodilation
- Decrease ventricular response rate
- Decrease excitability of the conduction system
- Decreased ventricular contractility
What are the two main types of lipids that we are interested in when looking at CVD?
What are the different types of lipoproteins?
Lipoproteins - Transport cholesterol & triglycerides around the body via the circulation
Main types:
1. Chylomicrons
2. Very Low Density Lipoprotein (VLDL)
3. Intermediate Density Lipoprotein (IDL)
4. Low Density Lipoprotein (LDL)
5. High Density Lipoprotein (HDL)
Classification by size and density - decreasing size and increasing density
Outline the creation/transport of lipoproteins in the body.
Sources - Lipids absorbed from the gut (exogenous lipid pathway) or created in the liver (endogenous lipid pathway)
Lipids are transported across the body to different tissues
Lipids can also be returned to the liver - reverse cholesterol transport - where they can be excreted
Outline what happens in the exogenous lipid pathway.
Dietary lipids – taken up in the small intestine – packaged in a chylomicron
Chylomircons are transported to the liver but on their way there they are broken down by Lipoprotein lipase (releasing glycerol and non-essential fatty acids), which are absorbed by targets (muscle and adipose)
Chylomircon remanent - left behind - absorbed by the liver
Outline what happens in the endogenous lipid pathway.
No dietary source of lipids – can be obtained from the liver
- Liver produces VLDL (very triglyceride rich – low cholesterol)
- Progressively broken down by LPL into glycerol and NEFA - taken up by tissues (muscle and adipose)
- Also forms Intermediate density lipoproteins - can be taken up by the liver and converted into LDL by the liver (transports cholesterol around the body)
- LDL has Apoe-B on it’s surface allowing it to interact with LDL receptors, which is needed for transport of LDL into tissues
Outline what happens during reverse cholesterol transport (via HDL).
Reverse cholesterol transport system
- HDL created both in the liver and gut – collects cholesterol
- Free cholesterol is transported out via ABC-A1 transported and taken up by HDL using LCAT
- HDL normally taken up by liver or sometimes taken up by VLDL
What are the different types of chylomircorns? What are their defining features? What type of receptors to they have on their surface?
Chylomicrons - ApoB48
VLDL, IDL and LDL - ApoB100
HDL - ApoA1
Lipoprotein behaviour determine by proteins on their surface
Summary of lipid metabolism - Triglycerides and cholesterol.
Outline the steps that result in lipid driven CV disease/atherosclerosis?
- Formation of fatty streaks: LDL + monocytes + O-free radicals - accumulation of lipids in the arterial wall - reacts with oxygen free-radiacals - consumed by macrophages to form foam cells - collection of foam cells = fatty streak - Inflammatory process
- Atheromatous plaque formation - smooth muscles cells stimulated by macrophages to migrate, proliferate, differentiate (fibroblasts) - producing collagen cap - Foam cells undergo necrosis or apoptosis to leave a pool of extracellular cholesterol - pool of cholesterol = atheroma
-
Plaque rupture
- Occludes blood flow – plaque remains stable – stable angina
- Unstable/clot formation/thrombosis – full blockage - unstable angina/MI
What monogenic genetic condition prediposes someone to lipid-driven CV disease?
Inherited disorders of lipoprotein metabolism
e.g. Familial Hypercholesterolaemia (FH)
- Autosomal dominant - monogenic
- Mutation in LDL receptor (or ApoB, PCSK9)
- Common ~1:500 to 1:200 (heterozygotes)
- High LDL-C levels (typically >4.9 mmol/L)
- Untreated leads to premature CHD onset
- Statin treatment shown to reduce CVD risk to that of general population
Be suspicious if…
- Family history of hyperlipidaemia / prem CVD
- Unusually high LDL-C despite v. healthy lifestyle
- History of hyperlipidaemia from young age
Cholesterol in FH can deposit in other areas of the body – builds up at tendons and in eyes
What is the the difference between primary and secondary CV prevention?
What is the main form of primary prevention? If someone needs extra treatment, how do we decide?
Mainstay of primary prevention is lifestyle change
Consensus: treat those at highest absolute risk - based on high risk (Diabetes over 40, Fam. hyperchol., Chronic kidney disease) or risk of CV event over 10 years - Use a risk calculator e.g. ASSIGN, QRISK etc.
UK national guidelines say:
Scotland - SIGN 149 (2017) - treat if >20% CV risk
England - NICE CG181 (2014) treat if >10% CV risk
Easy to predict for extreme risk-factors e.g. very high LDL-C in Familial Hypercholesterolaemia, or in severe hypertension…
However, usually… CV risk = product of several risk-factors
What are the effects of the lipid lowering drugs - statins, ezetimibe and fibrates?
What are the MOAs for the following lipid lowering drugs - statins, ezetimibe and fibrates?
Statins - block cholesterol synthesis in the liver, resulting in increase uptake form the circulation to compensate (upregulate LDL receptors)
Fibrates - increased LPL activity and hepatic fatty acid oxidation - reducing triglycerides & enhanced IDL, LDL uptake by liver as well as reduce VLDL synthesis
What is an example of an next generation lipid lowering drug?
PCSK9-inhibitors
- Monoclonal antibodies, delivered by fortnightly s/c injection
- Alirocumab, Evolocumab
- Capable of ~60% reduction of LDL-C (as adjunct to statin)
- Increase LDL receptor levels in hepatocytes by suppresing activity of PCSK9 (drives degradation of receptor) - increasing uptake
- PCSK9 have also been targetted by SI-RNA - 6 monthly injection
How do the sites of haematopoiesis change as we age?
Fetus
- Yolk sac - blood isalnds
- Taken over by AGM
- AGM turns into fetal liver - haematopoetic centre
Infant
- Cells move into the bone marrow - cells produced in all bone marrow
Adult
- Haematopoiesis focuses on adult centralized skeleton
How many cells are produced by haematopoeitic stem cells (HSC) in the bone each day?
~ 1 billion cells produced each day in healthy adult
What are the two main lineages produced by the HSC?
Two main lineages
1. Common myleiod progenitor - RBCs and cells of the innate immune system
2. Common lymphoid progenitor - NK cells and cells of the adaptive immune system
What are the main different blood cells circulating?
White cells are in order of abundance in the blood – Neutrophils to Basophils
How are the blood cell count references ranges decided?
95% range (ref interval) = mean +/- 2sd
Reference ranges for each parameter shown in the attached image – differ by age
What does iron deficiency anaemia look like (on a cellular level)?
Smaller, large central white areas, pale, pencil cells
Microcytic hypochromic anaemia
MCV < 80fl, MCH < 27 pg
What is megaloblastic anaemia? What is the normal cause?
Occurs when there is fefective DNA synthesis during RBC production causing cell growth without division
Macrocytic anaemia - increased MCV
Usually due to B12/folate deficiency
Test levels of B12/folate in blood & replace (+ remove cause of deficiency)
Example - RBCs as big as WBCs
What are some benign causes of elevated neutrophils, macrophages and eosinophiles?
What are the common causes of Neutropenia?
What is thrombocytopenia defined as? What are the associated symptoms?
Platelets < 150 x 10^9/l
Symptoms < 20x10^9/l
1. Bruising
2. Gum bleeding
3. Nose bleeds
4. Petechiae (skin rash)
5. Prolonged bleeding from cuts
What is this blood film showing?
What are the 3 distinct stages involved in the formation of a platelet rich thrombus?
- PLATELET ADHESION
- PLATELET ACTIVATION / SECRETION
- PLATELET AGGREGATION
Known as the primary hemostatic pathway
What is the secondary hemostatic pathway?
Secondary hemostatic pathway - formation of a fibrin mesh
Secondary hemostatic process involving the clotting factors – thrombin – causes cross-linking of fibrin meshes around aggregated platelet
What are purpuric rashes, how can they be classified?
Purpuric Rashes - Bleeding into the skin
Outline the different steps in the coagulation cascade - intrinsic and extrinsic.
Waterfall theory
Things to note…
- there is a competing pathway that breaks clots via fibrinolysis
- Reactions are catalysed by macromolecular complexes that sit on the surface of membranes - e.g. extrinsic tenase (VIIa + TF) and intrinsic tenase (VIIIa + IXa) convert factor X into Xa
What are the natural inhibitors of the coagulation cascade?
Prevention of over-activity of the coag cascade by natural inhibitors
- TF-VIIa complex/fXa inhibited by TFPI, tissue factor pathway inhibitor - extrinsic tenase
- Thrombin, fXa and fIXa activity inhibited by
Antithrombin - Protein C pathway inhibits fVa (required by Xa to convert prothrombin into thrombin) and fVIIIa
What are the different laboratory measurements used to assess the coagulation cascade?
What are the different hereditary coagulation deficiences?
Commonest Hemophilia – A
Willebrand – sex-linked to males
What is Haemophilia A?
What does the clinical severity of haemophilia A depend on?
Haemarthrosis - a condition of articular bleeding, that is into the joint cavity - can cause athropathy of the joint
What are the traditional forms of haemophilia management?
How do congential and acquired haemophilia compare?
What is Von Willebrand disease?
Most common hereditary condition for both men and women
Autosomal dominant inheritance!
Arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion.
How is Von Willebrand Disease managed?
What are some common causes of acquired coagulation disorders?
WHat new antibody is being used to treat haemophilia?
EMICIZUMAB (ACE910)
A humanised bi-specific antibody that binds to and bridges fIXa and fX
Acts as a FVIII-mimetic agent
What four measures indicate the presence of DIC?
